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January 2012

KEY ADVANCES IN MEDICINE


Access high quality clinical content written by international experts

January 2012 volume 9 no. 1 www.nature.com/reviews

January 2012 volume 8 no. 1 www.nature.com/reviews

ROBOTIC UROLOGIC SURGERY How best to train postgraduates and residents in robotic techniques?

January 2012 volume 8 no. 1 www.nature.com/reviews

Molecular biomarkers in bladder cancer Stratifying response to targeted therapies

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Mucosal pathogenesis and new concepts in the role of mucosal inflammation

Clinical applications of MRI in Crohn’s disease

January 2012 volume 8 no. 1 www.nature.com/reviews

13/12/2011 10:31

BIOLOGIC THERAPIES

Evaluating the extent of intestinal damage

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07/12/2011 16:34

Influence on cardiovascular risk parameters in RA

KISSPEPTINS

Metabolic regulation of puberty and fertility

Cellular and molecular mechanisms of fibrosis

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08/12/2011 11:47

January 2012 volume 8 no. 1 www.nature.com/reviews

An official publication of

Neuroendocrine neoplasms of the gut and pancreas

Knowledge, advances and controversies

METABOLOMICS Relevance and potential applications in kidney disease

Diagnostic and treatment options

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28/11/2011 15:31

January 2012 volume 9 no. 1 www.nature.com/reviews

Using breast cancer gene signatures in the clinic

NEPHROLOGY

Systemic sclerosis

CLINICAL ONCOLOGY

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RHEUMATOLOGY

ENDOCRINOLOGY GERD

January 2012 volume 9 no. 1 www.nature.com/reviews

UROLOGY

GASTROENTEROLOGY & HEPATOLOGY

January 2012 volume 9 no. 1 www.nature.com/reviews

MULTIPLE SCLEROSIS TRIALS New recommendations for MRI-based monitoring of immunomodulation

Time for a rethink to avoid overtreatment of older men and those at low risk

07/12/2011 15:55

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ATRIAL ARRHYTHMIAS Role of the autonomic nervous system

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Pathogenesis and diagnosis

02/12/2011 12:49

CARDIOLOGY

PROSTATE CANCER SCREENING

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NEUROLOGY

Acute kidney injury in multiple myeloma

Postural tachycardia syndrome Characteristics, neuroepidemiology and pathophysiological mechanisms

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Transcatheter aortic valve implantation Valves and approaches

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Key Advances in Medicine

T

he articles included in Nature Reviews Key Advances in Medicine were originally published in the February 2012 issues of the eight clinical Nature Reviews journals. The journals’ editors commissioned international experts to write a short essay highlighting up to five key papers that made the biggest contribution to their field in 2011. Between them, the eight clinical Nature Reviews journals published 43 articles, which are collated in this eBook; if you choose to cite an article, please use the original journal citation rather than citing the eBook. We hope you enjoy reading Nature Reviews Key Advances in Medicine. If you would like to find out more about the Nature Reviews series, please visit: http://www.nature.com/reviews/

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COPYRIGHT © 2012 Nature Publishing Group. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form (electronic or otherwise) without prior permission from the copyright holder.

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DISCLAIMER: Although every effort is made by the publishers to see that no inaccurate or misleading data, opinions or statements appear in this collection, they wish to make it clear that the data and opinions appearing in articles and advertisements herein are the responsibility of the contributor or advertiser concerned. The journal does include the personal opinions of the authors; therefore, it is not intended to be relied on solely as a guide to good practice or safe treatment. Accordingly, the publishers, employees, offices and agents accept no liability whatsoever for the consequences of any such inaccurate or misleading data, opinion or statement. Although every effort is made to ensure that drug doses and other quantities are presented accurately, readers are advised that the new methods and techniques involving drug usage and described within this journal should only be followed in conjunction with the drug manufacturer’s own published literature.

Nature Reviews Cardiology S1 acute coronary syndromes | Walking the tightrope between efficacy and bleeding Payal Kohli and Christopher P. Cannon S3 atrial fibrillation | Stroke prevention in AF Gregory Y. H. Lip S5 heart failure | Heart failure therapy—technology to the fore John J. V. McMurray S7 hypertension | New insights—from risk factors to treatment implications George L. Bakris S9 valvular disease | Breakthrough for intervention? Volkmar Falk

Nature Reviews Clinical Oncology S11 ovarian cancer | Mutations and non-inferiority analyses show a way forward Maurie Markman S12 prostate cancer | Hitting old targets better and identifying new targets Yu Chen and Howard I. Scher S14 hematological cancer | New therapeutic targets and treatment strategies Paula Cramer and Michael Hallek S16 melanoma | A new paradigm tumor for drug development Alexander M. M. Eggermont and Caroline Robert S18 bone cancer | Prevention and treatment of bone metastases Robert E. Coleman


Nature Reviews Endocrinology

Nature Reviews Neurology

S21 thyroid disease in pregnancy | Thyroid function—effects on mother and baby unraveled Anthony P. Weetman

S55 stroke | Major advances across the spectrum of stroke care Lee H. Schwamm

S22 primary aldosteronism | Towards a better understanding of causation and consequences Michael Stowasser S24 polycystic ovary syndrome | Genes, aging and sleep apnea in polycystic ovary syndrome Andrea Dunaif S26 epigenetics and metabolism | Epigenetics, the life-course and metabolic disease Peter D. Gluckman S28 osteoporosis | Osteoporosis therapy—dawn of the postbisphosphonate era Roland Baron

S57 movement disorders | Translating new research findings into clinical practice Christine Klein and Dimitri Krainc S58 multiple sclerosis | Advances in therapy, imaging and risk factors in MS Bianca Weinstock-Guttman and Murali Ramanathan S60 dementia | Microbleeds in dementia—singing a different ARIA Philip Scheltens and Jeroen D. C. Goos S62 epilepsy | Insights into epilepsy treatments and biomarkers Fernando Cendes

S30 type 1 diabetes mellitus | Heterogeneity of T1DM raises questions for therapy Paolo Pozzilli

Nature Reviews Gastroenterology & Hepatology

Nature Reviews Rheumatology

S33 hepatitis c | A new standard of care and the race towards IFN-free therapy Wolf Peter Hofmann and Stefan Zeuzem

S65 rheumatoid arthritis | Advances in diagnosis, treatment and definition of remission Gerd R. Burmester

S35 hepatocellular carcinoma | Genomics in hepatocellular carcinoma—a big step forward Ryosuke Tateishi and Masao Omata

S67 juvenile idiopathic arthritis | New takes on categorization and treatment Alberto Martini

S36 ibd | Advances in IBD management—towards a tailored approach Guillame P. Pineton de Chambrun and William J. Sandborn

S68 systemic lupus erythematosus | Deciphering the role of NETs and networks in SLE Thomas Dörner

S38 the gut microbiota | Translating the microbiota to medicine Fergus Shanahan S40 neurogastroenterology | Emerging concepts in neurogastroenterology and motility Keith A. Sharkey and Gary M. Mawe

S70 osteoarthritis | Age-related OA—a concept emerging from infancy? Thomas Aigner and Wiltrud Richter S72 systemic sclerosis | From mechanisms to medicines Luc Mouthon S74 vasculitis | The renaissance of granulomatous inflammation in AAV Stephan D. Gadola and Wolfgang L. Gross

Nature Reviews Nephrology

Nature Reviews Urology

S43 glomerular disease | New clues to environmental influences in glomerular disease Peter J. Nelson and Charles E. Alpers

S77 prostate cancer | Redefining the therapeutic landscape for CRPC Carmel Pezaro and Gerhardt Attard

S44 polycystic kidney disease | Connecting the dots toward a polycystic kidney disease therapy Vicente E. Torres and Peter C. Harris

S79 bladder cancer | The dawn of personalized medicine Thomas W. Flaig and Dan Theodorescu

S46 acute kidney injury | Biomarkers are transforming our understanding of AKI Lakhmir S. Chawla and John A. Kellum S48 nondialysis chronic kidney disease | Progression, prediction, populations and possibilities Adeera Levin S50 dialysis | Can cardiovascular risk in dialysis patients be decreased? Peter Stenvinkel and Peter Bárány S52 transplantation | New agents, new ideas and new hope Titte R. Srinivas and Bruce Kaplan

S80 sexual dysfunction | Advances in epidemiology, pathophysiology and treatment Eric Chung and Gerald B. Brock S82 male factor infertility | Semen quality, sperm selection and hematospermia Amichai Kilchevsky and Stanton Honig S84 kidney cancer | Objectifying risk for localized renal masses Marc C. Smaldone and Robert G. Uzzo


CARDIOLOGY ACUTE CORONARY SYNDROMES IN 2011

Walking the tightrope between efficacy and bleeding Payal Kohli and Christopher P. Cannon

Major advances in the diagnosis of acute coronary syndromes (ACS) have occurred in 2011, but physicians treating ACS still walk the tightrope between efficacy and bleeding. Key publications have shed light on this delicate balance and heralded a new era of novel oral anticoagulants for the treatment of ACS. Kohli, P. & Cannon, C. P. Nat. Rev. Cardiol. 9, 69–71 (2012); published online 20 December 2011; doi:10.1038/nrcardio.2011.206

The year 2011 has witnessed an evolution in all aspects of the management of acute coronary syndromes (ACS). The intro­duction of new-generation troponin assays has compli­ cated the diagnostic dilemma in ACS by increasing the number false positive diagnoses. One of the most-interesting studies of 2011 addressed whether the reduced threshold for detection of myocardial injury translated into improved clinical outcomes. Mills et al. undertook a prospective study of >1,000 patients who presented with possible ACS before and after the introduction of a lower diagnostic threshold (from 0.20 ng/ml to 0.05 ng/ml) for myocardial infarction (MI) using a high-sensitivity troponin assay with a low coefficient of variability (<10%).1 The study demonstrated that the lower threshold resulted in a 29% increase in detection of MI. Among patients with small increases in troponin (0.05–0.19 ng/ml), this diagnostic reclassification was also associated with improved risk stratification and better use of evidence-based therapies. Most importantly, the rate of death or recurrent MI was 52% lower (P = 0.01) during the period in which the lower troponin thres­hold was used.1 Therefore, we can surmise that changing the diagnostic threshold for myocardial injury has identified a new, previously misclassified high-risk patient population that was and has led to improvements in clinical outcomes. Individualized medicine and tailored treatments have continued to be a dominant theme of this decade. The ELEVATETIMI 562 and GRAVITAS3 studies tested the effects of high-dose clopidogrel on platelet reactivity and clinical outcomes, respectively. In ELEVATE-TIMI 56,2 hetero­zygote carriers of the CYP2C19*2 allele needed 225 mg of clopidogrel to achieve the same KEY ADVANCES IN MEDICINE

degree of platelet inhibition as noncarriers receiving 75 mg, suggesting that genotype could be important for choosing not only the type of antiplatelet agent, but also the dose. Homozygote carriers of CYP2C19*2 in ELEVATE-TIMI 56 were highly resistant to clopidogrel and maintained high degrees of platelet reactivity, even with 300 mg of the drug. Whereas ELEVATE-TIMI 56 confirmed the importance of pharmaco­genomic interactions in platelet reactivity, the GRAVITAS trial3 bridged the gap between laboratory findings and clinical outcomes and answered the question of whether increasing doses of clopidogrel would improve clinical outcomes. The investi­gators randomly assigned 2,214 patients with high on-­treatment platelet reactivity to high-dose (600 mg loading, 150 mg maintenance) or standard-dose (75 mg maintenance alone) clopidogrel. Key advances ■■ Use of a sensitive troponin assay with a lower threshold for diagnosis of MI reduced death and recurrent MI in high-risk patients1 ■■ Increased doses of clopidogrel are necessary to achieve platelet inhibition in CYP2C19*2 heterozygotes 2 ■■ Apixaban 5 mg twice daily increases bleeding without decreasing the risk of cardiovascular death, MI, and stroke in patients with ACS5 ■■ Adding very low dose rivaroxaban to dual antiplatelet therapy reduces cardiovascular death, MI, and stroke with no increase in fatal hemorrhage, despite a dosedependent increase in major bleeding6 ■■ A bleeding risk score derived and validated on the basis of baseline characteristics demonstrated effective risk stratification for major bleeding in patients with ACS8

Despite a 22% absolute reduction in high on-treatment platelet reactivity at 30 days and 6 months with the high-dose strategy (P <0.001), no difference was observed between the two groups in the incidence of cardiovascular death, MI, and stent thrombo­ sis or in the rate of severe or moderate bleeding at 6 months (although the overall number of events in the trial was small).3 These results emphasize that, despite variation in drug metabolism and activity, no clinical impact of altering the dosing regimen of clopidogrel has yet been demon­strated. Furthermore, the reduction in platelet reactivity with second generation thienopyridines appears marginal as the dose is increased, and the effects in homozygote carriers of CYP2C19*2 are severely limited. With the introduction of more-potent agents, including prasugrel and ticagrelor, many of these pitfalls can potentially be avoided. With the emergence of novel oral anti­ coagulants that require minimal monitoring, a new paradigm for treating ACS was ushered in—combining a low dose anticoagulant with dual antiplatelet therapy. With novel direct factor Xa inhibitors, such as apixaban, rivaroxaban, and darexaban, straightforward outpatient anticoagulation finally became a realistic option for patients with ACS. However, the road was not without its stumbling blocks. In a phase II trial of darexa­b an, increases in bleeding were demon­strated without an improvement in efficacy.4 The phase III APPRAISE‑2 trial5 of 7,392 patients with ACS was stopped early after an increase in major bleeding (HR 2.59, P = 0.001) emerged for apixaban (5 mg twice daily) without an improvement in efficacy.5 Against these headwinds, the results of the ATLAS ACS 2‑TIMI 51 trial6 were JANUARY 2012  |  S1


CARDIOLOGY 15 –

APPRAISE–2

Events* per 1,000 patients

Safety

Safety P = 0.001

10 –

5–

ATLAS ACS 2-TIMI 56

P = NS

TRACER Safety P <0.001

P <0.001

P <0.001 P = 0.03

P = 0.04

P = NS

0–

–5 –

P = NS Efficacy P = 0.002

–10 – P = 0.02 Efficacy

–15 – CVD, MI, stroke

CVD, MI, stroke, RI, UR

Death

P = NS Efficacy TIMI major bleeding

ICH

Figure 1 | Comparison of the results of the APPRAISE‑2,5 ATLAS ACS 2‑TIMI 56,6 and TRACER7 trials. The data are for the study drug versus placebo. Bleeding was increased in all studies; only the ATLAS ACS 2‑TIMI 56 trial demonstrated efficacy and decreased mortality (data for rivaroxaban 2.5 mg shown with modified intention-to-treat analysis). Follow-up times are as follows: APPRAISE‑2 median 8 months; ATLAS ACS 2‑TIMI 56 mean 13 months; TRACER median 16.5 months. *Events are reported on the basis of individual end points. Abbreviations: CVD, cardiovascular death; ICH, intracranial hemorrhage; MI, myocardial infarction; RI, recurrent ischemia with rehospitalization; UR, urgent coronary revascularization.

particu­larly favorably received. The investi­ gators randomly assigned 15,526 patients with ACS to rivaroxaban 2.5 mg or 5.0 mg twice daily, or placebo on a background of aspirin alone (stratum 1) or aspirin plus a thienopyridine (stratum 2; 93% of patients). Notably, the doses of rivaroxaban used were much lower than that used for full anticoagulation, such as in atrial fibrillation (20 mg once daily). In the pooled cohort, a highly significant 16% relative risk reduction (8.9% vs 10.7%, P = 0.008) in cardiovascular death, MI, and stroke was observed for rivaroxaban, with a similar reduction in all-cause mortality, MI, and stroke (9.2% vs 11.0%, P = 0.006) and a 31% (2.3% vs 2.9%, P = 0.02) reduction in stent thrombosis over a 2‑year period. A dose-dependent increase in TIMI major bleeding occurred (placebo: 0.6% vs rivaroxa­ban 2.5 mg: 1.8% and rivaroxaban 5 mg: 2.4%, P <0.001), but no increase in fatal bleeding was noted. Most importantly, a highly significant 34% reduction in cardiovascular mortality and a 32% reduction in total mortality was observed for rivaroxaban 2.5 mg twice daily.6 Despite its overwhelming efficacy, this trial reminded us that bleeding continues to be a limiting factor in studies of anticoagulant plus antiplatelet agents and that the window of efficacy needs to be carefully defined. S2  |  JANUARY 2012



Another major trial involved the oral thrombin receptor antagonist vorapaxar. The TRACER trial7 faced issues with bleeding and was terminated early. In this study, 12,944 patients with ACS were randomly assigned to receive vorapaxar or placebo in addition to standard care. Vorapaxar failed to reduce cardio­vascular death, MI, stroke, recurrent ischemia, and urgent revasculariza­tion. This drug led to a 3.4-fold increased risk for intracranial hemorrhage (P <0.001) and a 35% increase in bleeding.7 The results of this trial highlighted the ever-present hazards of increased bleeding when adding new antithrombotic agents to standard therapy, especially in patients who are at increased risk for intracranial hemorrhage. A second trial (TRA 2°P-TIMI 50) of vorapaxar in patients with stable coronary artery disease will be reported next year; thus the final word on this drug is still to come. Side-by-side comparison of the three major oral anticoagulant trials shows that only the ATLAS ACS 2‑TIMI 56 trial met its primary efficacy end point, reduced mortality, but all studies demon­strated significant increases in bleeding (Figure 1). Given the delicate balance between efficacy and bleeding, strategies to identify patients at high risk, and then triaging therapies accordingly, have generated much interest.

Mathews et al. included 90,273 patients with ST-segment elevation or ST-segment elevation MI from the ACTION registry– GWTG™ to derive (72,813 patients) and valid­ate (17,960 patients) a bleeding risk score using only baseline characteristics.8 Twelve patient characteristics and presenting factors emerged as predictors of major bleeding in the model. Notably, history of stroke or transient ischemic attack, which was present in only 8% of this cohort, did not emerge as risk factors for major bleeding in this model, although they have previously been identified as risk factors for intra­cranial hemorrhage.8 The risk stratification model by Mathews et al. could guide clinical practice with respect to patient selection for antiplatelet and anticoagulant agents, but the extent to which it can be generalized remains unknown. Ideally, the score should be validated in the setting of randomized trials, various agents, and in high-risk and low-risk patient populations before it is applied widely. The year 2011 was a historic landmark in the treatment of ACS. Major strides were made in diagnostic technology, tailored medical therapy, and the safe use of a very low-dose anticoagulant. Without doubt, the years to come will see many more trials to better educate physicians on how to walk the tightrope between efficacy and bleeding. TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 350 Longwood Avenue, 1st floor office, Boston, MA 02115, USA (P. Kohli, C. P. Cannon). Correspondence to: C. P. Cannon cpcannon@partners.org Competing interests C. P. Cannon declares associations with the following companies: Accumetrics, Alnylam Pharmaceuticals, AstraZeneca, Automedics Medical Systems, BristolMyers Squibb/Sanofi, GlaxoSmithKline, Intekrin Therapeutics, Merck, Novartis, Pfizer, and Takeda. P. Kohli declares no competing interests. 1.

2.

3.

4.

Mills, N. L. et al. Implementation of a sensitive troponin I assay and risk of recurrent myocardial infarction and death in patients with suspected acute coronary syndrome. JAMA 305, 1210–1216 (2011). Mega, J. L. et al. Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. JAMA 306, 2221–2228 (2011). Price, M. J. et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 305, 1097–1105 (2011). Steg, P. G. et al. RUBY‑1: a randomized, doubleblind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome. Eur. Heart J. 32, 2541–2554 (2011).

www.nature.com/reviews


CARDIOLOGY 5.

6.

7.

Alexander, J. H. et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N. Engl. J. Med. 365, 699–708 (2011). Mega, J. L. et al. Rivaroxaban in patients with a recent acute coronary syndrome. N. Engl. J. Med. http://dx.doi.org/10.1056/ NEJMoa1112277. Tricoci, P. et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes.

8.

N. Engl. J. Med. http://dx.doi.org/10.1056/ NEJMoa1109719. Mathews, R. et al. In-hospital major bleeding during ST‑elevation and non‑ST‑elevation myocardial infarction care: derivation and validation of a model from the ACTION Registry®-GWTG™. Am. J. Cardiol. 107, 1136–1143 (2011).

ATRIAL FIBRILLATION IN 2011

Stroke prevention in AF Gregory Y. H. Lip

In 2011, key trials with oral factor Xa inhibitors in patients with atrial fibrillation highlighted promising data on these novel anticoagulants. Patients with ≥1 stroke risk factors can be considered for oral anticoagulation. These novel, fixed-dose drugs are given without monitoring, so clinicians must learn to balance stroke and bleeding risks. Lip, G. Y. H. Nat. Rev. Cardiol. 9, 71–73 (2012); published online 20 December 2011; doi:10.1038/nrcardio.2011.203

The year 2011 saw the publication of three pivotal phase III trials for two oral direct factor Xa inhibitors, apixaban and rivaroxa­ ban,1–3 as well as important articles on bleeding risk assessment 4 and the net clinical benefit of thromboprophylaxis.5 Novel oral anticoagulants that are viable alternatives to warfarin have clearly changed the landscape of stroke prevention in patients with atrial fibrillation (AF).6 Until recently, the recommended approach was artificially to stratify patients with AF into low, intermediate, and high risk strata—despite stroke risk being a continuum—so that those classed as being at high risk could be targeted for an inconvenient (and potentially dangerous) drug, warfarin. Many studies, however, have shown that the categorization of patients into low, intermediate, or high risk strata has poor correlation with actual warfarin prescribing, and that the predictive value of risk schemes such as the CHADS2 score (Box 1) to identify high-risk patients is suboptimal.7 Consequently, guidelines now recommended the use of the CHA2DS2‑VASc score (Box 1) to complement the older (but simpler) CHADS2 score. Indeed, emphasis is now directed towards identification of ‘truly low-risk’ patients with AF by being more inclusive (rather than exclusive) of common risk factors for stroke, because these patients might not need any antithrombotic therapy. Meanwhile, patients with ≥1 risk factor for stroke should be considered for effective stroke prevention with oral anticoagulation, whether with (very) well-controlled warfarin or one of the KEY ADVANCES IN MEDICINE

novel agents, either an oral direct thrombin inhibitor (such as dabigatran) or an oral direct factor Xa inhibitor (for example, rivaroxaban or apixaban). 1 Indeed, the CHA2DS2‑VASc score has consistently been shown to outperform the CHADS 2 score in identification of truly low-risk patients and is as good as—and possibly better than—the CHADS2 score in the identification of high-risk patients who subsequently suffer thromboembolism.7,8 Key advances ■■ In the AVERROES trial, apixaban was superior to aspirin for stroke prevention in patients with atrial fibrillation (AF), with similar rates of major bleeding and improved tolerability1 ■■ In the ARISTOTLE trial, apixaban was superior to warfarin for prevention of stroke and systemic embolism in patients with AF, with significantly less major bleeding and improved survival2 ■■ In the ROCKET‑AF trial, rivaroxaban was noninferior to warfarin for stroke prevention in a high-risk population of patients with AF, with similar rates of major bleeding3 ■■ The HAS‑BLED score is well validated to predict major-bleeding events in patients receiving anticoagulation therapy, and outperforms other bleeding risk assessment schemes4 ■■ ‘Truly low-risk’ patients with a CHA2DS2‑VASc score of 0 do not require thromboprophylaxis; net clinical benefit is greatest in patients with a high HAS‑BLED score, where reduced ischemicstroke risk outweighs the increased intracranial-bleeding risk5

Attention has also been directed to assessment of bleeding risk. Common risk factors for bleeding (as well as potentially correctable risk factors, such as uncontrolled blood pressure and concomitant aspirin use in patients receiving anticoagulation therapy) can inform clinical decision-­making, especially with the novel oral anticoagulants that can come in high-dose and low-dose regimens.9 Investigators in the AVERROES trial1 studied 5,599 patients with AF and ≥1 risk factor for stroke, and who had refused war­ farin or been deemed unsuitable for war­farin by the investigators on the basis of the inclusion criteria. The trial was stopped early because of the clear superiority of apixaban over aspirin, with a 55% reduction in the primary end point of stroke and systemic embolism (HR 0.45, 95% CI 0.32–0.62, P <0.001), but with no significant difference between apixaban and aspirin for major bleeding (HR 1.13, 95% CI 0.74–1.75, P = 0.57) or intracranial hemorrhage. Furthermore, fewer drug discontinuations occurred with patients taking apixaban, which indicates that this drug is better tolerated than aspirin. Until now, patients who refused or were unsuitable for warfarin were treated with aspirin; therefore, this trial will certainly change clinical practice, especially given that the evidence for a beneficial (and safe) role for aspirin in patients with AF is weak.10 Researchers in the ARISTOTLE trial 2 randomly allocated 18,201 patients with AF to receive either warfarin or apixaban, and reported a 21% reduction in the primary end point of stroke and systemic embolism with apixaban (HR 0.79, 95% CI 0.66– 0.95, P <0.001 for noninferiority, P = 0.01 for superi­ority), with a 31% reduction in major bleeding (HR 0.69, 95% CI 0.60–0.80, P <0.001) and an 11% reduction in mortality (HR 0.89, 95% CI 0.80–0.99, P = 0.047). The primary end point was driven by the reduction in hemorrhagic stroke (HR 0.51, 95% CI 0.35–0.75, P <0.001), with no difference in ischemic stroke (HR 0.92, 95% CI 0.74–1.13, P = 0.42) between apixaban and warfarin. Another oral direct factor Xa inhibitor, rivaroxaban, was compared with warfarin in the ROCKET‑AF trial.3 A higher-risk cate­ gory of patients (n = 14,264, mean CHADS2 score = 3.5) was enrolled in ROCKET‑AF compared with the ARISTOTLE and AV E R ROE S t r i a l s ( m e an C HA D S 2 score = 2.1 in both). Also, 55% of the ROCKET‑AF population was a secondary prevention cohort (by contrast with 20% and 14% in the ARISTOTLE and AVERROES trials, respectively). Rivaroxaban was clearly JANUARY 2012  |  S3


CARDIOLOGY Box 1 | Abbreviations and definitions CHADS2 Congestive heart failure (1 point) Hypertension (1 point) Age ≥75 years (1 point) Diabetes mellitus (1 point) Stroke or thromboembolism (2 points) CHA2DS2‑VASc Congestive heart failure (1 point) Hypertension (1 point) Age ≥75 years (2 points) Diabetes mellitus (1 point) Sex, female (1 point) Vascular disease (1 point) Age 65–74 years (1 point) Stroke or thromboembolism (2 points) HAS‑BLED Hypertension (uncontrolled blood pressure) Abnormal renal or liver function Stroke Bleeding history or predisposition Labile international normalized ratio (INR) Elderly (age >65 years) Drugs concomitantly (for example, concomitant aspirin or nonsteroidal antiinflammatory drugs, or alcohol abuse) Net clinical benefit [ISR with no treatment – ISR on treatment] – 1.5*[IHR on treatment – IHR with no treatment] Abbreviations: IHR, intracranial-hemorrhage rate; ISR, ischemic-stroke rate.

noninferior to warfarin for the primary end point of stroke and systemic embolism (HR 0.79, 95% CI 0.66–0.96, P <0.001 for non­inferiority). In the more-conventional and conservative intention-to-treat analysis, rivaroxa­ban failed to achieve superiority (HR 0.88, 95% CI 0.74–1.03, P <0.001 for noninferiority, P = 0.12 for superiority), although a per-protocol, on-treatment analysis reported superiority for rivaro­ xaban (HR 0.79, 95% CI 0.65–0.95, P = 0.02). The primary safety end point, major and non­m ajor clinically relevant bleeding, was not different (HR 1.03, 95% CI 0.96– 1.11, P = 0.44), although hemorrhagic stroke, intracranial hemorrhage, and fatalbleeding events were lower with rivaroxaban than warfarin. Until the advent of novel oral anti­ coagulants, patients with AF who were receiving oral anticoagulation often came under the care of a warfarin clinic, which was responsible for anticoagulation monitoring and doses, rather than cardiologists per se. Now, clinicians will have to make informed decisions on doses of these novel drugs. Of the novel direct thrombin inhibitors, only dabigatran is approved for use for S4  |  JANUARY 2012



stroke prevention in patients with AF, and this drug is licensed at doses of 110 mg or 150 mg twice daily (or 75 mg twice daily for patients with severe renal failure in the USA). Apart from the criteria of age (>80 years) and concomitant drug use (such as verapamil), how should the dose of dabigatran be decided on the basis of bleeding risk? To help clinical decision-making, a simple acronym of common risk factors for bleeding (the HAS‑BLED score; Box 1) has been recommended in European and Canadian guidelines. Various validations of the HAS‑BLED score were published in 2011.4,5 In a large, contemporary, anti­coagulated population of patients with AF, the HAS‑ BLED score performed best of all the tested bleeding-risk schemes, and more-accurately discriminated patients on the basis of their bleeding risk (whether assessed by the c‑­s tatistic, or estimates of Net Reclassification Improvement and Integrated Discrimination Improvement), with a stepwise increase in rates of major bleeding with increasing HAS‑BLED score (P <0.0001 for trend).4 Multivariate analyses identified concurrent aspirin use (HR 2.10), renal impairment (HR 1.98), age ≥75 years (HR 1.63), diabetes mellitus (HR 1.47), and heart failure or left ventricular dysfunction (HR 1.32) as significant predictors of bleeding. What does this mean for clinicians in everyday practice, who have to balance the risks of stroke and bleeding? In a large, nationwide, ‘real-world’ cohort study from Denmark (n = 132,372), Olesen and colleagues balanced stroke risk (assessed by the CHADS2 and CHA2DS2‑VASc scores) with bleeding risk (assessed using the HAS‑BLED score), and the net clinical benefit (Box 1) of ischemic-stroke prevention versus intracranial-­hemorrhage risk was calculated.5 The net clinical benefit was not positive for aspirin at any stroke-risk or bleeding-risk strata, which led the investi­ gators to conclude that “aspirin should not be used for thromboprophylaxis in any patient with AF”.5 Unsurprisingly, the combination of warfarin plus aspirin did not confer any additional benefit in preventing thromboembolism, but substantially increased bleeding risk. In patients treated with warfarin, the only category where the net clinical benefit was negative was patients with a CHA2DS2‑VASc score of 0, which reflects their truly low-risk status. The net clinical benefit was non-­ negative (either neutral or positive) at a CHADS2 score ≥0 and a CHA2DS2‑VASc score ≥1. In addition, the net clinical benefit

was clearly positive, in favor of warfarin, in patients with increased risk of stroke or thromboembolism, and was even greater at high HAS‑BLED scores (≥3), which indicates that patients at high risk of bleeding are also at high risk of stroke or thrombo­embolism —and that the absolute benefit of warfarin in reducing the risk of ischemic stroke far outweighs the smaller absolute increase in the risk of serious bleeding. The practical use of the HAS‑BLED score also encourages clinicians to consider bleeding risk factors that can be corrected, such as uncontrolled blood pressure, concomitant use of aspirin or nonsteroidal anti-­inflammatory drugs, and time in therapeutic range if the patient is on warfarin (the H, D, and L in HAS‑BLED, respectively). The year 2011 has seen great advances in assessment of stroke and bleeding risks in patients with AF, and exciting new data on the novel oral anticoagulants. Prospects are much improved for patients with AF. University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Dudley Road, Birmingham B18 7QH, UK g.y.h.lip@bham.ac.uk Competing interests The author declares associations with the following companies and organizations: Astellas, AstraZeneca, Bayer, Biotronik, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi‑Sankyo, focusAF, Merck, Portola and Sanofi Aventis. See the article online for full details of the relationships. 1.

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3.

4.

5.

6.

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Connolly, S. J. et al. Apixaban in patients with atrial fibrillation. N. Engl. J. Med. 364, 806–817 (2011). Granger, C. B. et al. Apixaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 365, 981–992 (2011). Patel, M. R. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N. Engl. J. Med. 365, 883–891 (2011). Lip, G. Y., Frison, L., Halperin, J. L. & Lane, D. A. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS‑BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score. J. Am. Coll. Cardiol. 57, 173–180 (2011). Olesen, J. B. et al. Risks of thromboembolism and bleeding with thromboprophylaxis in patients with atrial fibrillation: a net clinical benefit analysis using a ‘real world’ nationwide cohort study. Thromb. Haemost. 106, 739–749 (2011). Ahrens, I., Lip, G. Y. & Peter, K. New oral anticoagulant drugs in cardiovascular disease. Thromb. Haemost. 104, 49–60 (2010). Karthikeyan, G. & Eikelboom, J. W. The CHADS2 score for stroke risk stratification in atrial fibrillation—friend or foe? Thromb. Haemost. 104, 45–48 (2010). Lip, G. Y. Stroke in atrial fibrillation: epidemiology and thromboprophylaxis. J. Thromb. Haemost. 9 (Suppl. 1), 344–351 (2011).

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CARDIOLOGY 9.

[ESC] Working Group on Thrombosis. Thromb. Haemostat. 106, 997–1011 (2011). 10. Lip, G. Y. The role of aspirin for stroke prevention in atrial fibrillation. Nat. Rev. Cardiol. 8, 602–606 (2011).

Lip, G. Y. H. et al. Bleeding risk assessment and management in atrial fibrillation patients: executive summary of a position document from the European Heart Rhythm Association [EHRA], endorsed by the European Society of Cardiology

HEART FAILURE IN 2011

Heart failure therapy—technology to the fore John J. V. McMurray

Studies published in 2011 in the field of heart failure have reinforced the benefit of cardiac resynchronization therapy in patients with mild symptoms and confirmed the value of left ventricular assist devices and CABG surgery in selected patients. Conversely, the efficacy of nesiritide in acute heart failure has been questioned. McMurray, J. J. V. Nat. Rev. Cardiol. 9, 73–74 (2012); doi:10.1038/nrcardio.2011.212

KEY ADVANCES IN MEDICINE

trials, in which recurrent events that are frequent and of great clinical significance than first HF events are ignored. A report from INTERMACS 2 also re-­ inforced the impressive technological progress made with left ventricular assist devices (LVADs). In a post-approval study required by the FDA, outcomes in the first 169 consecutive patients receiving a HeartMate II® (Thoratec Corporation, Pleasanton, CA, USA) device as a bridge-to-transplant were compared with those in 169 patients receiving different LVADs for the same indication over the same time period. The proportion of patients transplanted, recovered, or receiving continuing LVAD support at 6 months was 91% in the HeartMate II® group and 80% in the comparator group (85% and 70%,

© Newlight | Dreamstime.com

Although many interesting studies on epidemio­logy, pathophysiology, and biomarkers in heart failure (HF) were published in 2011, my focus in this article is on treatments that are available for use and can make an impact in everyday practice. Five important studies, covering device and drug therapy, and surgery in patients with HF will be discussed. In August 2011, a follow-up report from MADIT-CRT1 reinforced the impressive effect of cardiac resynchronization therapy (CRT) on outcomes among patients with HF, even in those with mild symptoms. The investigators showed that CRT plus a defibrillator, compared with a defibrillator alone, reduced the risk of a first episode of worsening HF by 46% (P <0.001) and, importantly, also reduced the risk of subsequent episodes by 38% (P = 0.003). Because patients experiencing a first episode of worsen­ing HF were at a substantially elevated risk of a further event, the absolute reduction in risk of subsequent episodes with CRT was large (from 72 to 44 events per 100 patient years of follow-up). The benefit was greatest in patients with left bundle branch block. In addition, a 19-fold increase in mortality risk was reported in patients experiencing a second episode of worsening HF.1 These findings are important for several reasons. Clearly, worsening of HF is extremely unpleasant for patients and usually leads to hospital admission with major consequences (economic and otherwise) for health-care systems, and is associated with an increased risk of death.1 These findings also highlight the limitations of the conventional ‘time to first-event’ analysis of

respectively, at 1 year). These excellent outcomes from ‘real-world’ practice at 77 centers in the USA are consistent with the findings of the pivotal, randomized HeartMate II® trial,3 which showed that this continuousflow device was superior to the comparator pulsatile-flow device. Monitoring devices are currently of immense interest in HF research and the findings of the CHAMPION study 4 were notable. This moderate-sized trial showed that a small, implantable hemodynamic monitor improved outcomes in patients with NYHA class III HF who had been hospitali­zed for HF in the previous year and were optimally treated. The monitor was placed transvenously in a pulmonary artery branch and allowed wireless non­ invasive measurement of pulmonary artery pressure. Physicians in the control group and patients in both groups did not have knowledge of pressure measurements; however, site investi­gators, the trial principal investi­gators, and sponsor (CardioMEMS, Atlanta, GA, USA) employees had access to pressure measurements and these were used to adjust therapy. Addition of nitrates and hydralazine and adjustment of diuretic therapy, including use of intravenous diure­ tics, were more frequent in the inter­vention group. The primary outcome was the rate of HF hospitaliza­tion over 6 months; 83 hospitaliza­tions occurred among 55 of the 270 patients in the intervention group, compared with 120 among 80 of the 280 patients in the control group (rate 0.31 vs 0.44; HR 0.70, 95% CI 0.60–0.84, P <0.0001). In absolute terms, 12.5 fewer hospitaliza­ tion events per 100 patients occurred over

JANUARY 2012  |  S5


CARDIOLOGY Key advances ■■ Cardiac resynchronization therapy reduced not only the first, but also subsequent, episodes of worsening heart failure (HF) in patients with systolic dysfunction and mild symptoms1 ■■ Use of the HeartMate II®(Thoratec Corporation, Pleasanton, CA, USA) continuous-flow left ventricular assist device was associated with excellent 6-month and 12-month survival in a ’real-world’ registry study2 ■■ Pharmacological intervention prompted by noninvasive pulmonary artery monitoring may reduce the risk of HF hospitalization in patients with moderately severe symptoms and previous admission for HF4 ■■ In selected patients with ischemic systolic HF and a life expectancy of more than 2 years, CABG surgery may reduce cardiovascular mortality and morbidity6 ■■ Nesiritide has a small and clinically insignificant effect on dyspnea and no effect on mortality or worsening HF in patients with acute HF7

6 months in the intervention group, meaning that eight patients needed to be treated to prevent one hospitalization. 4 Although these results are impressive, the trial has been criticized because of the active involvement of the sponsor in encouraging treatment changes in the intervention group, and whether the benefit would be as substantial when used in ordinary practice has been questioned. Nevertheless, the positive findings of the CHAMPION trial4 contrasted strikingly with those of other studies, such as the negative study DOT-HF5 in which an implantable intrathoracic impedance detection device was used. Another study that raised as many questions as answers was the STICH trial.6 In this study, 1,212 patients with a left ventric­ular ejection fraction <35%, coronary artery disease amenable to surgery, and no indica­ tion for revascularization (that is, left main disease or Canadian Cardiovascular Class III angina or greater) were randomly assigned to receive medical therapy or CABG surgery. The primary end point was death from any cause. Over a median follow-­up of 56 months, 218 of the 610 patients assigned to surgery and 244 of the 602  patients alloca­ted to medical therapy died (36% vs 41%; HR 0.86, 95% CI 0.72–1.04, P = 0.12). However, occurrence of the key secondary end points (cardiovascular death and death or cardiovascular hospitalization) was signifi­cantly less common in the surgical S6  |  JANUARY 2012



group, as was all-cause mortality in an adjusted intention-to-treat analysis and in a per protocol analysis. As in prior trials of CABG surgery, there was an initial mortality excess in the surgery group and benefit from surgery was not apparent until after approximately 2 years of follow-up.6 On balance, the STICH trial probably was a positive study, although the patients were highly selected and atypically young (mean age 60 years) for the majority with HF; two-thirds had symptoms of angina. Unexpectedly, pre­ operative evaluation of myocardial viability did not help to identify patients who would benefit from revascularization. The takehome message seems to be that, in carefully selected patients with systolic HF and coronary artery disease likely to survive for more than 2 years, CABG surgery leads to reduced long-term mortality and morbidity compared with medical therapy alone. The list of treatments that are ineffective in acute HF grew longer in 2011 with the publication of the results of ASCEND-HF,7 which showed that nesiritide (recombinant human B‑type natriuretic peptide) had only a small effect on dyspnea at 6 h and 24 h and no effect on mortality or worsening HF at 30 days. This trial ended a long-running controversy about the safety and efficacy of nesiritide and highlighted the difficulty of demonstrating a benefit for novel therapies over and above that of conventional treatment with diuretics and nitrates, which is rapid and substantial.8 Despite the lack of success with treatments for acute HF to date, interesting new drugs continue to be developed. One of these, with intriguing proof-of-concept data in patients, is a ‘first-in-class’ cardiac myosin activator, omecamtiv mercarbil, which is thought to improve cardiac performance by increasing the rate of transition from the weak myosin-acting binding state to the strongly bound (that is, force-generating) state. This agent increases the duration of systole without increasing heart rate or myocardial oxygen consumption.9 Finally, I would like to mention an important study relevant to the holistic care of patients with HF. Peterson and colleagues10 looked at health literacy in 1,494 patients with an emergency room visit or hospitaliza­ tion with HF using three brief screening questions—how often do you have someone help you read hospital materials; how often do you have problems learning about your medical condition because of difficulty reading hospital materials; and how confident are you filling out forms by yourself?

More than one in six patients showed a low level of health literacy, which was an indepen­dent predictor of all-cause mortality, after taking account of other prognostic variables.10 These findings argue for testing of the effect of interventions thought to improve health literacy on outcomes in HF. In summary, 2011 has been largely a year of consolidation for HF therapeutics. We have an array of effective drugs, devices, and surgical procedures for patients with systolic HF, but substantial progress has yet to be made in the treatment of patients with preserved ejection fraction and those with acute decompensation. British Heart Foundation Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK. john.mcmurray@glasgow.ac.uk Competing interests The author declares associations with the following companies: Amgen and Johnson & Johnson/Scios. See the article online for full details of the relationships. 1.

Goldenberg, I. et al. Reduction of the risk of recurring heart failure events with cardiac resynchronization therapy: MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy). J. Am. Coll. Cardiol. 58, 729–737 (2011). 2. Starling, R. C. et al. Results of the post‑US Food and Drug Administration-approval study with a continuous flow left ventricular assist device as a bridge to heart transplantation: a prospective study using the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support). J. Am. Coll. Cardiol. 57, 1890–1898 (2011). 3. Slaughter, M. S. et al. Advanced heart failure treated with continuous-flow left ventricular assist device. N. Engl. J. Med. 361, 2241–2251 (2009). 4. Abraham, W. T. et al. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet 377, 658–666 (2011). 5. van Veldhuisen, D. J. et al. Intrathoracic impedance monitoring, audible patient alerts, and outcome in patients with heart failure. Circulation 124, 1719–1726 (2011). 6. Velazquez, E. J. et al. Coronary-artery bypass surgery in patients with left ventricular dysfunction. N. Engl. J. Med. 364, 1607–1616 (2011). 7. O’Connor, C. M. et al. Effect of nesiritide in patients with acute decompensated heart failure. N. Engl. J. Med. 365, 32–43 (2011). 8. Felker, G. M. et al. Diuretic strategies in patients with acute decompensated heart failure. N. Engl. J. Med. 364, 797–805 (2011). 9. Cleland, J. G. et al. The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial. Lancet 378, 676–683 (2011). 10. Peterson, P. N. et al. Health literacy and outcomes among patients with heart failure. JAMA 305, 1695–1701 (2011).

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CARDIOLOGY HYPERTENSION IN 2011

New insights—from risk factors to treatment implications George L. Bakris

The results of several hypertension studies published in 2011 have contributed to our knowledge on the risks of and treatment for this condition, including the effects of slow-wave sleep, nocturnal dosing of medication, variability in post-stroke blood-pressure reduction, and the impacts of a low-sodium diet. Bakris, G. L. Nat. Rev. Cardiol. 9, 75–77 (2012); published online 13 December 2011; doi:10.1038/nrcardio.2011.202

Four key studies, completed and published in 2011, should affect the evaluation of patients with hypertension and practice patterns in this population. In one such trial, conducted in Spain, medications were dosed at night in order to improve the dipping status of blood pressure (BP). In this trial 661 patients with hypertension who were at various stages of chronic kidney disease (CKD) were randomly assigned to take all prescribed hypertension medications upon awakening or at least one drug before going to bed.1 At the end of follow-up (median 5.4 years), patients who took the nocturnal dose had an adjusted risk for total cardiovascular events that was approximately onethird that of patients who took medication upon awakening. 1 Patients who received nocturnal treatment also had a significantly lower mean BP during sleep and a greater proportion of these indivi­duals demonstrated controlled ambulatory BP compared with those taking medication upon awakening.1 These data are consistent with those from a shorter-term study of patients with stage 2–3 CKD and no signifi­cant proteinuria.2 However, a pilot study in the African American Study of Kidney Disease (AASK) cohort of ~100 patients with stage 4 CKD and proteinuria using similar methodo­logy as the Spanish group failed to show this benefit on BP dipping status or BP control in the morning after 1 year of dosing antihypertensive medications at night.3 One of the major differences between the studies was that 100% of the patients in the AASK cohort had proteinuria at various levels and stage 4 nephropathy, whereas only about 10% of the patients in the Spanish study fit this description. A nocturnal dosing strategy was also tested in the large CONVINCE trial, 4 but failed to show a reduction in cardio­vascular risk. However, the CKD and dipping status of the individuals enrolled in KEY ADVANCES IN MEDICINE

the trial was unknown. Given the increased cardiovascular risk among patients with stage 3 CKD, ambulatory BP monitoring (ABPM) is required to assess dipping status and indivi­dualize dosing regimens in people who meet the criteria as nondippers. As yet no ABPM data are available from large cohorts with stage 4 CKD and so the recom­ mendation cannot be extended to this group of patients. The second major advance in 2011 was the finding of an association between poor sleep quality and the development of hyper­ tension.5 This relationship is unrelated to sleep apnea and has more to do with the amount and type of sleep. Fung et al. evaluated whether incident hypertension is associ­ated with polysomnography measures of sleep-disordered breathing, sleep duration, and sleep architecture in older men (mean age 75 years).5 Participants included 784 community-dwelling, ambulatory men from the Outcomes of Sleep Disorders in Older Men Study who did not have Key advances ■■ Among patients with moderate-stage nephropathy, dosing medications at night has the advantage of improving blood pressure (BP) goal attainment in the early morning when cardiovascular risk is highest1 ■■ Failure to recognize insufficient quality of sleep secondary to frequent disturbances of awakening is a major contributing risk for hypertension development and poor BP control5 ■■ Lowering BP by more than 15–20% in patients with hypertension early in the post-stroke period can result in long-term cognitive consequences6 ■■ Low-sodium diets clearly reduce BP, but tend only to reduce cardiovascular events in trials; in populations, low-sodium diets reduce mortality8

hypertension at the time of their in-home sleep studies and who returned for followup after 2–4 years. By the end of follow-up (mean 3.4 years), 243 men met the criteria for incident hypertension. After adjustment for age, nonwhite race, study site, and BMI, the only sleep index to remain signifi­ cantly associated with incident hyper­tension was decreased stage N3 (or slow-wave) sleep. No attenuation of this association was seen after accounting for sleep duration, sleep fragmentation, and indices of sleepdisordered breathing. Thus, failure to get an appropriate amount of slow-wave sleep each night is a risk factor for development of hyper­tension. Reduced amounts of slowwave sleep are seen commonly in elderly patients and could be related to increased frequency of waking to urinate. Physicians should be aware of decreased deep sleep as a risk factor for hypertension and ensure that patients get an extended rest period at night by decreasing stimuli, such as caffeine and liquid intake. This strategy is used in my practice with a fair amount of success. A third important trial published in 2011 provides new information on the consequences of aggressive BP management in the setting of acute stroke. In SCAST,6 2,029 patients from northern Europe with acute ischemic or hemorrhagic stroke and systolic BP >140 mmHg were randomly assigned within 30 h of symptom onset to cande­sartan or placebo for 7 days. The dose was increased from 4 mg on day 1 to 16 mg on days 3–7. During the 7‑day treatment period, BP was 5/2 mmHg lower in the candesartan group than in the placebo group (mean BP 147/82 mmHg vs 152/84 mmHg). At the end of the 6 month follow-up, the risk of the primary composite vascular end point did not differ between treatment groups. The co-primary end point of functional outcome (modified Rankin scale), however, was associ­ated with a higher risk of poor outcome in the candesartan group. The results were interpreted by the investigators to suggest some harm and no benefit for BP lowering after acute stroke.6 To understand this finding, clinicians should be aware that current BP guidelines for the post-stroke period differ according to whether the stroke is hemorrhagic or ischemic. 7 In addition, the approach to BP management for the prevention of stroke is totally different from its management post stroke. In hemorrhagic stroke, current guidelines suggest cautious lowering of BP by no more that 20% in the first 24 h.7 Agents with rapid, short-term JANUARY 2012  |  S7


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CARDIOLOGY

action such as labetalol, nicardipine, and fenoldapam are preferred as nitroglycerin and nitroprusside can increase intra­cranial pressure. For patients with ischemic stroke who are not receiving thrombolytic therapy, BP should be lowered if markedly elevated (>220/120 mmHg). 7 In SCAST, baseline BP was 171/90 mmHg,6 so a reduction to ~140 mmHg is excessive given the recommendation and, therefore, the lack of benefit is not surprising. The fourth notable study published in 2011 is a meta-analysis in which the investigators aimed to assess the long-term effects of dietary salt reduction on mortality and cardiovascular morbidity and whether BP reduction is an explanatory factor in any effect of such dietary interventions.8 A total of 7 studies were included, 3 in normo­ tensive individuals, two in patients with hyper­tension, one in a mixed population, and one in patients with heart failure with end of trial follow-up of 7–36 months and longest observational follow up to 12.7 years. The data failed to show strong evidence for a reduced risk of all-cause mortality or cardio­vascular morbidity in normo­tensive indivi­duals and patients with hyper­tension on low-salt diets. The investigators suggest their review had insufficient power to exclude clinically important effects, since only 665 deaths occurred in 6,250 participants. They further state that their estimates of benefits from dietary salt restriction are consistent with the predicted small effects on clinical events attributable to the small BP reduction achieved. This information puts into perspective the limitations of clinical trials. The evidence that salt reduction lowers BP is clear and consistent. Since BP reduction is critical for reducing the risk of stroke and progression of CKD, low-salt diets should also be of benefit. S8  |  JANUARY 2012



However, most people do not consistently maintain a low sodium intake leading to fluctu­ation in BP, which is a major risk factor for stroke. The real impact of low sodium intake on mortality has been demonstrated in Japan and Finland where sodium reduction policies have been instituted for all foods sold in stores. In the USA, reducing dietary salt by 3 g per day is projected to reduce the annual number of all-cause deaths from 44,000 to 92,000.9 Hence, large numbers of indivi­ duals and years of follow-up are required to see the effect of consistent reduced sodium intake. Not surprisingly, therefore, trial data and even meta-­analyses cannot adequately demon­strate these effects. Clinicians should focus on the established fact that BP reduction is consistently associ­ated with reductions in cardio­vascular event rates and continue to stress the importance of a low-sodium diet to patients with hypertension. Finally, the multicenter, prospective, randomized Symplicity HTN‑2 trial, which was published in late 2010, 10 provided ground-breaking results for a new concept of treatment for refractory hypertension. Participants with systolic BP ≥160 mmHg (or ≥150 mmHg for those with type 2 diabetes mellitus) were randomly allocated to undergo renal denervation together with continuation of previous treatment or maintain previous treatment alone. Office-based BP measurements were reduced by 32/12 mmHg (baseline 178/96 mmHg) in the renal denervation group, control group BP values did not differ from the baseline of 178/97 mmHg, and between-group differences in BP at 6 months were 33/11 mmHg. No serious procedure or device-related complications occurred and adverse events did not differ between groups. The investi­gators concluded that catheterbased renal denervation is a safe and viable treatment for patients who cannot achieve

BP goals with pharmaco­therapy.10 In 2011, recruitment for the Symplicity HTN‑3 trial started in the USA; with a protocol that is more stringent than Symplicity HTN‑2 and involves more frequent ABPM. This new trial will include between-group differences in ABPM as a prespecified secondary end point. Hypertension management prior to study enrollment will be more intense and will include spironolactone. If the results of the Symplicity HTN‑3 trial are as gratifying as that of Symplicity HTN‑2, a true alternative to medications will exist for refractory hypertension. Many other ongoing clinical trials have been designed to address and, hopefully, answer important questions about specific approaches to reducing cardio­ vascular risk and the progression of CKD in patients with hypertension. Hypertensive Diseases Unit, Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Chicago Pritzker School of Medicine, 5841 South Maryland Avenue, MC 1027, Chicago, IL 60637, USA. gbakris@medicine.bsd.uchicago.edu Competing interests The author declares associations with the following companies: Abbott, CVRx, Eli Lilly, FDA, Forest Laboratories, Johnson & Johnson, Medtronic, Novartis, Relypsa, Servier, and Takeda. See the article online for full details of the relationships. 1.

2.

3.

4.

5.

6.

7.

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Hermida, R. C., Ayala, D. E., Mojon, A. & Fernandez, J. R. Bedtime dosing of antihypertensive medications reduces cardiovascular risk in CKD. J. Am. Soc. Nephrol. http://dx.doi.org/10.1681/ASN.2011040361. Minutolo, R. et al. Changing the timing of antihypertensive therapy to reduce nocturnal blood pressure in CKD: an 8‑week uncontrolled trial. Am. J. Kidney Dis. 50, 908–917 (2007). Rahman, M. & Appel, L. J. Should reducing nocturnal blood pressure be a therapeutic target in CKD? The time is ripe for a clinical outcomes trial. Am. J. Kidney Dis. 50, 901–903 (2007). Black, H. R. et al. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA 289, 2073–2082 (2003). Fung, M. M. et al. Decreased slow wave sleep increases risk of developing hypertension in elderly men. Hypertension 58, 596–603 (2011). Sandset, E. C. et al. The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebocontrolled, double-blind trial. Lancet 377, 741–750 (2011). Aiyagari, V. & Gorelick, P. B. Management of blood pressure for acute and recurrent stroke. Stroke 40, 2251–2256 (2009). Taylor, R. S., Ashton, K. E., Moxham, T., Hooper, L. & Ebrahim, S. Reduced dietary salt for the prevention of cardiovascular disease: a meta-analysis of randomized controlled trials (Cochrane review). Am. J. Hypertens. 24, 843–853 (2011).

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CARDIOLOGY 9.

Bibbins-Domingo, K. et al. Projected effect of dietary salt reductions on future cardiovascular disease. N. Engl. J. Med. 362, 590–599 (2010).

10. Esler, M. D. et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (the Symplicity HTN‑2 trial): a randomised controlled trial. Lancet 376, 1903–1909 (2010).

VALVULAR DISEASE IN 2011

Breakthrough for intervention? Volkmar Falk

In 2011, both the PARTNER‑A trial, in high-risk patients with severe aortic stenosis, and EVEREST II, in patients with mitral insufficiency, showed noninferiority of transcatheter interventions compared with surgery for the chosen primary end points. However, both of the trials, and important registry data, identified limitations of transcatheter valve interventions. Falk, V. Nat. Rev. Cardiol. 9, 77–78 (2012); published online 20 December 2011; doi:10.1038.nrcardio.2011.204

Data from two major randomized, controlled trials in which interventional therapy was compared with conventional surgery for the treatment of aortic stenosis in high-risk patients1 and for selected patients with mitral insufficiency 2,3 were published in 2011. Both trials showed noninferiority for their respective primary end points, but (together with data from national registries4,5) also highlighted limitations of interventional therapy. The most-important trial in the field of valvular heart disease that was published in 2011 was the PARTNER‑A trial,1 in which transcatheter aortic-valve implantation (TAVI) was compared with surgical aorticvalve replacement (SAVR) in a high-risk population of patients with severe aortic stenosis. From a total of 3,105 screened patients, 699 individuals (23%) were randomly allocated to either SAVR (n = 351) or TAVI (n = 348, transfemoral or trans­apical) using the Edwards SAPIEN ® (Edwards Lifesciences Corporation, Irvine, CA, USA) balloon-expandable valve. Patients were considered high risk on the basis of coexisting conditions associated with a risk of death ≥15% at 30 days. In the intention-to-treat analysis, death from any cause (the primary end point) was not different between the TAVI and SAVR groups at 30 days (3.4% vs 6.5%, respectively) or 1 year (24.2% vs 26.8%, respectively), which led to the conclusion that TAVI was non­inferior to SAVR. Patients in the TAVI group had a shorter length of stay in the intensive-care unit and a shorter index hospitalization compared with patients undergoing SAVR. Bleeding and new onset of atrial fibrillation were more frequent in the surgical group, whereas rates of vascular and neuro­logical complications were higher in KEY ADVANCES IN MEDICINE

the TAVI group. The rates of major stroke were 3.8% and 2.1% at 30 days, and 5.1% and 2.4% at 1 year, in the TAVI and surgical groups, respectively. At 1 year, TAVI was associated with a lower mean aorticvalve gradient compared with the surgical group, but with a higher rate of moderate or severe paravalvular regurgitation at 30 days (12.2% vs 0.9%) and 1 year (6.8% vs 1.9%). Functional improvement was significant for both groups after 1 year and not different between the groups. The results of the PARTNER‑A trial 1 demonstrate that TAVI is not only superior to medical therapy in non­surgical candidates, but also a true alternative to surgical replacement for a selected, high-risk subgroup of patients with aortic stenosis. Data from a number of national TAVI registries were published in 2011. The FRANCE registry 6 included data on 244 patients who received an Edwards SAPIEN® (68%) or CoreValve® (Medtronic CV Luxembourg S.a.r.l., Luxembourg; 32%) in 2009. Device success rate was 98.3% and 30‑day mortal­ity Key advances ■■ In high-risk patients with severe aortic stenosis, transcatheter aortic-valve implantation (TAVI) can be performed with similar 1‑year survival and functional outcomes as conventional surgery1 ■■ Moderate and severe paravalvular leakage after TAVI is an independent predictor of late mortality4,5 ■■ Percutaneous edge-to-edge mitral-valve repair can be safely performed with low periprocedural complications2 ■■ Residual moderate mitral regurgitation is more frequent after percutaneous edge-to-edge repair than surgery and might impair long-term results3

was 12.7%. Stroke and vascular complications occurred in 3.6% and 7.3% of patients, respectively. Data from the FRANCE 2 registry,7 which included 2,419 patients treated between January 2010 and July 2011, were presented at the ESC Congress in 2011. Device success rate was 97.1%, and 30‑day and 6‑month mortality were 9.9% and 17.2%, respectively. The stroke rate of 4.0% was similar to the rates reported in the PARTNER trials.1 The high incidence of stroke after TAVI is concerning, and might result from a substantial embolic load during the TAVI procedure, as has been demonstrated using transcranial Doppler imaging during implantation and cerebral MRI after the procedure. The UK TAVI registry 8 included 890 patients. Procedural success (97.2%) and stroke rate (4.1%) were similar to the French experience. Mortality at 30 days was 7.1%, and 1‑year and 2‑year survival were 78.6% and 73.7%, respectively. A degree of paravalvular aortic regurgitation (AR) regarded as suboptimal or unacceptable occurred in 61% of patients. The presence of moderate or severe AR (13% of patients) was an independent predictor of mortality at 1 year. In the German TAVI registry, 4 which comprised 690 patients (84% Medtronic CoreValve ® system), the rate of AR ≥2 was 17.2% and its presence was a strong, in­dependent predictor of in-hospital death (adjusted OR 2.43). In the Italian, multicenter registry 5 of 663 patients who underwent transfemoral TAVI with the third-generation 18 Fr CoreValve® device, the rate of paravalvular leak ≥2 after implantation was 21%, and independently associated with mortality between 30 days and 1 year (HR 3.79). Therefore, data from three national registries have shown that paravalvular leakage is an independent risk factor for mortality after TAVI.4,5,8 The development of improved prosthetic implants and implantation techniques is required. In the absence of long-term follow-up data after TAVI, the results of the PARTNER‑A trial1 and the data from the national registries4–8 must be interpreted with caution. Recommendations to individual patients must balance the obvious advantages of a less-invasive transcatheter approach compared with SAVR, with the increased risk of stroke and unfavorable longterm consequences of paravalvular leakage after TAVI. The landmark mitral-valve trial published in 2011 was EVEREST II.2 In total, 279 patients with severe mitral regurgitation JANUARY 2012  |  S9


CARDIOLOGY V

a

b

10

Figure 1 | Images from a patient in NYHA class IV because of ischemic cardiomyopathy with poor LV ejection fraction (<20%) and mitral-valve insufficiency III–IV, who underwent a MitraClip® (Abbott Vascular, Abbott Park, IL, USA) procedure. a | The preprocedural LV end-diastolic volume was assessed as 550 ml. b | At 1 year follow-up after the procedure, LV end-diastolic volume was reduced to 480 ml, the patient had improved to NYHA class II, and residual mitral-valve regurgitation was <1+. Abbreviation: LV, left ventricular.

(MR; grade 3+ or 4+) were randomly allocated to either surgery or percutaneous edgeto-edge clipping using the MitraClip® device (Abbott Vascular, Abbott Park, IL, USA). Acute procedural success was not achieved with the MitraClip® in 23% of patients, the majority of whom underwent subsequent mitral-valve surgery. The transvenous–­ transseptal approach was associated with fewer adverse events at 30 days compared with surgery. The composite end point of major adverse events was reached in 9.6% and 57% of patients in the MitraClip® and surgical groups, respectively. This striking difference was almost exclusively driven by the need for blood transfusion (8% vs 53%, respectively). Noninferiority for the clinicaleffectiveness 1‑year end point (freedom from death, mitral-valve surgery, mitral-valve dysfunction >90 days after the index procedure, and MR >2+ at 12 months) was met, despite the fact that 18.5% and only 3% of patients had residual mitral insufficiency >2+ at 1 year in the MitraClip® and surgical groups, respectively. Another 33% of patients in the MitraClip® group had residual mitral insufficiency = 2+, and more than 15% of patients in the device arm subsequently underwent mitral-valve surgery because of persistent, severe MR. The arbitrary end point of freedom from mitral insufficiency >2+ has triggered lively discussion. Residual mitral insufficiency >1+ after mitral repair is clearly unacceptable, and is an independent predictor of late mortality. If the EVEREST II investi­ gators had chosen presence of mitral insufficiency <2+ instead of absence of mitral S10  |  JANUARY 2012



insufficiency >2+ as part of the effectiveness end point, fewer than half of the patients (47.9%) treated with the MitraClip® would have fulfilled the combined criteria. Statistical noninferiority for effectiveness at 1 year was reached by definition, but the debate whether this result can be regarded as noninferior from a clinical perspective is likely to continue—particularly because the intention-to-treat analysis revealed that the primary composite end points at 2 years were still significantly better with surgery than percutaneous intervention.3 Longterm data are needed before the indication for this therapy can be extended to patients with degenerative mitral-valve disease, in whom the success rate of endoscopic surgical mitral-valve repair is >95%, with excellent short-term and long-term results.9 Mitralvalve repair after previous clip placement is often not possible because the device is encapsulated over time by fibrous tissue; the use of the MitraClip® should, therefore, be restricted to patients who are at high surgical risk. The unconvincing long-term results of downsizing annuloplasty in patients with severe leaflet tethering make the MitraClip® an attractive option in patients with functional MR. In the PERMIT trial,10 51 severely symptomatic nonresponders to cardiac resynchronization therapy with severe left ventricular dysfunction and functional MR underwent treatment with the MitraClip®. Residual MR ≥2+ was present in <20% of patients at discharge, and in only about 10% at 1 year follow-up. Periprocedural mortality was 5.8%, but was not less than surgery

in similar groups of patients. The NYHA functional class had already improved at discharge in 73% of patients. Reverse remodel­ ing was observed to continue at 6 months and 1 year (Figure 1). A randomized trial with larger patient numbers than in the PERMIT trial10 will be needed to confirm these findings and determine the role of the MitraClip® in patients with functional MR. The treatment of valvular heart disease continues to progress with the evolution of percutaneous approaches as alternatives to surgical therapy in selected patients. To provide patients with the best-possible treatment, short-term effectiveness must be balanced with long-term outcomes. Division of Cardiovascular Surgery, University of Zurich, Rämistrasse 100, Zurich CH‑8091, Switzerland. volkmar.falk@usz.ch Competing interests The author declares associations with following companies: Edwards Lifesciences, Medtronic, Philips, St Jude Medical, and Valtech. See the article online for full details of the relationships. 1.

Smith, C. R. et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N. Engl. J. Med. 364, 2187–2198 (2011). 2. Feldman, T. et al. Percutaneous repair or surgery for mitral regurgitation. N. Engl. J. Med. 364, 1395–1406 (2011). 3. George, J. C., Varghese, V., Dangas, G. & Feldman, T. E. Percutaneous mitral valve repair: lessons from the EVEREST II (Endovascular Valve Edge-to-Edge REpair Study) and beyond. JACC Cardiovasc. Interv. 4, 825–827 (2011). 4. Abdel‑Wahab, M. et al. Aortic regurgitation after transcatheter aortic valve implantation: incidence and early outcome. Results from the German transcatheter aortic valve interventions registry. Heart 97, 899–906 (2011). 5. Tamburino, C. et al. Incidence and predictors of early and late mortality after transcatheter aortic valve implantation in 663 patients with severe aortic stenosis. Circulation 123, 299–308 (2011). 6. Eltchaninoff, H. et al. Transcatheter aortic valve implantation: early results of the FRANCE (FRench Aortic National CoreValve and Edwards) registry. Eur. Heart J. 32, 191–197 (2011). 7. Gilard, M. et al. FRANCE 2: FRench Aortic National CoreValve and Edwards Registry http://spo.escardio.org/eslides/ view.aspx?eevtid=48&fp=3126 (2011). 8. Moat, N. E. et al. Long-term outcomes after transcatheter aortic valve implantation in high-risk patients with severe aortic stenosis: The U.K. TAVI (United Kingdom Transcatheter Aortic Valve Implantation) Registry. J. Am. Coll. Cardiol. 58, 2130–2138 (2011). 9. Mihaljevic, T. et al. Robotic repair of posterior mitral valve prolapse versus conventional approaches: potential realized. J. Thorac. Cardiovasc. Surg. 141, 72–80 (2011). 10. Auricchio, A. et al. Correction of mitral regurgitation in nonresponders to cardiac resynchronization therapy by MitraClip improves symptoms and promotes reverse remodeling. J. Am. Coll. Cardiol. 58, 2183–2189 (2011).

www.nature.com/reviews


CLINICAL ONCOLOGY OVARIAN CANCER IN 2011

Mutations and non-inferiority analyses show a way forward Maurie Markman

Highly clinically relevant ovarian cancer clinical research in 2011 focused on an increased understanding of the biology of the malignancy, limitations of strategies for early detection and screening, and the provocative reports of alternative primary and second-line management strategies. Markman, M. Nat. Rev. Clin. Oncol. 9, 69–70 (2012); published online 20 December 2011; doi:10.1038/nrclinonc.2011.200

Although there were a number of very interesting preliminary reports of thera­peutic advances in ovarian cancer in 2011 (for example, bevacizumab in the first-line and second-line management of the malignancy, and olaparib as maintenance therapy for high-grade serous cancers), as of the writing of this commentary these studies have not appeared in the peer-reviewed oncology literature. Despite the absence of major advances in the realm of treatment, several papers published in 2011 provide highly clinically relevant insight into the management and unique biology of ovarian cancer. Perhaps the most important paper in 2011 was the long-awaited final report from the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening randomized controlled trial dealing specifically with ovarian cancer.1 The study, involving 78,000 women with ages ranging from 55 to 74 years, randomly assigned participants to what was classified as ‘usual care’ or a rather-intensive screening strategy that included annual serum CA125 determinations and trans­ vaginal ultrasounds. It should be noted that this study did not specifically target women identified as being at ‘high risk’ for the develop­ment of ovarian cancer (for example, those with a family history of ovarian cancer). The screening protocol, undertaken from November 1993 to July 2001, was performed at one of 10 centers in the USA and the median follow-up period for the population was 12.4 years, with patients being followed until death or for a maximum of 13 years. The primary study end point was the rate of mortality from ovarian cancer (including primary peritoneal or fallopian tube cancer), with secondary end points of disease incidence and complications associ­ated with KEY ADVANCES IN MEDICINE

Table 1 | Influence of BRCA1 or BRCA2 on outcome in high-grade serous ovarian cancer6 Mutational status

3-year PFS (%)

5-year PFS (%)

HR compared with WT patients

3-year OS (%)

5-year OS (%)

HR compared with WT patients

BRCA1 mutation

22

13

0.81 (P = 0.44)

64

44

0.76 (P = 0.35)

BRCA2 mutation

44

39

0.40 (P = 0.004)

83

61

0.33 (P = 0.003)

BRCA WT

16

10

58

25

Abbreviations: HR, hazard ratio; OS, overall survival; PFS, progression-free survival; WT, wild type.

the screening strategy. The study revealed no difference in deaths from ovarian cancer or other causes between the screening and usual-care groups. Specifically, there were 212 cases of ovarian cancer and 118 deaths from the malignancy in the screening group versus 176 cases and 100 deaths in the routine-care population. Furthermore, and of considerable relevance, 1,080 surgeries were performed among the 3,285 women with false-positive screening tests, and 163 of these individuals developed at least a single ‘serious complication’.1 The important data from this screening trial provide no support for the routine use of annual CA125 determinations or vaginal ultrasounds for completely asymptomatic women as a screening strategy to detect ovarian cancer. However, it is again rele­vant to acknowledge that this trial did not specifically address the issue of screening a more high-risk population, nor did it attempt to define the utility of these tests in the detection of ovarian cancer in indivi­duals presenting with symptoms (for example, several weeks of persistent mild abdominal pain). A study that is somewhat related to the PLCO trial attempted to address the important question of whether an earlier diagnosis of ovarian cancer in a sympto­matic individual might be associated with an improved outcome.2 Australian investigators

retrospectively examined the survival of 1,300 patients with ovarian cancer seen by a physician within varying time intervals (55%, 70% and 92% of the women presented within 1, 2 and 6 months, respectively) from the onset of their initial symptoms. The investigators were unable to find any difference in survival based on the duration of symptoms before the time of diagnosis. Importantly, these data do not support the hypothesis that a somewhat earlier diagnosis (timeline measured in ‘months’) will be associ­ated with superior ovarian cancer-specific survival,3 although the more-timely recognition of the correct diagnosis will likely result in more-rapid initiation of a management plan that will hopefully favorably impact serious symptoms and the individual’s overall quality of life. It is well established that mutations in BRCA1 and BRCA2 are associated with an increased lifetime risk for the development of ovarian cancer. 4 Furthermore, highly provocative data from a number of ovarian cancer investigators have suggested that within the population of women with docu­ mented advanced-stage ovarian cancer, patients with BRCA mutations experience an overall superior survival (compared with patients with wild-type BRCA), a difference that is possibly related to increased sensiti­ vity to platinum-based chemotherapy.5 In a most-provocative report, investigators JANUARY 2012  |  S11


CLINICAL ONCOLOGY Key advances ■■ There are currently no evidence-based data supporting the clinical utility of any ovarian cancer screening strategy in non‑high-risk populations1 ■■ Provocative data suggest there may be a clinically meaningful difference between the presence of a BRCA1 or a BRCA2 mutation in influencing outcome in ovarian cancer6 ■■ Under specific circumstances (for example, neuropathy) it might be reasonable to substitute pegylated liposomal doxorubicin for paclitaxel in the front-line chemotherapy management of ovarian cancer7

conducted an observational study involving 316 women with high-grade serous ovarian cancer whose BRCA mutational status was established, to evaluate the impact of such mutations on outcome.6 Although the total sample size was limited (37 and 29 patients with BRCA1 and BRCA2 mutations, respectively), there was a rather striking difference in both the inherent chemosensitivity and survival between the two mutation groups, and compared with women without mutations (Table 1). Patients with BRCA2 mutations experienced a statistically significant improvement in 5‑year survival compared with BRCA1 deficient and BRCA ‘wild-type’ cases. Although these results will need to be confirmed by other investigative groups with larger sample sizes, they suggest the potential that these two genetic abnormalities might exert quite different influences on outcome in high-grade serous ovarian cancer. At the present time, there are no known thera­peutic implications associated with these findings, but it is possible that future research may result in recommendations for different management strategies for patients with BRCA1 or BRCA2 mutations. Finally, it is relevant to note an interesting (although unfortunately flawed) phase III randomized trial that directly compared a regimen of carboplatin plus paclitaxel to carboplatin plus pegylated liposomal doxorubicin as primary treatment for epithelial ovarian cancer.7 Although this potentially paradigm changing study included a total of 820 patients, it was specifically designed to demonstrate the therapeutic superiority (rather than non-inferiority with possibility an improved toxicity profile) of the investi­ gative pegylated liposomal doxorubicincontaining regimen. In fact, although the study demonstrated similar median progression-free survival times (19.0 months and 16.8 months) and median overall survival times (61.6 months and 53.2 months) S12  |  JANUARY 2012



for the carboplatin–pegylated liposomal doxorubicin and carboplatin–paclitaxel study arms, respectively, the trial failed to achieve its primary end point (the documentation of ‘superiority’ for the experimental arm over the established therapy arm). As a result of this failure, the investigators appropriately concluded that the investigative regimen “was not superior to carboplatin– paclitaxel which remains the standard firstline chemo­t herapy for advanced ovarian cancer.”7 However, it is reasonable to suggest that for patients unable to tolerate the taxane (for example, patients who develop neuro­ pathy early in the treatment course or severe paclitaxel-associated hypersensitivity reaction) the substitution of pegylated liposomal doxorubicin is not an unreasonable option. Thus, it is reasonable to characterize the ovarian cancer peer-reviewed literature in 2011 as providing modestly useful information regarding disease management and including important discussions of the limitations in our ability to modify the relatively early natural history of the malignancy. It is rather striking that in a clinical research world where unique targets have been discovered in multiple cancers (for example, HER2 overexpression in breast cancer, EGFR mutations in lung cancer, and BRAF mutations in melanoma) leading to exciting new treatment strategies, there remain no such molecular targets in ovarian cancer, the presence of which would lead to specific management paradigms to favorably impact outcome. It is clear that much work needs

to be done to improve our understanding of the fundamental biology of ovarian cancer to change this current state-of-affairs. Cancer Treatment Centers of America, Eastern Regional Medical Center, 1331 East Wyoming Avenue, Philadelphia, PA 19124, USA. maurie.markman@ctca-hope.com Competing interests The author declares an association with the following company: Genentech. See the article online for full details of the relationship. 1.

2.

3.

4.

5.

6.

7.

Buys, S. S. et al. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening randomized controlled trial. JAMA 305, 2295–2303 (2011). Nagle, C. M. et al. Reducing time to diagnosis does not improve outcomes for women with symptomatic ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J. Clin. Oncol. 29, 2253–2258 (2011). Anderson, M. R. et al. Combining a symptoms index with CA125 to improve detection of ovarian cancer. Cancer 113, 484–489 (2008). King, M. C. et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302, 643–646 (2003). Tan, D. S. et al. “BRCA-ness” syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J. Clin. Oncol. 26, 5530–5536 (2008). Yang, D. et al. Associations of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA 306, 1557–1565 (2011). Pignata, S. et al. Carboplatin plus paclitaxel versus carboplatin plus pegylated liposomal doxorubicin as first-line treatment for patients with ovarian cancer: The MITO‑2 randomized phase III trial. J. Clin. Oncol. 29, 3628–3635 (2011).

PROSTATE CANCER IN 2011

Hitting old targets better and identifying new targets Yu Chen and Howard I. Scher

Options to treat late-stage castration-resistant prostate cancer continued to increase in 2011, as three agents with different mechanisms of action prolonged life and a fourth reduced the morbidity of skeletal metastases. These outcomes contrasted with the heightened controversy generated by the recommendation against PSA screening and other early detection strategies. Chen, Y. & Scher, H. I. Nat. Rev. Clin. Oncol. 9, 70–72 (2012); published online 10 January 2012; doi:10.1038/nrclinonc.2011.213

In the Western world, one in six men will be diagnosed with prostate cancer and, of these, one in six will die of metastatic disease. Improving outcomes for men with prostate cancer depends on the one hand on developing more-effective systemic

therapies and, on the other hand, on early diagnosis and treatment, before the disease has metastasized. 2011 is the 70 th anniversary of when Charles Huggins established that prostate cancer is an androgen-dependent www.nature.com/reviews


CLINICAL ONCOLOGY malignancy and, until recently, docetaxel was the only non-hormonal therapy to prolong life. In 2010, sipuleucel‑T and cabazitaxel were shown to confer a survival benefit and were subsequently approved by the FDA. This trend continued in 2011, as three therapies, CYP17 inhibitor abiraterone acetate,1 bone-targeting agent radium‑223, 2 and androgen-signaling inhibitor MDV3100,3 were shown to prolong life in definitive phase III clinical trials (Figure 1), and the RANKL inhibitor, denosumab, was shown to be superior to zoledronic acid in reducing the morbidity associated with bone metastases.4 The demonstration that agents targeting unique aspects of the malignant process associated with tumor cell growth and survival could provide meaningful clinical benefits has highlighted the importance of understanding the biology of castrationresistant prostate cancer (CRPC). The trials established important principles, which will be discussed. The first principle is that CRPCs are not hormone refractory. CRPCs acquire diverse mechanisms to reactivate the androgen receptor signaling pathway in the environment of castrate levels of androgens, including an increase in the androgen biosynthetic machinery and overexpression of androgen receptor. Thus, further decreasing androgen levels by inhibiting steroid synthesis enzymes in the adrenal glands and tumor may be of benefit. CYP17 is a cytochrome P450 enzyme that catalyzes the rate-limiting step of androgen synthesis; abiraterone acetate is a structural analog of the CYP17 substrate pregnenolone that is rationally designed to be a specific and irreversible inhibitor of CYP17. A large international phase III trial (Cougar AA‑301) that compared abiraterone acetate plus prednisone (to prevent mineralocorticoid excess) and placebo plus prednisone in patients with CRPC who had received docetaxel showed an increase in median overall survival from 10.9 to 14.8 months (hazard ratio = 0.65; P <0.001).1 All major subgroups of patients benefitted and treatment was well tolerated. A separate trial assessing abiraterone acetate in chemotherapy-naive patients has completed accrual and the results are awaited (NCT00887198). Another drug supporting the principle that CRPCs are not hormone refractory is MDV3100, a next-generation anti-androgen that was rationally designed to overcome several deficiencies of available agents including modest receptor binding and agonist properties that can promote tumor KEY ADVANCES IN MEDICINE

Localized disease

Rising PSA

Clinical metastasis Non-castrate Rising PSA Castrate

Non-castrate prostate cancer Castrate prostate cancer Trial drug shown to improve survival in phase III trials

Clinical metastases Castrate Pre-docetaxel Sipuleucel-T

Clinical metastases Castrate First-line chemotherapy Docetaxel

Clinical metastases Castrate Post-docetaxel Cabazitexel Abiraterone

Radium-223 MDV3100

Figure 1 | Clinical states model of prostate cancer progression and systemic therapies shown to improve survival for castrate disease. Blue text represents FDA approved therapies.

growth. The drug displays no androgen receptor activation, blocks nuclear trans­ location of the receptor and completely inhibits the ability of androgen receptor to bind to DNA. 3 Promising activity of MDV3100 was demonstrated in a phase I– II trial in 140 patients, which led to the phase III AFFIRM trial in patients with chemotherapy-treated CRPC that compared MDV3100 with placebo. 3 This trial was stopped by the Data Safety and Monitoring Board in November 2011 when the first planned interim analysis showed a 37% reduction in mortality, and superior overall survival (median 18.4 versus 13.6 months) in favor of MDV3100.3 The second principle was that targeting the bone environment can confer benefits, independent of an effect on prostate-specific antigen (PSA). Bone is the most common site of prostate cancer spread and is responsible for the highest morbidity burden from the disease. Therapies directed at the bone microenvironment can be divided into three classes: osteoclast inhibitors of bone resorption, radiopharmaceuticals that target bone, and kinase inhibitors. Despite the radiographic appearance of osteoblastic lesions, there is heightened osteoclastic activity and bone turnover in metastatic prostate cancer lesions. Osteoclast inhibitors, including zoledronic acid, are used as an adjuvant therapy to maintain bone density and to decrease skeletal-related events (SRE) in patients with CRPC. Denosumab is a humanized monoclonal antibody that blocks RANKL, which is required for osteoclast activation and survival. In 1,904 patients with CRPC that had meta­stasized to the bone, denosumab delayed the median time to first SRE from 17.1 to 20.7 months (P = 0.008) compared to zoledronic acid, leading to FDA approval.4 The beta-emitting bone-seeking radioisotopes strontium‑89 and samarium‑153 lexidronam are approved for the palliation of pain, but neither has been shown to prolong life. Radium‑223 is a unique bone-directed radioisotope that emits high-energy alpha

particles that penetrate only several cell layers in tissue, significantly improving the radiation delivery to areas of sclero­ tic bone where the tumor resides while minimizing radiation to hematopoietic tissue. In a phase III trial in 922 patients with CRPC and bone pain, 6-monthly doses of radium‑223 conferred a significant overall survival benefit over placebo (14.0 versus 11.2 months; P = 0.00185);2 it is the first bone-directed agent to prolong overall survival. Multiple signaling cascades are critical for bone homeostasis and turnover. Two promising investigational agents targeting this axis deserve mention. Dasatinib inhibits kinases including Src family tyrosine kinases that are important for bone turnover; a single-agent phase II trial in patients with CRPC showed a marked decrease in bone turnover, disease stabilization5 and additive effects with docetaxel. A phase III trial comparing dasatinib with placebo in combination with docetaxel has completed accrual. Cabozantinib inhibits kinases including Ret, Met, and VEGFR2; in a randomized phase III discontinuation trial in patients with CRPC, treatment with cabozantinib was associated with normalization of radionuclide bone scans in 86% of patients, improvement of bone pain in 64% of patients, decline in bone marker levels, improvement of anemia, and a marked reduction in bone pain independent of an effect on PSA.6 Two phase III trials will be opened for recruitment soon: the first for an indication for the palliation of pain and a second for an improvement in overall survival in patients with CRPC. Limiting the use of agents shown to prolong life to men with advanced metastatic CRPC will not considerably decrease the number of men who die from prostate cancer. To do so requires the identification and treatment of those cancers that are destined to metastasize, produce symptoms and ultimately shorten a patient’s anticipated life expectancy when tumor burdens JANUARY 2012  |  S13


CLINICAL ONCOLOGY Key advances ■■ Abiraterone acetate and MDV3100 prolong overall survival in patients with docetaxel-treated castration-resistant prostate cancer (CRPC)1,3 ■■ Radium‑223 prolongs overall survival in patients with CRPC, bone pain from disease, and who are docetaxel-treated or ineligible for docetaxel treatment2 ■■ Denosumab delays skeletal-related events compared with zoledronic acid in patients with CRPC and bone disease4

are minimal. With this goal but without firm evidence, the advent of the PSA test led to widespread screening that has been accompanied by a marked increase in men diagnosed with localized disease who undergo radical prostatectomy and definitive radiotherapy with the associated morbidities. Over the past 2 years, the US PLCO trial showed no reduction in prostate cancer-specific mortality (PCSM) at 7‑years after the initiation of PSA screening; the European Randomized Study of Screening for Prostate Cancer showed a 20% decrease in PCSM at 9 years after the initiation of PSA screening; and the Göteborg randomized screening trial showed a 44% decrease in PCSM at 14 years after the initiation of screening.7–9 These results, along with an analysis of other early detection studies led the USPSTF to recommend against PSA screening because of “moderate or high certainty that the service has no net benefit or that the harms outweigh the bene­fits.”10 The recommendation triggered a firestorm of debate, proponents of screening highlighting flaws in methodology and interpretation and opponents the limited benefits, anxiety and morbidity a diagnosis produces, and the high societal costs. There is strong evidence prostatectomy and radiotherapy can decrease PCSM by approximately 50% in clinically localized disease. However, in low-risk disease where the 15-year PCSM is <2%, these benefits become tiny, especially in those with limited longevity. Despite this, more than half of the men treated with prostatectomy and radiotherapy in the USA have low-risk disease. It is important to note that the harms of screening come not from the PSA test, but from the chain of actions following PSA measurement. It has been ingrained into the psyche of physicians and patients that all cancers are rapidly lethal unless treated aggressively. The USPSTF recommendation is an appropriate pushback against nondiscriminate screening and subsequent S14  |  JANUARY 2012



treatment and argues that early detection strategies focus on diagnosing cancers that need treatment to reduce morbidity and mortality, and avoid finding highly prevalent indolent cancers for which any treatment is overtreatment. The two overarching objectives in the field are to decrease death and suffering but, at the same time, decrease those who are subjected to unnecessary treatment that can produce significant morbidity. It is clear that neither our current practice pattern nor the blanket discontinuation of PSA screening can adequately address these goals. The benefit-to-harm ratio can be shifted if both screening and treatment are targeted to high-risk populations and surveillance becomes more widely adopted for non-aggressive localized tumors. Human Oncology and Pathogenesis Program and Department of Medicine, Memorial Sloan– Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA (Y. Chen, H. I. Scher). Correspondence to: H. I. Scher scherh@mskcc.org Competing interests H. I. Scher declares associations with the following companies: Amgen, Dendreon, Exelixis, Medivation, Ortho Biotech Oncology Research & Development, Sanofi-Aventis. See the article online for full details of the relationships. Y. Chen declares no competing interests. 1.

de Bono, J. S. et al. Abiraterone and increased survival in metastatic prostate cancer. N. Engl. J. Med. 364, 1995–2005 (2011).

2.

Parker, C. et al. Overall survival benefit of radium‑223 chloride (Alpharadin™) in the treatment of patients with symptomatic bone metastases in castration-resistant prostate cancer (CRPC): a phase III randomized trial (ALSYMPCA) [abstract]. Eur. J. Cancer 47, a7003 (2011). 3. Medivation. Medivation and Astellas announce positive survival data from interim analysis of phase 3 AFFIRM trial of MDV3100 in men with advanced prostate cancer [online], http:// investors.medivation.com/releasedetail.cfm? releaseid=620500 (2011). 4. Fizazi, K. et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377, 813–822 (2011). 5. Yu, E. Y. et al. Phase II study of dasatinib in patients with metastatic castration-resistant prostate cancer. Clin. Cancer Res. 15, 7421–7428 (2009). 6. Hussain, M. et al. Cabozantinib (XL184) in metastatic castration-resistant prostate cancer (mCRPC): Results from a phase II randomized discontinuation trial [abstract]. J. Clin. Oncol. 29 (Suppl.), a4516 (2011). 7. Hugosson, J. et al. Mortality results from the Goteborg randomised population-based prostate-cancer screening trial. Lancet Oncol. 11, 725–732 (2010). 8. Schröder, F. H. et al. Screening and prostatecancer mortality in a randomized European study. N. Engl. J. Med. 360, 1320–1328 (2009). 9. Andriole, G. L. et al. Mortality results from a randomized prostate-cancer screening trial. N. Engl. J. Med. 360, 1310–1319 (2009). 10. Chou, R. et al. Screening for prostate cancer: a review of the evidence for the U. S. Preventive Services Task Force. Ann. Intern. Med. 155, 762–771 (2011).

HEMATOLOGICAL CANCER IN 2011

New therapeutic targets and treatment strategies Paula Cramer and Michael Hallek

2011 saw improvements in our understanding of B‑cell malignancies: insights into the genomic basis of chronic lymphocytic leukemia were achieved; reduced treatment intensity caused fewer toxic effects in early-stage Hodgkin lymphoma; first-line rituximab maintenance therapy improved outcome in follicular lymphoma; and selected patients with diffuse large-cell lymphoma benefited from the addition of bortezomib. Cramer, P. & Hallek, M. Nat. Rev. Clin. Oncol. 9, 72–74 (2012); published online 10 January 2012; doi:10.1038/nrclinonc.2011.212

Chronic lymphocytic leukemia (CLL) is a clonal B‑cell disorder initiated by genetic aberrations in B cells that increase resistance to apoptosis. The survival of CLL cells is strongly dependent on inter­actions with surrounding cells (macro­phages and dendritic cells), biochemical cues (chemokines) and specific receptors expressed on CLL cells. 2011 saw publication of three important papers providing new insights into

the pathogenesis of CLL. Kikushige et al.1 reported that the capacity to generate clonal B cells is acquired at the hematopoietic stem cell (HSC) stage in CLL, suggesting multi­ potent, self-renewing HSCs are involved in the initiation of CLL. These findings can lead to the development of new therapies that target these progenitor CLL cells. The study by Puente et al.2 reported the first data on whole-genome sequencing www.nature.com/reviews


in CLL. Four cases were analyzed and 46 somatic mutations were identified.2 Four genes with recurrent mutations were confirmed in 363 patients with CLL: NOTCH1, XPO1, MYD88 and KLHL6. Mutations in MYD88 and KLHL6 were predominantly found in patients with CLL who had a high number of somatic hypermutations in the variable region of IGHV, whereas mutations in NOTCH1 and XPO1 were mostly detected in patients who did not have IGHV mutations. These findings indicate a role for mutations in NOTCH1, MYD88 and XPO1 in the clinical evolution of CLL. In a similar study on 91 patients with CLL, Wang et al.3 performed massively parallel sequencing of 88 whole exomes and genomes. They found nine genes that are mutated at significant frequencies, including four with established roles (TP53 in 15% of patients, ATM in 9%, MYD88 in 10%, and NOTCH1 in 4%) and five genes without established roles (SF3B1, ZMYM3, MAPK1, FBXW7, and DDX3X). SF3B1, which functions at the catalytic core of the spliceosome, was the second most frequently mutated gene (15% of patients). SF3B1 mutations occurred primarily in tumors with deletions in chromosome 11q, which are associated with a poor prognosis. The authors also showed that mutations in SF3B1 induced alterations in pre–mRNA splicing. All three studies have considerable clinical implications for CLL. Firstly, the stem cell origin of CLL offers a plausible explanation for the fact that conventional chemo­ immunotherapies regularly fail to cure CLL. This type of therapy may not effectively eradi­cate the HSC pool that regenerates CLL cells. Secondly, our understanding of the genetic basis of CLL has improved. These advances will facilitate the development of better-targeted therapies for this disease. In the past 10 years, a remarkable improvement in overall survival was achieved for several types of B‑cell lymphomas. This improvement was largely a result of the use of rituximab, an antibody targeting CD20. In follicular lymphoma, several randomized trials have demonstrated that addition of rituximab to different chemotherapeutic regimens can prolong survival; therefore, rituximab-based chemoimmuno­therapy is the current standard first-line treatment. Disease progression usually occurs 3–5 years after initial therapy and rituximab maintenance therapy was previously shown to have a clinical benefit in patients with relapsed disease. The PRIMA study 4 evaluated the benefit of rituximab maintenance therapy KEY ADVANCES IN MEDICINE

after first-line treatment for follicular lymphoma. In this study, 1,019 patients who achieved a response after different chemo­ immunotherapies (rituximab plus cyclophosphamide, vincristine, doxo­r ubicin and prednisone [R-CHOP]; rituximab plus cyclophosphamide, vincristine and pred­ nisone; or rituximab plus fludarabine, cyclo­phosphamide and mitoxantrone) were randomly assigned to receive 2 years of maintenance therapy with rituximab (375 mg/m² every 8 weeks) or no further therapy (observation). The maintenance treatment was well tolerated. Infectious events were more common in the maintenance arm than the observation arm, but were mostly mild or moderate and only a few patients withdrew from the study because of toxicity. No signifi­ cant decrease in immunoglobulin levels was observed and patient quality of life was not affected by the repeated rituximab infusions. Maintenance therapy improved the quality of response and prolonged progression-free survival and event-free survival. No effect on overall survival was shown for rituximab maintenance therapy, which might be explained by a short follow-up period and the efficacy of salvage therapies. However, rituximab should be considered as maintenance therapy after first-line chemo­ immunotherapy in follicular lymphoma, as the duration of response to first-line therapy has prognostic value.5 The outstanding outcome observed in patients with Hodgkin lymphoma allowed researchers to consider a reduction in treatment intensity to reduce both acute and long-term adverse events, such as infertility and secondary neoplasias. The Key advances ■■ Genomic analyses of patients with chronic lymphocytic leukemia identified mutations in genes such as Notch1 and SF3B1 that have prognostic impact2,3 ■■ Rituximab maintenance therapy after first-line treatment with rituximab-based chemoimmunotherapy significantly improves the quality of response and prolongs progression-free survival in patients with follicular lymphoma4 ■■ In advanced-stage, high-risk Hodgkin lymphoma, reduction in treatment intensity has not improved outcome and further analyses are needed to define the optimal treatment intensity7 ■■ Patients with diffuse large B‑cell lymphoma, in particular, those with a non-germinal center B‑cell-like subtype, benefit from the addition of bortezomib to first-line chemoimmunotherapy9

© Eraxion | Dreamstime.com

CLINICAL ONCOLOGY

HD10 trial of the German Hodgkin Study Group (GHSG)6 showed that two cycles of ABVD (doxo­rubicin, bleomycin, vinblastine and dacarbazine) therapy followed by 20 Gy of involved–field radio­t herapy was as efficacious as four cycles of ABVD and 30 Gy of involved-field radiotherapy in patients with stage I or II disease and favorable risk factors. Reduced treatment intensity may be considered as the new standard treatment for early-stage, lowrisk Hodgkin lymphoma. By contrast, the reduction of treatment intensity is debated in advanced-stage Hodgkin lymphoma (stage II–IV or IIB with extranodal lesions or mediastinal mass). The results of the HD12 trial by Borchmann et al.7 were slightly disappointing, because the reduction of the intensity of chemotherapy from eight cycles of high-dose BEACOPP (bleomycin, etoposide, doxo­ rubicin, cyclophosphamide, vincristine, procarbazine and prednisolone) to four cycles of high-dose BEACOPP followed by four cycles of BEACOPP at the baseline dose did not reduce the severity of toxicity or treatment-related mortality, but could possibly reduce efficacy. Thus, the GHSG considers eight cycles of high-dose BEACOPP as the standard treatment for advancedstage Hodgkin lymphoma and is evaluating other individualized, PET-controlled dose reduction strategies in ongoing trials. Viviani et al.8 compared BEACOPP and ABVD in advanced-stage Hodgkin lymphoma. In this trial, 331 patients received either four cycles of high-dose BEACOPP plus four cycles of BEACOPP at baseline dose or six to eight cycles of ABVD; each treatment was followed by involved-field radiotherapy. The estimated 7‑year rate of freedom from first progression was 85% in patients treated with BEACOPP and 73% in patients treated with ABVD. However, all patients with a relapse or less than complete response after initial therapy were treated with multiple cycles of ifosfamidecontaining chemotherapy followed by JANUARY 2012  |  S15


CLINICAL ONCOLOGY high-dose chemo­t herapy with carmustine, etoposide, cytarabine, and melph­alan plus autologous hemato­p oietic stem-cell support. After completion of treatment including the salvage therapy, the 7‑year rate of overall survival was 89% in patients initially treated with BEACOPP compared to 84% in patients who had received ABVD. As this difference in overall survival was not significant, the authors concluded that treatment with BEACOPP resulted in a more effective disease control, but not in a better long-term outcome, compared with ABVD. They argued that while a major proportion of patients could be cured by the initial BEACOPP therapy, this clinical benefit might be neutralized by a high rate of longterm adverse events, in particular myelo­ toxicity, infections and secondary neoplasias. Viviani et al.8 deduced that the BEACOPP regimen presents an over­treatment strategy for a large number of patients and recommended ABVD for patients with advanced-stage or unfavorable Hodgkin lymphoma. This study has triggered an intense discussion about the need for an intensive BEACOPP therapy in advancedstage Hodgkin lymphoma, as few patients who relapse can be rescued with a high-dose salvage therapy. However, this trial8 was not powered to demonstrate a survival difference between the two treatments and the 7‑year overall survival differed by 5% in favor of the BEACOPP regimen. Moreover, median observation time (61  months) and the number of patients were low. As a result, an appropriate treatment intensity in advancedstage or unfavorable Hodgkin lymphoma is still debated. The improvements in our understanding of the molecular pathogenesis of non-Hodgkin lymphoma have led to the develop­ment of novel therapeutic agents that interfere with signaling pathways involved in lympho­ magenesis. For instance, the addition of the proteasome inhibitor bortezomib enhanced the activity of chemo­immunotherapy with R‑CHOP as first-line treatment for diffuse large B‑cell lymphoma (DLBCL) and mantlecell lymphoma.9 Ruan et al.9 demon­strated that, in particular, patients with a nongerminal center B‑cell-like (GCB) subtype, which is usually associ­ated with a worse outcome, benefit from the addition of borte­ zomib. This increased clinical benefit can be explained by the fact that the non-GCB subtype is characterized by a deletion in a tumor-suppressor gene that activates NF-κB and this activation is blocked by bortezomib. Thus, a worse prognosis in this subgroup of S16  |  JANUARY 2012



patients with DLBCL could be overcome by bortezomib treatment. Overall, 2011 saw exciting developments in the understanding and treatment of B‑cell lymphomas. Whereas research in Hodgkin lymphoma aims to reduce the adverse effects of first-line treatment, in most other lymphomas more-effective therapies are needed. The growing understanding of the pathogenesis of these lymphomas will facilitate the develop­ment of novel therapeutic agents. Department of Internal Medicine I and Center for Integrated Oncology Köln-Bonn, University of Cologne, Joseph-Stelzmann-Straße. 9, 50924 Cologne, Germany (P. Cramer, M. Hallek). Correspondence to: M. Hallek michael.hallek@uni-koeln.de

3.

4.

5.

6.

7.

Competing interests M. Hallek declares associations with the following companies: Celgene, Mundipharma, Roche. See the article online for full details of the relationships. P. Cramer declares no competing interests. 1.

2.

Kikushige, Y. et al. Self-renewing hematopoietic stem cell is the primary target in pathogenesis of human chronic lymphocytic leukemia. Cancer Cell 20, 246–259 (2011). Puente, X. S. et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 475, 101–105 (2011).

8.

9.

Wang, L. et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N. Engl. J. Med. http://dx.doi.org/10.1056/ NEJMoa1109016. Salles, G. et al. Rituximab maintenance for 2 years in patients with high tumor burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 377, 42–51 (2011). Bachy, E. et al. Long-term follow-up of patients with newly diagnosed follicular lymphoma in the prerituximab era: effect of response quality on survival - a study from the Groupe d’Etude des Lymphomes de l’Adulte. J. Clin. Oncol. 28, 822–829 (2010). Engert, A. et al. Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma N. Engl. J. Med. 363, 640–652 (2010). Borchmann, P. et al. Eight cycles of escalateddose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advancedstage Hodgkin’s lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group. J. Clin. Oncol. 29, 4234–4242 (2011). Viviani, S. et al. ABVD versus BEACOPP for Hodgkin’s lymphoma when high-dose salvage is planned. N. Engl. J. Med. 365, 203–212 (2011). Ruan, J. et al. Bortezomib plus CHOP-rituximab for previously untreated diffuse large B‑cell lymphoma and mantle cell lymphoma. J. Clin. Oncol. 29, 690–697 (2011).

MELANOMA IN 2011

A new paradigm tumor for drug development Alexander M. M. Eggermont and Caroline Robert

Melanoma has emerged as the paradigm tumor for drug development through mutation-targeted therapies (inhibitors targeting BRAF, MEK, and c‑KIT) and immunotherapy. Exploring the combinations of both approaches is a challenge that will require scientific rationale and the cooperation of the pharmaceutical industry. But, with these challenges comes another opportunity to change the paradigms in drug development. Eggermont, A. M. M. & Robert, C. Nat. Rev. Clin. Oncol. 9, 74–76 (2012); published online 10 January 2012; doi:10.1038/nrclinonc.2011.201

For the past 40 years no treatments developed for melanoma have significantly improved survival over dacarbazine, a drug with a response rate of around 10%. In the past decade, we have witnessed—in the fields of mutation-driven drug development and immuno­modulation—the establishment of treatments actively impacting survival. This is just the beginning of a promising journey to develop rational and biology-driven treatments for patients with melanoma with clini­ cally significant impact to greatly change the thera­peutic landscape. The treatment of melanoma has evolved from using non-selective inhibitors to more

selective agents, with BRAF, MEK and c‑KIT inhibitors leading the field. BRAF mutations are the most frequently occurring and most important mutations that provide drugable targets in melanoma. The first selective BRAF inhibitor developed in the clinical setting was vemurafenib. 1 In a randomized phase III trial published in 2011, this drug led to major tumor responses in 50% of patients, and minor responses in >30% of patients.2 The most common adverse events were arthralgia, fatigue, and cutaneous mani­festations such as rash, photo­sensitivity, pruritis, and squamous-cell carcinoma of the keratoacanthoma-type in around 20% www.nature.com/reviews


CLINICAL ONCOLOGY of patients.1,2 The phase III BRIM‑3 trial, in which vemurafenib was compared with dacarbazine in treatment-naive patients, showed an improvement in progressionfree survival (PFS) of 5.3 months for vemurafenib. The impact on overall survival has not yet been established and is probably similar because, as the trial was unblinded at the first interim analysis and cross over was allowed, changes in overall survival will be somewhat compromised by this cross over. Responses to vemurafenib are immedi­ ate and evident on PET scans within 1–2 weeks after treatment commencement. Disappointing, however, is the short median duration of these responses, and essentially all patients relapse, 50% in the first 5–6 months, 50% any time after 6 months. Various mechanisms of drug resistance have been described, mostly reflecting primary resistance (present from the beginning) and heterogeneity of the tumors. As BRAF inhibition leads to reactivation of the MAPK pathway and enhances cell growth through CRAF, combining a BRAF inhibitor with a MEK inhibitor may both prolong PFS and prevent the appearance of squamous-cell carcinomas. The report in 2011 of the use of a BRAF inhibitor (GSK436) combined with a MEK inhibitor (GSK212), clearly indicate these beneficial effects.3 NRAS mutations occur in about 20% of melanomas but RAS remains a rather elusive target in cancer, with no available drugs that can directly antagonize its signaling activity. Dual targeting of the MAPK and PI3K pathways might abrogate the effect of NRAS mutation (Figure 1). Mutations in c‑KIT are also important in melanoma, especially in mucosal and acral melanomas, in which mutations in c‑KIT are found in 20–30% of the cases. These types of melanoma represent less than 20% of all melanomas in the white population in the Western world, but incidence in the Key advances ■■ BRAF and MEK inhibitors are key agents in treating BRAF-mutated melanomas, and their combination is essential to optimize results2,3 ■■ Immunomodulators, such as antibodies blocking CTLA‑4 and PD‑1, establish immunotherapy as a key component of anti-tumor strategies, required for long-term responses and potential cure6 ■■ Ulcerated primary melanoma is a distinct biologic entity that indicates sensitivity to adjuvant IFN therapy determining when such treatment should be indicated10

KEY ADVANCES IN MEDICINE

Asian population is >70%.4 Response rates and PFS rates with imatinib are in the range of 15–20%, which is rather disappointing compared to the activity of this inhibitor in GIST tumors, and a reflection of a different pattern of mutations.4 These mutations make melanoma a tumor that often presents with multiple perturbed pathways and with many routes to escape from single or multiple drug exposure. Therefore, although combinations of drugs targeting two proteins in the same signaling pathway or in different pathways are currently being explored, it will be critical to combine targeted drugs with drugs that modulate the immune system. The cytotoxic T‑lymphocyte–associated antigen 4 (CTLA‑4) ligand is a negative regulator of T cells; therefore, blocking CTLA‑4 action augments T‑cell activation and proliferation, and inhibits immune system tolerance. The anti-CTLA‑4 monoclonal antibody ipilimumab has recently been assessed in randomized phase III trials. Improved overall survival (4 months) was demonstrated for ipilimumab alone or in combination with the gp100 peptide vaccine compared with the vaccine alone in patients who did not respond to prior treatment.5 Improved overall survival was also demonstrated for ipilimumab in the firstline setting when combined with dacarbazine (2.1 months).6 Thus, in 2011, the FDA approved ipilimumab for advanced melanoma at a dose of 3 mg/kg, administered every 3 weeks for a total of four doses for all patients with advanced melanoma in the first-line and second-line and settings. In the pivotal trial assessing the combination of dacarbazine with ipilimumab as first-line treatment at a dose of 10 mg/kg, a high percentage of liver enzyme alterations was observed.6 This adverse effect resulted in significant percentage of patients abandoning the treatment, which is believed to have reduced the impact of ipilimumab. Because ipilimumab reactivates immune responses that have been silenced, there is a risk that it may reactivate lingering subclinical auto­immune responses in certain patients, resulting in immune-related adverse events. Some of the most prominent were colitis, dermatitis, and hypo­physitis, all of which must be closely monitored as patients may need the immediate use of corticosteroids. Ipilimumab has a modest response rate of around 10%, but responses are almost always durable with a median of 20 months. Moreover, there was a clear separation of the survival curves in both trials, indicating durable responses that last

RTK

PI3K pathway PI3K

RAS

MAPK pathway

CRAF

BRAF GSK436

AKT

MEK GSK212

Inhibition mTOR

ERK

Cell growth, proliferation, survival

Figure 1 | Dual targeting of the MAPK and PI3K pathways in melanoma treatment. This figure illustrates how combining inhibition of BRAF and MEK (intra-pathway combined blocking) with AKT (inter-pathway combined blocking) might abrogate the effect of NRAS mutation.

for >3 years—with a significant number of patients that have not relapsed after 5 years—which may indicate potential cure. A reason why patients might have stopped taking the treatment is that it takes time for the responses to ipilimumab to develop. Responses may even be preceded by progression of disease at 6 or 8 weeks, which might reflect lymphocyte infiltration of the lesions that will subsequently regress. These observations have led to the development of novel, immune-related response criteria that might more accurately describe response to immunotherapy and avoid premature treatment cessation in patients with disease progression before response.7 Studies that combine BRAF inhibitors with cytokines such as IFN, IL2, GM-CSF and anti-angiogenic agents are currently under clinical development. Although early reports indicate improved response rates to these combinations, the interactions between these drugs are poorly understood, and in the absence of clear biomarkers to provide rational guidance as to which combinations should be used and how, serious efforts should be made in this area to allow for rational plans and progress. Green et al.8 have proposed that various chemotherapeutics may exert their action through immunogenic cell death (leading to antigen presentation and stimulating the immune system) or tolerogenic cell death (necrosis without immune-system priming but instead leading to immuno­logical tolerance).9 This approach could provide rational guidance to explore combination treatments. JANUARY 2012  |  S17


CLINICAL ONCOLOGY New immunomodulators are being tested in early-phase studies. Most promising are the results seen with the monoclonal antibody that acts against the programmed death‑1 receptor (PD-1R), the ligand of which (PD-1L) can be expressed directly on melanoma cells. Good responses have been observed in phase I studies with possibly fewer accompanying immune-related adverse events than observed with ipili­ mumab treatment. 9 Another immuno­ modulator, pegylated IFN‑α-2b, was approved in 2011 by the FDA as adjuvant therapy for patients with stage III lymphnode positive disease after lymph-node dissection, on the basis of a significant improvement of relapse-free survival (RFS).10 This EORTC 18991 trial (n = 1,256 patients) had been preceded by the EORTC 18952 trial, which evaluated intermediate doses of regular IFN‑α-2b in 1,388 patients.10 In both trials, patients were stratified according to nodal status and presence or absence of ulceration in the primary tumor. In both trials, low tumor-stage and the presence of ulceration significantly correlated with improved outcome in the IFN-treatment arms, as reported by the recently published meta-analysis of these trials.10 In patients with an ulcerated primary tumor and stage IIB or limited stage III disease (positive sentinel node) there was a highly significant reduction (30–40%) of the relative risk of RFS, distant metastasis-free survival and overall survival. In patients with stage III–N2 disease, these benefits were progressively lost. This finding strongly indicates that ulcerated melanoma represents a distinct biologic entity that will be assesed in the EORTC 18081 trial, which will evaluate pegylated-IFN-α-2b versus observation in node-negative patients with ulcerated primary melanomas. Adjuvant treatment with ipilimumab in patients with advanced stage IIIb/IIIc is under evalu­ ation in the EORTC 18071 trial that has now completed patient accrual. There has never been a more exciting and dynamic time in the treatment of melanoma. To explore all potential combinations is impossible. Thus, we need to stick to a rational approach—guided by principles such as immunogenic cell death—and translational research programs to identify biomarkers predictive for outcomes of both the immuno­ therapeutic and the mutation-driven drug development approach. Without such an approach we could revert to the empiric ways that characterized clinical drug development of the past, and that is no longer acceptable in the 21st century. S18  |  JANUARY 2012



Institut de Cancérologie Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, ParisSud, France (A. M. M. Eggermont, C. Robert) Correspondence to: A. M. M. Eggermont alexander.eggermont@igr.fr Competing interests The authors declare associations with the following companies: Bristol-Myers Squibb, GlaxoSmithKline, Merck, Roche. See the article online for full details of the relationships. 1.

2.

3.

Flaherty, K. T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809–819 (2010). Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011). Infante, J. R. et al. Phase I/II study to assess safety, pharmacokinetics, and efficacy of the oral MEK 1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral BRAF inhibitor GSK2118436 (GSK436) [abstract]. J. Clin. Oncol. 29 (Suppl.), CRA8503J (2011).

4.

Carvajal, R. D. et al. KIT as a therapeutic target in metastatic melanoma. JAMA. 305, 2327–2334 (2011). 5. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010). 6. Robert, C.  et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011). 7. Hoos, A.  et al. Improved endpoints for cancer immunotherapy trials. J. Natl Cancer Inst. 102, 1388–1397 (2010). 8. Green, D. R., Ferguson, T., Zitvogel, L. & Kroemer, G. Immunogenic and tolerogenic cell death. Nat. Rev. Immunol. 9, 353–363 (2009). 9. Brahmer, J. R. et al. Phase I study of single-agent anti-programmed death‑1 (MDX‑1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28, 3167–3175 (2010). 10. Eggermont, A. M. et al. Ulceration and stage are predictive of interferon efficacy in melanoma: results of the phase III adjuvant trials EORTC 18952 and EORTC 18991. Eur. J. Cancer. doi:10.1016/j.ejca.2011.09.028 

BONE CANCER IN 2011

Prevention and treatment of bone metastases Robert E. Coleman

Bone-targeting treatments have transformed the quality of life of patients with metastatic bone disease. 2011 saw the emergence of denosumab—a RANK ligand-specific antibody—as a more-effective alternative treatment to bisphosphonates and of data on the use of bone-targeting treatments to prevent metastasis from breast and prostate cancers. Coleman, R. E. Nat. Rev. Clin. Oncol. 9, 76–78 (2012); published online 20 December 2011; doi:10.1038/nrclinonc.2011.198

Bone disease accounts for substantial morbidity and mortality in patients with cancer. Advanced-stage solid tumors, notably those arising from the breast and prostate, and multiple myeloma are associated with a heavy burden of skeletal disease, with potentially debilitating or life-limiting skeletal-related events (SREs). As a result, bonetargeting treatments have been introduced alongside specific anticancer treatments to minimize skeletal morbidity and preserve the patients’ quality of life and physical function. An increased understanding of the interplay among the disseminated tumor cells, the bone marrow and both hostderived and tumor-derived growth factors has shown that the complex interactions in the bone marrow micro­environment provide candidate therapeutic targets. Modification of these inter­a ctions is emerging as an important anticancer treatment strategy and, in 2011, considerable developments have

Key advances ■■ Denosumab provides a more effective, convenient and well-tolerated alternative treatment to zoledronic acid for the prevention of skeletal morbidity2,3 ■■ The adjuvant use of zoledronic acid in early-stage breast cancer should be restricted to postmenopausal women, as women with residual ovarian function do not benefit from this treatment7 ■■ Denosumab delays the development of bone metastases in men with castration‑resistant prostate cancer10

occurred in the treatment and prevention of bone metastases. In the past 20 years, bisphosphonates have been the choice of treatment for preventing skeletal morbidity associated with malignant bone disease. However, recognition of the importance of the receptor activator of nuclear factor κ‑B ligand (RANKL) in bone www.nature.com/reviews


CLINICAL ONCOLOGY metastasis has provided a new specific therapeutic target. Denosumab is a fully human, synthetic IgG2 antibody that is administered via subcutaneous injection and binds with high affinity to RANKL, preventing the interaction of RANKL and RANK and inhibiting osteoclast function. In 2011, denosumab became available for clinical use after the publication of three large randomized double-blind registration studies. These trials included 5,723 patients with bone metastases secondary to breast cancer (n = 2,046), 1 castration-resistant prostate cancer (n = 1,901) 2 and other advanced-stage solid tumors including non-small-cell lung cancer (n = 702), other types of solid tumors (n = 894) and myeloma (n = 180).3 In these studies, patients were randomly assigned to receive denosumab or zoledronic acid every 3–4 weeks, plus calcium and vitamin D supplements. The primary end point was time to first onstudy SRE. Stopeck and colleagues1 showed that denosumab was statistically superior to zoledronic acid in delaying the first SRE in patients with bone meta­stasis secondary to breast cancer; the median time to first on-study SRE was 26.4 months in the zoledronic acid-treated group and has not been reached in the denosumab-treated group. Similarly, Fizazi and colleagues2 reported that denosumab was superior to zoledronic acid in delaying the first SRE in patients with bone meta­stasis secondary to prostate cancer; the median time to first on-study SRE was 17.1 months in the zoledronic acid-treated group and 20.7 months in the denosumab-treated group. In patients with bone metastasis secondary to advanced solid tumors and myeloma, Henry and colleagues3 showed that denosumab was not inferior to zoledronic acid in delaying the first SRE, but was not superior either. In an analysis of multiple events of SREs, denosumab was superior to zoledronic acid in patients with breast cancer 1 and prostate cancer 2 (Table 1). In all three studies, denosumab was well tolerated, and a key difference in the safety profiles of denosumab and zoledronic acid was the lack of an effect on kidney function with denosumab, which obviates the need for monitoring renal function that is mandated when treating patients with intravenous bisphosphonates. Similar to the use of intravenous bisphosphonates used in oncology settings, osteonecrosis of the jaw (ONJ) was the most important adverse event associated with denosumab, but it was uncommon. The cumulative incidence rates of ONJ were KEY ADVANCES IN MEDICINE

Table 1 | Phase III registration trials of denosumab in advanced-stage cancer Disease setting

End point

Hazard ratio

95% CI

P (relative to ZA)

Breast cancer1

Time to 1st SRE Time to 1st and subsequent SRE

0.82 0.77

0.71–0.95 0.66–0.89

P = 0.01 P = 0.001

CRPC2

Time to 1st SRE Time to 1st and subsequent SRE

0.82 0.82

0.71–0.95 0.71–0.94

P = 0.008 P = 0.008

OST and MM3

Time to 1st SRE Time to 1st and subsequent SRE

0.84 0.90

0.71–0.98 0.77–1.04

P = 0.03 P = 0.14

Total4

Time to 1st SRE Time to 1st and subsequent SRE

0.83 0.82

0.76–0.90 0.77–1.04

P <0.001 P <0.001

Abbreviations: CI, confidence interval; CRPC, castration-resistant prostate cancer; MM, multiple myeloma; OST, solid tumors other than breast or prostate cancer; SRE, skeletal-related event; ZA, zoledronic acid.

similar for both treatments: 0.5% and 0.8% in year 1, 1% and 1.8% in year 2, and 1.3% and 1.8% in year 3 for zoledronic acid and denosumab, respectively.4 The use of denosumab in patients with advanced-stage cancer is likely to be influenced by cost, in particular, because denosumab did not improve either progression-free survival or overall survival compared with zoledronic acid. However, collectively these trials show that denosumab is slightly more effective and convenient to administer, has some advantages in terms of safety over the current gold standard of treatment and represents an important advancement in the quality of life of patients with advanced-stage cancer. Other agents targeting the bone meta­ stasis pathway are in development. The most interesting novel strategy for bone metastasis treatment during 2011 was reported by Parker and colleagues. 5 In this study, 922 men with advanced-stage castration-resistant prostate cancer who had not responded or were considered unsuitable for chemotherapy were randomly assigned (2:1) to receive a bone-localizing α‑particle-emitting agent, 223RaCl 2 (also called alpharadin) or placebo. Median overall survival increased from 11.2 months to 14 months in patients receiving alpharadin (hazard ratio [HR] 0.695; 95% CI 0.552–0.875, P = 0.002).5 In addition to the effects of bone-targeting treatments on the risk of skeletal complications in patients with cancer, these agents could modify the course of the disease via inhibitory effects on the ‘vicious cycle’ of growth factor and cytokine signaling between tumor and bone cells within the bone marrow microenvironment. In patients with early-stage breast cancer, inconsistent effects on disease outcomes were previously reported in clinical trials of adjuvant bisphosphonate treatment. However, in 2009, the results of the

ABCSG‑12 trial 6 stimulated a considerable amount of interest in the field of targeting bone micro­environment to modify the course of early-stage breast cancer. Zoledronic acid treatment every 6 months for 3 years significantly improved diseasefree survival (DFS) in premenopausal women with endocrine-sensitive earlystage breast cancer previously treated with ovarian suppression therapy (goserelin) and tamoxi­fen or anastrozole.6 In 2011, the updated results of this trial7,8 showed that DFS was still improved with adjuvant zoledronic acid treatment and overall survival was also increased. Notably, these bene­ ficial effects of zoledronic acid were only seen in patients over 40 years of age; goserelin treatment induced post­menopausal levels of circulating reproductive hormones consistently in these patients. Improvements in DFS and overall survival was also reported in postmenopausal women in the AZURE trial, a large randomized adjuvant trial that was designed to determine whether treatment with zoledronic acid in addition to adjuvant therapy improved disease outcomes in most women with early-stage breast cancer.9 In this study, 3,360 patients were randomly assigned to receive standard adjuvant systemic therapy with or without zoledronic acid every 3–4 weeks for six doses, then every 3–6 months thereafter, for a total of 5 years.9 After a median follow-up of 59 months, no significant difference was seen in DFS or overall survival. However, in a prespecified subgroup analysis, a significant increase in DFS was detected with zoledronic acid in 1,041 postmenopausal women (who were postmenopausal for >5 years at the time of diagnosis): 5‑year invasive DFS was 71% in the control arm and 78.2% in those treated with zoledronic acid (adjusted HR 0.75; 95% CI 0.59–0.96, P = 0.02).9 In addition, zoledronic acid improved overall survival in this group of women, with 5‑year overall JANUARY 2012  |  S19


CLINICAL ONCOLOGY survival rates of 79% in the control group and 85% in patients treated with zoledronic acid (adjusted HR 0.74; 95% CI 0.55–0.98, P = 0.04). The data from both ABCSG‑12 and AZURE6,9 trials suggest that the bene­ ficial effects of adjuvant zoledronic acid treatment are dependent on an environment with low reproductive hormone levels. The mechanisms underlying this observation are under investigation. Prostate cancer has the propensity to metastasize almost exclusively to the bone and, therefore, provides the ideal clinical setting for the evaluation of bone-targeting treatments to modify the disease course. In a study by Smith and colleagues,10 1,432 men with non-metastatic castration-resistant prostate cancer at high risk for bone meta­ stasis (determined by either a PSA level ≥8.0 ng/ml and/or PSA doub­ling time of ≤10 months) were randomly assigned to receive a monthly treatment of denosumab (120 mg) or placebo. Bone metastasis-free survival was significantly increased with denosumab by a median of 4.2 months (HR 0.85; 95%CI 0.73–0.98, P = 0.028), and the onset of first symptomatic bone metastases was delayed. This effect, however, did not translate into any improvement in overall survival, and as the cumulative incidence of

ONJ was high (4% after 3 years), whether the efficacy of denosumab to reduce bone meta­stasis is sufficient to change clinical practice is unclear. Overall, 2011 saw important developments in the prevention and management of bone metastasis. Integrating the current bone-targeting treatments in routine clinical practice and achieving a better understanding of the cellular processes involved in bone metastasis are the challenges for the future. Sheffield Cancer Research Center, Academic Unit of Clinical Oncology, Weston Park Hospital, Whitham Road, Sheffield S10 2SJ, UK. r.e.coleman@sheffield.ac.uk Competing interests The author declares associations with the following companies: Amgen and Novartis. See the article online for full details of the relationships. 1.

2.

3.

Stopeck, A. T. et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J. Clin. Oncol. 28, 5132–5139 (2010). Fizazi, K. et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377, 813–822 (2011). Henry, D. H. et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients

with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J. Clin. Oncol. 29, 1125–1132 (2011). 4. Saad, F. et al. Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded activecontrolled phase III trials in cancer patients with bone metastases. Ann. Oncol. http:// dx.doi.org/10.1093/annonc/mdr435. 5. Parker, C. et al. Overall survival benefit of radium‑223 chloride (alpharadin) in the treatment of patients with symptomatic bone metastases in castration-resistant prostate cancer (CRPC): a phase III randomised trial (ALSYMPCA) [abstract]. Eur. J. Cancer 47 (Suppl. 2), a3 (2011). 6. Gnant, M. et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N. Engl. J. Med. 360, 679–691 (2009). 7. Gnant, M. et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG‑12 randomised trial. Lancet Oncol. 12, 631–641 (2011). 8. Gnant, M. et al. Overall survival with adjuvant zoledronic acid in patients with premenopausal breast cancer with complete endocrine blockade: Long-term results from ABCSG‑12 [abstract]. J. Clin. Oncol. 29 (Suppl. 15), a520 (2011). 9. Coleman, R. E. et al. Breast-cancer adjuvant therapy with and without zoledronic acid. N. Engl. J. Med. 365, 1396–1405 (2011). 10. Smith, M. R. et al. Denosumab and bone metastasis-free survival in men with castrationresistant prostate cancer: results of a global phase 3, randomised, placebo-controlled trial. Lancet http://dx.doi.org/10.1016/ S0140-6736(11)61226-9.

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ENDOCRINOLOGY THYROID DISEASE IN PREGNANCY IN 2011

Thyroid function—effects on mother and baby unraveled Anthony P. Weetman

The complex relationship between pregnancy and thyroid function, and its clinical effect on mother and baby, continued to stimulate research in 2011. Key advances were made on three important issues: how long maternal thyroid function affects fetal thyroid hormone levels; whether thyroid autoimmunity affects pregnancy outcome; and the prevalence of permanent hypothyroidism after postpartum thyroiditis. Weetman, A. P. Nat. Rev. Endocrinol. 8, 69–70 (2012); published online 6 December 2011; doi:10.1038/nrendo.2011.217

KEY ADVANCES IN MEDICINE

possibility that maternal thyroid function throughout pregnancy, rather than just the first trimester, is an important determinant of gestational outcome. Detailed sampling of maternal thyroid function is required to investigate this hypo­thesis further. In a related study from 2011, maternal thy­ roid function variables measured at 28 weeks gestation were compared with those measured in the umbilical cord at birth in 616 preg­nancies in the UK.3 Maternal free T4 and cord free T4 values showed a positive correlation, and maternal TSH levels were inversely corre­lated with cord free T4 levels. This evi­ dence by Shields and co-investigators is con­ sistent with that of the Dutch study 1 and sug­gests that maternal thyroid function has a measurable effect on fetal thyroid hormone levels throughout pregnancy. Shields et al. also examined the effect of thyroid hormone levels on various para­ meters of fetal growth. Cord free T4 levels were associated with birth weight, length and skin-fold thickness. These results imply that fetal thyroid hormone levels have an important role in regulating fetal growth, especially when taken in conjunction with the results of animal experiments. 4 An unexplained finding was that birth weight was negatively associated with maternal free T4 levels, given that maternal and cord free T4 levels were positively associated. Together, these two studies highlight the intricacy of the maternal–fetal relationship with regard to thyroid function and its clinically important effects on fetal growth and ges­tational age. Studies with detailed assessment of maternal thyroid function throughout the third trimester that incorpo­r ate assess­ment of placental deiodinase activity

are needed. Variable iodine intake is also a con­founding factor that needs addressing, given the surprising discovery in 2011 of inade­quate dietary supplies in the UK and in other countries.5 Multiple studies have shown that euthyroid pregnant woman with positive thyroid peroxidase (TPO) antibodies have an increased risk of spontaneous mis­carriage and possibly preterm delivery. Two mechanisms might be responsible. Firstly, even though ‘euthyroid’, these women may have subtle impairment of thyroid function, and the effects of maternal thyroid function on the fetus, as discussed above, are responsible. Secondly, thyroid auto­immunity dis­torts the immunological balance required to maintain tolerance to the fetal semi-allograft.6 In 2011, a study of 245 TPO-antibodypositive women with TSH levels <2.5 mU/l has shown that very preterm delivery (<34 weeks of gestation) and respiratory dis­tress at birth were more common than

© Gabriel Blaj | Dreamstime.com

The fetal thyroid gland starts to develop at 12 weeks of gestation, and for the first half of pregnancy, transplacental passage of maternal thyroid hormone is essential for normal fetal development. Failure to deliver sufficient thyroid hormone to the fetus causes impaired neurological development, although whether other elements of fetal development are also affected remains unclear. The essentially normal outcome in neonates with congenital hypothyroidism promptly treated with levothyroxine after birth suggests that maternal thyroid hormones also have a fetal role in the second half of pregnancy. In a prospective survey of 886 pregnant Dutch women published in 2011, neonates born to mothers who had high-normal TSH levels (above the 97.5th percentile) one or more times during pregnancy had lower total T4 levels when routine screening was performed for congenital hypothyroidism than neonates born to mothers whose TSH levels had remained below the 97.5th percentile.1 This result contrasts with that of a previous study that showed no relationship between maternal and neonatal thyroid function,2 a difference possibly related to the use of pregnancy-specific refer­ence ranges for TSH measurement in the 2011 study. Although the women with high-normal TSH levels had normal free T4 levels, the TSH levels might reflect a resetting of the ­pituitary–thyroid axis, which resulted in less T4 being available to cross the placenta. Alternatively, an unsuspected increase in placental deiodinase activity might have been responsible for low T4 availability to the fetus. Low gestational age was associated with low neonatal thyroxine levels in this and previous studies, which raises the

JANUARY 2012  |  S21


ENDOCRINOLOGY in pregnancies of women who were negative for TPO antibodies.7 No association with TPO-antibody positivity was observed for 12 other adverse outcomes, including preterm delivery between 34–37 weeks. Although corrected for multiple comparisons, the statistical tests applied were onetailed rather than two-tailed. Given that the association with respiratory distress is novel, this finding could be a type 1 statis­tical error. The key feature of this study was that all the par­ticipants were chosen to have low-normal TSH levels, and thus the results appear to show that autoimmunity per se is responsible for these adverse out­comes. How­ever, miscarriage rates, pre­viously shown to be increased in TPO-antibody-positive women, were not specifically increased and although below 2.5 mU/l, TSH levels were significantly higher in the TPO-antibody-positive women than in control women. Although the results clearly show that a trial of levothyroxine during pregnancy is warranted in this subset of TPO-antibody-positive women with lownormal TSH levels, the pathogenic mechanism behind the adverse outcomes of such pregnancies is still in question. Postpartum thyroiditis is a transient flaring of pre-existing autoimmune thyroidi­tis in the year after delivery, which seems to be a consequence of the restoration of nor­mal immune function after a period of altered immuno­r egulation during pregnancy. 6 Tran­sient abnormalities of thyroid dysfunction are common in postpartum thyroiditis; however, as has been clear for over two decades, 2–21% of such patients have permanent hypo­thyroidism at the end of the year after delivery, and this figure rises during follow-up over subsequent years. A survey of 4,394 women from Southern Italy reported in 2011 that 3.9% had postpartum thyroiditis and 54% of these were hypo­thyroid at 1 year after delivery.8 This figure for the prevalence of post­partum thyroiditis is rather low compared with that in many other studies, a difference that could be related to the exclusion of women with any thyroid dysfunction during the first trimester of pregnancy in the 2011 study. In addition, the women in this Italian study were only screened twice postpartum, so some cases of dysfunction might have been missed. By contrast, the figure for the prevalence of hypothyroidism at 1 year is strikingly high. This finding might also be related to the study design—if women with milder forms of postpartum thyroiditis were excluded because of limited sampling, this exclusion could have distorted the overall prevalence results, given that such women are S22  |  JANUARY 2012



Key advances ■■ Maternal thyroid function has a measurable effect on fetal thyroid hormone levels throughout pregnancy1,3 ■■ Fetal thyroid hormone levels have an important role in regulating fetal growth, as measured by birth weight, length and skin-fold thickness3 ■■ Very preterm delivery (<34 weeks of gestation) and respiratory distress may be associated with maternal thyroid peroxidase antibody positivity7 ■■ Hypothyroidism following an episode of postpartum thyroiditis could be more common in some populations than previously described, and the risk of this outcome correlates with the severity of the preceding destructive thyroiditis8,9

probably less likely to become hypothyroid. In this context, a related study has shown that low urinary iodine levels postpartum are associated with long-term hypothyroidism, probably because the low iodine excretion reflects more severe destructive thyroiditis that causes a discharge of thyroid iodine content.9 Together, these results reinforce the need for careful clinical evaluation of all women who have postpartum thyroiditis at 1 year after delivery and annually thereafter. In summary, five studies from 2011 have shown a pervasive effect of maternal thyroid function on the fetus throughout pregnancy. Abnormalities in maternal or fetal thyroid function are associated with an increasing number of adverse pregnancy outcomes. The additional role of autoimmunity per se on pregnancy, rather than through its effect on maternal thyroid function, remains to be

fully established. However, no doubt exists that changes to the maternal autoimmune response in the postpartum period have considerable clinical effects on the mother’s thyroid reserve. Department of Human Metabolism, University of Sheffield, The Medical School, Beech Hill Road, Sheffield S10 2RX, UK. a.p.weetman@sheffield.ac.uk Competing interests The author declares no competing interests. 1.

2.

3.

4.

5.

6.

7.

8.

9.

Kuppens, S. M. et al. Neonatal thyroid screening results are related to gestational maternal thyroid function. Clin. Endocrinol. (Oxf.) 75, 382–387 (2011). Oken, E. et al. Neonatal thyroxine, maternal thyroid function, and child cognition. J. Clin. Endocrinol. Metab. 94, 497–503 (2009). Shields, B. M., Knight, B. A., Hill, A., Hattersley, A. T. & Vaidya, B. Fetal thyroid hormone level at birth is associated with fetal growth. J. Clin. Endocrinol. Metab. 96, E934–E938 (2011). Bassett, J. H. et al. A lack of thyroid hormones rather than excess thyrotropin causes abnormal skeletal development in hypothyroidism. Mol. Endocrinol. 22, 501–512 (2008). Vanderpump, M. P. et al. Iodine status of UK schoolgirls: a cross-sectional survey. Lancet 377, 2007–2012 (2011). Weetman, A. P. Immunity, thyroid function and pregnancy: molecular mechanisms. Nat. Rev. Endocrinol. 6, 311–318 (2010). Negro, R. et al. Thyroid antibody positivity in the first trimester of pregnancy is associated with negative pregnancy outcomes. J. Clin. Endocrinol. Metab. 96, E920–E924 (2011). Stagnaro-Green, A. et al. High rate of persistent hypothyroidism in a large-scale prospective study of postpartum thyroiditis in southern Italy. J. Clin. Endocrinol. Metab. 96, 652–657 (2011). Stuckey, B. G. et al. Low urinary iodine postpartum is associated with hypothyroid postpartum thyroid dysfunction and predicts long-term hypothyroidism. Clin. Endocrinol. (Oxf.) 74, 631–635 (2011).

PRIMARY ALDOSTERONISM IN 2011

Towards a better understanding of causation and consequences Michael Stowasser

With primary aldosteronism now widely acknowledged as common and associated with both hypertension-related and non-hypertension-related pathology, research interest into its causes and consequences continues to grow. In 2011, major breakthroughs occurred in understanding the role and nature of underlying genetic disturbances and elucidating the pathophysiology of its cardiovascular sequelae. Stowasser, M. Nat. Rev. Endocrinol. 8, 70–72 (2012); published online 13 December 2011; doi:10.1038/nrendo.2011.223

The concept that primary aldo­steronism has a genetic basis is not new. Origi­nally reported in 1966,1 the rare, glucocorticoid-remediable

familial hyperaldosteronism type 1 (FH‑I) is due to inherit­ance of a hybrid gene containing the regulatory elements of CYP11B1—a www.nature.com/reviews


ENDOCRINOLOGY

KEY ADVANCES IN MEDICINE

or because testing of family members was inconclusive.4 In a major breakthrough towards further understanding the genetic basis of pri­ mary aldosteronism, Choi and col­leagues reported somatic mutations (Gly151Arg and Leu168Arg) in KCNJ5, which encodes an inwardly-rectifying K+ channel, in eight of 22 patients with APA.5 A third, germline mutation in KCNJ5 (Thr158Ala) had pre­viously been identified in affected members of a US family with a new familial form of pri­ mary aldosteronism (FH-III).6 The affected father and two daughters demon­strated very severe primary aldo­steronism, with childhood-onset hyper­tension, hypo­kalemia and markedly elevated aldosterone and sup­pressed renin levels. As in patients with FH‑I, 18-hydroxycortisol and 18-­oxocortisol levels were elevated, albeit to a greater degree. How­ever, the primary aldosteronism was not ­glucocorticoid-suppressible, and the hybrid gene mutation was not present. Resected adrenal glands showed marked, diffuse hyperplasia of the ZF, with the combined weight of both adrenal glands in one daughter reaching 81 g (normal <12 g).6 None of the three KCNJ5 mutations had been reported in genetic databases. Choi et al. discovered that all three amino acid sub­ stitutions were in close proximity to the channel’s selectivity filter and, when expressed in human embryonic kidney (HEK293T) cells, were associated with the loss in channel selectivity for K+.5 These findings suggest that KCNJ5 mutations pre­dispose indivi­duals to chronic adreno­cortical cell membrane depolarization via increased channel Na+ permeability, the extra­cellular concentrations of which are much higher than those of K+. The resulting influx of Ca2+, in turn, leads to upregulation of enzymes involved in al­dosterone synthesis and cell proliferation.5 In normal adrenal glands, expression of wild-type KCNJ5 is restricted to the ZG,5 but the massive hyperplasia seen in patients with FH-III involved the ZF.6 The fact that these patients had markedly elevated hybrid steroid levels also suggests that, as in FH‑I, the adrenal cells express both aldosterone synthase and 17α-hydroxylase and, hence, have molecular characteristics of both the ZG and the ZF. Neither hybrid steroid levels nor the cellular composition of the tumors were reported for patients with APA. However, on the basis of findings in patients with FH‑III, those with somatic KCNJ5 mutations are likely to have elevated levels of hybrid s­ teroids, and their APAs probably consist of mostly ZF-like cells.

Capsule Aldosterone ZG Aldosterone synthase

ZF

Cortex

gene that encodes steroid 11β-hydroxylase and is regulated by adrenocorticotropic hor­mone (ACTH)—and coding sequences from CYP11B2—a gene that encodes aldosterone synthase and is primarily regulated by angiotensin II. Expression of this hybrid gene leads to ACTH-regulated aldo­sterone overproduction.2 Glucocorticoids, in small doses, suppress hybrid gene expression and ameliorate primary aldosteronism and hypertension. Because wild-type CYP11B1 is expressed in the zona fasciculata (ZF) of the adrenal cortex, so is the hybrid gene (Figure 1). Thus, aberrant aldosterone synthase activity, normally restricted to the zona glomerulosa (ZG), occurs in the ZF. In contrast to the ZG, which lacks the steroid 17α-hydroxylase enzyme necessary for the formation of cortisol precursors, cortisol is available as a substrate for aldosterone synthase in the ZF. Hence, cortisol is converted into the ‘hybrid steroids’ 18-hydroxycortisol and 18-oxocortisol, the levels of which are elevated in patients with FH‑I.2 The second recognized form of fami­ lial hyperaldosteronism (FH-II) is neither gluco­corticoid-suppressible nor associ­ated with the hybrid gene mutation.3 Approxi­ mately 30% of patients with FH‑II have uni­lateral forms of primary aldosteronism (mostly due to an aldosterone-producing ade­n oma [APA]), with the remainder being bilateral (due to bilateral adrenal hyper­plasia [BAH]). The genetic basis of FH‑II remains uncertain and is almost certainly hetero­geneous; several families have demon­strated linkage of FH‑II with a locus at chromosome 7p22.3 In 2011, Mulatero and colleagues assessed prevalence rates of familial hyper­aldo­stero­ nism among 300 patients consecutively diag­nosed with primary aldosteronism, after exclud­ing those suspected or diagnosed as having a form of familial primary aldo­steronism.4 Hybrid gene testing yielded only two (0.7%) patients with FH‑I. Of the remaining 298 study participants, 199 had relatives available for and consenting to bio­chemical screening by aldosterone– renin ratio (ARR) testing and, where positive, definitive confirmation or exclusion of primary aldo­steronism by saline infusion testing. This analysis revealed that 12 patients had at least one affected relative, result­ing in a preva­lence of FH‑II of at least 6% (almost 10-fold that of FH‑I). The prevalence could be higher, as another 54 patients were classified as having ‘uncertain’ status, either because not all family members with hypertension underwent ARR testing

Cortisol Steroid 17αhydroxylase Steroid 11βhydroxylase

ZR

Figure 1 | Cellular and functional zones of steroid synthesis in the adrenal cortex. Normally, production of cortisol is restricted to ZF and ZR, owing to the enzymatic activity of steroid 17α-hydroxylase (encoded by CYP17A1) and 11β-hydroxylase (encoded by CYP11B1). Similarly, production of aldosterone is restricted to ZG, as enzymatic activity of aldosterone synthase (encoded by CYP11B2) is limited to this zone. In familial hyperaldosteronism type I, aldosterone synthase is active in ZF and ZR, as the hybrid CYP11B1/CYP11B2 gene has regulatory elements derived from CYP11B1. Hence, aldosterone synthase has access to cortisol as a substrate, leading to the production of 18-hydroxycortisol and 18-oxocortisol. Abbreviations: ZF, zona fasciculata; ZG, zona glomerulosa; ZR, zona reticularis.

Gordon et al. previously described two dis­tinct forms of APA.7,8 Angiotensin-II-­ unresponsive APA are composed predominantly of ZF-like cells; patients with this form of APA have elevated hybrid steroid levels and lack responsiveness of aldo­sterone to upright posture or angiotensin-II infusion. Angiotensin-II-responsive APA contain predominantly non-ZF-like morphology (ZG or hybrid ZF/ZG), and patients with this form usually have normal hybrid steroid levels and are aldosterone-responsive to upright posture or angiotensin-II infusion. Taking the above findings into account, APAs bear­ing KCNJ5 mutations are likely to be of the angiotensin-II-unresponsive subtype. Further studies comparing patients with APAs with or without mutations in terms of histology, steroid hydroxylase expression, aldosterone responsiveness to posture and/or ­angiotensin-II, and peripheral hybrid steroid levels are awaited with great interest. If KCNJ5 mutation-bearing cells have both ZG and ZF characteristics, what is JANUARY 2012  |  S23


ENDOCRINOLOGY Key advances ■■ Familial hyperaldosteronism type II (FH-II) may account for at least 6% of primary aldosteronism cases and is approximately 5–10 times more common than FH‑I4 ■■ A germline mutation in KCNJ5 is associated with severe, early-onset familial primary aldosteronism, and somatic KCNJ5 mutations are common in aldosterone-producing adenoma5 ■■ Patients with primary aldosteronism have reduced circulating levels of endothelial progenitor cells, which might contribute to the development of vasculopathy in these individuals9 ■■ The degree of left ventricular enlargement in primary aldosteronism is largely determined by dietary salt; dietary salt restriction might reduce cardiovascular risk in this condition10

their origin? Do KCNJ5 mutations bestow ZF-like characteristics (including his­tol­ ogy, 17α-hydroxylase expression, hybrid steroid formation, and loss of aldosterone responsive­ness to angiotensin-II) to ZG cells, or are ZG-like characteristics (aldo­ sterone synthase expression) bestowed onto ZF cells? Further studies should shed light on this fascinating issue. Other studies in 2011 have focused on the mechanisms underlying adverse cardio­ vascular effects of aldosterone excess. In a novel study by Wu et al.,9 levels of endothelial progenitor cells (EPCs), which are thought to protect against cardiovascular disease by repairing endothelial injury, were lower in 113 patients with primary aldo­ steronism (APA n = 87; BAH n = 26) than in 55 patients with essential hypertension.9 Differences in pulse-wave velocity, a marker of arterial stiffness, and high-­s ensitivity C‑reactive protein (hsCRP) levels, a marker of cardiovascular inflammation, and EPC counts were attenuated following uni­ lateral adrenalectomy or during treatment with aldosterone antagonists. Overall, the findings suggest that increased circulating aldosterone levels in patients with primary aldosteronism contribute to vasculopathy by reducing EPC numbers, partly by activating EPC mineralocorticoid receptors and possibly indirectly by raising hsCRP levels.9 Animal studies have demonstrated a cri­ tical role for salt in the development of aldosterone-induced cardiovascular damage; how­ever, corroborative data in humans were lack­ing. In a case–control study of 21 patients with primary aldosteronism and 21 matched individuals with essential hyperten­sion, Pimenta and co-workers reported in 2011 S24  |  JANUARY 2012



that patients with primary aldosteronism had greater thickness of the left ventricular wall, end-diastolic dia­meter and mass. More­ over, urinary sodium excretion, a mar­ker of dietary salt intake, positively correlated with and was an indepen­dent predictor of left ventricular wall thickness and mass in patients with pri­mary aldosteronism, but not in those with essential hypertension.10 Hence, as in animal studies, salt appears to interact with auto­nomous aldosterone excess to bring about cardio­vascular damage in patients with primary aldosteronism. The lack of a posi­tive correlation between plasma aldoster­one and left ventricular dimen­sions in patients with primary aldosteronism raises the possibility that, above a certain thres­hold, aldosterone plays a more permissive part, whereas salt has a more graduated effect. Either way, these results argue for a role of dietary salt restriction to reduce the risk of cardiovascu­lar disease in patients with primary aldosteronism. Endocrine Hypertension Research Center, University of Queensland School of Medicine, Greenslopes and Princess Alexandra Hospitals, Ipswich Road, Woolloongabba, Brisbane 4102, Australia. m.stowasser@uq.edu.au Competing interests The author declares no competing interests. 1.

Sutherland, D. J., Ruse, J. L. & Laidlaw, J. C. Hypertension, increased aldosterone secretion and low plasma renin activity relieved by

dexamethasone. Can. Med. Assoc. J. 95, 1109–1119 (1966). 2. Lifton, R. P. et al. Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase. Nat. Genet. 2, 66–74 (1992). 3. Stowasser, M., Pimenta, E. & Gordon, R. D. Familial or genetic primary aldosteronism and Gordon syndrome. Endocrinol. Metab. Clin. North Am. 40, 343–368, viii (2011). 4. Mulatero, P. et al. Prevalence and characteristics of familial hyperaldosteronism: the PATOGEN study (Primary Aldosteronism in TOrino-GENetic forms). Hypertension 58, 797–803 (2011). 5. Choi, M. et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 331, 768–772 (2011). 6. Geller, D. S. et al. A novel form of human mendelian hypertension featuring nonglucocorticoid-remediable aldosteronism. J. Clin. Endocrinol. Metab. 93, 3117–3123 (2008). 7. Gordon, R. D., Hamlet, S. M., Tunny, T. J. & Klemm, S. A. Aldosterone-producing adenomas responsive to angiotensin pose problems in diagnosis. Clin. Exp. Pharmacol. Physiol. 14, 175–179 (1987). 8. Tunny, T. J., Gordon, R. D., Klemm, S. A. & Cohn, D. Histological and biochemical distinctiveness of atypical aldosteroneproducing adenomas responsive to upright posture and angiotensin. Clin. Endocrinol. (Oxf.) 34, 363–369 (1991). 9. Wu, V. C. et al. Endothelial progenitor cells in primary aldosteronism: a biomarker of severity for aldosterone vasculopathy and prognosis. J. Clin. Endocrinol. Metab. 96, 3175–3183 (2011). 10. Pimenta, E. et al. Cardiac dimensions are largely determined by dietary salt in patients with primary aldosteronism: results of a case– control study. J. Clin. Endocrinol. Metab. 96, 2813–2820 (2011).

POLYCYSTIC OVARY SYNDROME IN 2011

Genes, aging and sleep apnea in polycystic ovary syndrome Andrea Dunaif

Polycystic ovary syndrome (PCOS) is a complex genetic disease that affects approximately 7% of women of reproductive age worldwide. From novel pathways implicated in the etiology of PCOS through genome-wide association to characterization of the reproductive and metabolic changes that occur in ageing women with PCOS, the year 2011 has seen a number of studies published that highlight the intricacies of this condition. Dunaif, A. Nat. Rev. Endocrinol. 8, 72–74 (2012); published online 20 December 2011; doi:10.1038/nrendo.2011.227

The year 2011 saw the advent of the first genome-wide association study (GWAS) in polycystic ovary syndrome (PCOS).1 GWAS have been widely used, since the publication of the human haplotype map in 2005, to localize susceptibility genes for com­plex traits, such as obesity and type 2 dia­betes

mellitus (T2DM).2 This analysis per­mits an unbiased examination of the entire genome for novel disease susceptibility loci and, unlike candidate gene approaches, is ­hypothesis-generating. 2 The first GWAS of PCOS was conducted in Han Chinese women with PCOS, who were diagnosed www.nature.com/reviews


ENDOCRINOLOGY using the Rotterdam cri­teria (two of three of the following findings: oligomenor­rhea, hyperandrogen­ism and/or poly­cystic ovaries detected on ultrasono­graphy).1 Asso­cia­tions achiev­ing genome-wide levels of significance3 between PCOS and loci on chromosomes 2p16.3 (OR 0.71), 2p21 (OR 0.67) and 9q33.3 (OR 1.34) were observed in a dis­covery sample of 744 PCOS cases and 895 con­trols and in two indepen­dent replication cohorts of 2,840 PCOS cases and 5,012 ­controls, and 498 PCOS and 780 controls.1 Several known genes are located near the locus at 2p16.3, which showed the great­est association with PCOS, includ­ing GTF2A1L and LHCGR. GTF2A1L, which encodes TFIIAα/β‑like factor (ALF), is a germ-cell-specific transcription factor that is highly expressed in adult testis and may play a part in spermato­genesis. How variation in GTF2A1L might contribute to PCOS is unclear. LHCGR encodes the lutropin–­ choriogonadotropic hormone recep­t or (LH/CG‑R) and is a highly plau­­si­ble PCOS candidate gene. The strongest asso­ci­ation at the locus on chromo­some 2p21 was with THADA, a gene origi­nally iden­tified in thy­­ roid adenomas. A GWAS in white indivi­ duals of European ances­t ry reported an associa­tion of THADA with T2DM.4 The region on chromosome 9q33.3 associ­ated with PCOS was located within DENND1A, which encodes a domain differen­t ially expressed in normal and neoplastic cells (DENN) that can bind to and negatively regulate endo­plasmic reticulum amino­ peptidase 1. Elevations of circulating endoplasmic reti­culum amino­peptidase 1 have been reported in obese women with PCOS. Thus, it is possible that varia­tion in THADA and DENND1A contribute to T2DM and obesity risk in women with PCOS. Confirmation that the GWAS signals reflect a variation in these genes, rather than in other genes that are in linkage dis­ equilibrium with these loci, requires fur­ ther genetic analyses. In addition, the roles of these loci in PCOS suscepti­bility in other racial or eth­nic groups and in other pheno­ types, for instance, in women with PCOS diag­nosed using the National Insti­tute of Child Health and Human Develop­ment (NICHD) criteria (history of oligo­menorrhea and clinical and/or biochemi­cal evidence of hyper­androgenism), will require further investigation. Studies in monozygotic twins indicate that the herit­ability of PCOS is close to 80%. However, the loci identified in the PCOS GWAS confer modest (~30%) changes in disease risk and do not account KEY ADVANCES IN MEDICINE

Key advances ■■ Three genetic susceptibility loci have been mapped by genome-wide association study in Han Chinese women with PCOS1 ■■ Increased ovarian and adrenal androgen production and insulin resistance persist in postmenopausal women with PCOS6,7,8 ■■ Obstructive sleep apnea contributes to insulin resistance and continuous positive airway pressure improves insulin sensitivity in women with PCOS10

for the observed herit­ability of PCOS.5 This so-called ‘missing heritability’ has been seen in other common complex traits, such as T2DM, and might reflect the fact that rare rather than common variants contribute to complex diseases.5 Nevertheless, GWAS has been important for implicating novel b­iologic pathways in disease pathogenesis. Little was known about the reproductive and metabolic changes that occur with age in women with PCOS. In 2011, two crosssectional studies compared postmenopausal women in the sixth decade of life with and without PCOS.6,7 In both studies, the diagnosis of PCOS was made on the basis of the NICHD diagnostic criteria, although the study by Puurunen et al. 7 also contained premenopausal women with PCOS diagnosed by the Rotterdam criteria and a control group consisting of reproductively normal, premenopausal women. The study by Markopoulos et al. 6 found that postmenopausal women with PCOS had significantly elevated levels of circulating total testosterone, androstenedione, dehydro­ epiandrosterone sulfate (DHEAS) and 17-hydroxyprogesterone and an increased free androgen index (FAI). Sex hormonebinding globulin (SHBG) levels, how­ever, were significantly decreased compared with the control group. No evidence of increased sensitivity to corticoliberin (also known as corticotropin-­releasing hormone) or adreno­ cortico­t ro­pic hormone was reported in women with PCOS, which suggests that increases in adrenal androgen production did not result from changes in responsiveness to tropic hor­mones. Dexamethasone suppression sug­gested that elevated total testosterone and DHEAS levels were partly adrenal in origin. Puurunen et al.7 also found increased androstenedione levels, basally and in response to chorio­gonado­t ropin,

in postmenopausal women with PCOS compared with postmenopausal control women. Furthermore, they found persistent evidence for insulin resistance and increased inflammation, independent of BMI, in post­ menopausal women with PCOS compared to those without the disease. In a 2011 prospective study, Schmidt et al.8 diagnosed PCOS on the basis of ovarian histology from ovarian wedge resec­tion or unilateral oophorectomy per­formed in 1956– 1965. These women were examined in 1987 and compared with control women from a population-based study. Both groups were recalled for repeat examination in 2008, in their eighth decade of life. The PCOS group had higher FAI and lower follitropin (also known as follicle-stimulating hormone; FSH) and SHBG levels than the control group, as was the case in 1987. DHEAS, total testo­sterone and androstenedione levels were significantly increased in premenopausal women with PCOS in 1987, but were similar to those of the control group after menopause. The prevalence of hypo­thyroidism was lower in post­menopausal women with PCOS than in control individuals. Taken together, these three studies6,7,8 sug­ gest that hyperandrogenism of both ova­rian and adrenal origin, as well as insulin resistance, persist in postmenopausal women with PCOS. Increased androgen levels declined with age in older post­menopausal women with PCOS such that only differences in FAI were present in women aged >70 years.8 By contrast, decreases in SHBG and FSH levels persist into old age. All of the studies are limited by small sample sizes, which might account for the differences in the prevalence of hypothyroidism. In

JANUARY 2012  |  S25


ENDOCRINOLOGY the cross-sectional studies, the accuracy of diagnosis of PCOS on the basis of medical records is a potential limitation, although oligo­menorrhea and symptoms of androgen excess, such as hirsutism, have been shown to be excellent proxies for PCOS.9 The prevalence of obstructive sleep apnea (OSA) is significantly increased in women with PCOS, independent of obesity—a wellknown risk factor for OSA. Androgen levels and insulin resistance are positively associated with OSA in PCOS. In 2011, Tasali and colleagues proposed that OSA contributes to insulin resistance in PCOS, as it does in other OSA populations.10 The investigators directly tested this hypothesis by treating affected women with continuous positive airway pressure (CPAP), which resulted in a modest but significant improvement in insulin sensitivity.10 A dose–response effect of CPAP on insulin sensitivity was observed, with greater improvements in sensitivity with longer duration of CPAP. A significant decrease in circulating norepinephrine levels was also reported, without changes in epinephrine, cortisol or leptin levels. This observation suggests that the decrease in insulin sensitivity is mediated by sympathetic nervous system activation. Diastolic blood pressure, which was not elevated in women with PCOS who had OSA, decreased significantly with CPAP. The limitations of this study were the small number of women (n = 9) who completed the CPAP intervention with acceptable compliance (≥4 h of use per night).10 Further­ more, the study population was extremely obese, with a mean BMI of 48.4 kg/m 2. The improvements in insulin sensitivity, although significant, were very modest (on average 7%); the study par­ticipants remained profoundly insulin resistant after CPAP treatment. Modeling of the data suggested that the beneficial effect of CPAP would be greater in overweight or mildly obese patients with PCOS. How­ever, the robustness of the model is questionable given the small sample size. Never­the­less, this study suggests that OSA con­tributes to insulin resistance in PCOS and that CPAP improves insulin sensitivity in affected women. In conclusion, these 2011 publications will have a major effect on the field. It is now clear from an adequately powered and replicated study that genetic variation contri­ butes to the etiology of PCOS. Furthermore, reproductive and metabolic features of the dis­order persist beyond the reproductive years, increasing the impact of PCOS as a leading women’s health issue. Finally, a S26  |  JANUARY 2012



component of the insulin resistance associated with PCOS is secondary to OSA and improves with CPAP treatment. Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Tarry 15‑745, Chicago, IL 60611, USA. a-dunaif@northwestern.edu Competing interests The author declares no competing interests. 1.

2.

3.

4.

Chen, Z. J. et al. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nat. Genet. 43, 55–59 (2011). Hirschhorn, J. N. & Daly, M. J. Genome-wide association studies for common diseases and complex traits. Nat. Rev. Genet. 6, 95–108 (2005). Hoggart, C. J., Clark, T. G., De Iorio, M., Whittaker, J. C. & Balding, D. J. Genome-wide significance for dense SNP and resequencing data. Genet. Epidemiol. 32, 179–185 (2008). Zeggini, E. et al. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat. Genet. 40, 638–645 (2008).

5.

Manolio, T. A. et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009). 6. Markopoulos, M. C. et al. Hyperandrogenism in women with polycystic ovary syndrome persists after menopause. J. Clin. Endocrinol. Metab. 96, 623–631 (2011). 7. Puurunen, J. et al. Unfavorable hormonal, metabolic, and Inflammatory alterations persist after menopause in women with PCOS. J. Clin. Endocrinol. Metab. 96, 1827–1834 (2011). 8. Schmidt, J., Brännström, M., LandinWilhelmsen, K. & Dahlgren, E. Reproductive hormone levels and anthropometry in postmenopausal women with polycystic ovary syndrome (PCOS): a 21-year follow-up study of women diagnosed with PCOS around 50 years ago and their age-matched controls. J. Clin. Endocrinol. Metab. 96, 2178–2185 (2011). 9. Taponen, S. et al. Hormonal profile of women with self-reported symptoms of oligomenorrhea and/or hirsutism: Northern Finland Birth Cohort 1966 Study. J. Clin. Endocrinol. Metab. 88, 141–147 (2003). 10. Tasali, E., Chapotot, F., Leproult, R., Whitmore, H. & Ehrmann, D. A. Treatment of obstructive sleep apnea improves cardiometabolic function in young obese women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 96, 365–374 (2011).

EPIGENETICS AND METABOLISM IN 2011

Epigenetics, the life-course and metabolic disease Peter D. Gluckman

Clinical and experimental studies suggest that early life experiences, perhaps spanning multiple generations, affect lifelong risk of metabolic dysfunction through epigenetic mechanisms. Data published in 2011 suggest that epigenetic analysis could potentially have utility as a marker of early metabolic pathology and might enable early life prophylaxis. Gluckman, P. D. Nat. Rev. Endocrinol. 8, 74–76 (2012); published online 20 December 2011; doi:10.1038/nrendo.2011.226

Both population and individual variation in sus­ceptibility to an obesogenic environ­ ment exist. Genome-wide association studies have been disappointing in explaining this variation, and there is a growing focus on possible epigenetic explanations. Epigenetic variation is most likely to arise early in the life-course. An extensive body of experimental, clini­cal and epidemiological evidence demon­strates that early life develop­mental factors—­including the maternal diet, but operating within the normative range of develop­mental exposures—affect the risk of developing meta­bolic disease later in life.1 This phe­nomenon is sometimes termed developmental programming. The early observations were largely ignored because of the absence of a plausible biological

mechanism, but explana­t ions developed over the past decade have been framed in terms of developmental p ­ lasticity—the adaptive processes enabling an organism to respond to environmental cues acting in early life and adjust its develop­mental trajectory. Developmental plasticity is at least partly underpinned by epigenetic mecha­ nisms, including DNA methylation and histone modifications. A number of papers published during 2011 have re­inforced the validity of these conclusions. Extensive previous work has shown that rats whose mothers are underfed during preg­nancy and lactation develop an insulin resis­t ant and obese phenotype in adulthood. Moreover, mice lacking the transcription factor hepatocyte nuclear factor 4α www.nature.com/reviews


ENDOCRINOLOGY

© Paul Hakimata | Dreamstime.com

(HNF‑4α), a crucial regulator of gene expression in pancreatic islet β cells, have impaired glucose tolerance. In 2011, Sandovici et al. reported how maternal diet in rats affects the epigenetic regulation of the Hnf4a locus in pancreatic islets of offspring.2 The researchers found that a low-protein maternal diet led to underexpression of Hnf4a in the islets of the offspring. Mechanistically, the under­ expression could be attributed in part to his­tone modifications at the gene enhancer region of Hnf4a, which led to changes in chromatin looping that ultimately weakened the interaction between the enhancer region and a specific promoter region. The normative age-dependent epigenetic silencing of the Hnf4a locus was exacerbated in rats exposed in utero to a low-protein diet. These data add to the growing experimental literature showing epigenetic consequences from the manipulation of early life undernutrition in metabolically relevant tissues. Previous studies in rats have shown that neonatal administration of the adipokine leptin can reverse developmental programming leading to metabolic compromise as well as some of the associated epi­genetic changes. 3 Such studies are provocative in that they suggest that develop­mental program­ming in humans might be reversi­ ble. Pinney et al. examined how adminis­ tration of exenatide, an analogue of the incretin glucagon-like peptide 1, acts to prevent the development of glucose intolerance in adulthood in rats subjected to intrauterine growth restriction.4 Rats subjected to this abnormal intrauterine environ­ment develop glucose intolerance and are charac­ terized by progressive epi­genetic silencing of pancreatic islet transcription factor Pdx1. The 2011 paper found that injection of exenatide during postnatal day 1–6 in rats after intrauterine growth restriction increased Pdx1 transcription by normalizing post-translational and epigenetic changes

KEY ADVANCES IN MEDICINE

Key advances ■■ Changes in promoter–enhancer interactions underlie the epigenetic regulation of a transcription factor in rat pancreatic islets induced by poor maternal diet 2 ■■ The trajectory towards onset of type 2 diabetes mellitus (T2DM) in the growth-compromised newborn rat can be reversed by an incretin analogue that normalizes epigenetic modifications associated with pancreatic β‑cell dysfunction4 ■■ Strong relationships exist between epigenotype at birth and later adiposity, and between maternal nutrition and offspring epigenotype in humans6 ■■ The epigenetic states of genes associated with T2DM and obesity might be a presymptomatic marker of the lifetime risk of T2DM in humans7 ■■ The phenotypic effects of early life overnutrition can be transgenerationally transmitted through the paternal line in mice9

related to this gene, including Pdx1 activator phosphorylation, histone acetylation and trimethylation, and DNA methylation at the CpG island in the Pdx1 promoter. Exenatide is already in use in the treatment of adults with type 2 diabetes mellitus (T2DM), and this study provides an experimental proof of concept for its usage early in life prior to disease onset. Prophylactic treatment of at-risk indivi­ duals early in life is generally more effica­ cious and provides greater health and cost benefits than treatment after a disease de­velops. This is particularly the case for diseases such as diabetes mellitus, where the cost of treat­ing associated morbidities and complica­tions compounds over many years. How­­ever, beyond the obvious research program that would be needed to validate such interventions, a challenge remains: how do we identify infants whose particular developmental programming has placed them at increased metabolic risk? Birth weight is not a satisfactory proxy, given that metabolically adverse developmental programming can occur independent of birth weight.5 A recent paper by Godfrey et al. —to which I contributed—has suggested that the epigenetic state at birth can both predict childhood adiposity and be a measure of prenatal nutritional exposures.6 Umbilical cord tissue-derived DNA was sourced from two independent large-scale prospective cohorts, and the methylation status at specific CpGs in the promoter region of RXRα, which encodes a transcription factor involved in fat metabolism and insulin sensitivity, was measured after a preliminary genome-wide scan. A positive correlation between degree of RXRα methyla­tion at one specific site in the promoter and childhood body adipo­ sity at age 6 years or 9 years was found in both within-cohort and between-cohort replicates. Additionally, a negative association was observed between mater­nal carbo­ hydrate intake during the first tri­mes­ter of pregnancy and the degree of methylation at

this site. In contrast to the small effect sizes typically seen with genetic polymorp­hisms associated with metabolic disease risk, this single site epigenotype could account for at least 25% of the variance in child­hood adipo­sity. This association was obser­ved across a healthy population, indicating that develop­mental programming of metabolic risk and associated epigenetic variation occurs across the normative range of developmental experiences. Genes for which polymorphisms have strong associations with disease risk might be anticipated to have epimutations (aberrant epigenetic marks). One such gene is FTO, which has been identified by genomewide association studies as being involved in obesity risk. In a prospective study of nonsymptomatic indivi­duals of a mean age of 30 years by Toperoff et al.,7 those who showed hypomethylation at an intronic CpG site of FTO in blood samples had an increased risk of develop­ing impaired glucose metabolism by a mean age of 43 years. This pattern was also seen in a sepa­rate case–control analysis, although the level of hypomethylation in cases relative to controls was small, as was the effect size.7 These findings were made in a tissue not specifically related to metabolic function, and the differential methylation levels may have been established in early develop­ ment before major cell differentiation had occurred, although this inference is contingent on the long-term stability of the FTO epigenotype after its establishment. The methylation levels could not be explained by the presence or absence of the risk allele, indicating that their association with disease risk was independent of DNA sequence. Global prevalence of maternal obesity and ges­tational diabetes mellitus is rising, and both are risk factors for the develop­ ment of meta­­bolic disorder in offspring;8 there­fore, the potential for an escalating prevalence of intergenerationally induced T2DM is a par­ticular concern. Epigenetic JANUARY 2012  |  S27


ENDOCRINOLOGY mechanisms could underlie the inter­ generational transmis­sion of predisposition to T2DM, but unraveling the mechanisms involved is highly complex owing to the multiple pathways by which nongenomic inheritance, involving either direct or indirect epi­genetic mechanisms, could occur. Dunn and Bale utilized a maternal high-fat diet mouse model and sought to eliminate maternal physiological or behavioral effects and grand-maternal effects by studying pheno­typic outcomes up to the F3 generation through the paternal line.9 They found that female-specific increased body weight and length was inherited through the pater­nal, not the maternal, lineage. Taken together with other research show­ing that specific histone marks located at developmental loci in sperm are maintained beyond spermio­genesis,10 this research suggests that the phenotype was transmitted through the male germline via stable epigenetic marks in sperm. Our knowledge of developmental path­ ways to metabolic disease is rapidly increas­ ing. It is becoming apparent that epi­genetic variations induced early in life or that are present later in life are associated with metabolic risk. How far environ­mentally induced plasticity, associated with epi­genetic changes that have metabolic sequelae, operates into the life-course is, how­e ver, not yet clear. Research to date has largely been based on a candidate gene approach, but newer metho­ dologies in sequencing that enable whole genome approaches, such as ChIP-Seq (chromatin immuno­precipitation together with massively parallel DNA sequencing), should allow more rapid develop­ment of understandings. Many potential metho­ dological pitfalls exist, and the importance of validation across multiple cohorts is emphasized in the work of Godfrey et al., who found an apparently impressive associa­ tion between adiposity and methylation at the endothelial nitric oxide synthase gene NOS3, which could not be validated in a second cohort. Strategies could emerge whereby epi­ genetic state at birth or in infancy could be used to assess developmental exposures, to pre­dict metabolic risk and to assist in the iden­tification of new preventative or therapeutic approaches. Indeed the work with exena­tide discussed above4 could be con­ sidered an experimental proof of concept; the chal­lenge would be to find valid risk markers and acceptable interventions. The outlook for epigenetic research in human metabolic and other diseases is promising. S28  |  JANUARY 2012



Liggins Institute, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. pd.gluckman@auckland.ac.nz Acknowledgments F. Low provided assistance with reviewing the literature. Competing interests The author declares no competing interests. 1.

2.

3.

4.

Fernandez-Twinn, D. S. & Ozanne, S. E. Early life nutrition and metabolic programming. Ann. NY Acad. Sci. 1212, 78–96 (2010). Sandovici, I. et al. Maternal diet and aging alter the epigenetic control of a promoter–enhancer interaction at the Hnf4a gene in rat pancreatic islets. Proc. Natl Acad. Sci. USA 108, 5449–5454 (2011). Gluckman, P. D. et al. Metabolic plasticity during mammalian development is directionally dependent on early nutritional status. Proc. Natl Acad. Sci. USA 104, 12796–12800 (2007). Pinney, S., Jaeckle Santos, L., Han, Y., Stoffers, D. & Simmons, R. Exendin-4 increases histone acetylase activity and reverses epigenetic modifications that silence

Pdx1 in the intrauterine growth retarded rat. Diabetologia 54, 2606–2614 (2011). 5. Gale, C. R. et al. Maternal diet during pregnancy and carotid intima-media thickness in children. Arterioscler. Thromb. Vasc. Biol. 26, 1877–1882 (2006). 6. Godfrey, K. M. et al. Epigenetic gene promoter methylation at birth is associated with child’s later adiposity. Diabetes 60, 1528–1534 (2011). 7. Toperoff, G. et al. Genome-wide survey reveals predisposing diabetes type 2-related DNA methylation variations in human peripheral blood. Hum. Mol. Genet. http://dx.doi.org/ 10.1093/hmg/ddr472. 8. Poston, L., Harthoorn, L. F. & Van Der Beek, E. M. on behalf of contributors to the ILSI Europe workshop. Obesity in pregnancy: implications for the mother and lifelong health of the child. a consensus statement. Pediatr. Res. 69, 175–180 (2011). 9. Dunn, G. A. & Bale, T. L. Maternal high-fat diet effects on third-generation female body size via the paternal lineage. Endocrinology 152, 2228–2236 (2011). 10. Hammoud, S. S. et al. Distinctive chromatin in human sperm packages genes for embryo development. Nature 460, 473–478 (2009).

OSTEOPOROSIS IN 2011

Osteoporosis therapy—dawn of the post-bisphosphonate era Roland Baron

Over the past decade, investigators have actively searched for safer therapeutic approaches to replace or complement the use of bisphosphonates and/or parathyroid hormone, exploring both antiresorptive and osteoanabolic pathways. Besides marked progress in basic research, the year 2011 has seen several compounds for the treatment of osteoporosis enter or progress within clinical trials. Baron, R. Nat. Rev. Endocrinol. 8, 76–78 (2012); published online 6 December 2011; doi:10.1038/nrendo.2011.207

Osteoporosis is characterized by a marked decrease in BMD and strength, resulting in fragility fractures associated with high morbidity and mortality. The development of bis­phosphonates has substantially altered the course of the disease in treated patients. This class of drugs binds rapidly to the mineral­ized skeleton and impairs the process of bone resorption, which leads to a progressive increase in BMD and a decrease in the risk of fractures, albeit mostly in verte­ bral rather than hip or other non­vertebral fractures. However, as bone resorption and bone formation are linked by the process of bone remodeling, the anti­resorptive effect of these drugs rapidly decreases bone formation and tissue turnover, limiting the gain in BMD. This progressive decrease in bone turnover and the persistent effect of

bis­phosphonates even years after their withdrawal might contribute to two undesirable long-term adverse effects: osteonecrosis of the jaw and atypical femoral fractures. In addition to bisphosphonates, within the past few years osteoporosis treatment has seen the arrival of the first osteo­anabolic drugs: injectable parathyroid hormone (PTH) fragments. When administered daily, PTH, unlike bisphosphonates, initially induces clear increases in the levels of bone formation markers, bone turnover and BMD. The combination of PTH with bisphosphonates, especially when the latter are given at long intervals, has some additive effects over monotherapy with either compound.1 Yet, the effects of PTH wane with time, and a concomitant increase in bone resorption can be observed. Moreover, www.nature.com/reviews


ENDOCRINOLOGY some concerns have been raised over the drug’s oncogenic potential. As a result, academic and industry laboratories have been engaged in active research over the past decade to find safer therapeutic approaches, both antiresorptive and osteoanabolic, to replace or complement the use of bis­ phosphonates and/or PTH. Besides significant advances in basic science, the year 2011 has seen several compounds enter or progress within clinical trials. Mutations in the gene encoding sclero­ stin, an osteocyte-derived Wnt antagonist, cause sclerosteosis or van Buchem disease, two high-bone-mass syndromes.2,3 Together with pre­vious findings, these observations made a strong case for develop­ing antagonists to this protein. The year 2011 has seen the first clinical trial of a humanized monoclonal antibody to sclerostin (AMG785) in healthy men and postmenopausal women.4 In this phase I, randomized, double-blind, placebo-­controlled study, 72 healthy indivi­ duals received a single subcutaneous or intravenous injection of ascending doses of the antibody and were followed up for a maximum of 85 days. The results showed not only a dose-dependent increase in the levels of several bone formation markers but also a decrease in those of bone resorption markers. Despite the short duration of the study, significant increases in BMD of up to 5% in the spine and 3% in the hip were measured. In this short period, the compound was safe and well-tolerated. Six patients, however, developed anti-AMG785 antibodies, which were neutralizing in two individuals—a reason for some con­cern. Never­t heless, this trial demonstrates the valid­ity of this novel therapeutic approach, which stands out not only because of its efficacy but also owing to its mechanism of action, being possibly both anabolic and antiresorptive. A phase II study has been completed, and next year will undoubtedly bring more data on this development program. In the long term, and despite the fact that haploinsufficient sclerosteosis or van Buchem mutation carriers experience no significant adverse effects, the risks of foramen closures due to bone overgrowth and the potential oncogenicity of this thera­peutic approach will have to be carefully examined. The search for antiresorptive compounds that do not remain in bone for long periods of time and/or that decrease bone resorption without negative effects on bone formation has also been active. One approach has been to block the differentiation of osteoclasts by KEY ADVANCES IN MEDICINE

Key advances ■■ A single injection of humanized antibodies to sclerostin, an endogenous Wnt antagonist secreted mostly by osteocytes, markedly raised markers of bone formation and decreased markers of bone resorption, increasing BMD over a short period of time in a phase I clinical trial4 ■■ Orally delivered inhibitors of cathepsin K increased BMD continuously at all bone sites over a 3‑year period in extensions of phase II clinical trials9,10 ■■ Antibodies to RANKL reduced the incidence of vertebral and hip fractures in women at high risk7 ■■ Discontinuation of cathepsin K inhibitors or antibodies to RANKL induced a rapid increase in bone turnover and return to pre-treatment BMD values8,9

antagonizing RANKL, a cytokine that is required for osteoclast formation, through the use of antibodies. Detailed analysis of the effect of denosumab, a human mono­ clonal antibody against RANKL, on bone turnover markers confirmed that it induces a very rapid, profound and sustained decrease in bone resorption markers, but also in bone formation markers.5 This find­ ing con­firmed that denosumab induces a marked decrease in bone turnover, which indeed reaches levels below the pre­ menopausal reference interval. Although this decrease could be of some concern on the basis of our previous experi­ence with bis­phosphonates, no adverse skeletal effects were noted after 3 years of denosumab therapy in the FREEDOM trial.6 The study is being extended for 10 years, which should adequately address long-term safety issues. Des­pite these theoretical concerns, another study in postmenopausal women at high risk of fractures has demonstrated that denosumab efficiently reduces the incidence of new vertebral and hip fractures in highrisk sub­groups.7 Of the 7,808 women enrol­ led in the FREEDOM trial in 213 centers worldwide, a subgroup with known risk factors (multiple prevalent vertebral fractures, aged ≥75 years and/or with a femoral neck BMD T‑score of ≤–2.5) was analyzed post hoc.7 In all three groups, denosumab significantly reduced the risk of fracture to a degree consistent with that in low-risk patients. Thus, denosumab has a consistent antifracture efficacy in patients with varying degrees of fracture risk. Interestingly, the higher absolute risk observed in the highrisk group was associated with the greatest denosumab-induced risk reduction.

Another novel antiresorptive approach has been to antagonize not the differen­tiation but the function of osteoclasts through inhi­bition of cathepsin K, an enzyme utilized by osteoclasts to degrade the dense col­lagen that constitutes most of the bone matrix. Following the report of a 2‑year phase II trial,8 Eisman et al.9 reported in 2011 the results of a 1‑year extension study. Con­tinued treatment of postmenopausal women with 50 mg odanacatib (orally once a week for 3 years) produced significant increases from baseline and from year 2 in BMD at both the spine and the hip. Bone resorption markers remained suppressed, whereas the bone formation marker BALP was unchanged from baseline, a feature that distinguishes this treatment modality from other antiresorptive therapies, including bisphosphonates and denosumab (see above). Confirming this unique profile of cathepsin K inhibition, Eastell et al.10 showed that another inhibitor (ONO‑5334), given to postmenopausal women orally once daily for 12 months, also resulted in significant increases in BMD at the lumbar spine, total hip and femoral neck. These studies sug­gest that inhibition of cathepsin K, which does not decrease osteoclast differentiation, can reduce osteoclast acti­vity while maintaining the ‘coupling’ to bone formation and osteoblast activity, thereby efficiently increasing BMD. Interestingly, this approach has a less negative effect on bone turnover than bisphosphonates or denosumab. The year 2011 also saw the first reports on a novel and potentially troublesome phenomenon: the resolution of drug effects.8,9 Whereas most therapeutic fields would not expect anything other than a resolution of effect upon discontinuation of treatment, the osteoporosis field was somewhat caught by surprise. This surprise can be explained by the fact that, for the past 20 years, we have been used to the bisphosphonates, a class of drugs which remains bound to the skeleton and continues to have therapeutic acti­vity for several years after cessation of treat­ment. This characteristic has both advantages (nothing happens when you stop treat­ment) and drawbacks (possible long-term adverse effects). A more troublesome finding is that the studies on discontinuation of treatment of both denosumab8 and odanacatib9 have shown not only a resolution of effect—that is, rapid reversibility of treatment, which would be an advantage over ­bisphosphonates—but also a ‘rebound’ effect. High bone turnover activity has been shown to rapidly (within JANUARY 2012  |  S29


ENDOCRINOLOGY 6–12 months) return the patient’s BMD (at least spine and hip) to values found before initiation of treatment. Biologically, these results illustrate the long-suspected existence of a ‘skeletal mechanostat’ whereby BMD is determined by the balance of a large number of factors intrinsic to each individual. Unsurprisingly, if these factors remain unchanged, the ‘excess’ bone generated by antiresorptive treatments is rapidly removed by excessive bone resorption once we allow osteoclasts to do their job. Yet, this phenomenon will create new challenges for osteoporosis treatment, probably calling for the combined or sequential use of several thera­peutic principles. Already, the use of bis­phosphonates to stabilize bone gains after PTH treatment has been suggested. Whether a similar resolution of effect will occur with other anabolic therapies, in particular sclero­stin anti­bodies, will be an important ­question to answer in the coming years. In summary, 2011 has seen significant pro­gress in the understanding and implementation of several new therapeutic options for the treatment of osteoporosis, in what could be called the post-­bisphosphonate era. Although very promising novel anti­ resorptive and anabolic agents have entered or been further assessed in clinical trials, showing extraordinary efficacies and pro­ mises for the future, they will have to be tested in the long term to better establish their safety relative to bisphosphonates. These studies have also uncovered novel chal­lenges, in particular the resolution of drug effects, which will need to be addressed in order for novel therapeutic strategies to be implemented for osteoporosis. Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Endocrine Unit, 188 Longwood Avenue, Boston, MA 02115, USA. roland_baron@hms.harvard.edu Competing interests The author declares associations with the following companies: Amgen, Arcarios, Bone Therapeutics, Merck, Novartis, Roche. See the article online for full details of the relationships. 1.

2.

3.

Cosman, F. et al. Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1–34)] in postmenopausal osteoporosis. J. Bone Miner. Res. 26, 503–511 (2011). Balemans, W. et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum. Mol. Gen. 10, 537–543 (2001). Balemans, W. et al. Identification of a 52kb deletion downstream of the SOST gene in patients with van Buchem disease. J. Med. Genet. 39, 91–97 (2002).

S30  |  JANUARY 2012



4.

5.

6.

7.

Padhi, D. et al. Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J. Bone Miner. Res. 26, 19–26 (2011). Eastell, R. et al. Effects of denosumab on bone turnover markers in postmenopausal osteoporosis. J. Bone Miner. Res. 26, 530–537 (2011). Cummings, S. R. et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N. Engl. J. Med. 361, 756–765 (2009). Boonen, S. et al. Treatment with denosumab reduces the incidence of new vertebral and hip fractures in postmenopausal women at high risk. J. Clin. Endocrinol. Metab. 96, 1727–1736 (2011).

8.

Bone, H. G. et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J. Clin. Endocrinol. Metab. 96, 972–980 (2011). 9. Eisman, J. A. et al. Odanacatib in the treatment of postmenopausal women with low bone mineral density: three-year continued therapy and resolution of effect. J. Bone Miner. Res. 26, 242–251 (2011). 10. Eastell, R. et al. Safety and efficacy of the cathepsin K inhibitor ONO-5334 in postmenopausal osteoporosis: the OCEAN study. J. Bone Miner. Res. 26, 1303–1312 (2011).

TYPE 1 DIABETES MELLITUS IN 2011

Heterogeneity of T1DM raises questions for therapy Paolo Pozzilli

Research in 2011 regarding β‑cell destruction, early immunointervention trials and development of late complications in type 1 diabetes mellitus have highlighted the heterogeneity of this disease. Patient phenotyping should be performed for the implementation of tailored therapies, especially taking into account the age at which the disease is diagnosed. Pozzilli, P. Nat. Rev. Endocrinol. 8, 78–80 (2012); published online 20 December 2011; doi:10.1038/nrendo.2011.228

Type 1 diabetes mellitus (T1DM) is an autoimmune disorder involving the destruction of pancreatic β cells. Why T1DM develops is still debated, but a role of oxidative stress in genetically susceptible individuals has been proposed in the past few years. Oxidative stress in these individuals might be caused by a lack of antioxidant enzymes and/or by environ­mental triggers such as viral infections, and has been linked to β‑cell cyto­ toxicity; 1,2 however, the role of reactive oxygen species (ROS) in the pathogenesis of T1DM remains controversial. In 2011, Thayer et  al. 3 reported the required cellular sources of ROS for T1DM induction in mice models of T1DM. The researchers showed that nonobese, diabetic (NOD) mice were protected from T1DM as a consequence of macrophage and neutrophil depletion. Interestingly, depletion of neutrophils alone did not protect or delay the onset of the disease. In other experiments, using mice with spleno­c ytes genetically altered to prevent the production of ROS, development of T1DM was significantly delayed. These findings suggest that ROS produced by macrophages are critical factors in inducing damage to the β cells and that targeting

this mechanism could be a novel approach worth considering for T1DM prevention and early treatment. The results of two trials published in 2011 revealed the potential of immunotherapy to protect β‑cell function in patients with recent onset of T1DM. 4,5 Abatacept is a drug already in use in the treatment of rheumatoid arthritis. This fusion protein of cytotoxic T‑lymphocyte protein 4 and

Key advances ■■ Signaling of reactive oxygen species appears to be a relevant mechanism for the initiation of β‑cell autoimmunity by T cells in mice3 ■■ Immunointervention trials in patients with recent onset of type 1 diabetes mellitus did not meet everyone’s expectations4,5 ■■ Poor glycemic control is associated with an increased risk of heart failure in adult patients with T1DM8 ■■ Protective factors for late complications exist in some patients with type 1 diabetes mellitus,9 and their identification would help prevention of retinopathy, neuropathy and cardiovascular disease

www.nature.com/reviews


immunoglobulin modulates costimulatory receptors to prevent full T‑cell activation. In a multi­center, double-blind, random­ized controlled trial of abatacept, 112 patients with recent onset of T1DM received abatacept or placebo infusions intravenously on days 1, 14, 28 and monthly for a total of 27 infusions over 2 years.4 The pri­mary outcome was the C‑peptide response following a mixed meal evaluated at 2 years. Abata­cept, as compared to placebo, increased the adjusted C‑peptide area under the curve (AUC) by 59%, with a difference between the two groups persisting through­out the trial and with a delay in the reduc­tion of C‑peptide of 9.6 months using abata­cept. The investigators concluded that modulation of T cells with abatacept slowed reduction in β‑cell function over 2 years; however, after the 6-months time point, the decrease in β‑cell function in the abata­cept group was parallel to that in the placebo group, which suggests that the effect of a­batacept declined over time. The second trial tested the capacity of a humanized, anti-CD3 monoclonal anti­body (teplizumab) to preserve β‑cell func­t ion and decrease insulin needs in patients with T1DM of recent onset aged 8–35 years.5 In a phase III trial, 516 patients diag­nosed with T1DM for <3 months were randomly allocated to receive various doses of teplizumab or placebo at baseline and at 26 weeks. The primary composite outcome was the percentage of patients with insulin dose <0.5 U/kg per day and HbA1c <6.5% at 1 year. The pri­ mary outcome did not differ between groups; however, 5% of patients in the teplizumab groups were not taking insulin at 1 year compared with no patients in the placebo group. Why did immunointervention not achieve what everyone expected? The answer lies in patient heterogeneity, the chosen sample size and the dose of drugs used. T1DM is a hetero­geneous disease in terms of age at onset, HLA genotype, residual β‑cell function at the time of diagnosis, insulin resistance, compliance to insulin treatment and HbA1c level. These two trials included patients diagnosed with the disease as chil­ dren and those diagnosed as adults. Com­ pared with children diagnosed with T1DM, those diagnosed as adults show higher C‑peptide secretion 6 and higher insulin resistance. If the primary end point of an immuno­intervention trial is the C‑peptide response following a mixed meal (as is the case in nearly all recent trials), the above variables should have been taken into account when calculating the tar­get sample size. The problem is that the decline of KEY ADVANCES IN MEDICINE

C‑peptide after diagnosis varies among different age groups, which means that large sample sizes are required if strict age groups are not used. If this issue is not sorted out, we will inevitably continue to fail. Experience shows that subgroups of patients exist who respond to immuno­intervention and indeed their β cells still function, especi­ally in those with low risk HLA genotypes.7 By means of post-hoc analysis and/or meta-analysis of data we should be able to identify what fac­ tors determine a beneficial effect of a specified treatment so that future trials can be designed accordingly. Poor glycemic control is associated with microvascular and macrovascular complications in T1DM, but is it associated with heart failure? In 2011, Lind et al. revealed the association in 20,985 patients with T1DM identified from the Swedish national dia­ betes registry.8 Patients aged ≥18 years with T1DM and no known heart failure were followed up until hospital admission for heart failure, death or end of follow-up. Patients had a mean age of 38.6 years at baseline. During a median follow-up of 9 years, 635 (3%) of the patients were admitted to hospital with a diagnosis of heart failure, which corresponds to an incidence of 3.38 events per 1000 patient-years. In patients with an HbA1c ≥10.5%, as compared with a reference group with an HbA1c <6.5%, the hazard ratio for developing heart failure was 3.98 (95% CI 2.23–7.14). Increased age and duration of the disease raised the risk of heart failure. Therefore, it looks like that by achieving good metabolic control, prevention of heart failure can be obtained in patients with T1DM. Evidence for a decline in the inci­dence of microvascular complications in T1DM dur­ing the past few decades has been reported; therefore, the question arises whether protective factors for late dia­betic com­plications in T1DM can be identi­fied. To assess complication prevalence and identify protective factors in patients with T1DM of ≥50 years duration, a complication-free sub­group was analyzed. A cross-sectional, observational study was carried out in 351 US residents who survived with T1DM for ≥50 years (known as the Medalists).9 A substantial number of Medalists did not develop proliferative retinopathy (42.6%), nephropathy (86.9%), neuropathy (39.4%) or cardiovascular disease (51.5%). Meta­ bolic control (current and over the pre­vious 15 years) was unrelated to complica­tions, whereas a 7.2-fold increased risk was obser­ ved in patients with raised plasma levels of

© Dml5050 | Dreamstime.com

ENDOCRINOLOGY

the advanced glycation end pro­ducts (AGEs) carboxyethyl-lysine and pentosidine. The population of Medalists is of interest, as protective factors are probably present in these patients. Once identified, such factors could be used to protect other patients with the disease from the development of longterm chronic complications. A link between formation or processing of AGE and the development of diabetic vasculo­pathy is a well-known finding. One possible mechanism of damage occurs via CML-collagen, mediated through the soluble receptor for AGE (RAGE).10 The measurement of circulating RAGE in the Medalists would have aided understanding of the protection from complications achieved by these patients. What have we learnt about T1DM in 2011? If one looks at disease patho­genesis, protection of β cells from apoptosis or at the development of or protection from late complications, the disease appears more heterogeneous than ever. Therapeutic approaches, in whichever field, should be established with this concept in mind. Too often, pharma­ceutical companies aim to tackle a clinically relevant issue by treating the entire population of patients with a disease with one target drug; unfortunately, this approach does not work for T1DM. Specific patient subgroups must be integral in the design of studies either for etiopathogenesis or the prevention and treatment of β‑cell damage. The same concept applies for late diabetic complications, as different process pathways might be involved. Therapies should be designed accordingly. JANUARY 2012  |  S31


ENDOCRINOLOGY Department of Endocrinology and Diabetes, University Campus Bio-Medico, Via Álvaro del Portillo, 21, 00128 Rome, Italy. p.pozzilli@unicampus.it Competing interests The author declares associations with the following companies: Andromeda Biotech, Bristol-Meyers Squibb, GlaxoSmithKline, Novartis, Sanofi-Aventis. See the article online for full details of the relationships. 1.

2.

Bottino, R. et al. Response of human islets to isolation stress and the effect of antioxidant treatment. Diabetes 53, 2559–2568 (2004). Tran, P. O et al. Adenoviral overexpression of the glutamylcysteine ligase catalytic subunit protects pancreatic islets against oxidative

3.

4.

5.

6.

stress. J. Biol. Chem. 279, 53988–53993 (2004). Thayer, T. C, et al. Superoxide production by macrophages and T cells is critical for the induction of autoreactivity and type 1 diabetes. Diabetes 60, 2144–2151 (2011). Orban, T. et al. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet 378, 412–419 (2011). Sherry, N. et al. Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial. Lancet 378, 487–497 (2011). Klinke, D. J. Age-corrected beta cell mass following onset of type 1 diabetes mellitus correlates with plasma C-peptide in humans. PLoS ONE 6, e26873 (2011).

7.

Buzzetti, R. et al.C-peptide response and HLA genotypes in subjects with recent-onset type 1 diabetes after immunotherapy with DiaPep277: an exploratory study. Diabetes 60, 3067–3072 (2011). 8. Lind, M. et al. Glycaemic control and incidence of heart failure in 20,985 patients with type 1 diabetes: an observational study. Lancet 378, 140–146 (2011). 9. Sun, J. K. et al. Protection from retinopathy and other complications in patients with type 1 diabetes of extreme duration: the Joslin 50-Year Medalist Study. Diabetes Care 34, 968–974 (2011). 10. Thomas, M. C, et al. Soluble receptor for AGE (RAGE) is a novel independent predictor of allcause and cardiovascular mortality in type 1 diabetes. Diabetologia 54, 2669–2677 (2011).

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GASTROENTEROLOGY & HEPATOLOGY HEPATITIS C IN 2011

A new standard of care and the race towards IFN-free therapy Wolf Peter Hofmann and Stefan Zeuzem

Chronic HCV infection is a leading cause of liver-related morbidity and mortality. In 2011, treatment options for patients infected with HCV genotype 1 changed dramatically with the approval of two nonstructural protein 3 protease inhibitors—boceprevir and telaprevir—by the FDA and the European Medicines Agency. Hofmann, W. P. & Zeuzem, S. Nat. Rev. Gastroenterol. Hepatol. 9, 67–68 (2012); published online 20 December 2011; doi:10.1038/nrgastro.2011.249

In phase III clinical trials, the combination of boceprevir or telaprevir with PEGIFN-α–ribavirin has been shown to result in increased sustained virological response (SVR) rates compared with PEG-IFN-α– ribavirin (67–75% and 38–44%, respectively) in therapy-naive patients. 1,2 As these new triple therapies also resulted in increased rapid virological response (RVR; undetectable levels of HCV RNA at week 4 of triple therapy) rates, response-guided therapy to shorten the duration of treatment from 48 weeks to 24–28 weeks is now possible for a large proportion of patients. Additional phase III clinical trials showed that many patients who did not respond 100 – 90 –

well to previous PEG-IFN-α–ribavirin therapies also benefited from re-treatment with PEG-IFN-α–ribavirin and boceprevir or telaprevir.3,4 Patients who had previously relapsed achieved SVR rates of 69–88% when re-treated, and previous partial responders showed SVR rates of 40–59%. In those who had a previous null response, SVR rates following re-treatment were still poor (33% for telaprevir).4 Despite these encouraging achievements for patients infected with HCV genotype 1, the low tolerability, particularly for PEGIFN-α, and the emergence of resistant variants associated with treatment failure of triple therapies that include boce­previr

or telaprevir are still major drawbacks. Furthermore, current dosing schedules are complex and the pill burden is high, which might result in suboptimal adherence to treatment. Combination therapies with two direct-acting antiviral agents (DAAs) that have different modes of action, and an alloral IFN-free DAA therapy should overcome resistance, reduce the incidence of adverse events and improve treatment adherence. Different substance classes with anti-HCV activity include nonstructural protein (NS) 3 protease inhibitors, NS5A inhibitors, and nucleoside inhibitors and non-nucleoside inhibitors of the HCV NS5B polymerase. Results of several trials of DAA combination

RVR SVR

RVR and SVR (%)

80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – 0– BMS-790052 + BMS-650032

BMS-790052 + BMS-650032 + PEG-IFN-α–RBV

Study 1

BMS-790052 + BMS-650032 Study 2

PSI-7977

PSI-7977 + RBV12

PSI-7977 + RBV12 + PEG-IFN-α (4)

PSI-7977 + RBV12 + PEG-IFN-α (8)

PSI-7977 + RBV12 + PEG-IFN-α (12)

Study 3

Figure 1 | The effectiveness of an all-oral IFN-free therapy for patients with HCV has been demonstrated in some study arms of three recent trials. Patients in study 1 had HCV genotype 1a or 1b infection and previously a null response to PEG-IFN-α–RBV.8 These patients received 200 mg of the protease inhibitor BMS‑650032 twice a day plus 60 mg of the NS5A inhibitor BMS‑790052 once a day with or without PEG-IFN-α–RBV for 24 weeks. Patients with viral breakthrough during dual therapy received PEG-IFN-α–RBV and achieved SVR thereafter (not shown). Patients in study 2 all had HCV genotype 1b and had previously had a null response to PEG-IFN-α–RBV.9 These patients received 200 mg of the protease inhibitor BMS‑650032 twice a day and 60 mg of the NS5A inhibitor BMS‑790052 once a day for 24 weeks. Patients in study 3 had HCV genotypes 2 or 3 and were treatment naive.10 These patients all received 400 mg of the nucleoside inhibitor PSI‑7977 once a day as monotherapy or with RBV for 12 weeks. Three arms also received PEG-IFN-α for 4, 8 or 12 weeks. Abbreviations: RBV, ribavirin; RVR, rapid virological response; SVR, sustained virological response.

KEY ADVANCES IN MEDICINE

JANUARY 2012  |  S33


GASTROENTEROLOGY & HEPATOLOGY Key advances ■■ The newly licensed protease inhibitors boceprevir and telaprevir substantially increase sustained virological response rates in treatment-naive1,2 patients infected with HCV genotype 1 and those who failed previous therapy ■■ Several IFN-free regimens that combine protease inhibitors and polymerase inhibitors with or without ribavirin achieve undetectable HCV RNA levels early during therapy5,6

therapies that had at least one IFN-free treatment arm were published in 2011 and open the race for an all-oral combination therapy for patients with chronic hepatitis C. In the SOUND‑C1 study, 32 patients who were infected with HCV genotype 1 were randomly assigned to receive the protease inhibitor BI 201335 in combination with one of two doses of the non-­nucleoside inhibitor BI 207127 and ribavirin for 4 weeks, followed by PEG-IFN-α–­ribavirin and BI 201335 until week 24.5 Only patients without optimal initial virologic response received PEGIFN-α–ribavirin until week 48. Patients in the high-dose treatment group achieved better RVR and SVR rates than those in the low-dose treatment group (100% and 94% versus 73% and 73%). The all-oral triple combination administered for 4 weeks was generally well tolerated and did not cause serious adverse events. In a phase II trial, 46 treatment-naive patients infected with HCV genotype 1 were assigned to receive one of three regimes: the protease inhibitor GS‑9256 in combination with the non-nucleoside inhibitor tego­ buvir (dual combination); GS‑9256, tegobuvir and ribavirin (triple combination); or GS‑9256, tegobuvir, PEG-IFN-α and riba­ virin (quadruple combination) for 4 weeks.6 All patients received PEG-IFN-α–ribavirin thereafter, or immediately if they did not respond or had virological breakthrough. In the dual, triple and quadruple combination therapy arms, RVR rates were 7%, 38% and 100%, respectively. The low RVR rate in the dual DAA combination was mainly attributable to the emergence of resistant variants, particularly in patients infected with HCV genotype 1a. The addition of ribavirin to the DAA combina­tion further reduced viral levels and decreased viral breakthrough. None of the patients receiving the quad­ruple therapy experienced viral plateau or breakthrough during the 4 weeks of treatment. The combination of GS‑9256 and tegobuvir was generally well tolerated S34  |  JANUARY 2012



and a transient increase in levels of bilirubin was observed in all treatment arms. In the ZENITH study, 106 patients were randomly assigned to receive telaprevir in combination with two different doses of the non-nucleoside inhibitor VX‑222 either as a dual DAA therapy or as a quadruple therapy in combination with PEG-IFN-α– ribavirin for 12 weeks.7 Patients received PEG-IFN-α–ribavirin for an additional 12 or 24 weeks, depending on their virological results at weeks 2 and 8. The RVR rates in the low-dose and high-dose VX‑222 dual DAA combination arms were 17% and 59%, respectively, and a significant proportion of patients developed virological breakthrough. In the quadruple combination arms, RVR rates for patients receiving low-dose and high-dose VX‑222 were 86% and 87%, respectively, and no virologic breakthrough was observed. The DAA combina­tion was generally well tolerated. In two independent trials from the USA and Japan, small cohorts of patients with HCV genotype 1 infection who were previous null responders were treated with the protease inhibitor BMS‑650023 in combination with the NS5A inhibitor BMS‑790052 with or without PEG-IFN-α–ribavirin (Figure 1).8,9 In the US study, patients with HCV genotype 1a and 1b infection who received quadruple therapy with PEGIFN-α–ribavirin had a better response than those who received dual DAA combination therapy.8 Treatment failure with the dual therapy was mainly associated with HCV genotype 1a. In the Japanese study, 10 patients, all infected with HCV genotype 1b, who had previously not responded to therapy completed IFN-free DAA combina­tion therapy with BMS‑650023 and BMS‑790052 for 24 weeks.9 HCV RNA was undetectable from treatment week 8, and all patients achieved SVR. In addition, a separate study found that 100% of patients infected with HCV geno­ types 2 or 3 who were treated with the nucleoside inhibitor PSI‑7977 plus ribavirin for 12 weeks achieved an SVR (Figure 1).10 The combination with ribavirin (but not PEG-IFN-α) remained necessary, as relapses occurred with PSI‑7977 monotherapy in four of 10 patients. A new standard of care is now available for patients infected with HCV genotype 1. Furthermore, exciting results from several clinical trials demonstrate that a high proportion of patients can achieve undetectable levels of HCV RNA during therapy with an all-oral IFN-free combination of

DAAs. Treatment failure of IFN-free DAA combina­tions is associated with host factors, virus factors and the barrier to resistance of different compounds and substance classes. In this context, the future role of host-­ targeting antiviral agents such as alis­porivir (cyclophilin inhibitor) and miravirsen (miR‑122 inhibitor) must be explored. The development of a pan-genotypic and an all-oral regimen for patients with chronic hepatitis C is rapid and promising. POLIKUM Friedenau Berlin, POLIKUM MVZ GmbH, Rubensstraβe 119, 12157 Berlin, Germany (W. P. Hofmann). Medizinische Klinik 1, Klinikum der Johann Wolfgang GoetheUniversität, Theodor Stern-Kai 7, Frankfurt am Main 60590, Germany (S. Zeuzem). Correspondence to: S. Zeuzem zeuzem@em.uni-frankfurt.de Competing interests W. P. Hofmann declares associations with the following companies: Bristol-Meyers Squibb, Gilead, Roche, MSD and Janssen Cilag. S. Zeuzem declares associations with the following companies: Abbott, Achillion, Boehringer Ingelheim, Bristol-Meyers Squib, Gilead, iTherX, Merck, Pharmasset, Roche, Santaris, Tibotec and Vertex. See the article online for full details of the relationships. 1.

Poordad, F. et al. Boceprevir for untreated chronic HCV genotype 1 infection. N. Engl. J. Med. 364, 1195–1206 (2011). 2. Jacobson, I. M. et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N. Engl. J. Med. 364, 2405–2416 (2011). 3. Bacon, B. et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N. Engl. J. Med. 364, 1207–1217 (2011). 4. Zeuzem, S. et al. Telaprevir for retreatment of HCV infection. N. Engl. J. Med. 364, 2417–2428 (2011). 5. Zeuzem, S. et al. Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection. Gastroenterology 141, 2047–2055 (2011). 6. Zeuzem, S. et al. The protease inhibitor GS‑9256 and non-nucleoside polymerase inhibitor tegobuvir alone, with RBV or peginterferon plus RBV in hepatitis C. Hepatology http:// dx.doi.org/10.1002/hep.24744. 7. Di Bisceglie, A. et al. VX‑222 with TVR alone or in combination with peginterferon alfa2a and ribavirin in treatment-naive patients with chronic hepatitis C: ZENITH study interim results [abstract]. J. Hepatol. 54, S540 (2011). 8. Lok, A. S. et al. Quadruple therapy with BMS‑790052, BMS‑650032 and PEG-IFN/RBV for 24 weeks results in 100% SVR12 in HCV genotype 1 null responders [abstract]. J. Hepatol. 54, S536 (2011). 9. Chayama, K. et al. Dual oral combination therapy with the NS5A inhibitor BMS‑790052 and the NS3 protease inhibitor BMS‑650032 achieved 90% sustained virologic response (SVR12) in HCV genotype 1b-infected null responder [LB-4]. Hepatology 54 (Suppl. 1), 100A (2011). 10. Gane, E. et al. Once daily PSI‑7977 plus RBV: pegylated interferon-ALFA not required for complete rapid viral response in treatment-naive patients with HCV GT2 or GT3 [abstract 34]. Hepatology 54 (Suppl. 1), 377A (2011).

www.nature.com/reviews


GASTROENTEROLOGY & HEPATOLOGY HEPATOCELLULAR CARCINOMA IN 2011

Key advances

Genomics in hepatocellular carcinoma—a big step forward

■■ Next-generation high-throughput sequencing has enabled the comprehensive description of genomic alterations throughout the genome at extremely high resolution; the first report using this technology in hepatocellular carcinoma (HCC) from an individual with chronic hepatitis C revealed previously uncharacterized mutation patterns, intra-chromosomal rearrangements and genetic heterogeneity within the tumor4 ■■ The first application of genome-wide association studies to HCV-related HCC has identified new susceptibility loci6,7

Ryosuke Tateishi and Masao Omata

Despite enthusiastic efforts using the latest advanced molecular technologies, no specific universal genetic alteration has been found in hepatocellular carcinoma (HCC). The application of whole-genome sequencing using next-generation sequencing technologies is starting to clarify the intraindividual and intratumoral diversity in genomic alterations in HCC. A new sequencing era in HCC has begun. Tateishi, R. & Omata, M. Nat. Rev. Gastroenterol. Hepatol. 9, 69–70 (2012); published online 10 January 2012; doi:10.1038/nrgastro.2011.255

Primary liver cancer is the fifth most frequently diagnosed cancer worldwide in men and the seventh in women.1 Hepatocellular carcinoma (HCC) is the predominant histological type, accounting for 70–85% of total liver cancers.1 Globally, chronic HBV infection is the most prevalent cause of HCC, followed by chronic HCV infection. Although HCC is a typical example of a virus-related cancer, it is also strongly associated with certain lifestyle factors. Chronic alcoholism is a classic risk factor; obesity is also recognized to strongly affect HCC development compared with other malignancies.2 In either case (virus-related or lifestyle factors), it is assumed that accumulated DNA damage, caused by long-standing necroinflammation and regeneration, has a major role in the process of hepatocarcinogenesis. Despite enthusiastic efforts using the latest advanced molecular technologies, no specific universal genetic alteration has been found in HCC. However, the success of sorafenib, a multikinase inhibitor of Raf‑1 and B‑Raf, has provided proof that molecularly targeted agents have a role in the treatment of HCC.3 An understanding of the comprehensive picture of mol­ecular alterations in HCC is now profoundly needed (Figure 1). The International Cancer Genome Consortium (ICGC) is an international project aiming to obtain a comprehensive description of genomic, transcriptomic and epigenomic changes in 50 different tumor types and/or subtypes that are of clinical and societal importance across the globe. Japanese and French researchers are investigating virus-related and virusunrelated HCC, respectively. A study by Totoki et al.4 is the first report in HCC as part of this project. The authors sequenced HCV-related HCC and lymphocytes from KEY ADVANCES IN MEDICINE

alleles harbored this substitution, which demonstrates the variability of genetic alterations among cancer cells. Li et al.,5 in the USA, also used wholeexome sequencing to determine the sequences of approximately 18,000 proteincoding genes in the cancers and normal tissues of ten individuals with HCV-related HCC. They identified 689 potential somatic mutations, including 429 non­synonymous somatic mutations in 411 genes. Five genes that were found to be mutated in more than one tumor (CTNNB1 in four tumors, TP53 in three tumors and ARID2, DMXL1 and NLP1 in two tumors each) were selected for further analysis. Li et al.5 investigated the coding exons of these five genes in 23 additional HCV-related HCCs, which revealed that CTNNB1, TP53, ARID2, DMXL1 and NLRP1 were mutated in eight (24.2%), four (12.1%), six (18.2%), two (6.1%) and two (6.1%) of the total 33 HCCs, respectively. Among these genes, the authors identified ARID2 as a novel tumor suppressor gene in

a Japanese male using massively parallel sequencing. By comparing tumor and nontumor sequences, they identified 11,731 somatic mutations in the tumor. The prevalence of somatic substitutions was substantially less in the genic (intronic, noncoding exon and coding exon) regions relative to the intergenic regions, which suggests that negative selection of lethal mutations or repair of transcribed regions occurs. Totoki et al.4 also detected 90 somatic substitutions and seven small somatic insertions and deletions in protein-coding regions, including in two well-known tumor suppressor genes for HCC (TP53 and AXIN1). They found somatic alterations in five genes that have previously been reported in other cancers but were unknown in HCC. Whole-exome sequencing revealed 47 somatic substitutions. Among the validated substitutions, a nonsense substitution in TSC1 was not detected by whole-genome sequencing as only 13.2% of the tumor

X 21

Y

Outer ring: chromosome ideograms

1

22 2

20 19

Somatic mutations in coding regions Blue: substitution Red: small deletion Orange: small insertion

18 3

17 16

4

15

14 5

Copy number changes Red: copy number loss Green: copy number gain

13 12

6 11

7 10

9

8

Inner circle: chromosomal rearrangements Green: inversion Red: deletion Purple: translocation

Figure 1 | Whole-genome view of somatically acquired alterations in the liver cancer genome. Permission obtained from Nature Publishing Group © Totoki et al. Nat. Genet. 43, 464–469 (2011).

JANUARY 2012  |  S35


GASTROENTEROLOGY & HEPATOLOGY HCC, as mutations were found throughout the coding region of this gene, all of which were predicted to inactivate protein function. They evaluated the prevalence of ARID2 mutations in 106 additional HCC samples of other etiology; the results revealed that ARID2 mutations were more common in HCV-related HCC (14%) compared with HBV-related HCC (2.0%). In addition, the prevalence of TP53 mutations was significantly higher in HCC of individuals from China than those from the USA and Europe. These findings could be another proof of principle that etiological background and mutation profiles are mutually correlated. In 2011, two genome-wide association studies (GWASs) by Japanese investigators reported on genetic susceptibility to HCVrelated HCC. Kumar et al. 6 performed a GWAS using 432,703 autosomal single nucleotide polymorphisms (SNPs) in 721 individuals with HCV-related HCC and 2,890 HCV-negative controls of Japanese origin. The validation study in 673 patients with HCC and 2,596 controls using eight candidate SNPs identified a locus in the 5' flanking region (rs2596542) of the gene encoding major histocompatibility complex class I polypeptide-related sequence A (MICA) protein as strongly associated with HCV-related HCC (odds ratio 1.39). MICA is a membrane protein that activates natural killer cells and CD8 + T cells by acting as a ligand for NKG2D. The risk allele of rs2596542 was associated with low levels of soluble MICA, which were shown to be proportional to levels of membranebound MICA, which suggests that MICA potentially has a suppressive role in HCV infection (and thus progression to HCC). Miki et al.7 applied the same technique in 212 individuals with HCV-related HCC and 765 individuals with chronic HCV without HCC. The validation study in 710 cases and 1,625 controls identified one intronic SNP in the DEPDC5 gene as associated with susceptibility to HCV-related HCC (odds ratio 1.75). Carcinogenesis is basically a collapse in a biological system caused by the random accumulation of genomic, transcriptomic and epigenomic alterations. Using highthroughput sequencing, Totoki et  al. 4 found more than 10,000 mutations in the HCC tumor, which suggests that many of these are meaningless passenger mutations. To find a major player or a driver mutation, whole-genome sequencing in large sample sets is needed; the ICGC S36  |  JANUARY 2012



intend sample sets of 500 (in fact the study group updated its whole-genome data on 27 HCCs as of July 2011).8 Increasing the number of sample sets will contribute not only to finding common genetic alterations among indivi­duals but also to the establishment of molecular classifications of cancers. GWASs are an undoubtedly powerful tool for elucidating genetic susceptibility to cancer development. However, the odds ratios in both of the studies described here were less than two. Given that clinical risk factors for HCC are well established by past epidemiological studies (for example, it is widely recognized that males are at least two times more susceptible to HCC than females), genetic risk factors revealed by GWASs should yield odds ratios much higher than two in order to influence daily clinical practice. Thus, the 1000 Genomes Project,9 which intends to develop a catalog of common human genetic variants with a frequency of ≥1% by using next-generation sequencing technologies, could have an important role. Despite difficulties in handling large amounts of data, next-generation sequencing technologies will lead to revolutionary change in biomedical research. We have reason to be optimistic; if the major problems are associated with limited computing resources, according to Moore’s law (that is, the number of transistors on a chip doubles approximately every 2 years), these resources are likely to progress rapidly. A new sequencing era in HCC has begun.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7‑3‑1 Hongo, Bunkyo-ku, Tokyo 113‑8655, Japan (R. Tateishi). Yamanashi Prefectural Hospital Organization, 1‑1‑1, Fujimi, Kofu-shi, Yamanashi-ken 400‑8506, Japan (M. Omata). Correspondence to: M. Omata momata-tky@umin.ac.jp Acknowledgements The authors appreciate the advice given by Dr Yoshinari Asaoka in preparing the manuscript. Competing interests The authors declare no competing interests. 1. 2.

3.

4.

5.

6.

7.

8.

9.

Jemal, A. et al. Global cancer statistics. CA Cancer J. Clin. 61, 69–90 (2011). Calle, E. E., Rodriguez, C., Walker-Thurmond, K. & Thun, M. J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults. N. Engl. J. Med. 348, 1625–1638 (2003). Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008). Totoki, Y. et al. High-resolution characterization of a hepatocellular carcinoma genome. Nat. Genet. 43, 464–469 (2011). Li, M. et al. Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat. Genet. 43, 828–829 (2011). Kumar, V. et al. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat. Genet. 43, 455–458 (2011). Miki, D. et al. Variation in the DEPDC5 locus is associated with progression to hepatocellular carcinoma in chronic hepatitis C virus carriers. Nat. Genet. 43, 797–800 (2011). International Cancer Genome Consortium. Dataset Summary. International Cancer Genome Consortium [online], http:// dcc.icgc.org/pages/summary/ (2011). 1000 Genomes. About the 1000 Genomes Project. 1000 Genomes [online], http://1000genomes.org/page.php (2011).

IBD IN 2011

Advances in IBD management —towards a tailored approach Guillaume P. Pineton de Chambrun and William J. Sandborn

Important advances have been made in the management of IBD in 2011. Research has focused on optimizing the currently available therapies and taking a more tailored approach to each individual patient. Pineton de Chambrun, G. P. & Sandborn, W. J. Nat. Rev. Gastroenterol. Hepatol. 9, 70–72 (2012); published online 10 January 2012; doi:10.1038/nrgastro.2011.248

During the past decade, large genome-wide association studies in patients with Crohn’s disease or ulcerative colitis have brought new insights into IBD patho­g enesis. 1 Despite this improved understanding of the underlying mechanisms regulating mucosal inflammation, most of the newly developed

targeted therapies for IBD are yet to reach clinical practice. Anti-tumor necrosis factor (TNF) agents, immuno­suppressive drugs (thiopurines and methotrexate), steroids and mesalazine remain the only thera­ peutic options for patients with IBD. A large part of IBD clinical research in 2011 was www.nature.com/reviews


GASTROENTEROLOGY & HEPATOLOGY focused on the optimization of currently available therapies. One important advance in 2011 was an extension of the indications for currently available IBD drugs. Three anti-TNF agents are presently available for Crohn’s disease— infliximab, adalimumab and certolizumab pegol (only approved in the USA)—whereas infliximab is the only approved agent for ulcerative colitis.2 A 2011 phase III trial3 evaluated the efficacy of two adalimumab dosing regimens in patients with moderateto-severe ulcerative colitis. Patients (n = 390) were randomly assigned to receive one of two adalimumab induction protocols: ADA160/80 (adalimumab subcutaneously 160 mg at week 0, 80 mg at week 2 and 40 mg at week 4 and 6); and ADA80/40 (adalimumab subcutaneously 80 mg at week 0, 40 mg at weeks 2, 4 and 6) or placebo. At week 8, the rates of clinical remission were 18.5% and 10% in patients treated with ADA160/80 and ADA80/40, compared with 9.2% in those on placebo. In the subgroup analysis, increased baseline C‑reactive protein concentrations and body weight were associated with reduced remission rates at week 8 (especially in the ADA160/80 group), indicating that some patients might require a higher dose of adalimumab to induce remission. These data provide the basis for extension of adalimumab to ulcerative colitis, and raises the possibility that treatment optimization (potentially through therapeutic drug monitoring) could further increase drug efficacy. In this context, new research should be undertaken to tailor IBD treatment to each individual. Research addressing the selection of patients and drugs based on predefined and validated criteria that predict treatment efficacy and the need for treatment intensification or even treatment discontinuation are required to further improve the outcome of patients with IBD. Among potential criteria useful for treatment decision-­making, complete mucosal healing has emerged as an important surrogate marker of ‘deep remission’ in IBD and evidence is accumulating that mucosal healing can alter the course of the disease when achieved.4 Indeed, anti-TNF agents can induce and maintain mucosal healing in patients with IBD, and mucosal healing was associated with longer clinical remission and fewer disease-related hospitalizations in patients with Crohn’s disease treated with infliximab.4 In 2011, data from the ACT‑1 and ACT‑2 studies demonstrated the importance of mucosal KEY ADVANCES IN MEDICINE

Key advances ■■ Adalimumab, a fully humanized recombinant monoclonal antibody against tumor necrosis factor, is effective for induction of remission in patients with moderate-to-severe active ulcerative colitis3 ■■ Early achievement of mucosal healing in patients with ulcerative colitis treated with infliximab decreases the risk of colectomy during follow-up5 ■■ Switching to adalimumab for reasons of convenience or cost in patients with Crohn’s disease in clinical remission on maintenance therapy with infliximab is not advised7 ■■ In Crohn’s disease, discontinuing infliximab in those in remission on combination therapy (infliximab and thiopurines) might be possible in selected patients, but cannot as yet be recommended in clinical practice8 ■■ Thiopurines do not increase the risk of complications during pregnancy in women with IBD10

healing as a therapeutic goal in patients with ulcerative colitis.5 Patients with refractory, moderate-­to-severe active disease (n = 364 in each study) received intravenous placebo, inflix­imab 5 mg/kg or infliximab 10 mg/kg at weeks 0, 2 and 6 and then every 8 weeks until week 46 in ACT‑1 and week 22 in ACT‑2. The 2011 re-analysis of previously published data showed that infliximabtreated patients with mucosal healing at week 8 after treatment were less likely to progress to colectomy during the first year of follow-up.5 Thus, early evaluation of a ‘hard’ end point such as mucosal healing during the treatment induction phase could be useful to determine which patients need treatment intensification, and to decrease disease-related complica­tions. The optimal strategy for inducing and maintaining remission for 1 year in Crohn’s disease is combination therapy with antiTNF agents and thiopurines. 6 For those in clinical remission on anti-TNF maintenance therapy, a number of questions exist regarding switching between or discontinuing these agents. In Crohn’s disease, both inflix­imab and adalimumab are more effective than placebo for the maintenance of clinical remission, 7 but prospective trials directly comparing the efficacy of infliximab and adalimumab are lacking. Although switching between these two agents is effective in patients with Crohn’s disease who previously responded to one agent and then lost response, switching in

patients in clinical remission has not been studied. Because adalimumab can be selfadministered, patients and physicians might wish to consider switching from infliximab to adalimumab for convenience or costs. The clinical outcome of electively switching from infliximab to adalimumab in patients with Crohn’s disease who were in clinical remission on infliximab maintenance therapy was investigated in a 2011 prospective trial.7 Patients (n = 73) treated with a stable infliximab regimen (infusion intervals at least every 6 weeks) for the past 6 months were randomly assigned to continue infliximab (5 mg/kg intravenously) at the same interval or to switch to adali­ mumab (80 mg subcutaneously at inclusion, then 40 mg every other week). At 1 year, discontinuation of treatment was observed in 10 of 36 (six due to intolerance, four due to loss of efficacy) patients in the adalimumab group and one patient in the infliximab group. Moreover, markedly more patients preferred subcutaneous adalimumab over intravenous infliximab. Nevertheless, within 1 year, almost one in three patients who switched to adalimumab returned to infliximab therapy to control Crohn’s disease. On the basis of this inferior clinical outcome, switching should be reserved only for those with loss of response or intolerance. Another important issue is whether, and when, to stop treatment with antiTNF agents in patients on maintenance therapy who have long-standing remission. Indeed, patients and physicians might wish to consider discontinuation of treatment for a variety of reasons—concerns about long-term safety, perceived risk during pregnancy and costs. A 2011 prospective study 8 investigated the risk of relapse after withdrawal of infliximab in patients with Crohn’s disease (n = 125 on infliximab and anti­metabolite combination therapy) in long-standing remission. Overall, 52 relapses occurred in 115 patients who stopped inflix­i mab and continued anti­ metabolites, with an estimated risk of relapse over 1 year and 2 years of 43.9% and 52.2%, respectively. Factors associated with low risk of relapse were identified, most corresponding to surrogate markers of intestinal inflammation (Box 1). Re-treatment of relapsing patients with inflix­imab was generally effective and well tolerated when evaluated just before the third infusion. Notably, about one-half of selected patients who stopped infliximab—those receiving combination therapy for at least JANUARY 2012  |  S37


GASTROENTEROLOGY & HEPATOLOGY Box 1 | Relapse in Crohn’s disease* Risk factors ■■ Corticosteroid use 6–12 months before infliximab discontinuation ■■ No previous surgical resection ■■ Male sex ■■ Hemoglobin level ≤145 g/l ■■ Leukocyte count >6 × 109 per l ■■ CDEIS >0 ■■ hsCRP level ≥5 mg/l ■■ Infliximab trough level ≥2 mg/l ■■ Fecal calprotectin level ≥300 μg/g Clinical relapse rates‡ ■■ <4 risk factors: <20% ■■ 4 risk factors: ≈40% ■■ 5–6 risk factors: ≈80% ■■ >6 risk factors: 100% *Factors associated with time to relapse in patients with Crohn’s disease in clinical remission on maintenance infliximab therapy and antimetabolites who stopped infliximab.8 ‡ Number of risk factors before infliximab discontinuation. Abbreviations: CDEIS, Crohn’s disease endoscopic index of severity; hsCRP, high-sensitivity C-reactive protein.

1 year and in corticoid-free clinical remission—experienced a clinical relapse within 1 year. By comparison, such patients would be expected to have ~10% relapse rate over 1 year with continued stable combination therapy. Overall, the risk of relapse is high after discontinuing anti-TNF therapy and, at the individual patient level, the ability to predict sustained remission after withdrawal of anti-TNF therapy is limited. These data should help the design of future clinical trials, but should not be used as a basis for changing clinical practice at present. One reason for the interest in discontinuing anti-TNF therapy relates to their long-term safety. Similar concerns exist for thiopurines, the alternative long-term therapy for patients with IBD. In 2009, results from the French CESAME cohort 9 demonstrated that patients receiving thiopurines for IBD have a fivefold increased risk of developing lymphoproliferative disorders; the absolute risk of developing lymphoproliferative disorders was largely limited to older patients (>65 years), with thiopurines fairly safe in younger patients (<50 years). Thus, selection of patients and treatment type should include criteria that predict drug safety. In particular, the use of thiopurines during pregnancy is still controversial. In 2011, a nested study 10 in the CESAME cohort (19,486 patients with IBD total; 11,006 women) investigated the safety of thiopurines during pregnancy. Of 215 pregnancies reported in 204 women, no differences were observed between the S38  |  JANUARY 2012



patient groups—those on thiopurines, other IBD drugs or no medication—in terms of the risk of pregnancy failure, prematurity, low birth weight or intrauterine growth retardation. Although further epidemio­ logical studies are needed to evaluate the frequency of low event rates (such as fetal malformations), use of thiopurines in women with IBD who wish to become pregnant seems to be generally safe and should not be discouraged. Development of new promising mol­ ecules (for example, ustekinumab or vedolizumab) is ongoing and the results of large therapeutic clinical trials are expected soon. However, currently, tailoring available thera­pies to each patient’s needs might be the best opportunity to improve the treatment outcomes in IBD and is a key message of the 2011 findings. Inserm U995, Université Lille Nord de France, Lille F‑59000, France (G. P. Pineton de Chambrun). Division of Gastroenterology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093‑0956, USA (W. J. Sandborn). Correspondence to: W. J. Sandborn wsandborn@ucsd.edu Competing interests W. J. Sandborn declares associations with the following companies: Abbott, Janssen, Merck. See the article online for full details of the relationships. G. P. Pineton de Chambrun declares no competing interests.

1.

Barrett, J. C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat. Genet. 40, 955–962 (2008). 2. Rutgeerts, P. et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 353, 2462–2476 (2005). 3. Reinisch, W. et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut 60, 780–787 (2011). 4. Pineton de Chambrun, G., Peyrin-Biroulet, L., Lemann, M. & Colombel, J. F. Clinical implications of mucosal healing for the management of IBD. Nat. Rev. Gastroenterol. Hepatol. 7, 15–29 (2010). 5. Colombel, J. F. et al. Early mucosal healing with infliximab is associated with improved longterm clinical outcomes in ulcerative colitis. Gastroenterology 141, 1194–1201 (2011). 6. Colombel, J. F. et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N. Engl. J. Med. 362, 1383–1395 (2010). 7. Van Assche, G. et al. Switch to adalimumab in patients with Crohn’s disease controlled by maintenance infliximab: prospective randomised SWITCH trial. Gut http:// dx.doi.org/gutjnl‑2011‑300755. 8. Louis, E. et al. Maintenance of remission among patients with Crohn’s disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology http://dx/ doi.org/10.1053/j.gastro.2011.09.034. 9. Beaugerie, L. et al. Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet 374, 1617–1625 (2009). 10. Coelho, J. et al. Pregnancy outcome in patients with inflammatory bowel disease treated with thiopurines: cohort from the CESAME Study. Gut 60, 198–203 (2011).

THE GUT MICROBIOTA IN 2011

Translating the microbiota to medicine Fergus Shanahan

Interest in the gut microbiota has escalated with growing appreciation of the role of indigenous microbes in the health of the host and in the pathogenesis of several intestinal and extraintestinal disorders. The microbiota has become a plausible target for drug and dietary therapy and a repository from which bioactive agents or new drugs can be mined. Shanahan, F. Nat. Rev. Gastroenterol. Hepatol. 9, 72–74 (2012); published online 20 December 2011; doi:10.1038/nrgastro.2011.250

The commensal microbiota is one of the hottest areas in medicine, with converging interests from diverse disciplines including nutrition and food science, micro­biology, gastroenterology, immunology and metabolic medicine. Microbial signaling is required for the development and maintenance of digestive, immunologic and neurobiologic

functions within the host. Therefore, it can be anticipated that the list of disorders within and outside the gut involving some disturbance of host–microbe interactions will increase. Several high impact publications attest to the scope and richness of human micro­biome explora­tion, a representative sample of which from 2011 is addressed here. www.nature.com/reviews


GASTROENTEROLOGY & HEPATOLOGY Microbes account for 10-fold more cells and 100-fold more genes than those of their human host. The information encoded in the microbiome supplements that of the human genome by provision of trophic, metabolic and protective signals to the host. Although metagenomic sequencing has shown a predominance of two major families or phyla in the human gut in roughly equal proportions (Firmicutes and Bacteroidetes), a report on over 20 newly sequenced metagenomes from four countries, in combination with previous data, demonstrated that variation of the micro­ biota at the species level is not continuous and tends to congregate within distinct clusters or enterotypes. 1 These enterotypes are identifiable by their enrichment in Bacterioides (enterotype 1), Prevotella (enterotype 2) or Ruminococcus (enterotype 3) and are known to be unrelated to nationality or host characteristics such as BMI, age or gender, although their diag­ nostic potential remains to be explored. Diet seems to be the main lifestyle or environ­m ental modifier of the microbiota, and it is noteworthy that although short-term dietary interventions have a rapid influence on microbial composition in the gut, only long-term diets are associated with the microbial enterotypes. For example, dietary protein and animal fat favors Bacteroides, whereas carbohydrates seem to favor Prevotella.2 The relationship between diet, microbes and the metabolic health of the host, including the risk of obesity and diabetes, continues to generate intriguing information.3 The translation of this information to clinical medicine took a step forward in 2011 with the discovery of a direct link between the gut microbiota and the risk of athero­ sclerosis caused by microbial-­dependent metabolism of dietary phospholipids and the generation of pro-atherosclerotic metabolites. 4 Three metabolites of the dietary lipid phosphatidylcholine were identified by a metabolomics approach to predict the risk of cardiovascular disease. The participation of the microbiota in the generation of the metabolites is obligate and suggests that a pro­biotic or other form of dietary manipulation may have prophy­lactic potential against heart disease. Although the microbiota shapes intestinal immunity and the metabolic welfare of the host, host–microbe interactions are bidirectional. The mucosal immune system influences the composition and pro­inflammatory potential of the gut KEY ADVANCES IN MEDICINE

Diet Antibiotics Hygiene Urbanization Family size

Mucosal immunity

1013 human cells

Trophic, metabolic and protective signals

1014 microbial cells

Disease risk Cardiovascular Metabolic Inflammatory Other

+

Metabolome

Repository of bioactive agents (e.g. antimicrobial, anti-inflammatory, metabolic)

Figure 1 | Clinical importance of the gut microbiota. The human metabolome is the composite product of the human genome and the microbiome, the latter providing trophic, metabolic and protective signals to the host that are crucial for development and homeostasis. Host–microbe signaling is bidirectional; in susceptible individuals, aberrant host–microbe interactions represent a risk factor for disease. Several aspects of a modern lifestyle influence the composition of the microbiota, with the most important being diet. Microbe–host signaling, as well as microbe–microbe signaling, within the gut represents a rich repository from which bioactive agents for drug discovery can be mined.

microbiota, and disturb­a nces of innate immunity have been linked with aberrant expansion of components of the microbiota that have been associated with risk of inflammatory and metabolic disease. For example, mice lacking Toll-like receptor (TLR) 5 develop obesity and metabolic syndrome, which seems to be dependent on alterations in the microbiota.5 Other models of defective innate immunity have been associated with the emergence of a ‘colitogenic’ microbiota with the capacity to transfer colitis to normal recipients and, in one report, Koch’s postulates were fulfilled in a host-genotype-specific way.6 The regulatory mechanisms used by the host to maintain compositional equilibrium within the microbiota are uncertain, but a newly identified molecular pathway highlights the pivotal role of intestinal epithelial cells.7 The epithelium contributes to both afferent and efferent limbs of the mucosal immune response by detecting microbeassociated molecular patterns (MAMPs), using surface receptors and intra­cellular sensors, and by responding to danger signals with the production of bacteriocides, cytokines or chemokines. Intracellular inflammasomes are multiprotein complexes comprised, in part, of nod-like receptors (NLRs), such as NLRP6, and they sense endogenous and exogenous stress or damage-associated molecular patterns. In response to pathogenic components of the commensal microbiota, the intestinal

epithelium mobilizes the NLRP6 inflamma­ some, triggering a cascade of events that includes activation of caspase 1, maturation of IL‑18, recruitment of γ‑interferonproducing natural killer cells and T cells and enhanced bactericidal activity of local macrophages. When NLRP6 is deficient, the epithelium fails to respond appropriately to pathogens and the composition of the commensal bacteria may become colito­ genic. This provokes epithelial production Key advances ■■ The diversity of species within the gut microbiota is organized into identifiable clusters or enterotypes that are correlated with long-term but not short-term dietary patterns1,2 ■■ A direct link between the intestinal microbiota, dietary phosphatidylcholine and risk of atherosclerosis has been identified4 ■■ Mechanisms by which the host distinguishes harmless commensals from pathogens are uncertain, but a molecular cascade within enteric epithelial cells (triggered by the NLRP6 inflammasome) could have a role in maintaining a balanced composition within the microbiota7 ■■ The metabolic diversity within the microbiota represents a repository from which bioactive agents can be mined, as shown with the discovery of an antimicrobial bacteriocin with specific activity against Clostridium difficile10

JANUARY 2012  |  S39


GASTROENTEROLOGY & HEPATOLOGY of the CCL5 chemokine, which recruits neutrophils and manifests as IBD.7 The identity of the activating trigger for the NLRP6 inflammasome in epithelial cells is unknown. The trigger might be a damageinduced molecular pattern, which is one mechanism by which the host could distinguish harmless commensals from pathogens, both of which express similar molecular patterns as ligands for TLRs. However, in some instances, the pathogen and commensal dichotomy might simply relate to the context of their encounter with the immune system. Thus, a commensal in the wrong place will be treated as a pathogen; likewise, the handling of commensals in certain genetically susceptible individuals might be similar to that of pathogens. Another explanation for immunologic discrimination between pathogens and commensals could involve recognition of symbiotic bacterial molecules in a process that favors colonization with commensals.8 An immunomodulatory polysaccharide produced by the prominent gut commensal, Bacteroides fragilis, has been reported to suppress T H17 effector cells by signaling through TLR2 on regulatory T cells, thereby enabling the commensal to avoid an adverse immune response and successfully colonize the host. The response to polysaccharide is distinct from that seen with other TLR2 ligands that promote clearance of pathogens. The immunomodulatory properties of polysaccharide also have efficacy in an animal model of IBD, confirming the potential for mining the microbiota for drug discovery (Figure 1). Other examples of bacterial-derived metabolites with therapeutic potential include the production of a soluble protein ligand for the epidermal growth factor receptor by Lactobacillus rhamnosus GG (which attenuates intestinal inflammation by inhibiting cytokine-induced apoptosis in intestinal epithelial cells), and the discovery of an antimicrobial agent with narrow-­ spectrum activity against Clostridium difficile.9,10 The latter was uncovered by an extensive screen of fecal colonies for antimicrobial producers and resulted in the identification of a strain of B. thuringiensis that produces a heterodimeric bacteriocin, thuricin CD, which has potent activity against C. difficile. Using a distal colon model, thuricin CD was shown to be as effective as vancomycin and metronid­azole but exhibited a narrower spectrum of activity without causing ‘collateral damage’ to the dominant phyla within the surrounding commensal microbiota. S40  |  JANUARY 2012



What can we expect from this field in the immediate future? Microbial enterotypes are likely to be refined and correlated with human genotypes with respect to disease risk, and longitudinal studies will shed light on the impact of lifestyle variables over time. However, as molecular profiling continues apace, studies of the microbiota should be complemented with a return to culturebased in vitro studies to fulfil the promise of mining the microbiota and to understand the molecular basis of host–microbe interactions in health and disease. Department of Medicine, Clinical Sciences Building, Cork University Hospital, Wilton, Cork, Ireland. f.shanahan@ucc.ie Acknowledgments F. Shanahan is supported, in part, by Science Foundation Ireland. Competing interests The author declares associations with the following companies: Alimentary Health Ltd, GlaxoSmithKline, Procter & Gamble. See the article online for full details of the relationships. 1.

Arumugam, M. et al. Enterotypes of the human gut microbiome. Nature 473, 174–180 (2011).

2.

Wu, G. U. et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 334, 105–108 (2011). 3. Shanahan, F. & Murphy, E. The hybrid science of diet, microbes, and metabolic health. Am. J. Clin. Nutr. 94, 1–2 (2011). 4. Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011). 5. Vijay-Kumar, M. et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328, 228–231 (2010). 6. Bloom, S. M. et al. Commensal Bacteroides species induce colitis in host‑genotype‑specific fashion in a mouse model of inflammatory bowel disease. Cell Host Microbe 9, 390–403 (2011). 7. Elinav, E. et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745–757 (2011). 8. Round, J. L. et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332, 974–977 (2011). 9. Yan, F. et al. Colon-specific delivery of a probiotic-derived soluble protein ameliorates intestinal inflammation in mice through an EGFR-dependent mechanism. J. Clin. Invest. 121, 2242–2253 (2011). 10. Rea, M. C. et al. Effect of broad- and narrowspectrum antimicrobials on Clostridium difficile and microbial diversity in a model of the distal colon. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4639–4644 (2011).

NEUROGASTROENTEROLOGY IN 2011

Emerging concepts in neurogastroenterology and motility Keith A. Sharkey and Gary M. Mawe

Neurogastroenterology encompasses intrinsic and extrinsic neural processes that regulate gut functions, sensation and related behaviors such as ingestion. In 2011, key advances were made in understanding gut–brain interactions, visceral sensation, serotonin signaling, neurogenesis and neuromuscular transmission. Sharkey, K. A. & Mawe, G. M. Nat. Rev. Gastroenterol. Hepatol. 9, 74–76 (2012); published online 13 December 2011; doi:10.1038/nrgastro.2011.247

Neural control of the gastrointestinal tract in both health and disease is a rapidly evolving and intriguing subject area. Key advances have been made on several fronts in neurogastroenterology in 2011. Here, we highlight a breadth of studies that represent major milestones in our understanding of the effect of nutrients and gut microbiota on emotion and food intake; the role of stress in visceral hypersensitivity; the concept that enteric glia can serve as neuronal pre­ cursors; and the roles of serotonin signaling in the gut. In addition, we discuss the identifica­tion of a novel class of cells that

could mediate inhibitory neuromuscular signaling in the gastrointestinal tract. It is becoming increasingly clear that signals arising in the lumen of the gastro­ intestinal tract can lead to changes in emotional state and behaviors such as food intake. The notion that foods with a high fat content are ‘comfort foods’ was substantiated this year by MRI studies demon­strating that intragastric infusion of fatty acid positively enhanced emotional states, decreased hunger scores and increased neural activity in the regions of the brain that process emotions. 1 These findings indicate that www.nature.com/reviews


GASTROENTEROLOGY & HEPATOLOGY luminal nutrients can have acute effects on mood as well as satiety. Evidence indicates that endocannabinoid signaling in the gut regulates fat consumption. Thus, the capacity to regulate fat intake exists within the gut, and this process could, in turn, have an effect on emotional state and long-term energy balance. In addition to nutrients, gut–brain communication can also be influenced by enteric microflora, including resident microbes and ingested probiotics. A recent study has shown that probiotic bacteria influence emotional behavior by modulating the subunits of receptors of the neuro­ transmitter γ-aminobutyric acid, and attenuate anxiety via activation of vagal pathways.2 Probiotic treatment strategies might, therefore, prove to be beneficial in stress-related disorders (such as anxiety and depression), which are common comorbidi­ ties of functional and inflammator y bowel disorders. Although stress is known to potentiate visceral pain and discomfort, a lack of adequate animal models has meant that the mechanisms that underlie this form of visceral hypersensitivity have not been resolved. Advances in the past year have provided insights into peripheral and central mechanisms and have helped to explain how stress exacerbates visceral pain. Following the resolution of infectious colitis in mice, induction of stress resulted in exaggerated peripheral nociceptive signaling—which is analogous to post­infectious IBS.3 The hyperexcitabity of primary afferent neurons in this model is associated with enhanced expression of β-adrenergic and gluco­c orticoid receptors in these cells. Interestingly, the effects of stress are mimicked by agonists of these receptors, thus providing potential new therapeutic targets. In addition to changes in primary afferent neurons, stressinduced activation of astroglial cells in the spinal cord also seems to contribute to visceral hypersensitivity through the modulation of glutaminergic signaling.4 These novel observations highlight the importance of spinal glia and glutamate metabolism in the sensation of pain. Glia in the brain and gut serve a wide array of functions beyond their original definition as the ‘glue’ that holds neurons together. In the gut, these functions are known to include metabolic regulation, neurotransmission and support of barrier integrity. Two independent studies published during the past year provide compelling evidence that enteric glia have the KEY ADVANCES IN MEDICINE

Key advances ■■ Nutrients and bacteria in the lumen of the gut can affect mood and ingestive behavior through vagal pathways1,2 ■■ Peripheral and central mechanisms contribute to stress-induced visceral hypersensitivity3,4 ■■ Enteric glia can give rise to new enteric neurons5,6 ■■ Neuronal serotonin protects the integrity of the enteric nervous system and regulates gastrointestinal motility and inflammation7–9 ■■ Fibroblast-like cells mediate inhibitory purinergic neuromuscular transmission10

potential to give rise to neurons in adult gut or in culture under certain restricted conditions. Laranjeira and colleagues5 used genetic lineage tracing to confirm previous results showing that neurogenesis does not seem to occur in the enteric nervous system under steady state conditions. This observa­t ion was corroborated by Joseph and colleagues6 who used incorporation of a thymidine analogue to investigate cell division. Remarkably, after injury to the myenteric plexus, glia were shown to generate new neurons in vivo.5 However, the conditions under which neurons can be replaced seem to be limited to injury to the plexus. Gliogenesis was observed both in steady-state conditions and in response to injury, but the function of new glial cells remains to be determined. In culture conditions, enteric glia could readily form new neurons, which indicates that endogenous pre­c ursors exist within a patient’s own bowel and could be used for transplantation to replace neurons lost or damaged as a result of idiopathic or acquired enteric neuropathies. Serotonin (5-hydroxytryptamine; 5-HT) in the gastrointestinal tract can trigger motor, secretory and vasodilator reflexes under physiological conditions, and acts as a proinflammatory mediator and stimulator of emesis, pain and discomfort in pathophysiological conditions. Changes in serotonin signaling have been reported in patients with functional gastrointestinal disorders; however, the causative role of serotonin in the symptoms of these conditions is not yet fully established. A report suggests that mucosal serotonin could contribute to visceral pain in these individuals.7 In patients with IBS, spontaneous serotonin release from the mucosa is increased, which correlates with the severity of abdominal pain. Moreover, biopsy supernatants

from these individuals activate discharge of extrinsic afferent fibers in an ex vivo rat preparation, and this response is inhibited by granisetron—an antagonist of the 5-HT3 receptor. The majority of serotonin is synthesized, stored and released by entero­chromaffin cells in the gastrointestinal mucosa; serotonin also serves as an enteric neuro­ transmitter, but the physiological role of enterochromaffin cell and neuronal serotonin signaling has not been fully determined. Li and colleagues8 addressed this issue using mice that lack the genes for tryptophan hydroxylase 1 or 2 (enzymes required for serotonin biosynthesis in enterochromaffin cells and neurons, respectively). Although mice lacking mucosal serotonin did not exhibit a clear phenotype with regard to gut function, mice deficient in neuronal serotonin exhibited lower neuronal density, slower intestinal transit and accelerated gastric emptying when compared with healthy mice. These findings indicate that neuronal serotonin protects the integrity of the enteric nervous system and contributes to normal gastrointestinal motility. Mucosal serotonin can act as a proinflammatory mediator, but Tsuchida et al.9 demonstrated that activation of 5-HT4 receptors on enteric nerve terminals triggers an anti-inflammatory effect. 5-HT4 agonists facilitate acetylcholine release, which, in turn, can dampen proinflammatory cytokine induction via α7 nicotinic receptors on macrophages. This finding suggests that 5-HT4 agonists might, by inhibiting the inflammatory response and promoting propulsive motility, have a bene­ ficial effect in certain conditions, such as postoperative ileus. One of the ongoing controversies in neuro­gastroenterology over the past decade has been the mechanism by which smooth muscle cells receive inhibitory purinergic signals from enteric motor neurons. These signals do not seem to be mediated either directly by smooth muscle or indirectly by interstitial cells of Cajal because mice lacking interstitial cells of Cajal still exhibit purinergic inhibitory junction potentials, and isolated smooth muscle cells exhibit mixed excitatory and inhibitory responses to ATP. Kurahashi and colleagues 10 shed light on this dilemma in a report demonstrating that a novel class of excitable cells (referred to as ‘fibroblast-like cells’), which express platelet-derived growth factor receptor α, exhibit all of the properties necessary to detect and transmit puri­nergic JANUARY 2012  |  S41


GASTROENTEROLOGY & HEPATOLOGY signals from nerve terminals to smooth muscle. These interstitial cells should be investigated for potential contributions to gastrointestinal motor disorders. The gastrointestinal dysfunctions that fit under the umbrella of neurogastro­ enterology represent a considerable burden to society with limited treatment options. Continued efforts, such as those highlighted here, will provide a better understanding of these enigmatic disorders and open new avenues for therapies of the future. Hotchkiss Brain Institute & Snyder Institute of Infection, Immunity and Inflammation, Department of Physiology & Pharmacology, University of Calgary, AB T2N 4N1, Canada (K. A. Sharkey). Department of Anatomy & Neurobiology, University of Vermont, Burlington, VT 05405, USA (G. M. Mawe).

Correspondence to: K. A. Sharkey ksharkey@ucalgary.ca Competing interests The authors declare no competing interests. 1.

2.

3.

4.

Van Oudenhove, L. et al. Fatty acid-induced gutbrain signaling attenuates neural and behavioral effects of sad emotion in humans. J. Clin. Invest. 121, 3094–3099 (2011). Bravo, J. A. et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc. Natl Acad. Sci. USA 108, 16050–16055 (2011). Ibeakanma, C. et al. Brain-gut interactions increase peripheral nociceptive signaling in mice with postinfectious irritable bowel syndrome. Gastroenterology 141, 2098–2108 (2011). Bradesi, S. et al. Role of astrocytes and altered regulation of spinal glutamatergic neurotransmission in stress-induced visceral hyperalgesia in rats. Am. J. Physiol. Gastrointest. Liver Physiol. 301, G580–G589 (2011).

5.

Laranjeira, C. et al. Glial cells in the mouse enteric nervous system can undergo neurogenesis in response to injury. J. Clin. Invest. 121, 3412–3424 (2011). 6. Joseph, N. M. et al. Enteric glia are multipotent in culture but primarily form glia in the adult rodent gut. J. Clin. Invest. 121, 3398–3411 (2011). 7. Cremon, C. et al. Intestinal serotonin release, sensory neuron activation, and abdominal pain in irritable bowel syndrome. Am. J. Gastroenterol. 106, 1290–1298 (2011). 8. Li, Z. et al. Essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons. J. Neurosci. 31, 8998–9009 (2011). 9. Tsuchida, Y. et al. Neuronal stimulation with 5hydroxytryptamine 4 receptor induces antiinflammatory actions via α7nACh receptors on muscularis macrophages associated with postoperative ileus. Gut 60, 638–647 (2011). 10. Kurahashi, M. et al. A functional role for the ‘fibroblast-like cells’ in gastrointestinal smooth muscles. J. Physiol. 589, 697–710 (2011).

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NEPHROLOGY GLOMERULAR DISEASE IN 2011

New clues to environmental influences in glomerular disease Peter J. Nelson and Charles E. Alpers

Research into genetic susceptibilities for proteinuric glomerular diseases has uncovered key pathogenic contributions from inheritable defects in podocytes. However, much less is known about environmental factors that may initiate or propagate podocyte injury. Seminal reports in 2011 provided new mechanistic insights into how this may occur. Nelson, P. J. & Alpers, C. E. Nat. Rev. Nephrol. 8, 65–66 (2012); published online 13 December 2011; doi:10.1038/nrneph.2011.214

Over the past 10 years, numerous high-­ profile studies in forward and reverse genetics have mapped several genetic causes for proteinuric glomerular diseases. 1 Many identified genes encode mutant proteins (for example, nephrin, podocin, or TRPC6) or variant proteins (for example, APOL1 or HLA-DQ) that render podocytes susceptible to injury, highlighting the critical contribution of podocytes to the glomerular filtration barrier (GFB). This research is leading towards prog­n ostic strategies to gauge hereditary risk for disease and response to treatment in protein­uric glomerular diseases. The findings have also, however, exposed the comparatively little attention given to identi­fying environmental factors that unmask genetic susceptibilities. One reason for this imbalance of research in gene–environment interactions in protein­uric glomerular diseases is the lack of validated methods to measure and integrate effects from the environment.2 Unlike genome-wide association studies, there is a lack of techniques for ‘environment-wide’ association studies that can identify and assign hierarchy to complex exposures from diet, the microbiome, xenobiotics, and other potential environmental insults that contribute to podocyte injury. With this deficiency in mind, we briefly review seminal studies in proteinuric glomerular diseases published in 2011 which reported new pathogenic mechanisms that may heighten the focus of research in glomerular disease on the role of the environment. Membranous nephropathy, among the most common causes of nephrotic syndrome in adults, results from the forma­t ion of glomerular subepithelial KEY ADVANCES IN MEDICINE

antibody–antigen immune complexes that injure podocytes. Studies have shown that antibodies to bovine serum albumin (BSA) can induce membranous nephropathy in animals, and exposure to BSA is common in the human diet. Based on these findings, Debiec, Ronco and colleagues hypothesized that antibody–BSA immune complexes cause secondary membranous nephro­pathy in humans.3 The authors found that 11 of 50 patients with idiopathic membranous nephropathy, but only two of 172 controls, harbored high-titer serum antibody that recognized epitopes in BSA not present in human albumin. Seven of the 11 patients with membranous nephropathy, but no controls, also had higher than normal serum levels of BSA, and in four of these patients the cationic BSA colocalized with the BSAspecific antibody in their subepithelial immune complex deposits. Key advances ■■ Bovine serum albumin has been identified as a dietary cause of membranous nephropathy,3 raising the possibility that other dietary antigens may also cause membranous nephropathy ■■ Soluble urokinase-type plasminogen activator receptor is a likely cause of focal segmental glomerulosclerosis that can be induced by lipopolysaccharide,5 and probably by other pathogen-associated molecular patterns, potentially linking podocyte injury to heightened exposure to commensal and non-commensal microbes ■■ Overactivation of the podocyte mammalian target of rapamycin pathway in response to the dysregulated nutrient environment of diabetes may contribute to the development of diabetic nephropathy9

The study by Debiec, Ronco and colleagues is a landmark study in that it identi­fied a circulating exogenous antigenic protein derived from dietary exposure that is deposited in glomerular walls and serves as a ‘planted’ antigen to induce membranous nephro­ pathy. The findings of this study raise the possibility that other dietary antigens may also cause secondary membranous nephropathy. Peripheral tolerance to protect podocytes and the GFB from dietary antigens filtered within the kidney is maintained by the renal mononuclear phagocytic system. 4 This system may not operate when immunogenic dietary antigen is retained at the anionic GFB, such as may occur for cationic BSA, leading to its recognition by antibody and subsequent immune complex formation in situ. Without epidemio­logic or experimental clues, however, the challenge that lies in the untargeted discovery of other dietary antigens in idiopathic membranous nephropathy will be in knowing how best to sample candidates and map them to dietary sources and potentially to other environmental stimuli. Wei, Reiser and colleagues similarly translated knowledge gained through animal studies to discover that soluble urokinase-­ type plasminogen activator receptor (suPAR) is a probable cause of recurrent focal segmental glomerulosclerosis (FSGS).5 The system involving suPAR, urokinase-type plasminogen activator receptor (uPAR) and urokinase-­ type plasminogen activator (uPA) is an innate immune mediator of tissue remodeling during inflammation.6 Wei, Reiser et al. showed that endotoxin (lipopolysaccharide), produced by commensal bacteria in the gut and ubiquitous in the environment,7 caused proteinuria in mice by inducing systemic JANUARY 2012  |  S43


NEPHROLOGY release of suPAR, which crossed the GFB and activated podocyte β3 integrin in both native uPAR+/+ kidneys and transplanted uPAR –/– kidneys. The researchers also found that experi­mentally sustained secretion of suPAR from sites outside the kidney induced FSGS. In addition, they found that serum suPAR level was significantly elevated in patients with primary FSGS (but not in those with minimal-change disease or membranous nephro­pathy) compared with levels in healthy people; among those with FSGS, serum suPAR levels were highest in those who developed recurrent FSGS after transplanta­tion. In patients in whom FSGS recurred, glomerular lesions showed activated podocyte β3 integrin, and suPAR removed from serum by plasma­pheresis correlated with remission of recurrent FSGS. The results of this study provide a major breakthrough in the study of FSGS on several fronts. They identify a long-sought-after circulating factor that is causative of recurrent FSGS, is a potential biomarker for the development of or the risk of development of FSGS, and is a new potential therapeutic target for treating a disease in which current therapies show limited efficacy. Although not emphasized in the article, this study also provides suggestive evidence that FSGS may be an outcome of otherwise ‘clinically silent’ inflammation from environ­mental pathogens. The marked upregulation of suPAR by lipopolysaccharide in mice suggests that chronic, heightened exposure to lipopolysaccharide or other pathogen-associated mol­ecular patterns (PAMPs) derived from commensal or non-commensal microbes might cause elevated suPAR in humans, resulting in FSGS in susceptible individuals.8 If found to be true, this hypothesis could lead to prophylactic strategies that manipulate the microbiome to lessen exposure and secondary damage to podocytes from these PAMPs. Podocytes may also be injured by serving as sensors and not simply by being bystanders of environmental insults. The mammalian target of rapamycin (mTOR) signaling pathways are of great interest at present; sirolimus (also known as rapamycin), a drug that targets these pathways, is clinically useful in immune suppression, as an antiproliferative agent in cardiac stenting, and as a potential therapeutic agent for the treatment of renal cancer and polycystic disease. More recently it has been shown that mTOR pathways control aging in multiple model systems. In 2011, the mTOR pathway in podocytes emerged as a key molecular sensor of the nutrient environment. Godel, Huber S44  |  JANUARY 2012



and colleagues examined gene expression in microdissected glomeruli from human kidneys with early diabetic nephropathy.9 They found marked upregulation of target genes of the mTOR pathway, suggesting that overactivation of this pathway in response to the dys­regulated nutrient environment of diabetes contributes to the development of diabetic nephropathy.9 To test this hypothesis, the authors bred mice haplo­insufficient for mTORC1 in podocytes, thereby curtailing the activity of the mTOR pathway, and then induced experimental diabetic nephro­pathy with streptozotocin. Intriguingly, the mice showed significant amelioration of diabetic nephropathy, clearly demonstrating that podocyte gene–environment interactions can drive the progression of diabetic nephro­ pathy, and also identifying mTOR pathways as a potential thera­peutic target to abrogate the progression of diabetic nephropathy. This selection of studies published in 2011 highlight three seemingly disparate glomerular diseases, each with a different pathogenesis, but which together account for the majority of cases of nephrotic syndrome and end-stage renal disease in adults. Each of these studies has identified new and compelling mechanisms underlying glomerular injury. A common feature of these studies is that each also indicates the importance of under­standing the complex role of the environ­ment in mediating proteinuric glomerular diseases. Although we may continue to hope that gene replacement therapy can eliminate inheritable disease risks, we also need to identify concurrent modifiable

environ­mental factors to protect susceptible patients from developing disease. These studies are signaling the way forward in this quest. Division of Nephrology (P. J. Nelson), Division of Nephrology and Department of Pathology (C. E. Alpers), University of Washington Medical Center, 1959 NE Pacific Street, Seattle, WA 98195, USA. Correspondence to: P. J. Nelson nelsonpj@uw.edu Competing interests The authors declare no competing interests. 1.

2.

3.

4.

5.

6.

7.

8.

9.

Machuca, E., Benoit, G. & Antignac, C. Genetics of nephrotic syndrome: connecting molecular genetics to podocyte physiology. Hum. Mol. Genet. 18, R185–R194 (2009). Renz, H. et al. Gene-environment interactions in chronic inflammatory disease. Nat. Immunol. 12, 273–277 (2011). Debiec, H. et al. Early-childhood membranous nephropathy due to cationic bovine serum albumin. N. Engl. J. Med. 364, 2101–2110 (2011). Nelson, P. J. et al. The renal mononuclear phagocytic system. J. Am. Soc. Nephrol. (in press). Wei, C. et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat. Med. 17, 952–960 (2011). Smith, H. W. & Marshall, C. J. Regulation of cell signalling by uPAR. Nat. Rev. Mol. Cell Biol. 11, 23–36 (2010). Michel, O. Severity of asthma is related to endotoxin in house dust. Am. J. Respir. Crit. Care Med. 154, 1641–1646 (1996). Kau, A. L, Ahern, P. P., Griffin, N. W., Goodman, A. L. & Gordon, J. I. Human nutrition, the gut microbiome and the immune system. Nature 474, 327–336 (2011). Godel, M. et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J. Clin. Invest. 121, 2197–2209 (2011).

POLYCYSTIC KIDNEY DISEASE IN 2011

Connecting the dots toward a polycystic kidney disease therapy Vicente E. Torres and Peter C. Harris

Understanding the complex interactions between the various pathways disrupted in polycystic kidney and liver disease is essential to identify and optimize therapies for these disorders. Studies published in the past year have demonstrated a functional interaction between the main proteins implicated in these diseases and identified novel therapeutic approaches. Torres, V. E. & Harris, P. C. Nat. Rev. Nephrol. 8, 66–68 (2012); published online 13 December 2011; doi:10.1038/nrneph.2011.196

The enlarged kidneys and liver character­istic of polycystic kidney disease (PKD) have for centuries attracted attention. Pathologists in the 19th century debated whether cysts are develop­mental or the result of tubular

obstruction or excessive epithelial cell prolifera­t ion. Microdissection, electron micro­scopy and physiology studies carried out during the 20th century showed that cysts in patients with autosomal dominant PKD www.nature.com/reviews


NEPHROLOGY (ADPKD) detach from renal tubules and grow as blind sacs by a process that requires cell prolifera­tion, net fluid secretion and remodeling of extracellular matrix. After the PKD1 and PKD2 genes and their encoded proteins, polycystin‑1 and polycystin‑2, were identified in 1994 and 1996, respectively, research in this area greatly accelerated. In the following years, genes mutated in autosomal recessive PKD (PKHD1 encoding fibro­cystin) and in autosomal dominant polycystic liver disease (PRKCSH encoding glucosidase 2 subunit β, and SEC63 encoding translocation protein SEC63 homolog) were identified. Polycystin‑1, polycystin‑2 and fibrocystin are membrane glyco­proteins, whereas glucosidase 2 subunit β and SEC63 are endoplasmic reticulum resident proteins needed for translocation and folding of integral membrane proteins and secreted proteins. Polycystin‑1, polycystin‑2 and fibrocystin have numerous interacting partners and their disruption affects multiple signaling pathways. Despite the multi­plicity of genes and signaling pathways involved in PKD, interventions affecting many diverse targets have been effective in animal models of PKD, which indicates the presence of connections between the various pathways. Understanding these complex interactions will be essential to effectively treat PKD. Fedeles et al. used mouse mutants to show that the main proteins implicated in ADPKD, autosomal recessive PKD and autosomal dominant polycystic liver disease functionally interact.1 Loss of gluco­sidase 2 subunit β or SEC63 reduces polycystin‑1 and, to a lesser extent, polycystin‑2 expression, blocks polycystin‑1 trafficking to primary cilia, causes renal and hepatic cysts, worsens cystic disease in hetero­z ygous Pkd1 +/− and Pkd2 +/− mice and induces renal cystogenesis in Pkhd1 del 4/del 4 mice. Transgenic overexpression of poly­cystin‑1, but not polycystin‑­2, rescues the renal and hepatic pheno­type of tissue-­selective Prkcshknockout or Sec63-knockout mice and the renal phenotype of Pkhd1del4/del4 mice. Polycystin‑1 is the rate-limiting component in the polycystin‑1/poly­cystin‑2 complex as its level of expression determines the severity of the cystic pheno­type, but some functional polycystin‑2 is essential for polycystin‑1 to exert this effect. Immunocytochemical analysis revealed that the collecting duct is the segment most susceptible to the cystogenic effect of reduced polycystin‑1 dosage. Proteasome inhibition increases poly­cystin‑1 levels and attenuates cystic disease in Prkcshknockout models, thus offering a conceptual KEY ADVANCES IN MEDICINE

Key advances ■■ The main proteins implicated in polycystic kidney disease (PKD)—polycystin‑1, polycystin‑2 and fibrocystin—and in autosomal dominant polycystic liver disease (glucosidase 2 subunit β and SEC63) functionally interact1 ■■ The vasopressin V2 receptor antagonist, tolvaptan, inhibits cystogenesis in vitro,2 and reduced the volume of polycystic kidneys after 1 week of treatment, and slowed the growth of polycystic kidneys in a 3‑year, open-label study of patients with PKD3 ■■ Two insulin-sensitizing drugs used to treat type 2 diabetes mellitus, metformin and a peroxisome proliferator-activated receptor‑γ agonist, inhibit cyst growth in rodent models of PKD by different and possibly complementary mechanisms4–6 ■■ Macrophage infiltration contributes to the proliferation of cyst-lining cells and PKD progression7 ■■ STAT3, a transcription factor that is essential during development but dispensable postnatally, is a novel therapeutic target in PKD8–10

therapeutic approach to auto­somal dominant polycystic liver disease and possibly ADPKD. The central role of cyclic AMP in PKD, and the ability to hormonally modulate cyclic AMP in a cell-specific manner, enables targeting of an important cystogenic pathway with relative safety. Among hormonal systems that affect renal cyclic AMP is the vasopressin–V2 receptor axis. This target is attractive because V2 receptors are mostly restricted to the thick ascending limb and collecting ducts, which are main sites of cystogenesis where vasopressin is the major agonist of cyclic AMP. These sites are continuously subjected to tonic vaso­pressin action. Circulating vaso­ pressin levels are increased in ADPKD and V2 receptors are overexpressed in poly­ cystic kidneys. Pharmacological and genetic inhibition of vasopressin or V2 receptor expression has been shown to be effective in rodents. Reif et al. examined the effects of tolvaptan on human ADPKD cyst epithelial cells.2 Low concentrations inhibited vaso­ pressin-induced cyclic AMP production, cell prolifera­tion, chloride secretion and cyst growth in collagen matrices. Other analyses showed that tolvaptan administration for 1 week reduced total kidney volume by 3.1% in patients with ADPKD, and that 3 years of tolvaptan therapy reduced kidney growth by 70% compared to historical controls (1.7% versus 5.8% increase per year, respectively).3 Changes in kidney volume and in

estimated glomerular filtration rate were significantly and negatively correlated. This finding supports the use of kidney volume as a biomarker to monitor ADPKD progression. Further evaluation of tolvaptan for the treatment of patients with ADPKD awaits the conclusion of a randomized, double-blind clinical trial (NCT00428948) in 2012. Metformin and peroxisome proliferatoractivated receptor (PPAR)‑γ agonists are widely used to treat type 2 diabetes melli­tus. Takiar et al. found that metformin stimulates the energy-sensing molecule AMP-activated protein kinase (AMPK), inhibits the activities of AMPK-dependent cystic fibrosis transmembrane conductance regulator (CFTR) and mammalian target of rapamycin in Madin–Darby canine kidney renal epithelial cells, and attenuates cyclic AMP-dependent growth of Madin–Darby canine kidney cysts in collagen matrices and of cysts in metanephric organ explants, and cystogenesis in constitutive and inducible Pkd1-knockout mice.4 Yoshihara et al. and Blazer-Yost et al. found that the PPAR‑γ agonist pioglitazone inhibits renal and hepatic cystogenesis in PCK rats by possibly complementary mechanisms through the inactivation of mitogen-­ activated protein kinase 3 and mammalian target of rapa­mycin,5 and inhibition of CFTR synthesis and cyclic AMP-activated chloride secretion.6 Because metformin and PPAR‑γ agonists exert salutary effects by affecting the same pathways through different mechanisms (such as phosphoryla­tion and inhibition of CFTR by metformin and inhibi­tion of CFTR synthesis by pioglitazone), clinical trials of metformin and PPAR‑γ agonist combinations in early ADPKD should be considered to exploit their possible synergism. Evidence accumulated over the past two decades points to the importance of inflamma­t ion in PKD. Karihaloo et al. hypothesized that macrophage infiltration contributes to the proliferation of cyst-lining cells and PKD progression.7 This premise was based on work showing that macrophages homing to the kidney after ischemia–­ reperfusion undergo a transition from classically activated, pro­inflammatory cells to alternatively activated cells that promote epithelial cell proliferation. The investigators found that Pkd1-null cells secrete large amounts of the macrophage chemo­ attractant C‑C motif chemokine 2 (also known as monocyte chemotactic protein 1) and C‑X‑C motif chemokine 16. Kidneys from conditional Pkd1-knockout mice and the Pkd2WS25/– mouse model of PKD2 exhibit a 10-fold increase in the number of JANUARY 2012  |  S45


NEPHROLOGY macrophages (most with an alternatively activated phenotype and aligned along cyst walls). Macrophage depletion by intra­ peritoneal liposomal clodronate administra­ tion inhibits epi­thelial cell proliferation and cyst growth and improves renal function.7 How the loss of polycystin expression leads to increased cytokine production remains to be determined. Approaches that inhibit the expression or action of homing and prolifera­ tion signals provide novel strategies for treating PKD. Three studies have shown marked upregula­tion of the signal transducer and transcription activator (STAT)3 in patients with ADPKD and in rodent PKD models.8–10 In the STAT3 signaling pathway, activation of various cell surface growth factor receptors and cytokine receptors induces specific tyrosine phosphorylation of the receptors, which creates docking sites for latent cytoplasmic STAT3. STAT3 is then phosphorylated at tyrosine 705 by intrinsic tyrosine kinase activity of the activated growth factor receptors or by cytokine receptor-associated Janus kinase. The trigger for phosphorylation and activation of STAT3 in PKD is uncertain. Talbot et al. showed that phosphorylated STAT3 is highly expressed in cyst-lining cells and normal-­appearing tubules and inter­stitial cells in proximity to cysts.8 This finding suggests that diffusible factors such as cytokines and growth factors are involved in the activation of STAT3. Phosphorylated STAT3 homo­ dimers translocate to the nucleus and bind to promoter elements of genes that regulate cell differentiation, proliferation, apoptosis and angiogenesis. Because STAT3 is critical during development (deletion of STAT3 leads to embryonic lethality), but is dispensable postnatally in conditional knockouts, targeting STAT3 might be well tolerated in patients with PKD. Takakura et al. screened a small-molecule library using a cell-based functional assay and found that pyrimethamine, a drug used to treat malaria and toxoplasmosis, inhibits STAT3 signaling.9 Pyrimethamine and S3I‑201, an inhibitor of STAT3 homodimer complex formation, suppressed epithelial cell proliferation and cystogenesis in an inducible Pkd1-knockout mouse model without toxic effects. In another study, Leonhard et al. found that curcumin, a compound with anti-inflammatory and antiproliferative properties, reduced STAT3 activation, attenuated cell proliferation and cysto­genesis and delayed renal failure from 105 to 119 days in an inducible Pkd1knockout model.10 As curcumin has poor bioavailability, however, novel analogues with S46  |  JANUARY 2012



improved pharmacological profiles might be more effective than curcumin itself. In summary, insights into the complex network of signaling pathways disrupted in PKD have increasingly led to the identifica­ tion of potential therapies, some of which are currently used for other indications. Those compounds best supported by preclinical studies and with the desired pharmaco­ logical profile should be prioritized for clinical trials. Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA (V. E. Torres, P. C. Harris). Correspondence to: V. E. Torres torres.vicente@mayo.edu Acknowledgments V. E. Torres and P. C. Harris are supported by the NIH grant DK090728. Competing interests V. E. Torres declares an association with the following company: Otsuka Pharmaceuticals. See the article online for full details of the relationship. P. C. Harris declares no competing interests. 1.

Fedeles, S. V. et al. A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation. Nat. Genet. 43, 639–647 (2011).

2.

Reif, G. A. et al. Tolvaptan inhibits ERKdependent cell proliferation, Cl– secretion, and in vitro cyst growth of human ADPKD cells stimulated by vasopressin. Am. J. Physiol. Renal Physiol. 301, F1005–F1013 (2011). 3. Higashihara, E. et al. for the TEMPOFormula and 156‑05‑002 Study Investigators. Tolvaptan in autosomal dominant polycystic kidney disease: three years’ experience. Clin. J. Am. Soc. Nephrol. 6, 2499–2507 (2011). 4. Takiar, V. et al. Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. Proc. Natl Acad. Sci. USA 108, 2462–2467 (2011). 5. Yoshihara, D. et al. PPAR-γ agonist ameliorates kidney and liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease. Am. J. Physiol. Renal Physiol. 300, F465–F474 (2011). 6. Blazer-Yost, B. L. et al. Pioglitazone attenuates cystic burden in the PCK rodent model of polycystic kidney disease. PPAR Res. 2010, 274376 (2010). 7. Karihaloo, A. et al. Macrophages promote cyst growth in polycystic kidney disease. J. Am. Soc. Nephrol. 22, 1809–1814 (2011). 8. Talbot, J. J. et al. Polycystin-1 regulates STAT activity by a dual mechanism. Proc. Natl Acad. Sci. USA 108, 7985–7990 (2011). 9. Takakura, A. et al. Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways. Hum. Mol. Genet. 20, 4143–4154 (2011). 10. Leonhard, W. N. et al. Curcumin inhibits cystogenesis by simultaneous interference of multiple signaling pathways: in vivo evidence from a Pkd1-deletion model. Am. J. Physiol. Renal Physiol. 300, F1193–F1202 (2011).

ACUTE KIDNEY INJURY IN 2011

Biomarkers are transforming our understanding of AKI Lakhmir S. Chawla and John A. Kellum

Acute kidney injury (AKI) is a syndrome of decreased renal function that is associated with an increased risk of death. Studies from 2011, particularly in the field of AKI biomarkers, have provided important insights into the diagnosis, prognosis, and treatment of AKI. These advances are now being brought to the bedside to improve diagnosis and treatment of AKI. Chawla, L. S. & Kellum, J. A. Nat. Rev. Nephrol. 8, 68–70 (2012); published online 17 January 2012; doi:10.1038/nrneph.2011.216

Over 2  million people are afflicted by acute kidney injury (AKI) worldwide. 1 AKI is a serious complication of acute illness, typically occurring as a result of underlying conditions such as sepsis, and is independently associated with death. It has become increasingly clear that AKI is associated with the development of endstage renal disease (ESRD) and chronic kidney disease (CKD).2,3 Individuals fortunate enough to survive a severe episode of AKI are therefore at risk of develop­ing CKD-related disease.

Our understanding of AKI has advanced over the past decade, with a unified definition and standard criteria for staging, a quantification of renal replacement therapy (RRT) dosing, and the emergence of biomarkers related to AKI. In 2011, multiple studies were published that improve our understanding of AKI through the use of various biomarkers. Perhaps the most illuminating study published in 2011 was one by Paragas et al. that examined the expression of neutrophil-related gelatinase lipocalin (NGAL) using a luciferase reporter assay.4 www.nature.com/reviews


NEPHROLOGY Although NGAL has been shown in multiple large cohort studies to be a biomarker for early AKI diagnosis and for AKI prognosis,5 NGAL is expressed in multi­ple organs and is thus not kidney specific. Understanding how non-kidney sources of NGAL impact the urinary NGAL signal and indeed establishing the sources of NGAL in AKI is essential. Paragas and colleagues4 conducted their novel experiment by creating a reporter mouse for NGAL. They inserted a double-fusion reporter gene that encoded luciferase‑2 and mCherry (Luc2-mC) in the locus for NGAL (lcn‑2). In so doing, the investigators could assess the endogenous NGAL message in real time and assess in which organs the message was being trans­ cribed. In separate experiments, mice were subjected to unilateral renal ischemia, bilateral renal ischemia or nephrotoxic injury with cisplatin. In addition, the investigators tested whether NGAL-Luc2-mC was activated in pre-renal azotemia and ascertained the segments of the nephron responsible for urinary NGAL (uNGAL) production in AKI. The investi­gators determined that the principal or exclusive source of uNGAL was the thick ascending limb and the collecting ducts of the nephron. In addition, in the prerenal azotemia model, serum creatinine level rose, but NGAL-Luc2-mC was not activated and no increase in uNGAL level occurred. These data show that uNGAL is an appropriate kidney-injury-specific biomarker despite not being exclusively expressed in the kidney. Another study involving NGAL displayed the range of methods by which AKI biomarkers can assist clinicians caring for patients with AKI. NGAL has been primarily thought of as a biomarker for the early diagnosis of AKI,5 but utility of this biomarker and others may be much broader. Using a large multicenter cohort of patients with community-acquired pneumonia, Srisawat and colleagues6 examined plasma of patients on the first day they experienced severe AKI (defined as RIFLE‑F by the Risk, Injury, Failure, Loss and ESRD (RIFLE) criteria). In this study, recovery was defined as being alive and neither requiring RRT during hospitalization nor having a persistent RIFLE‑F classification at hospital discharge. The investigators found that elevated plasma NGAL (pNGAL) levels were associated with renal non-recovery. Although the absolute predictive value of pNGAL alone was only fair (area under the receiver operating characteristic curve 0.74), the reclassification of risk of not KEY ADVANCES IN MEDICINE

Key advances ■■ The source of urinary neutrophil-related gelatinase lipocalin (NGAL) seems to be nearly exclusively from the renal tubule and does not seem to be released during pre-renal azotemia in healthy animals4 ■■ Plasma NGAL level helps predict which patients with severe acute kidney injury (AKI) will recover renal function6 ■■ Urine output remains an important ‘biomarker’ of AKI, and predicts death even in the absence of a rise in serum creatinine level7 ■■ Micro RNAs are a new class of AKI biomarkers that may prove to be important new tools in the diagnosis and treatment of AKI8

recovering renal function was increased by 17%. These data are most notable for two reasons. First, because AKI can cause CKD and ESRD, decisions regarding longterm care (for example, use of dialysis, vascular access, and follow-up) are often made in a piecemeal approach. If objective metrics coupled with clinical assessment can improve prognostic accuracy, a better informed decision can be made for survivors of AKI. Second, the association between pNGAL and renal non-recovery suggests that renal injury is ongoing, and even if a patient is under­going dialysis, thera­pies directed at mitiga­t ing ongoing injury may have a role in AKI treatment.

‘‘

...some existing biomarkers such as NGAL will begin to shape clinical practice...

’’

Within the advancing field of AKI, the oldest known biomarker is urine output. The precise utility of oliguria has been controversial, and within the Acute Kidney Injury Network (AKIN) staging system, there has been discussion on the precise definition of oliguria over time (for example, consecutive hours of oliguria versus average urine output over a period of time). To further the understanding, Macedo and colleagues7 utilized high-fidelity urimeters to compare various definitions of oliguria in critically ill patients. In their study, 317 patients had speciali­zed high-accuracy urimeters placed on their urinary catheters in order to measure their urine output hourly. Serum creatinine was measured every 12 h, and definitions of AKI based on urine output were compared with those based on serum creatinine. Urine output was classified in

three ways: consecutive hours of oliguria (oligo6-cons), an average amount of olig­ uria over a fixed block of time (<3 ml/kg in the period from 6.00 am to 12.00 midday), or any episode of oliguria over a set period of time (<3 ml/kg for any 6 h period). Of these variables, oligo6-cons was the most specific when compared with the AKIN stage I serum creatinine standard (sensitivity 34%, specificity 71%). The other two metrics, olig­ uria 6 h fixed (oligo6-fixed) and oliguria 6 h floating (oligo6-float), were more sensitive, but less specific (sensitivities 47% and 53%, and specificities 62% and 54%, respectively). Of the patients with oliguria for 6 h, 79% of oligo6-cons advanced to AKIN stage II, while 64% of oligo6-fixed and 52% of oligo6float advanced to AKIN stage II. Using the urine output definition of AKI increased the observed incidence of AKI to 52% as compared with an AKI incidence of 24% using serum creatinine definitions alone. The mortal­ity rate of patients with AKI defined by urine output alone was comparable to that of patients with AKI defined by serum creati­nine alone (8.8% versus 10.4%). Moreover, oliguria was a more sensitive marker of AKI, and tended to occur earlier than did change in serum creatinine level. These data endorse current AKIN definitions that incorporate changes in both urine output and serum creatinine level. 2011 was also notable for the development of whole new classes of bio­markers for various diseases including AKI. Whereas most biomarkers are small peptides, microRNAs (miRs) are small ribonucleotides that regulate gene expression, and have been shown to have disease-specific roles in pre-clinical studies. Lorenzen and colleagues8 demonstrated in 77 critically ill patients with AKI and appropriate controls that patients with AKI had downregulation of miR‑320 and miR‑16 levels and upregula­ tion of miR‑210 levels. Additionally, miR‑210 level predicted mortality in a multivariable analysis that included severity of illness. miR‑210 is a plausible biomarker for AKI as it is involved in the molecular response to stress. For example, hypoxia-inducible factor causes induction of miR‑210.9 miRNAs have potential advantages over plasma proteins as biomarkers. They are very stable in plasma and might serve as a noninvasive tool for assessing intra­cellular events. Because miRNAs have significant gene regulatory capacity, these molecules may offer an entire new vantage point from which to understand the pathophysiology of AKI. JANUARY 2012  |  S47


NEPHROLOGY Also in 2011, investigators sought new AKI biomarkers that are more directly related to the injury itself. Munshi and colleagues10 reported a study where potential biomarker candidates were chosen from urinary excretion of injury-induced mRNAs. The investigators posited that the resulting proteins of these mRNAs might be good AKI biomarkers and may offer pathogenic information in addition to diag­nostic information. Munshi et al. quantified the urinary excretion of the mRNAs for one of these candi­date proteins, monocyte chemo­attractant protein‑1 (MCP‑1). The investi­gators conducted multiple preclinical studies wherein various forms of AKI were induced and MCP‑1 was compared with a known representative AKI biomarker, NGAL. In the models of AKI, MCP‑1 protein and mRNA levels increased more than corresponding increases in NGAL. Uremia, without kidney injury, induced the NGAL gene, but not MCP‑1, which suggests that MCP‑1 may be more specific for AKI. These findings were tested in a candidate cohort of Acute Physiology and Chronic Health Evaluation (APACHE)-II-matched critically ill patients with and without AKI. In these patients, MCP‑1 levels were significantly higher in those with AKI. In our view, these studies advanced the field in 2011 and collectively provide important information on the current state of medi­cine pertaining to AKI as well as suggesting future directions. We believe that some existing biomarkers such as NGAL will begin to shape clinical practice while new biomarkers will continue to be discovered. This ongoing process of new discovery and reinvention of existing tools (including those as primitive as urine flow) will advance the field further and we will eventually emerge with a set of tools that will not only help us diagnose AKI, but will also help us determine its cause, monitor its course and predict response to therapy. We eagerly await this bright future. Department of Anesthesiology and Critical Care Medicine, George Washington University Hospital, 900 23rd Street, NW Room G‑105, Washington DC 20037, USA (L. S. Chawla). 604 Scaife Hall, Department of Critical Care Medicine, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA 15261, USA (J. A. Kellum). Correspondence to: J. A. Kellum kellumja@ccm.upmc.edu Competing interests L. S. Chawla declares associations with the following companies: Abbott, Alere, Astute Medical.

S48  |  JANUARY 2012



J. A. Kellum declares associations with the following companies: Abbott, Alere, Astute Medical, Roche. See the article online for full details of the relationships. 1. 2.

3.

4.

5.

Hoste, E. A. et al. Epidemiology of acute kidney injury. Contrib. Nephrol. 165, 1–8 (2010). Chawla, L. S., Amdur, R. L., Amodeo, S., Kimmel, P. L. & Palant, C. E. The severity of acute kidney injury predicts progression to chronic kidney disease. Kidney Int. 79, 1361–1369 (2011). Ishani, A. et al. The magnitude of acute serum creatinine increase after cardiac surgery and the risk of chronic kidney disease, progression of kidney disease, and death. Arch. Intern. Med. 171, 226–233 (2011). Paragas, N. et al. The Ngal reporter mouse detects the response of the kidney to injury in real time. Nat. Med. 17, 216–222 (2011). Shemin, D. & Dworkin, L. D. Neutrophil gelatinase-associated lipocalin (NGAL) as a

biomarker for early acute kidney injury. Crit. Care Clin. 27, 379–389 (2011). 6. Srisawat, N. et al. Plasma neutrophil gelatinaseassociated lipocalin predicts recovery from acute kidney injury following community-acquired pneumonia. Kidney Int. 80, 545–552 (2011). 7. Macedo, E., Malhotra, R., Bouchard, J., Wynn, S. K. & Mehta, R. L. Oliguria is an early predictor of higher mortality in critically ill patients. Kidney Int. 80, 760–767 (2011). 8. Lorenzen, J. M. et al. Circulating miR‑210 predicts survival in critically ill patients with acute kidney injury. Clin. J. Am. Soc. Nephrol. 6, 1540–1546 (2011). 9. Fasanaro, P. et al. MicroRNA‑210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine kinase ligand Ephrin‑A3. J. Biol. Chem. 283, 15878–15883 (2008). 10. Munshi, R. et al. MCP‑1 gene activation marks acute kidney injury. J. Am. Soc. Nephrol. 22, 165–175 (2011).

NONDIALYSIS CHRONIC KIDNEY DISEASE IN 2011

Progression, prediction, populations and possibilities Adeera Levin

In 2011, studies of chronic kidney disease (CKD) were published in abundance. The articles selected here represent the growing appreciation of the importance of CKD as a modifier of outcomes, breakthroughs in understanding the pathobiology and genetics of specific conditions, and clinical trials of treatment strategies that offer hope to patients with CKD. Levin, A. Nat. Rev. Nephrol. 8, 70–72 (2012); published online 6 December 2011; doi:10.1038/nrneph.2011.195

In 2011, almost a decade after the initial publication that described a new system of evaluation, classification, and definition of chronic kidney disease (CKD), this condition has become of mainstream interest. Articles published in 2011 reflect an increase in sophistication of analysis, collaboration and real attempts at understanding the impact of CKD on individuals and health-care systems, the importance of predicting disease progression, and, perhaps most crucially, the effect of specific therapies on outcomes such as cardio­vascular disease. Selecting the most influential papers of 2011 is subject to bias and perspectives of the reviewer, but the selection here represents the spectrum of studies that I believe will influence thinking and practice for the next decade. Although controversies regarding the identification and definition of CKD in the general population still exist, Peralta and colleagues determined that the addition of cystatin C to traditional measures of kidney function (creatinine and albumin­u ria)

better identifies individuals with ‘true’ CKD and those who are likely to progress to endstage renal disease (ESRD) than using a one-marker or two-marker approach.1 Much controversy surrounding CKD staging has related to individuals with higher values of estimated glomerular filtration rate (eGFR). The study by Peralta et al., which used eGFR derived from cystatin C in a general popula­ tion cohort within the REGARDS study, confirms that this additional biomarker can reliably identify those at high risk of adverse events (death, cardiovascular disease, or renal replacement therapy). This finding is extremely important for the large group of patients who have been identified as having milder stages of CKD, but for whom outcomes are uncertain. Peralta et al. demonstrate that knowledge of cystatin C values, used in an eGFR equation, will reclassify individuals and distinguish important prognostic differences (a threefold increased risk of death and fourfold increased risk of ESRD in this study). This simple observation could profoundly affect patients and care providers www.nature.com/reviews


NEPHROLOGY with respect to care-plan modification. Confirmation that this simple test helps to appropriately reclassify these patients is important. Further studies will facilitate our understanding. Variability in outcomes between ethnic groups and within CKD populations with similar diseases, has been another source of confusion over the past decades. Two important breakthroughs were made in 2011 with respect to genetic determinants of kidney disease. Firstly, the importance of the apolipoprotein L1 (APOL1) gene in predicting any form of progressive CKD in African Americans,2 will have a profound impact on clinical care (by suggesting alternative treatment), familial donation strategies and our understanding of progressive disease in this vulnerable population. Secondly, in another study, the finding that soluble urokinase-type plasminogen activator receptor (suPAR) is an important propagator of focal segmental glomerulosclerosis (FSGS), given its ability to activate podocyte β2 integrin, provides new insights into this condition.3 In an elegant set of experiments, Wei et al. demonstrated the importance of elevated levels of suPAR in patients with FSGS, and found that lowering of suPAR levels with plasmapheresis led to remission of disease.3 Using a series of mouse models, Wei and collaborators clearly identified a relationship between suPAR and podocyte damage. Although the reason for the elevation in suPAR levels remains to be determined, the fact that not all patients with FSGS have high levels of this protein further confirms that FSGS is a response to injury rather than a specific disease. Improving diagnostics and identifying new therapies based on a better understanding of the pathobiology is becoming possible with discoveries such as those described above.

‘‘

Overall, 2011 was an astounding year in terms of publications focusing on nondialysis CKD

’’

Predicting progression of CKD and outcomes of patients with CKD has been the focus of many publications over the past 2 years. Increasingly, investigators have identified aspects of kidney disease that portend poorer outcomes. A series of papers have described the ability of simple laboratory parameters to predict progression to ESRD over 5  years, 4 and highlighted that the rate of eGFR decline needs KEY ADVANCES IN MEDICINE

Key advances ■■ Consensus is increasing in the clinical and scientific community that classification of chronic kidney disease (CKD) needs to evolve to a more complex staging system that includes etiology, albuminuria, estimates of glomerular filtration rate and other available parameters1,4,7 ■■ More sophisticated methods of genotyping and phenotyping individuals have led to an improved ability to predict outcomes in patients with CKD2,3,8 ■■ The SHARP trial determined that a lipid-lowering strategy safely reduced atherosclerotic events in patients with CKD; these findings, which showed that the benefits were proportional to the lipid lowering achieved, irrespective of initial lipid values, have huge implications for clinical care10

to be considered in prediction equations,5 as well as the need to incorporate urine albumin excretion and estimates of GFR into risk prediction models6 in patients with established CKD. The report of the consensus conference arranged under the KDIGO (Kidney Disease Improving Global Outcomes) organizational banner helped to consolidate a series of key conceptual issues relating to prognosis and risk stratification.7 Another important paper was that by Isakova et al., who demonstrated the importance of fibroblast growth factor 23 (FGF23) in predicting adverse outcomes in patients with CKD.8 Levels of FGF23 demonstrated a stepwise increase in association with mortal­ity and ESRD. Within the context of our increasing knowledge of the unique role of FGF23 in cardiac hypertrophy and potential therapeutic interventions, this study has refocused the nephrology community on the utility of newer biomarkers in risk stratification and in understanding the underlying biological processes involved in disease progression. The importance of well-conducted clinical trials that answer questions of key importance cannot be overstated. Two such papers were published in 2011, one addressing a new compound that might delay dialysis in patients with CKD, and the other addressing atherosclerotic events in patients with CKD. A study examining the effect of bardoxolone (an oral antioxidant, anti-inflammatory modulator) in patients with diabetes and CKD, demonstrated an improvement in eGFR at 24 weeks and 52 weeks in the participants.9 This study is the first to potentially offer some hope to patients with CKD, although issues related to mechanism of

action of the medication, long-term effects of increasing eGFR (that is, potential for accelerated progression), and utility in all clinical circumstances were not addressed in this phase II study. However, these findings, which show that therapeutic agents that might improve kidney function exist, are a source of optimism for the millions of patients with CKD. The SHARP study, an international 5‑year randomized, placebo-controlled trial of >9,000 patients with CKD, found that active lipid-lowering treatment (simva­statin 20 mg and ezetimibe 10 mg) was effective in reducing atherosclerotic events in patients both on and off dialysis.10 This study is seminal in that it is the largest trial ever conducted in CKD, and enables clini­cians to appreciate the benefit and very low risk profile of a fixed dose of lipid-lowering medication for this population. Although the study was not powered to examine mortality, the results did demon­strate a 17% reduction in major atherosclerotic events. Publication of this study in the Lancet further validates the importance of these findings and the impact it is likely to have on general care. Moreover, the consistent finding that for any lowering of LDL-cholesterol levels, there was a benefit to patients with CKD similar to that found in the general population, adds credence to the hypothesis that atherosclerotic events can be ameliorated by targeted therapy in a wide range of patients. The SHARP study also reminds us that morbidity and mortality in CKD is more complex than simply being linked to atherosclerotic events, and thus highlights that there is more research to be done. Overall, 2011 was an astounding year in terms of publications focusing on non­ dialysis CKD. The majority of these papers are in general medical journals,1,3,4,8–10 which is further testimony to the recognition of the importance of this area of medicine. The overall message from these studies is that CKD is important, identi­f iable by simple means, is variable in its expression and outcomes, and both progressive disease and associated comorbidi­ties are amenable to thera­peutic interventions, which is reassuring for patients and their caregivers. Ongoing genomic and proteomic studies will further unravel the mystery of CKD progression and outcomes. The breadth and depth of nephrology insights and understandings continues to grow, as is evidenced in this landmark year. With such growth, we would anticipate an exciting future for both science and clinical care in the years to come. JANUARY 2012  |  S49


NEPHROLOGY Division of Nephrology, Department of Medicine, St Paul’s Hospital, University of British Columbia, 1081 Burrard Street, Room 6010-A, Vancouver, BC V6Z 1Y6, Canada. alevin@providencehealth.bc.ca Competing interests A. Levin declares an association with the following company: Merck. See the article online for full details of the relationship. 1.

2.

3.

4.

5.

Peralta, C. A. et al. Detection of chronic kidney disease with creatinine, cystatin C, and urine albumin‑to‑creatinine ratio and association with progression to end-stage renal disease and mortality. JAMA 305, 1545–1552 (2011). Friedman, D. J., Kozlitina, J., Genovese, G., Jog, P. & Pollak, M.R. Population-based risk assessment of APOL1 on renal disease. J. Am. Soc. Nephrol. 22, 2098–2105 (2011). Wei, C. et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat. Med. 17, 952–960 (2011). Tangri, N. et al. A predictive model for progression of chronic kidney disease to kidney failure. JAMA 305, 1553–1557 (2011). Perkins, R. M. et al. GFR decline and mortality risk among patients with chronic kidney

disease. Clin. J. Am. Soc. Nephrol. 6, 1879–1886 (2011). 6. Astor, B. C. et al. and the Chronic Kidney Disease Prognosis Consortium. Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative metaanalysis of kidney disease population cohorts. Kidney Int. 79, 1331–1340 (2011). 7. Levey, A. S. et al. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int. 80, 17–28 (2011). 8. Isakova, T. et al. for the Chronic Renal Insufficiency Cohort (CRIC) Study Group. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA 305, 2432–2439 (2011). 9. Pergola, P. E. et al. for the BEAM Study Investigators. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N. Engl. J. Med. 365, 327–336 (2011). 10. Baigent, C. et al. on behalf of the SHARP Investigators. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 377, 2181–2192 (2011).

DIALYSIS IN 2011

Can cardiovascular risk in dialysis patients be decreased? Peter Stenvinkel and Peter Bárány

More than 1.4 million patients are on renal replacement therapy worldwide. Mortality in patients with end-stage renal disease (ESRD) is as high as that seen in some types of metastatic cancer, and premature cardiovascular disease is the major killer in ESRD. Several publications in 2011 addressed how interventions can modify cardiovascular risk factors and improve outcomes. Stenvinkel, P. & Bárány, P. Nat. Rev. Nephrol. 8, 72–74 (2012); published online 13 December 2011; doi:10.1038/nrneph.2011.212

Although nephrologists have witnessed many technical advances in dialysis therapy over the past few decades, these improvements have translated into only minor reductions in mortality rate. Another major concern in nephrology is that several randomized controlled trials (RCTs) have not been able to demonstrate a significant effect of targeting various traditional and nontraditional risk factors on outcomes in this high-risk patient group. Inflammation seems to be a major driving force for the uremic phenotype and the majority of dialy­sis patients have signs of persistent lowgrade inflammation with repetitive bursts of increased inflammatory activity. Because increased levels of circulating inflammatory biomarkers, such as C‑reactive protein S50  |  JANUARY 2012



(CRP), pentraxin 3, and IL‑6, consistently predict poor outcome in dialysis patients, inflammation seems to be a logical therapeutic target for putative anti-inflammatory nutritional and pharmaco­logical interventions in this high-risk patient group. Recent observational studies suggest that the presence of persistent inflammation via a catalytic effect magnifies the risk of poor outcome via mechanisms related to selfenhancement of the inflammatory cascade and exacerbation of wasting and vascular calcification processes.1 Results from a 2011 study in a cohort of 225 hemodialysis patients followed over a period of 13 years support the catalyst hypothesis: inflamma­ tion was shown to amplify the risk of death and cardio­vascular events associated

with high asymmetric dimethylarginine (ADMA) levels.2 Given the multi­factorial origin of uremic inflammation, treatment is complex and the nephrologist needs to consider both factors related to the dialysis procedure (such as dialysis catheters and quality of dialysate) and factors unrelated to the dialysis procedure per se (such as infectious complica­tions and volume overload). Nevertheless, following the exclusion of such factors, no apparent reason for persistent low-grade inflammation would be found in a consider­able proportion of patients on dialysis. In a small RCT of 22 patients published in 2011, Hung et al. 3 demonstrated that 4 weeks of treatment with a recombinant human IL‑1 receptor antagonist (anakinra) significantly reduced mean CRP level (by 53%) and mean IL‑6 level (by 40%), while mean prealbumin level increased by 23%. Moreover, the anti-­ cytokine treatment was well tolerated and safe. Although the small patient number and the short treatment period limit the value of this study, it still provides important information to the nephrology community. It is the first study showing that targeted anticytokine treatment decreases inflamma­ tion parameters in this patient group. Thus, long-term studies should be initiated to study the impact of anti-­inflammatory treatment strategies on cardiovascular outcomes, quality of life, nutritional status and death in patients on dialysis.

‘‘

Inflammation seems to be a major driving force for the uremic phenotype...

’’

The Study of Heart and Renal Protection (SHARP), also published in 2011, is the largest randomized study ever conducted in nephrology and included 9,270 patients random­ized to receive either 20 mg simva­ statin plus 10 mg ezetimibe daily or placebo. 4 One-third of the participants were dialysis dependent (2,527 on hemodialysis and 496 on peritoneal dialysis) and median follow-up was 4.9 years. In the whole cohort, treatment with simvastatin plus ezetimibe resulted in a 17% reduction in the primary end point of the risk of major athero­sclerotic events (relative risk 0.83; 95% CI 0.74–0.94). Significant reductions in revascularization procedures and non­hemorrhagic strokes contributed most to the effect on the primary end point. Importantly, treatment with simvastatin plus ezetimibe was not associ­ated with www.nature.com/reviews


NEPHROLOGY any survival benefit or a renal protective effect. Although the effect on the primary end point was similar in all subgroups, the risk reduction was less prominent in patients on dialysis (relative risk 0.90; 95% CI 0.75–1.08) than in nondialysis patients (relative risk 0.78; 95% CI 0.67–0.91). Thus, the modest effect on cardiovascular risk in patients on dialysis is of a similar magnitude to that reported in previous studies of statins (nonsignificant risk reductions of 8% in the 4D study and 4% in AURORA). Persistent inflammation and comorbidities may influence the effects of lipid-­lowering treatment in patients on dialysis. Although the precise role of these factors and the mechanism/s through which they interact with statin treatment are not yet evident, it can be speculated that if persistent inflammation serves as a catalyst and magnifies risk,1 the effect of long-term statin treatment may differ in patients on dialysis with and without inflammation; these groups should be analyzed separately. Comorbidities, such as diabetes, may also influence the cardiovascular effects of statin treatment in this patient group. To determine whether rosuvastatin might reduce the risk of cardiac events in 731 hemo­dialysis patients with diabetes, a post hoc analysis of the AURORA cohort was performed.5 Rosuvastatin treatment significantly reduced the rates of cardiac events by 32% among patients with diabetes. However, it is a concern that although there was no difference in overall stroke incidence between the rosuvastatin and the placebo groups, rosuvastatin-treated patients with diabetes had a higher risk of hemorrhagic strokes than the placebo group (relative risk 5.21; 95% CI 1.17–23.27). The high prevalence of atrial fibrillation is another major clinical problem in dialysis units. In a recent study based on 2.5 million observations of hemodialysis patients, Winkelmayer et al.6 showed that the prevalence of atrial fibrillation had increased threefold from 1992 (3.5%) to 2006 (10.7%). They also showed that mortality was twice as high among hemodialysis patients with atrial fibrillation compared to those without atrial fibrillation. In 2011, the same group also reported data from 2,313 hemodialysis patients with new-onset atrial fibrillation. Whereas patients treated with warfarin had double the risk of hemorrhagic stroke compared with nonusers, the risk of ischemic stroke did not differ between users and nonusers of warfarin.7 As warfarin treatment does not reduce the risk of ischemic stroke and, in addition to increasing the risk of KEY ADVANCES IN MEDICINE

Key advances ■■ Inflammation interacts with other cardiovascular risk factors in the uremic milieu, such as asymmetric dimethylarginine, and increases the risk of poor outcomes2 ■■ Short-term treatment with a recombinant human IL‑1 receptor antagonist reduces inflammatory biomarkers in patients on hemodialysis3 ■■ Lipid-lowering treatment is associated with beneficial effects on major atherosclerotic events in the entire chronic kidney disease population; the effect is less pronounced in the subpopulation of dialysis patients4 ■■ The prevalence of atrial fibrillation in North American hemodialysis patients increased threefold between 1992 and 20066 ■■ Whereas warfarin treatment does not reduce the risk of ischemic stroke, it increases the risk of hemorrhagic stroke in older hemodialysis patients with atrial fibrillation7

hemorrhagic stroke, may have a role in both the progression of vascular calcification and in the life-threatening condition calciphylaxis, the risks of war­farin treatment seem to outweigh its potential bene­ficial effects in dialy­sis patients with atrial fibrilla­tion. Thus, until an adequately powered RCT settles the important question as to whether warfarin reduces the overall risk of stroke and improves survival it seems advisable not to prescribe vitamin K antagonists, such as warfarin, to patients on dialysis with atrial fibrillation. This finding should also prompt the initiation of studies to evaluate the safety and efficacy of novel anti­coagulant treatment strategies in patients with advanced chronic kidney disease, such as drugs targeting factor IIa (dabigatran) and factor Xa (rivaroxaban, apixaban and edoxaban) in the coagulation cascade. Indeed, in a recent RCT conducted in 18,201 patients with atrial fibrillation (but without kidney disease), apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality.8 The effects of the intensity of dialysis on morbidity and mortality was first studied in the 1981 National Cooperative Dialysis study, which suggested that a longer hemodialysis duration aiming at a predialysis blood urea nitrogen level of 20 mmol/l resulted in less morbidity than a shorter hemodialysis duration. The results of the 2002 HEMO study 9 showed that aiming

at a higher dialysis dose did not result in signifi­cant benefits on mortality or morbidity (over standard doses) in patients undergoing thrice-weekly hemo­dialysis. In 2010, the randomized study by the Frequent Hemodialysis Network (FHN) studied the effect of frequent hemo­dialysis versus conventional hemodialysis (six times weekly versus three times weekly) in 245 patients followed up for 1 year.10 Frequent hemo­ dialysis was associated with significant beneficial effects on the risk of an increase in left ventricular muscle mass and the risk of worse physical health scores as well as improved control of hypertension and hyperphosphatemia. The drawback was a 71% increase in the risk of requiring interventions related to vascular access. Although frequent hemodialysis is a promising modality, the cost–benefit ratio over longer follow-up periods than in the FHN study remains to be evaluated. In conclusion, several studies published in 2011 have provided the nephrology community with new small pieces of knowledge to add to the complex puzzle of the increased risk of premature cardio­ vascular death in patients on dialysis. Based on current knowledge, we conclude that inflammatory biomarkers and an assessment of atrial fibrillation should be included in the risk factor profile monitored by nephrologists. Whereas statin therapy seems to have a modest, but signifi­ cant, beneficial effect on cardiac events, vitamin K antagonist treatment cannot be advocated in dialysis patients with atrial fibrillation until an RCT has proved its safety and efficacy. Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska University Hospital at Huddinge, Karolinska Institutet, SE 141 86 Stockholm, Sweden (P. Stenvinkel, P. Bárány). Correspondence to: P. Stenvinkel peter.stenvinkel@ki.se Competing interests P. Stenvinkel declares an association with the following company: Gambro. See the article online for full details of the relationship. P. Bárány declares no competing interests. 1.

2.

3.

Carrero, J. J. & Stenvinkel, P. Of persistent inflammation as a catalyst for other risk factors in chronic kidney disease. a hypothesis proposal. Clin. J. Am. Soc. Nephrol. 4, S49–S55 (2009). Tripepi, G. et al. Inflammation and asymmetric dimethylarginine for predicting death and cardiovascular events in ESRD patients. Clin. J. Am. Soc. Nephrol. 7, 1714–1721 (2011). Hung, A. M., Ellis, C. D., Shintani, A., Booker, C. & Ikizler, T. A. IL‑1β receptor antagonist reduces

JANUARY 2012  |  S51


NEPHROLOGY

4.

5.

6.

inflammation in hemodialysis patients. J. Am. Soc. Nephrol. 22, 437–442 (2011). Baigent, C. et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 377, 2181–2192 (2011). Holdaas, H. et al. Rosuvastatin in diabetic hemodialysis patients. J. Am. Soc. Nephrol. 22, 1335–1341 (2011). Winkelmayer, W. C., Patrick, A. R., Liu, J., Brookhart, M. A. & Setoguchi, S. The increasing prevalence of atrial fibrillation among hemodialysis patients. J. Am. Soc. Nephrol. 22, 349–357 (2011).

7.

Winkelmayer, W. C., Liu, J., Setoguchi, S. & Choudhry, N. K. Effectiveness and safety of warfarin initiation in older hemodialysis patients with incident atrial fibrillation. Clin. J. Am. Soc. Nephrol. http://dx.doi.org/10.2215/ CJN.04550511. 8. Granger, C. B. et al. Apixaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 365, 981–992 (2011). 9. Eknoyan, G. et al. Effect of dialysis dose and membrane flux in maintenance hemodialysis. N. Engl. J. Med. 347, 2010–2019 (2002). 10. Chertow, G. M. et al. In-center hemodialysis six times per week versus three times per week. N. Engl. J. Med. 363, 2287–2300 (2010).

TRANSPLANTATION IN 2011

New agents, new ideas and new hope Titte R. Srinivas and Bruce Kaplan

The past year was marked by several excellent studies that represent important therapeutic advances in kidney transplantation or that further our understanding of the genetic basis of chronic allograft dysfunction, clinical tolerance and outcomes of kidney transplantation. Srinivas, T. R. & Kaplan, B. Nat. Rev. Nephrol. 8, 74–75 (2012); published online 20 December 2011; doi:10.1038/nrneph.2011.215

The year 2011 was marked by the addition of an important alternative to calcineurin inhibitors for immuno­suppression in kidney transplantation. Calcineurin inhibitor-based combina­tions are the most frequently utilized immuno­s uppressive regimens in kidney transplantation, but they carry a metabolic burden and may be associated with both short-term and possibly progressive diminution in graft function. Belatacept is a costimulation blocker that binds to CD80 and CD86 on antigen-­presenting cells and provides

Key advances ■■ 3-year follow-up of BENEFIT demonstrates that belatacept provides superior renal function outcomes to ciclosporin3 ■■ Sensitized patients treated with a desensitization regimen have better survival than patients on dialysis or sensitized patients who undergo compatible transplantation4 ■■ Discovery of APOL1 variants in African Americans points to a biological influence rather than race underlying transplantation outcomes6 ■■ Increased cold ischemia times of extended criteria donor kidneys are associated with delayed graft function, but do not affect graft survival10

S52  |  JANUARY 2012



effective immuno­suppression while being devoid of renal and nonrenal metabolic adverse effects. 1 A phase  III study of belatacept (BENEFIT) published in 2010 reported superior renal function and an improved cardiovascular and metabolic risk profile compared with a ciclosporinbased regimen.2 In this trial, 686 de novo kidney transplant recipients (of living and standard criteria deceased donor kidneys) were randomly assigned to more-intensive or less-intensive belatacept regimens or to ciclosporin. All patients received basiliximab induction therapy, mycophenolate mofetil and corticosteroids. Equivalent rates of graft and patient survival were noted despite an increased frequency and severity of early rejection episodes and increased frequency of post-transplant lympho­proliferative disorder associated with belatacept.2 Vincenti et al. have now reported on the efficacy and safety of belatacept at 3 years post-transplantation in the BENEFIT study.3 Graft survival was equivalent across all regimens. At year 3 post-­transplantation, the mean estimated glomerular filtration rate (eGFR) was 21 ml/min/1.73 m2 higher in the belatacept groups than in the ciclosporin group. More importantly, from month 3 through to month 36, the slope

of eGFR in the belatacept groups averaged 1.1 ml/min/1.73 m 2 per year versus –2.0 ml/min/1.73 m 2 per year with ciclosporin. Neither a significant increase in acute rejection episodes nor new cases of post-transplant lymphoproliferative dis­ order after 18 months post-transplantation were observed.3 Taken together, these findings are indeed gratifying and represent the emergence of a non-nephrotoxic and efficacious immunosuppressive regimen in renal transplantation. This study also demon­strated a disconnect between rejection rates and graft survival and function, which either reflects short follow-up or reasons that prompt reconsideration of the relationship between classic T‑cellmediated rejection and outcomes. Although initial results from BENEFIT are promising, their generalizability to clinical practice at large will depend on a paradigm shift from oral maintenance therapy to infusion-based therapy. As such, whether the promising initial results are sustainable on logistical and economic grounds needs further study. Sensitized transplant candidates have prolonged waiting times, a reduced transplanta­tion rate and an increased rate of death compared with nonsensitized candidates. Although numerous centers report successful utilization of desensitization regimens in renal transplantation, they are plagued by the absence of suitable control groups. Montgomery et al. compared outcomes in 211 HLA-sensitized live donor kidney transplant recipients treated with low-dose intra­v enous immuno­ globulin and plasma­pheresis with that of two matched control groups drawn from the United Network for Organ Sharing kidney transplant waiting list who either remained on dialysis (dialysis-­only group) or who were dialyzed or under went HLA-compatible renal transplantation (dialysis-or-­t ransplantation group).4 In the desensitized group, estimates of patient survival were 90.6%, 85.7% and 80.6% at 1, 3 and 5 years, respectively, versus 91.1%, 67.2% and 51.5% in the dialysis-only group and 93.1%, 77.0% and 65.6% in the dialysis-or-transplantation group (overall P <0.001; differences were not statistically significant after 1 year).4 Although these results are encouraging, several unanswered questions remain. For instance, this report does not address actual long-term graft survival or antibody-­mediated rejection in the popula­tion studied. Furthermore, the costs of a desensitization regimen followed by transplantation are considerable and www.nature.com/reviews


NEPHROLOGY have not been compared systematically to the cost of remaining on dialysis. In addition, this study compared patient survival with living donor transplantation following desensitiza­tion with those accrued on the waitlist. Whether these encouraging observa­t ions could extend to deceased donor transplantation after successful desensitization remains to be seen. African Americans are at increased risk of end-stage renal disease compared with white individuals. Recent studies suggest an association between variants of the apolipoprotein L1 gene (APOL1) and nondiabetic nephropathy among African Americans.5 In a single-center study, kidneys from African American deceased donors with two APOL1 risk variants were more likely to fail (HR 3.48, P = 0.008) than kidneys from individuals with one or no APOL1 risk variants.6 These associations outweighed the risk of graft loss associated with African American ancestry. This study highlights that transplant outcomes are more likely to be based on biology than on arbitrary and often culturally based definitions of race. Whether or not donor genotype or donor– recipient genotype interactions influence transplant outcomes through nonimmunological mechanisms demands confirmation. More importantly, the application of these associations to improve matching of donors and recipients in organ allocation schemes merits further study. Successful transplantation in the clinical arena is inseparable from the pharmacopeia that facilitates successful transplantation. Immunosuppressive drugs are associated with well-known immunological and nonimmunological adverse effects. However, it is increasingly apparent that a small number of recipients of renal and liver allografts continue to have excellent graft function many years (sometimes decades) after stopping immunosuppression. Such individuals are described as being operationally tolerant. A unique B-cell expression signature associated with increased numbers of naive and transitional B cells in peripheral blood has been described in operationally tolerant kidney transplant recipients.7 A recent study comparing character­istics of liver and kidney transplant recipients who are operationally tolerant showed

KEY ADVANCES IN MEDICINE

that the gene-expression signatures of peripheral blood mononuclear cells in these individuals was very different, with no significant detectable overlap between their immuno­phenotypic profiles.8 By contrast, tolerant and non­tolerant liver recipients had similar peripheral blood B-cell phenotypic markers.8

‘‘

...transplant outcomes are more likely to be based on biology than on arbitrary ... definitions of race

’’

It is important to note that the studies discussed above represent associations and do not imply causal relationships. Patients who maintain excellent graft survival despite discontinuing immuno­suppression might differ considerably from those who reject under similar circumstances; findings drawn from operationally tolerant individuals could therefore be affected by survivorship bias. Whether genomic and immunophenotypic markers associated with prolonged discontinuation of immuno­suppression and excellent graft survival could be identified prospectively and enable programmed discontinuation of immunosuppression in selected recipients earlier in the course of transplantation deserves further systematic study. Extended criteria donor (ECD) kidneys permit successful transplantation especially among transplant candidates with poor expected waitlist survival, such as the elderly and those with diabetes.9 However, delays in the placement of ECD kidneys are associated with increased cold ischemia times (CITs) and a high rate of discard of such organs. A recent study using data from the Scientific Registry of Renal Transplant Recipients examined the effect of increasing CITs on graft survival among recipients of paired kidneys (kidneys from the same deceased donor transplanted to two different recipients where one donor had delayed graft function and the other did not). 10 Longer CITs were associated with increasing incidence of delayed graft function. However, graft survival did not signifi­cantly differ across the range of CITs studied. Although this study is limited by

its retrospective nature and is prone to selection bias, it provides some impetus to reconsider discard of ECD kidneys with higher CITs and optimize ECD utilization and acceptance. The articles summarized above provide food for thought and prospects for further inquiry in coming years. We look forward to fruitful developments in these and related areas in clinical transplantation. Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA (T. R. Srinivas). Division of Nephrology, University of Arizona School of Medicine, 1501 North Campbell Avenue, Tucson, AZ 85724, USA (B. Kaplan). Correspondence to: B. Kaplan bkaplan@deptofmed.arizona.edu Competing interests The authors declare no competing interests. 1.

Larsen, C. P. et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am. J. Transplant. 5, 443–453 (2005). 2. Vincenti, F. et al. A phase III study of belataceptbased immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am. J. Transplant. 10, 535–546 (2010). 3. Vincenti, F. et al. Three-year outcomes from BENEFIT, a randomized, active-controlled, parallel-group study in adult kidney transplant recipients. Am. J. Transplant. http://dx.doi.org/ 10.1111/j.1600–6143.2011.03785.x. 4. Montgomery, R. A. et al. Desensitization in HLAincompatible kidney recipients and survival. N. Engl. J. Med. 365, 318–326 (2011). 5. Friedman, D. J., Kozlitina, J., Genovese, G., Jog, P. & Pollak, M. R. Population-based risk assessment of APOL1 on renal disease. J. Am. Soc. Nephrol. 22, 2098–2105 (2011). 6. Reeves-Daniel, A. M. et al. The APOL1 gene and allograft survival after kidney transplantation. Am. J. Transplant. 11, 1025–1030 (2011). 7. Newell, K. A. et al. for the Immune Tolerance Network ST507 Study Group. Identification of a B cell signature associated with renal transplant tolerance in humans. J. Clin. Invest. 120, 1836–1847 (2010). 8. Lozano, J. J. et al. Comparison of transcriptional and blood cell-phenotypic markers between operationally tolerant liver and kidney recipients. Am. J. Transplant. 11, 1916–1926 (2011). 9. Merion, R. M. et al. Deceased-donor characteristics and the survival benefit of kidney transplantation. JAMA 294, 2726–2733 (2005). 10. Kayler, L. K., Srinivas, T. R. & Schold, J. D. Influence of CIT-induced DGF on kidney transplant outcomes. Am. J. Transplant. 11, 2657–2664 (2011).

JANUARY 2012  |  S53


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NEUROLOGY STROKE IN 2011

Major advances across the spectrum of stroke care Lee H. Schwamm

Several pivotal clinical trials that could have a major impact on the care of patients with stroke were published in 2011. The studies cover a wide range of stroke-care aspects, including stroke prevention, imaging to select patients for thrombolysis, therapies for stroke recovery, and stroke registries to improve care quality. Schwamm, L. H. Nat. Rev. Neurol. 8, 63–64 (2012); published online 10 January 2012; doi:10.1038/nrneurol.2011.225

The current framework for analyzing the complete spectrum of stroke care is conceptualized in the ‘stroke systems of care’ model1 (Figure 1), as delineated in a policy statement of the American Stroke Association in 2005. The model specifies seven domains of care—primary prevention; community education; notification and response of emergency medical services; acute stroke treatment; subacute stroke treatment and secon­dary prevention; rehabili­tation; and con­tinuous quality improvement ­activities—and emphasizes the links between them. In 2011, five domains of the stroke systems of care model have witnessed major breakthroughs that have the potential to dramati­cally influence the delivery of stroke care now and in the future, thereby further eroding the therapeutic nihilism that still surrounds much of stroke treatment. Nonvalvular atrial fibrillation is a major preventable cause of first ever and recurrent stroke. Warfarin has been the mainstay of therapy for almost half a century, but it has a narrow therapeutic range that is difficult to maintain in many patients, requires frequent monitoring, and is highly susceptible to drug and food interactions. The ARISTOTLE trial2 compared the oral direct factor Xa inhibitor apixaban with warfarin for efficacy in stroke prevention in over 1,800 patients with atrial fibrillation and an elevated stroke risk score. In both groups, just under 15% of patients had a prior myocardial infarction, and 20% had a prior stroke, transient ischemic attack or systemic embolism. The results showed that apixaban is superior to warfarin in reducing the risk of stroke or systemic embolism (incidence rates 1.27% versus 1.60% per year; HR 0.79; P <0.001 for non­inferiority; P = 0.01 for superiority). For every 1,000 patients treated for 1.8 years, use of apixaban KEY ADVANCES IN MEDICINE

instead of warfarin prevented a stroke in six patients, major bleeding in 15 patients, and death in eight patients. The superior efficacy of apixaban for stroke prevention manifested early during treatment, seeming to reach a maximum after about 12 months, whereas the reductions in major bleeding associated with this drug were evident throughout the 30 month trial period. Two recent trials identified alternative drugs that are as effective as warfarin in stroke prevention: dabigatran,3 an oral direct thrombin inhibitor, and rivaroxaban,4 another factor Xa inhibitor. These new drugs represent major advances for stroke prevention, but they offer convenience at a higher cost, and no rapid reversal agents exist to manage acute, life-threatening bleeding resulting from these agents. Whether the benefits of these new drugs are maintained in the clinic, and whether the reduced medical contact for patients receiving oral anticoagulation has deleterious effects, remains to be seen. Intracranial atherosclerotic stenosis is a major risk factor for stroke. This risk was quantified in the WASID trial,5 with approxi­ mately 20% of patients who received war­farin or aspirin experiencing a stroke in the affected brain area over 1.8 years. The increased mortality associated with war­farin, and the lack of any difference between warfarin and aspirin in stroke prevention, justified evaluation of a more aggressive intervention than warfarin or aspirin alone. In the SAMMPRIS trial,6 patients with sympto­matic intra­cranial artery stenosis of at least 70% received inten­sive medical therapy (dual antiplatelet therapy for 90 days, lipid-lowering drugs, hyper­tension control, and lifestyle modification) alone or in combination with intracranial stenting. The trial was halted early owing to un­expectedly

Continuous quality improvement activities

–5 – –4 – –3 – –2 – –1 – –0

Primary prevention

Rehabilitation

Community education

EMS response

Secondary prevention

Acute treatment

Figure 1 | The ‘stroke systems of care’ model defines a spectrum of seven domains that cover all aspects of stroke care. 2011 saw key advances in primary prevention, acute treatment, secondary prevention, rehabilitation, and continuous quality improvement activities. Abbreviation: EMS, emergency medical services. MRI scan adapted from Asdaghi, N. & Coutts, S. B. Nat. Rev. Neurol. 7, 6–7 (2011).

high rates of stroke or death associated with stenting. The SAMMPRIS trial design was based on estimates of adverse-event rates in open-label stent registries, which were probably too low. Importantly, the increased rate of adverse events in the stenting group was not associated with operator inexperience, and seems, therefore, to be a patient-related or device effect. Of equal importance, the SAMMPRIS trial6 highlights the fact that historical controls or placebo arms of prior trials may not reflect the impact of modern intensive risk-­reduction strategies on l­owering rates of stroke. JANUARY 2012  |  S55


NEUROLOGY Key advances ■■ Apixaban is superior to warfarin in reducing the risk of stroke or systemic embolism, and is safer in reducing the risk of major bleeding or death2 ■■ Intracranial stenting produces higher rates of stroke and death than an intensive medical management strategy for severe symptomatic atherosclerotic stenosis6 ■■ A standardized computer algorithm for post-processing of MRI scans may be superior to individual visual estimation for selecting patients for thrombolytic therapy8 ■■ A combination of fluoxetine and physical therapy could produce greater improvements in limb motor function after stroke than physical therapy alone9 ■■ Hospitals are rapidly adopting stroke quality improvement registries, which could reduce mortality, cost and complications of stroke by increasing the use of evidence-based therapies10

When prevention fails, acute stroke manage­ment begins. Early reperfusion of ische­mic tissue is the primary goal, which is reflec­ted in the mechanism of action of the only FDA-approved therapy for improving stroke outcomes: tissue plasminogen activator. The proportion of patients who are eligible for thrombolysis, however, remains disappointingly low, owing largely to the narrow time window for this treatment and exclusion of patients with mild stroke. Considerable efforts have been made to develop imaging biomarkers of the acute ischemic ‘penumbra’—brain tissue surrounding the lesion core that is vulnerable but salvageable with early reperfusion—in an attempt to expand the number of patients who can receive reperfusion therapy. Supporters of MRI-based patient selection for thrombolysis were dealt a blow 3 years ago when the DIAS-2 trial7 failed to meet its primary end point, as it used a widely accepted definition of the penum­bra based on a mismatch between the volumes of ische­mic brain tissue measured on diffusion versus perfusion MRI. The MRI-mismatch approach to patient selection could be improved by the use of a standard­ized computer algorithm for post-processing of MRI scans, as suggested by a recent pooled analysis8 of the EPITHET and DEFUSE trials. The study emphasizes the importance of human error and inter-operator variability when visual inspection, rather than automated techniques, is used to determine suitability for reperfusion treatment. Ongoing trials are evaluating alternative strategies of MRI-based patient selection for intravenous S56  |  JANUARY 2012



reperfusion (MR WITNESS and EXTEND) or intra-arterial reperfusion (MR RESCUE). Patients with acute ischemic stroke are almost always left with a degree of dis­ability that requires rehabilitative treatment. Early studies suggested that constraint therapy (immobilization of the ‘good’ arm to encourage use of the affected arm) and pharmacological stimulants could modulate brain plasticity after stroke and reduce the residual neurological deficit and subsequent dis­ ability. However, large-scale, well-designed randomized controlled trials to support these initial findings have not been performed. Important evidence for a beneficial effect of the antidepressant fluoxetine in stroke recovery was provided in 2011 by the FLAME trial.9 In this phase II study, all patients received physiotherapy, and those who were randomly assigned to the fluoxe­ tine group showed significantly greater improvement in motor function of the affected arm and leg at 90 days poststroke than did those assigned to the placebo group. Interestingly, differences between the study groups were still signifi­cant after adjustment for depression or thrombolytic use, sug­gesting that fluoxetine could be beneficial across many subgroups. The findings, which need to be confirmed in larger trials, hold promise for thousands of stroke survivors who may benefit from this and other re­covery strategies to facilitate brain plasticity. With mounting pressure on funding and resources in the current economic down­ turn, efficient health-care delivery is becoming increasingly important. The Ameri­can Heart Association’s ‘Get with The Guide­ lines®-Stroke’ (GWTG-Stroke) quality improve­ment registry tracks characteristics, performance measures, and in-hospital outcomes in nearly 2 million patients admitted to almost 2,000 US hospitals with stroke or transient ischemic attack, and provides valuable information on the effectiveness and safety of care delivery.10 This registry has played a vital part in the defini­tion, assessment and validation of hospital performance metrics that have become the standard for measuring stroke-care quality. The latest GWTG-Stroke study 10 suggests that although in-hospital mortality may be lower at registry sites, the results are largely generalizable to patients in non-registry hospitals. The measures defined by GWTG-Stroke are among the first to be incorporated into a new, electronically derived set of quality measures in the Meaningful Use program, which aims to shift health records to an electronic system

and define quality metrics in a more affordable, actionable and cost-effective manner. Strategies that seek to minimize the costly practice of capturing patient-level clinical information while maximizing the use of more cost-effective, administratively derived health records are likely to form the backbone of future quality improvement efforts. Together, the advances described above reflect progress across the spectrum of stroke care (Figure 1). From novel drug or device development to new uses for approved drugs, every step forward takes us closer to the ultimate goal of better outcomes at lower cost for patients with stroke and their families. Department of Neurology-ACC 720, Harvard Medical School, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. lschwamm@partners.org Competing interests The author declares no competing interests. 1.

Schwamm, L. H. et al. Recommendations for the establishment of stroke systems of care: recommendations from the American Stroke Association’s Task Force on the Development of Stroke Systems. Circulation 111, 1078–1091 (2005). 2. Granger, C. B. et al. Apixaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 365, 981–992 (2011). 3. Diener, H.‑C. et al. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischemic attack or stroke. Lancet Neurol. 9, 1157–1163 (2010). 4. Patel, M. R. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N. Engl. J. Med. 365, 883–891 (2011). 5. Chimowitz, M. I. et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N. Engl. J. Med. 352, 1305–1316 (2005). 6. Chimowitz, M. I. et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N. Engl. J. Med. 365, 993–1003 (2011). 7. Hacke, W. et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion–diffusion weighted imaging or perfusion CT (DIAS‑2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol. 8, 141–150 (2009). 8. Lansberg, M. G. et al. RAPID automated patient selection for reperfusion therapy: a pooled analysis of the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) and the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) study. Stroke 42, 1608–1614 (2011). 9. Chollet, F. et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol. 10, 123–130 (2011). 10. Reeves, M. J. et al. Representativeness of the Get With The Guidelines-Stroke Registry: comparison of patient and hospital characteristics among medicare beneficiaries hospitalized with ischemic stroke. Stroke http://dx.doi.org/10.1161/ STROKEAHA.111.626978.

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NEUROLOGY MOVEMENT DISORDERS IN 2011

Translating new research findings into clinical practice Christine Klein and Dimitri Krainc

The discovery of mutations that contribute to movement disorders has facilitated the identification of converging pathways and novel therapeutic targets. Successful translation of these research findings into clinical practice will require identification of early markers of disease progression, and recent research indicates that progress is being made in this area. Klein, C. & Krainc, D. Nat. Rev. Neurol. 8, 65–66 (2012); published online 20 December 2011; doi:10.1038/nrneurol.2011.212

The prevalence of Parkinson disease (PD) and other neurodegenerative disorders is rapidly increasing worldwide and is expected to double by 2030,1 yet not a single disease-modifying treatment exists for this disorder. Thus, translation of research findings into all aspects of clinical practice—that is, diagnosis, monitoring and treatment—in movement disorders is a high priority. One of the major challenges of translational research in movement disorders has been the apparent lack of specific molecular tar­ gets as platforms for drug development. How­e ver, as highlighted by a number of important studies published in 2011, the emergence of various forms of genetic PD has offered us an exciting opportunity to identify such targets.

‘‘

Identification and monitoring of the earliest disease stages … is of great importance

’’

Most mutations that have been linked to PD and related synucleinopathies seem to converge on lysosomal and mito­chondrial pathways, suggesting that disruptions of these pathways have key roles in disease pathogenesis. The importance of lysosomal function in synucleinopathies was highlighted in a recent study by Mazzulli and colleagues that examined Gaucher disease, a rare lysosomal storage disorder caused by mutations in the glucocerebro­sidase (GBA1) gene.2 Patients with Gaucher disease and their relatives have an increased incidence of PD, and patients with idiopathic PD have an elevated prevalence of mutations in GBA1. Interestingly, accumulated α‑synuclein interferes with trafficking of glucocerebro­ sidase from the endo­p lasmic reticulum to the Golgi apparatus, which in turn leads to decreased glucocerebrosidase activity and KEY ADVANCES IN MEDICINE

more accumulation of α‑synuclein. The bidirectional effects of α‑synuclein and glucocerebro­sidase form a positive feedback loop that, beyond a certain threshold, leads to self-propagating disease. The findings suggest that this molecular pathway applies also to patients with idiopathic PD or other synucleinopathies who carry a normal GBA1 gene. The results indicate that therapeutic targeting of mutated or normal gluco­cerebrosidase to lysosomes would be expected to prevent or diminish the formation of toxic α‑synuclein oligomers and break the vicious circle of α‑synuclein aggregation and toxicity. Importantly, these findings were confirmed in human neurons derived from induced pluripotent stem cells,2 which represent a major advance for the modeling of neurodegenerative and other diseases.3 The importance of lysosomal pathways in PD was further highlighted in two backto-back publications by Vilarino-Guell et al.4 and Zimprich et al.5 that described a dominantly inherited mutation in the vacuo­lar protein sorting 35 (VPS35) gene as a novel, albeit rare, cause of late-onset PD. As a component of the retromer complex, VPS35 sorts cargo from endosomes back to the trans-Golgi network, and disruptions in this pathway are expected to affect lysosomal function. Intriguingly, both studies detected the same VPS35 mutation (Asp620Asn), in Swiss and Austrian kindreds, respectively, and the same mutation was also recently identified in a German pedigree.6 When the analyses were extended to additional families from various ethnic backgrounds, both initial studies confirmed the Asp620Asn mutation in independent cases and found two additional variants in the VPS35 gene.4,5 On the basis of these studies, and previous data showing that the retromer regulates endosomal sorting of amyloid precursor

protein in models of Alzheimer disease, it will be interesting to examine the role of VPS35 in the pathogenesis of PD. These studies also highlight the importance of next-generation sequencing for the dis­ covery of genetic factors—many of which are likely to be rare—that cause or ­contribute to complex movement disorders.7 Besides improving our understanding of disease biology, the identification of monogenic forms of movement disorders has opened up a new window into the pre­motor stage of neurodegenerative conditions—the historical frontrunner being Huntington disease—whereby individuals at risk can be studied prospectively. Identification and monitoring of the earliest disease stages, during which treatment and neuro­ protection are expected to be most effective, is of great importance. Selection of carefully characterized and homogeneous cohorts of patients or at-risk individuals will be vital for the development of new drugs for PD and other movement disorders. This task would be greatly facilitated by employing adequate biomarkers for diagnosis of the disease, and for monitoring its course and potential effects of treatment. In a study published in PLoS ONE, Yanamandra et al. hypothesized that autoimmune reactivity towards specific proteins and self-assembled complexes that are involved in disease pathology may serve as sensitive biomarkers of neuro­ degeneration.8 The researchers measured Key advances ■■ α-Synuclein and glucocerebrosidase form a bidirectional pathogenic loop, providing an important pathophysiological mechanism in the development of Parkinson disease (PD)2 ■■ Next-generation sequencing has led to the discovery of a new gene (VPS35) associated with late-onset PD; this finding implicates retrograde transport in PD pathogenesis4,5 ■■ α-Synuclein-reactive antibodies may serve as a new biomarker for PD, especially in its early phase8 ■■ Induced pluripotent stem cell-derived neurons represent a patient-specific cellular model with great potential for the study of disease biology2 ■■ The first double-blind, sham-surgerycontrolled, randomized trial of viral gene transfer of glutamic acid decarboxylase resulted in improved motor scores in patients with PD, and the treatment was not associated with severe adverse events9

JANUARY 2012  |  S57


NEUROLOGY levels of auto­antibodies against α‑synuclein, the main component of Lewy bodies, in the serum of patients with PD in early and late stages of the disease. Significantly higher auto­antibody levels were found in patients than in controls, but the antibody response decreased as the condition became more advanced. The authors interpreted this find­ing in the context of a protective role for auto­immunity in PD that seems to be stronger in the early phases of the disease, and may be of value as a biomarker, especially at this crucial stage of PD pathogenesis.

‘‘

…the treatment of PD has been limited to symptomatic drug therapy and deep brain stimulation

’’

In the absence of neuroprotective therapies, the treatment of PD has been limited to symptomatic drug therapy and deep brain stimulation. To explore the potential of gene therapy, LeWitt and colleagues performed the first double-blind, shamsurgery-­c ontrolled, randomized trial of in vivo gene transfer in patients with PD.9 The investigators used adeno-associated viral vector (AAV2) for transduction of the gene encoding glutamic acid decarboxylase (GAD), an enzyme that catalyzes the decarb­oxylation of glutamate to γ‑aminobutyric acid and is expected to increase the inhibitory tone in the basal ganglia. The trial involved 55 patients aged 30–75 years with levodopa-responsive PD, who were randomly assigned to sham surgery (n = 23) or AAV2–GAD infusions (n = 22) at baseline. At the 6‑month study end point, 21 and 16 patients were assessed in the shamtreated and gene-therapy groups, respectively. The mean Unified Parkinson’s Disease Rat­ing Scale (UPDRS) motor score was found to have decreased by 8.1 points (23.1%) in the AAV2–GAD group and by 4.7 points (7.0%) in the sham group. 9 Over­all, the study is encouraging, since the group dif­ference was highly significant and no serious adverse events were observed in either group. Caveats of this study include rela­tively small group sizes, a heterogeneous patient population in terms of age of onset, more-severe dis­e ase in the sham group, limited dis­criminatory power of the UPDRS (maximum 108 points) in the lower range, and the relatively short follow-up period. In conclusion, these studies highlight the importance of identifying the molecular S58  |  JANUARY 2012



underpinnings of disease pathways to uncover therapeutic targets. The discovery of genetic mutations in these pathways has sug­gested converging mechanisms in the patho­genesis of movement disorders. In order to rapidly translate research advances into the clinic, it is critically important to iden­t ify markers of disease progression, especially in individuals who are at risk of developing a neurodegenerative disease. Department of Neurology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany (C. Klein). Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Room 2007, Charlestown, MA 02129, USA (D. Krainc). Correspondence to: C. Klein christine.klein@neuro.uni-luebeck.de Acknowledgments C. Klein is funded by a career development award from the Hermann and Lilly Schilling Foundation. D. Krainc is supported by the National Institute of Neurological Disorders and Stroke and the CHDI Foundation. Competing interests The authors declare no competing interests.

1.

2.

3.

4.

5.

6.

7.

8.

9.

Dorsey, E. R. et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology 68, 384–386 (2007). Mazzulli, J. R. et al. Gaucher disease glucocerebrosidase and α‑synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 146, 37–52 (2011). Kiskinis, E. & Eggan, K. Progress toward the clinical application of patient-specific pluripotent stem cells. J. Clin. Invest. 120, 51–59 (2011). Vilarino-Guell, C. et al. VPS35 mutations in Parkinson disease. Am. J. Hum. Genet. 89, 162–167 (2011). Zimprich, A. et al. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am. J. Hum. Genet. 89, 168–175 (2011). Kumar, K. W. et al. Frequency of the D620N mutation in VPS35 in Parkinson disease. Arch. Neurol. (in press). Lill, C. M. & Bertram, L. Complex genetics of neurodegenerative diseases. Semin. Neurol. (in press). Yanamandra, K. et al. α‑Synuclein reactive antibodies as diagnostic biomarkers in blood sera of Parkinson’s disease patients. PLoS ONE 6, e18513 (2011). LeWitt, P. A. et al. AAV2–GAD gene therapy for advanced Parkinson’s disease: a double-blind, sham-surgery controlled, randomised trial. Lancet Neurol. 10, 309–319 (2011).

MULTIPLE SCLEROSIS IN 2011

Advances in therapy, imaging and risk factors in MS Bianca Weinstock–Guttman and Murali Ramanathan

Multiple sclerosis research in 2011 produced a combination of new therapeutic developments and innovative findings. Teriflunomide showed beneficial effects in a phase III trial, quantification methods for MRI lesions that should improve monitoring of disease progression were devised, and a link between high cholesterol and low vitamin D emerged. Weinstock–Guttman, B. & Ramanathan, M. Nat. Rev. Neurol. 8, 66–68 (2012); published online 10 January 2012; doi:10.1038/nrneurol.2011.213

For multiple sclerosis (MS), the research milestones of 2011 were a combination of new therapeutic developments and innovative findings that might help to explain the heterogeneity in both disease progression and responses to therapy in patients with MS. The new oral therapy teriflunomide showed beneficial effects in a large phase III clinical trial,1 which provides hope for better and more-convenient control of MS in the future. The identification of new methods to quantify cortical lesions on MRI will improve our ability to monitor disease progression,2 and studies have identified raised cholesterol and reduced vitamin D levels as detrimental factors in patients with MS.3,4

From a therapeutic standpoint, 2011 will be remembered as a defining year for MS. Following a successful clinical trial, reported in 2010, 5 fingolimod—an oral d ­ isease-modifying therapy for MS— received regulatory approval and became available to patients in over 50 countries including the USA, the European Union and, most recently, Japan. The results from a phase III clinical trial of teriflunomide (another oral therapy for MS) were published in October 2011 in The New England Journal of Medicine.1 Teriflunomide is the active metabolite of leflunomide, which is already approved for the treatment of patients with rheumatoid arthritis, and it www.nature.com/reviews


NEUROLOGY acts by reversi­bly inhibiting dihydroorate dehydrogenase, a key mitochondrial enzyme involved in pyrimidine synthesis, to block the proliferation of rapidly dividing lymphocytes that are thought to drive inflammation in MS. The trial reported by O’Connor et al.1 involved 1,088 patients with active relapsing– remitting MS (RRMS)—defined as one or more relapse in the previous year or two or more relapses in the previous 2 years— ranging in age from 18–55 years. Patients were randomly assigned to receive either teriflunomide (7 mg or 14 mg), or placebo, once daily for 108 weeks. The primary end point was the annualized relapse rate, and the secon­dary end point was confirmed progression of dis­ability for at least 12 weeks. Compared with placebo, teriflunomide reduced the annualized relapse rate by 31.2% and 31.5% in the 7 mg and 14 mg dose groups, respectively (P <0.001). The proportion of patients with confirmed disability progression was 27.3% with placebo, 21.7% with 7 mg teriflunomide (P = 0.08), and 20.2% with 14 mg teriflunomide (P = 0.03). Teriflunomide therapy reduced the risk of disability progression by 23.7% (P = 0.008) for 7 mg and 29.8% (P = 0.03) for 14 mg.

‘‘

From a therapeutic standpoint, 2011 will be remembered as a defining year for MS

’’

Both teriflunomide doses were sup­ erior to placebo on multiple MRI end points, including change in lesion volume from base­line, number of gadolinium contrast-enhancing lesions, and unique active lesions. How­ever, no differences in brain atrophy were observed between the teriflunomide-treated and placebo-treated groups. Adverse events, such as diarrhea, nausea and hair thin­n ing, were more common in t­ eriflunomide-treated patients than in patients who received placebo, and the incidence of elevated ala­nine aminotransferase levels (a sign of liver damage) was higher in patients who received teriflunomide at 7 mg and 14 mg (54.0% and 57.3%, respectively) than in those who received placebo (35.9%). The incidence of serious infections was similar across the two treatment groups and the placebo group. The beneficial therapeutic effects and safety profile seen in teriflunomidetreated patients suggests that this new oral drug should be considered in the evolving therapeutic a­ rmamentarium for MS. KEY ADVANCES IN MEDICINE

The Expanded Disability Status Score (EDSS) is often used as an outcome measure­ ment in clinical trials; however, the poor sensitivity of this scoring system limits its usefulness. The idea that lesions in patients with MS occur not only in the white matter, but also in cerebral gray matter, especially in the cerebral cortex, is now well-accepted.6 Reporting in PLoS ONE, Sormani et al.2 used double inversion recovery imaging—an MRI technique that enables selective imaging of gray matter—to detect cortical lesions in patients with RRMS. Cortical lesions could be seen in patients at the earliest clinical stages of MS, and lesion burden correlated positively with the severity of physical and cognitive impairments. Sormani and colleagues showed that the zero-inflated Poisson distribution accurately modeled the distribution of new cortical lesions that developed over 12 and 24 months.2 The researchers also estimated the sample size needed for clinical trials that use emergence of new cortical lesions as the primary outcome measure. A clinical trial with an assumed treatment effect of 50%, with 90% power and a significance level of 5%, would require a sample size that ranged from 72 to 200 patients per treatment group for a 1‑year trial and from 48 to 110 patients for a 2‑year trial. Assuming a treatment effect of 30%, the estimated sample size was 212 to 630 patients per arm for a 1‑year trial and 150 to 320 for a 2‑year trial. These results suggest that clinical trials with the number of new cortical lesions as the primary outcome are feasible. Cortical lesion measurements may become a useful marker of disease progression in patients with MS, especially in the evaluation of the neuroprotective and regenerative effects of new therapeutic agents. 2011 has seen an increase in research into the roles of environmental risk factors, genetic and environmental interactions, and comorbidities in determining the severity of disease in patients with MS. High cholesterol is a well-established risk factor for cardio­ vascular disease, but the role of lipids as a risk factor for MS has not been extensively investigated. In a study from our group, published in October 2011 in The Journal of Neuroinflammation, we used clinical and MRI metrics to identify lipid profiles that were associated with disease progression.3 492 patients with MS (age 47.1 ± 10.8 years; disease duration 12.8 ± 10.1 years), who had baseline and follow up EDSS assessments after a mean period of 2.2 ± 1.0 years, were included in the study. Quantitative MRI

Key advances ■■ Teriflunomide—a new oral immunomodulatory therapy—showed significant benefit in reducing relapses and slowing disease progression in a large phase III clinical trial in patients with multiple sclerosis (MS)1 ■■ New MRI methods that used double inversion recovery imaging were shown to detect cortical lesions, which may be useful as measurements of disease progression in clinical trials2 ■■ Disease progression in MS was linked to lipid profiles; high cholesterol was shown to negatively affect vitamin D levels in patients with the disease3,4

findings at baseline were available for 210 patients. Worsening of disability was associ­ ated with higher baseline LDL (P = 0.006) and total cholesterol levels (P = 0.001), and patients with higher triglycerides showed a trend towards worse EDSS outcomes (P = 0.025). However, no association was observed between baseline HDL levels and clinical outcome. A similar association between high LDL and disease worsening was found when we used the MS severity scale. However, patients with high HDL levels had lower contrastenhancing lesion volumes than patients with low HDL (P <0.001) and high total chol­ esterol was associated with a trend for lower brain parenchymal fraction (P = 0.033). These data suggest that high cholesterol and triglycerides have a negative influence on disease course, and that high HDL levels have a favorable influence on acute MRI inflammatory activity in patients with MS.

‘‘

Cortical lesion measurements may become a useful marker of disease progression in patients with MS…

’’

High levels of serum cholesterol and lipids may have both direct and indirect effects on MS disease progression. Lipoproteins could directly enhance inflammation in patients with MS, and as 7‑dehydrocholesterol is a substrate for the endogenous synthesis of vitamin D in the skin, high cholesterol may have indirect effects on vitamin D. Indeed, we found that patients with a high ratio of cho­lesterol to HDL had reduced levels of vita­min D.4 Lifestyle changes to improve serum lipid profiles, such as adoption of a healthier diet and regular exercise, may be beneficial for patients with MS. JANUARY 2012  |  S59


NEUROLOGY In summary, research in 2011 conveyed new findings to help us to understand, treat and prevent disease progression in patients with MS. Better imaging of cortical lesions could provide insights into the patho­biology of MS and may yield new outcome measures for MS clinical trials. Advances in understanding the environmental factors that are associated with disease progression in MS could facilitate the development of better therapies and personalized management for patients with this disabling disease. Jacobs Neurological Institute, Buffalo General Hospital, University at Buffalo, State University of New York, Building E, 2nd Floor, 100 High Street, Buffalo, NY 14203, USA (B. Weinstock‑Guttman). Department of Pharmaceutical Sciences and Neurology, State University of New York, 427 Cooke Hall, Buffalo, NY 14260, USA (M. Ramanathan). Correspondence to: B. Weinstock–Guttman bguttman@thejni.org Acknowledgments The authors would like to thank the Department of Defense, the Jog for The Jake Foundation, National Multiple Sclerosis Society, National Science Foundation and NIH for providing financial support for their research activities.

Competing interests B. Weinstock–Guttman declares associations with the following companies and organizations: Acorda, Biogen Idec, Cyberonics, EMD Serono, Novartis, Pfizer, Teva Neuroscience. M. Ramanathan declares associations with the following companies and organizations: Allergan, the American Association of Pharmaceutical Scientists, Biogen Idec, EMD Serono, Netezza, Novartis, Pfizer. See the article online for full details of the relationships. 1.

2.

3.

4.

5.

6.

O’Connor, P. et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N. Engl. J. Med. 365, 1293–1303 (2011). Sormani, M. P. et al. Modeling the distribution of new MRI cortical lesions in multiple sclerosis longitudinal studies. PLoS ONE 6, e26712 (2011). Weinstock-Guttman, B. et al. Serum lipid profiles are associated with disability and MRI outcomes in multiple sclerosis. J. Neuroinflammation 8, 127 (2011). Weinstock-Guttman, B., Zivadinov, R. & Ramanathan, M. Inter-dependence of vitamin D levels with serum lipid profiles in multiple sclerosis. J. Neurol. Sci. 311, 86–91 (2011). Kappos, L. et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N. Engl. J. Med. 362, 387–401 (2010). Calabrese, M., Filippi, M. & Gallo, P. Cortical lesions in multiple sclerosis. Nat. Rev. Neurol. 6, 438–444 (2010).

DEMENTIA IN 2011

Microbleeds in dementia —singing a different ARIA Philip Scheltens and Jeroen D. C. Goos

In 2011, researchers used imaging techniques to investigate brain microbleeds in patients with dementia and highlighted how lobar microbleeds could be used as a marker for amyloid pathology and for predicting mortality. New guidelines on the inclusion and exclusion of participants with microbleeds in anti-amyloid clinical trials were also published. Scheltens, P. & Goos, J. D. C. Nat. Rev. Neurol. 8, 68–70 (2012); published online 10 January 2012; doi:10.1038/nrneurol.2011.222

Following initial reports of small dotlike lesions on gradient-echo MRI in the brains of patients with dementia (Figure 1), many investigators set out to describe the prevalence and incidence of these lesions—later designated as micro­bleeds or m ­ icrohemorrhages—in both healthy people and individuals with this condition. Prevalence rates varied from 10% in healthy elderly individuals to 60% in patients with vascular dementia.1 Interest in these lesions peaked when the first cases of incident micro­bleeds along with increased signal inten­sity on fluid-attenuated inversion recovery imaging, thought to represent vaso­genic edema, were reported in patients receiving S60  |  JANUARY 2012



amyloid-lowering therapy. During the 2010 Inter­national Conference on Alzheimer Disease (AD), turmoil ensued over a cautionary letter from the FDA, which suggested drastic cut-offs in randomized clinical trials of amyloid-lowering drugs, both in terms of excluding patients with a single microbleed and terminating the participation of patients who developed a new microbleed during the study. In response, a series of important papers regarding the detection, prevalence and clinical relevance of microbleeds in patients with dementia-related disease appeared in 2011, includ­ing a consensus statement from an inter­national working group that introduced new terminology.

At the beginning of 2011, Cordonnier and van der Flier reviewed the available litera­ture on brain microbleeds in patients with AD. 1 The authors suggested that these lesions were associated with amyloid pathology and may have a crucial role in the pathophysiology of AD. Microbleeds were proposed to represent a link between the amyloid cascade hypo­thesis and the vascular ­hypothesis—both popular explanatory models for the pathogenesis of AD. Further­ more, the location of the microbleeds was suggested to indicate their underlying etio­ logy: lobar microbleeds would presumably be associated with cerebral amyloid angio­ pathy (CAA), whereas microbleeds in deep brain regions would be associated with hypertensive vasculopathy and increased risk of vascular complications. The clinical implications of microbleeds in patients with dementia were also stressed. Besides an association with cognition, micro­bleeds have been linked to mortality, especially in cases of multiple lesions, as described by Henneman et al. in a 2009 study.2 These investigators did not, however, assess the cause of death in their patients. Throughout 2011—within months of publication of the review by Cordonnier and van der Flier 1—reports were published on several studies that have substantially extended our knowledge on microbleeds in patients with dementia-associated diseases. The suggestion that micro­b leeds were closely linked to amyloid pathology was supported by the findings of Yates et al. for the Australian Imaging, Bio­m arkers and Lifestyle Study of Ageing Research Group.3 They found that even in healthy con­trols, lobar microbleeds (detected using 3T ­susceptibility-weighted imaging [SWI]) were associated with higher amyloid burden, as seen on 11C-Pittsburgh compound B (PiB) PET imaging. Moreover, PiB-positive scans were more prevalent in participants with multiple lobar microbleeds (86%) than in those with only one lobar microbleed (67%). In agreement with these findings, results from a study by Goos et al.,4 in which cerebro­spinal fluid amyloid biomarkers were used to assess amyloid burden, confirmed the relationship between lobar microbleeds and amyloid pathology. Altmann–Schneider and colleagues studied the relationship between microbleeds and mortality (with assessment of the cause of death) in a population of 435 elderly people with pre-existing vascular dis­ease.5 Individuals with more than one microbleed had a sixfold increase in the risk www.nature.com/reviews


NEUROLOGY of stroke-related death compared with those with no lesions. The location of the lesions also affected the risk of poor clinical outcomes: compared with individuals without any lesions, patients with nonlobar microbleeds had a twofold increase in the risk of cardiovascular death, and indivi­duals with probable CAA type (lobar) microbleeds had a sevenfold increase in the risk of strokerelated death. These findings support the hypothesis that microbleeds have separate etiologies depending on their location in the brain,1 and may provide an indication for the use of anticoagulant treatment in patients with these lesions—in particular, those with lobar microbleeds. The importance of detecting microbleeds before and during clinical trials was underlined in an extensive review on amyloidrelated imaging abnormali­ties (ARIA) by Sperling et al. for the Alzheimer’s Associ­ ation Research Roundtable Work­g roup.6 These imaging abnormalities, seen on MRI, are thought to represent a spectrum of ‘leaky vessels’ that occur following anti-­amyloid immunization therapy. The working hypo­ thesis was that vasogenic edema (now called ARIA-E) caused leakage only of protein­ aceous fluids from the vessels, whereas microbleeding—under the new umbrella term ARIA-H (for h ­ emorrhage)—caused more-extensive leakiness of the vessels that allowed blood cells to cross the blood– brain barrier. For patients in clinical trials, the presence of microbleeds at baseline may be a risk factor for developing ARIA, Key advances ■■ Lobar microbleeds in patients with dementia were found to be associated with high amyloid burden3 ■■ Microbleeds were shown to have different etiologies and associated risk of mortality on the basis of their location in the brain5 ■■ New terminology for amyloid-related imaging abnormalties (ARIA) and a new cut-off point for microbleeds in participants of amyloid-modifying clinical trials were introduced6 ■■ Susceptibility-weighted imaging showed enhanced sensitivity for detecting microbleeds compared with gradientecho imaging, and may help in future for identifying associations between microbleeds and clinical outcomes7 ■■ Studies that compared imaging with histopathology of microbleeds suggest that further refinement of imaging techniques is required to accurately detect these lesions8

KEY ADVANCES IN MEDICINE

as the number of lobar lesions is assumed to ­correlate with the presence and severity of CAA. Given the uncertainty regarding the risk of ARIA and concerns about CAA severity, Sperling et al. recommended a cut-off value for the exclusion of participants in trials of amyloid-modifying therapies for AD at four microbleeds.6 This new guideline allows for variability in imaging measurements and reflects the uncertainty regarding the clinical relevance of small numbers of microbleeds. The authors further stated that occurrence of new asymptomatic microbleeds in patients during trials should not auto­matically disqualify them from receiving further treatment; however, owing to a lack of data, no exact cut-off for dis­qualification could be given. As the authors stressed, counting of microbleeds is not an exact science, and the uncertainty is further complicated by the varying sensitivities of different MRI techniques for detecting these lesions. Reporting in Stroke in May 2011, Goos et al.7 compared conventional gradient-echo imag­ing with SWI to detect microbleeds in 140 patients from a memory clinic, and also to determine whether microbleeds were associated with patient and clinical characteristics. As expected, use of the more-advanced SWI technique enabled identi­fication of patients with microbleeds with a greater sensitivity than could be achieved with gradient-echo imaging (40% versus 23%). SWI also detected a higher num­b er of microbleeds per patient than did gradient-echo imaging. However, the corre­lation between lesion numbers, clinical out­comes and other radiological outcomes was limited. The clinical relevance of microbleeds will probably depend more on their location and size, than on the total number of lesions per se. The authors concluded, therefore, that although new imaging techniques can show a higher number of lesions, conventional imaging methods can already detect the majority of clinically relevant lesions. New imaging methods might help in identifying any associations between lesions and clinical and radiological outcomes; however, these new techniques are in urgent need of validation. De Reuck et al. 8 made an interesting attempt to validate MRI findings with patho­logy, as reported in Cerebrovascular Disorders. The researchers investigated 20 post­mortem brains from patients with AD with different cerebrovascular lesions. Images of 45 large sections of the cerebral hemi­spheres, brainstem and cere­b ellum

Figure 1 | Brain microbleeds on MRI. Numerous lobar microbleeds with sparing of the basal ganglia and thalamus, suggestive of severe cerebral amyloid angiopathy in a 71-year-old patient with dementia with Lewy bodies. Image obtained using susceptibility-weighted imaging at 3T.

obtained using 7.0T T2*-weighted MRI were paired with images showing histo­ logical detection of hematomas and microbleeds. In the cortico-­subcortical regions, the sensitivity, specificity, and positive and negative predictive values of T2* imag­ ing to detect microbleeds were excellent. How­e ver, analysis of MRI alone resulted in an over­e stimation of microbleeds in the stria­tum due to the presence of iron de­p osits that were, in fact, not related to real hemor­rhages. Furthermore, 31% of T2* hypo­signals in the deep white matter were shown to be vessels filled with post­mortem thrombi. Judging from these findings, more studies are needed before we can fully understand the correlations between MRI and pathology in patients with AD. From this selection of studies published in 2011, we can conclude that lobar micro­ bleeds are a marker for underlying amyloid patho­logy, are associated with strokerelated mortality, and should be adequately investi­g ated in patients participating in anti-­amyloid clinical trials. Optimizaton of imaging methods to detect microbleeds will be of the utmost importance, and emerging techni­ques will need to be evaluated and calibrated using clinical and pathological correlates. VU University Medical Center, Alzheimer Center, Department of Neurology, De Boelelaan, 1118 1081 HZ Amsterdam, The Netherlands (P. Scheltens, J. D. C. Goos). Correspondence to: P. Scheltens p.scheltens@vumc.nl

JANUARY 2012  |  S61


NEUROLOGY Competing interests The authors declare no competing interests.

5.

1.

6.

2.

3.

4.

Cordonnier, C. & van der Flier, W. M. Brain microbleeds and Alzheimer’s disease: innocent observation or key player? Brain 134, 335–344 (2011). Henneman, W. J. et al. MRI biomarkers of vascular damage and atrophy predicting mortality in a memory clinic population. Stroke 40, 492–498 (2009). Yates, P. A. et al. Cerebral microhemorrhage and brain β-amyloid in aging and Alzheimer disease. Neurology 77, 48–54 (2011). Goos, J. D. C. et al. Microbleeds relate to altered amyloid-β metabolism in Alzheimer disease. Neurobiol. Aging http://dx.doi.org/ 10.1016/j.neurobiolaging.2011.10.026.

7.

8.

Altmann–Schneider, I. et al. Cerebral microbleeds are predictive of mortality in the elderly. Stroke 42, 638–644 (2011). Sperling, R. A. et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 7, 367–385 (2011). Goos, J. D. C. et al. Clinical relevance of improved microbleed detection by susceptibility-weighted magnetic resonance imaging. Stroke 42, 1894–1900 (2011). De Reuck, J. et al. Comparison of 7.0‑T T2*magnetic resonance imaging of cerebral bleeds in post-mortem brain sections of Alzheimer patients with their neuropathological correlates. Cerebrovasc. Dis. 31, 511–517 (2011).

EPILEPSY IN 2011

Insights into epilepsy treatments and biomarkers Fernando Cendes

Research published in 2011 identified important factors related to serious adverse effects of antiepileptic drugs and sudden unexpected death in epilepsy, along with a potential new treatment and a promising marker of epileptogenesis. Further advances in these areas are urgently needed to improve the lives of people with epilepsy. Cendes, F. Nat. Rev. Neurol. 8, 70–71 (2012); published online 10 January 2012; doi:10.1038/nrneurol.2011.223

Epilepsy affects people of all ages, is highly prevalent, and can have a good out­c ome with appropriate anti­e pileptic drugs (AEDs). However, seizures are often refractory to clinical treatment, with ­detrimental—and even life-threatening— consequences. 1 Unpredictable events, such as serious adverse effects of AEDs and sudden unexpected death in epilepsy (SUDEP), make this condition even harder to manage. The fact that epilepsy still carries a great stigma, with many people hiding their condition, hinders public awareness and, in addition, makes it more difficult for the condition to be recog­nized as a serious public health problem, resulting in reduced availability of research resources compared with other common diseases. Despite such obstacles, however, considerable advances are being made on a number of fronts, as illustrated by several key papers published during 2011. Sudden unexpected death is 20 times more frequent in people with epilepsy than in the general population, but the risk factors identified for SUDEP have not been consistent across the literature. A recent study by Hesdorffer et al. has helped to identify groups of people with epilepsy who are S62  |  JANUARY 2012



‘‘

The currently available AEDs do not prevent or cure epilepsy, and are merely antiseizure medications

’’

at particular risk of SUDEP.2 In this pooled analysis of four case–control studies, earlyonset refractory symptomatic epilepsy, frequent generalized tonic–clonic seizures, and use of AED polytherapy were all found to be significant risk factors for SUDEP. Such studies are extremely important for drawing attention to the need to achieve complete seizure control in people with epilepsy. The currently available AEDs do not prevent or cure epilepsy, and are merely antiseizure medications. This fact underscores our lack of knowledge about the exact mechanisms of seizure genesis and modes of action of AEDs. In this context, a paper by Jeon et al.3 was another important publication in 2011. The researchers studied the effects of cell-free extract derived from human adipose stem cells (ASCs) on the acute and chronic phases of the pilocarpine epilepsy model in mice.4 Pretreatment with the extract did not affect

seizure susceptibility to pilocarpine, but it did reduce the number of EEG spikes in the acute phase, and subsequently diminished sponta­neous recurrent seizures (SRS) in the chronic epileptic stage.3 Furthermore, continuing treatment in the chronic epileptic stage suppressed or inhibited SRS and had a positive effect on animal behavioral tests. In addition, animals treated with the extract had less damage to blood–brain barrier integrity than did untreated controls. Interestingly, heat-treated ASC extract had no beneficial effect, suggesting the importance of cytosolic proteins in the positive effects of this agent. Studies have suggested that stem or precursor cells may rescue degenerating neurons by modulating the host environment via a chaperone-like mechanism, or by altering immune-like functions including inflammatory responses.5 Thus, some cell-based therapies might rely more on a ‘bystander’ mechanism involving secretion of soluble factors—such as cytokines and chemokines—than on replacement of damaged neurons by neurogenesis.3 The ASC extract used by Jeon et al. may act by modulating inflammatory events during epileptogenesis.3 During 2011, important contributions were also made to our understanding of serious adverse effects of AEDs, including risks of allergic reactions and terato­ genesis.6,7 Carbamazepine, one of the most important AEDs, causes various forms of hypersensitivity reaction, ranging from maculopapular exanthema to severe and potentially lethal conditions such as Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS–TEN). In a key publication, McCormack et al. 6 showed that the presence of the HLA‑A*3101 allele is associated with carbamazepineinduced hypersensitivity reactions among Europeans. The overall prevalence of carba­ mazepine hypersensitivity is 5.0%; presence of the HLA‑A*3101 allele increased the risk to 26.0%, whereas absence of the allele reduced the risk to 3.8%. Another HLA allele, HLA‑B*1502, is strongly correlated with carbamazepine-induced SJS–TEN in Asian populations but not in Europeans.8 Another serious adverse effect of AEDs is the increased risk of malformations in the offspring of women who use these medications during pregnancy. Clear evidence is available that some AEDs, such as valproic acid, pose major risks of terato­genesis, and the perception is that some of the newer AEDs, including lamotrigine, could be safer. www.nature.com/reviews


NEUROLOGY Key advances ■■ Early-onset refractory symptomatic epilepsy, frequent generalized tonic– clonic seizures, and use of antiepileptic drug (AED) polytherapy are all significant risk factors for sudden unexpected death in epilepsy2 ■■ A cell-free extract from human adipose stem cells has antiseizure and antiepileptogenic effects in mice3 ■■ The HLA‑A*3101 allele is associated with carbamazepine-induced hypersensitivity reactions among Europeans6 ■■ The risk of malformation in offspring of woman taking AEDs depends not only on the type of medication, but also on the AED dose and the parental history of congenital malformation7 ■■ Interictal high-frequency oscillations measured with scalp electrodes can reliably delineate the seizure-onset zone in patients with focal epilepsy9

In a recent important publication, Tomson et al.7 compared the relative teratogenicity of four common AEDs—carbamazepine, pheno­b arbital, valproic acid and lamo­ trigine—on the basis of data from the EURAP epilepsy and pregnancy registry. The authors showed that the risk of major congenital malformations increased in a dose-dependent manner with all four assessed AEDs. Particu­ larly high malformation rates were observed with valproic acid doses >1,500 mg per day.7 The treatment associ­ated with the lowest rate of malforma­tions—lamotrigine at a dose of <300 mg per day—served as a reference for internal comparisons. Compared with this reference, the risk of major congenital malformations was significantly elevated with all doses of valproic acid and phenobarbital, and with the highest doses of carb­amazepine (>1,000 mg per day). Valproic acid doses of <700 mg per day were associated with a malformation rate in a similar range to those with carba­mazepine at <1,000 mg per day, pheno­ barbital at <150 mg per day, and lamotrigine at >300 mg per day.7 Therefore, lamotrigine at high doses is no safer than valproic acid at lower doses. A parental history of major congenital malformations was indepen­ dently associated with a fourfold greater risk of teratogenesis. Despite a continuous increase in the range of AED options, as many as 40% of

KEY ADVANCES IN MEDICINE

people with focal epilepsy will not achieve adequate seizure control with AEDs, and are considered to have drug-resistant epilepsy.1 Surgical treatment can produce seizure freedom or substantial improvement in many of these patients. However, a significant proportion of patients cannot undergo surgery due to lack of adequate localization of the seizure-onset zone (SOZ). This situation underscores the need for reliable bio­markers that may help to identify and predict the severity of epilepsy and the location of the epileptogenic tissue. EEG has great potential for investigating the presence or severity of epilepsy (epilepto­g enicity) and its development (epilepto­genesis) in vivo and in vitro, owing to the capacity to utilize both macro­ electrodes and microelectrodes, and to record normal and abnormal neuronal firing with excellent time resolution.9,10 As reported in 2011, Andrade-Valença et al.9 investigated the possibility of noninvasive detection of interictal high-frequency oscillations (HFOs) via scalp EEG recordings for more-precise delineation of the SOZ in patients with focal epilepsy.9 Recording of HFOs with scalp electrodes was previously thought to be virtually impossible.10

‘‘

Surgical treatment can produce seizure freedom or substantial improvement in many … patients

’’

Andrade-Valença et al.9 analyzed the rates of gamma (40–80 Hz) and ripple (>80 Hz) oscillations, as well as their co-occurrence with spikes, and the number of channels with HFOs inside and outside the SOZ. The accuracy with which the SOZ could be identified was 43% for spikes, 70% for gamma oscillations, and 81% for ripples. This neuro­p hysiological method could become an important scalp biomarker for the SOZ.
In conclusion, 2011 has seen advances in our understanding of the prevention and treatment of epilepsy and the avoidance of life-threatening adverse effects of AEDs, along with the development of a potential new biomarker. Investigation of HFOs is of great importance, since these oscillations

can reveal fundamental mechanisms of epilepto­genesis and epileptogenicity, and also have possible clinical value.9,10 The exciting finding that ASC extracts may be effective in modulating epileptogenesis in addition to their antiseizure effects is likely to open new lines of continuing research.3 The studies involving risk factors of SUDEP2 and AEDinduced life-threatening hypersensitivity 6 are major breakthroughs with important practical applications. The evidence that the risk of major congenital malformations is influenced not only by the type of AED, but also by dose and other variables, should be taken into account in the management of epilepsy in women of childbearing potential.7 Department of Neurology, FCM, University of Campinas (UNICAMP), Rua Vital Brasil, 251, Cidade Universitária, Campinas, SP 13.083‑888, Brazil. fcendes@unicamp.br Competing interests The author declares no competing interests. 1.

Kwan, P. et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 51, 1069–1077 (2010). 2. Hesdorffer, D. C. et al. Combined analysis of risk factors for SUDEP. Epilepsia 52, 1150–1159 (2011). 3. Jeon, D. et al. A cell-free extract from human adipose stem cells protects mice against epilepsy. Epilepsia 52, 1617–1626 (2011). 4. Cavalheiro, E. A. et al. Long-term effects of pilocarpine in rats: structural damage of the brain triggers kindling and spontaneous recurrent seizures. Epilepsia 32, 778–782 (1991). 5. Vezzani, A., French, J., Bartfai, T. & Baram, T. Z. The role of inflammation in epilepsy. Nat. Rev. Neurol. 7, 31–40 (2011). 6. McCormack, M. et al. HLA‑A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N. Engl. J. Med. 364, 1134–1143 (2011). 7. Tomson, T. et al. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol. 10, 609–617 (2011). 8. Chen, P. et al. Carbamazepine-induced toxic effects and HLA‑B*1502 screening in Taiwan. N. Engl. J. Med. 364, 1126–1133 (2011). 9. Andrade-Valença, L. P., Dubeau, F., Mari, F., Zelmann, R. & Gotman, J. Interictal scalp fast oscillations as a marker of the seizure onset zone. Neurology 77, 524–531 (2011). 10. Cendes, F. & Engel, J. Jr. Extending applications for high-frequency oscillations: the ripple effect. Neurology 77, 518–519 (2011).

JANUARY 2012  |  S63


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RHEUMATOLOGY RA IN 2011

Advances in diagnosis, treatment and definition of remission Gerd R. Burmester

Evidence presented in 2011 suggests that rheumatoid arthritis might comprise two separate diseases—each with different etiological underpinnings—and that kinase inhibitors could soon be added to the therapeutic armamentarium. Together with new definitions of remission, these advances could aid the development of personalized, treat-to-target strategies. Burmester, G. R. Nat. Rev. Rheumatol. 8, 65–66 (2012); published online 10 January 2012; doi:10.1038/nrrheum.2011.201

Here, I discuss the progress that has been made in RA research over the past year, focusing on studies that have increased our understanding of the genetic basis of the disease, that have demonstrated the efficacy of new treatment modalities, and that have more clearly defined our current goal—the state of remission. The development of laboratory tests for the detection of anti-citrullinated protein anti­ bodies (ACPAs) has been a major advance in the diagnosis of RA, and has been recog­nized as such through inclusion of these assays in the most up-to-date American College of Rheumatology (ACR)–European League Against Rheumatism (EULAR) disease classi­f ication criteria.1 However, why the immune system of patients with RA errone­ ously identifies endogenous citrullinated proteins as foreign or as molecular danger signals—sometimes mounting an enormous response directed at these antigens—remains an unsolved riddle. Despite our incomplete understanding of ACPAs, they have become a cornerstone in the diagnosis of RA. In 2011, Padyukov et al.2 went one step further when they questioned whether the presence or absence of ACPAs could be used to define two distinct subsets of RA or even two genetically-­distinct diseases. The investigators attempted to answer this question by performing a genome-wide associ­ation study to identify differences in risk allele frequency between patients with and without ACPAs. Analysis of single nucleotide polymorphisms (SNP) in ACPAnegative patients with RA revealed that no SNP tested achieved genome-wide significance in comparison with control indivi­ duals.2 However, in a case–case association KEY ADVANCES IN MEDICINE

Key advances ■■ Anti-citrullinated protein antibody (ACPA) status might define two different subtypes of rheumatoid arthritis (RA) with different underlying etiologies2 ■■ Kinase inhibitors continue to show promise in the treatment of RA, particularly tofacitinib,5 a janus-associated kinase inhibitor ■■ The publication of remission criteria for RA8 will facilitate treat-to-target strategies and standardize the reporting of trial outcomes

study between these ACPA-negative indivi­ duals with RA and ACPA-positive patients with RA, marked differences were identified in the HLA region.2 Notably, only a few SNPs were shared between ACPA-negative and ACPA-positive disease, and these shared alleles provide only a minor contribution to the overall genetic risk of developing RA.2 These findings suggest that no obvious common denominator determines overall genetic susceptibility to RA when ACPAnega­tive and ACPA-positive forms are considered together, but different risk alleles probably underlie development of each of these disease subsets. In contrast to ACPA-negative RA, ACPApositive RA was associated with variation in genes that have been linked to other auto­immune diseases, such as type 1 diabetes and systemic lupus erythematosus.2,3 Further­more, most of the genes associated with ACPA-positive RA, including PTPN22, CD40 and STAT4, are implicated in inflammatory pathways. The odds ratios for some of these genetic associations with RA were low; nevertheless these links could point to important mechanistic similarities and/or

differences between RA and other inflammatory diseases. Increased understanding of the etiology of RA derived from such data could lead to the identification of new th­erapeutic targets.3 That RA does indeed comprise ‘two diseases’, one ACPA-negative and one ACPApositive, now seems reasonable to conclude. This discovery will have important implications for the future management of this disorder, particularly for diagnosis and therapy. However, many important questions remain unanswered; chiefly, what value do ACPAs hold in the prediction of subsequent response to treatment? Prognostic value has been demon­strated for B-cell-depletion therapy,4 but ACPAs seem to provide less or no information pertaining to the success of treatment of RA using cytokine blockade. Once a patient has been diagnosed with RA, whether ACPA-negative or ACPApositive, the next consideration is treatment of the disease. An extensive armamenta­ rium of therapeutics is currently available for the treatment of RA; however, consider­ able unmet medical need still exists as some patients fail to respond to treatment, whereas many others suffer relapses after initially demonstrating clinical improvement. Many failures have been encountered with small molecule drugs targeted at proteins involved in signal transduction, both with regard to efficacy and toxicity. Never­theless, some persistent researchers in industry and academia have continued to develop new agents, notably targeting tyrosine kinases. Comprehensive drug development programs are underway, the most advanced of which seems to involve tofacitinib—a Janus-associated kinase (JAK) inhibitor. JANUARY 2012  |  S65


RHEUMATOLOGY Treatment population

Treatment options

Treatment goal

Glucocorticoids Conventional DMARDs

Cytokine inhibition

ACPA-positive

B-cell depletion

ACPA-negative

Remission (defined by TJC, SJC, PtG and CRP [mg/dl] all ≤1, or SDAI ≤3.3)

Inhibition of costimulation

Inhibition of tyrosine kinases

Figure 1 | Treatment flow in RA. After diagnosis, it might be important to further stratify a patient with RA according to ACPA status. A variety of treatment options then exist for RA. Tyrosine kinases represent promising new agents that might be efficacious in the treatment of RA. The ultimate aim of treatment is to induce a state of remission. Abbreviations: ACPA, anti-citrullinated protein antibodies; CRP, C-reactive protein; PtG, patient global assessment score; RA, rheumatoid arthritis; SDAI, simplified disease activity index; SJC, swollen joint count; TJC, tender joint count.

Tofacitinib binds to and inhibits the important intracellular enzymes JAK1, JAK2 and JAK3, which are involved in immune cell activation, production of proinflammatory cytokines and cytokine signaling. A major step towards the introduction of tofacitinib to the clinic was made in 2011 with the publi­cation of the results of a phase IIb, 24-week, doubleblind, randomized controlled trial of this compound by Fleischmann et al.5 The patient populations enrolled in this study comprised indivi­duals with RA and an inadequate response to DMARDs, who were assigned to receive monotherapy of various dosages of tofacitinib, the TNF inhibitor adalimumab or placebo. Treatment with tofacitinib resulted in a rapid clinical response, with ACR 20% improvement criteria (ACR20) response at week 12 ranging from 59.2% (5 mg) to 71.9% (15 mg), and the response was maintained at 24 weeks.5 By contrast, ACR20 was achieved by 22% of the placebo group and an adali­ mumab response rate of 35.9% was recorded —notably, the latter drug was also used as a monotherapy without metho­trexate.5 Markedly improved ACR50 and ACR70 responses as well as disease activity score in 28 joints (DAS28) remission were observed for tofacitinib, compared with placebo.5 The adverse events associated with tofacitinib treatment included urinary tract infections, diarrhea and anemia.5 These data confirmed the efficacy of tofacitinib, and have led to the initiation of a large phase III program for this drug in patients with RA. Thus, the therapeutic options available to rheumatologists could soon be increased by the addition of new orally administered small molecules, especially when one con­siders that fostamatinib, another tyrosine kinase inhibitor that targets spleen tyrosine kinase (Syk), has also demonstrated con­siderable S66  |  JANUARY 2012



efficacy in RA.6 Naturally, important questions remain unanswered, particularly with regard to long term safety in the ‘real world’, where these agents will be used in combination with a multitude of other drugs that treat comorbid diseases. Moreover, it remains to be seen whether doctors and patients will prefer 60 tablets per month over a syringe that can be self-­administered once a week, or even once per month. The introduction of new treatment modalities, such as tofacitinib and fostamatinib, could help us to reach our current goal in RA therapy, namely a state of remission, particularly if a treat-to-target approach is used.7 However, what does ‘remission’ really mean? Last year, a group of American and Euro­pean experts came together to explore this important question and to generate a stringent definition of this state of minimal disease activity.8 On the basis of the evidence from large trials that analyzed the development of radiologically evident joint destruction or loss of function, the panel representing ACR–EULAR came up with a definition for remission,8 in which a number of different individual disease activity measures are considered together. Using this approach, remission is said to be achieved when the number of tender and swollen joints, the level of CRP (mg/dl) and the patient global assessment score (0–10 scale) are all ≤1.8 An alternative definition is an SDAI (simplified disease activity index) of not more than 3.3.8 In clinical practice and in trials, these definitions have been applied successfully.9,10 However, to achieve a patient global assessment of ≤1 will be a challenge. Although the goals set by ACR–EULAR are demanding, the 2011 remission criteria define clear targets for the management of patients with RA and will

probably change our approach to treating this debilitating disease, especially immediately after onset. As a result of key breakthroughs made in 2011, we are now able to define RA much more effectively, we could soon have new thera­peutics at our disposal and we have clear goals to aim at when treating patients with this previously devastating disease (Figure 1). Hope­fully, the progress made last year will improve patient care and lead to further ­evolution of the field in 2012 and beyond. Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany. gerd.burmester@charite.de Competing interests The author declares associations with the following companies: Abbott and Pfizer. See the article online for full details of the relationships. 1.

Aletaha, D. et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann. Rheum. Dis. 69, 1580–1588 (2010). 2. Padyukov, L. et al. Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study group. A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis. Ann. Rheum. Dis. 70, 259–265 (2011). 3. Stahl, E. A. et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat. Genet. 42, 508–514 (2010). 4. Chatzidionysiou, K. et al. Highest clinical effectiveness of rituximab in autoantibodypositive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed: pooled data from 10 European registries. Ann. Rheum. Dis. 70, 1575–1580 (2011). 5. Fleischmann, R. et al. Phase 2B dose-ranging study of the oral JAK inhibitor tofacitinib (CP690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to DMARDs. Arthritis Rheum. http://dx.doi.org/10.1002/art.33383. 6. Weinblatt, M. E. et al. An oral spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis. N. Engl. J. Med. 363, 1303–1312 (2010). 7. Smolen, J. S. et al. T2T Expert Committee. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann. Rheum. Dis. 69, 631–637 (2010). 8. Felson, D. T. et al. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann. Rheum. Dis. 70, 404–413 (2011). 9. Shahouri, S. H. et al. Remission of rheumatoid arthritis in clinical practice. Application of the American College of Rheumatology/European League Against Rheumatism 2011 remission criteria. Arthritis Rheum. 63, 3204–3215 (2011). 10. Klarenbeek, N. B. et al. Association with joint damage and physical functioning of nine composite indices and the 2011 ACR/EULAR remission criteria in rheumatoid arthritis. Ann. Rheum. Dis. 70, 1815–1821 (2011).

www.nature.com/reviews


RHEUMATOLOGY JIA IN 2011

New takes on categorization and treatment Alberto Martini

In 2011, new treatment recommendations for juvenile idiopathic arthritis (JIA) were proposed, inroads were made towards understanding the heterogeneity of this disease, and data were presented demonstrating the potential efficacy of DMARD combination therapies for JIA treatment. These advances hold promise for improved management of JIA in 2012 and beyond. Martini, A. Nat. Rev. Rheumatol. 8, 67–68 (2012); published online 10 January 2012; doi:10.1038/nrrheum.2011.198

2011 has witnessed the publication of a number of important pieces of information that increase our understanding of juvenile idiopathic arthritis (JIA) hetero­geneity, which guide treatment decisions and pave the way for future studies regarding the potential efficacy of combination therapies with inexpensive DMARDs. Here, I dis­cuss these advances and their potential to improve the management of JIA throughout the world. JIA is not a defined disease, but rather an exclusion diagnosis encompassing all forms of arthritis with symptoms that onset before the age of 16 years, persist for more than 6 weeks, and for which the cause is unknown. In the absence of defined pathogenic underpinnings, attempts have been made to classify this collection of hetero­ geneous disorders into homogeneous, mutually exclusive subgroups on the basis of clinical and laboratory features.1 Some of the official JIA categories developed by the International League Against Rheumatism (ILAR)1 seem to represent distinct disease entities (systemic, polyarticular rheumatoid factor (RF) positive, enthesitis-related arthritis and oligoarticular), whereas others seem to define heterogeneous conditions (polyarticular RF‑negative, psoriatic). In Western countries most individuals with JIA classified as oligoarticular belong to a well-defined subset of patients with disease that is charac­terized by several common features: asymmetric arthritis; early onset of symptoms (before 6 years of age); female predominance; the presence of antinuclear anti­bodies (ANA); high risk of developing chronic iridocyclitis; and associ­ation with specific HLA alleles. However, on the basis of a 2003 literature review,2 it was suggested that patients with the same disease—ANA positive, early-onset oligo­articular JIA—could be included into several different JIA categories: oligo­articular, polyarticular RF‑negative KEY ADVANCES IN MEDICINE

or psoriatic. Therefore, patient age at onset of symptoms, the presence of symmetric or asymmetric arthritis, and ANA positivity were proposed as potentially more suitable criteria for disease classification than the number of joints involved or the presence of psoriasis.2

‘‘

2011 has witnessed important new advances in the understanding and management of JIA...

’’

A key paper published by Ravelli et al.3 in 2011 provides strong evidence to support this hypothesis, particularly the potential use of ANA status in JIA categoriza­ tion. In a retro­spective study that enrolled more than 900 patients with JIA, this group compared the features of ANA-positive and ANA-negative individuals. Impor­ tantly, the authors provi­ded a definition of ANA ­positivity: antibody titers of ≥1:160 detected in ≥2 tests performed at least 3 months apart.3 Many other publications have neglected to define ANA positivity, which could provide a source of confusion. Ravelli and colleagues3 found that ANApositive patients, despite being classified under different ILAR-defined JIA categories, were similar in terms of age at dis­ease onset, female-to-male ratio, and fre­quency of asymmetric arthritis and irido­cyclitis, independent of the number of joints involved or the presence of psoriasis. Perti­nent in this respect are the findings of Barnes and coworkers.4 These investi­gators studied gene expression in peripheral blood mononuclear cells of 104 patients with recent-onset JIA (39 with oligo­articular JIA, 45 with polyarticular RF‑negative disease and 20 with syste­ mic JIA), as well as in cells from 56 healthy controls. Their results reveal that a B‑cell gene expression signature charac­terizes

patients with early-onset arthritis (≤6 years of age), indepen­dent of the number of joints involved.4 Of note, a different cluster of genes related to cellular immunity and myeloid cell lineages was expressed at higher levels in patients with late-onset oligo­articular JIA compared with individuals with early-onset dis­ease.4 Thus, these data suggest that age at onset of symptoms can also be of relevance in unravel­ing disease heterogeneity among patients with oligoarticular JIA. Taken together, the findings I have des­ cribed strongly substantiate the hypo­thesis that age at onset of disease and ANA positivity could be used to identify a homo­genous subset of patients with JIA—patients who are currently included in multiple different JIA categories on the basis of the ILAR classification criteria. However, future studies need to investigate whether, as might be expected, patients with a B‑cell signature and early disease onset are also ANA positive. Over the past decade, dramatic improvements in the treatment of JIA have been made. This progress has been made possible not only by the introduction of biologic agents to the clinic, but also by the implementation of the so called ‘pediatric rule’5 by the FDA and the European Medicines Agency (EMA). This rule states that when the pharmaceutical industry attempts to register a new drug for any given adult dis­ease, data must also be provided on the safety and efficacy of that drug in ­children—provided a pediatric form of the disease exist. This stipulation has opened up the opportunity for several randomized controlled trials with new biologic therapies to be performed in patients with JIA. The rapid advances made in the treatment of JIA have presented new thera­peutic options and made the decision-making processes more complex for rheumatologists. Therefore, a major step forward was provided last year by the publication of the American College of Rheumatology (ACR)-endorsed 2011 recommendations for the treatment of Key advances ■■ Age at disease onset and antinuclear antibody status seem to define a distinct category of juvenile idiopathic arthritis (JIA)3 ■■ New treatment recommendations for JIA are an important tool,6 but will soon need to be updated ■■ Combination DMARD therapy might be more efficacious than methotrexate alone,10 which could influence treatment of JIA worldwide

JANUARY 2012  |  S67


RHEUMATOLOGY JIA.6 They represent the first official treatment recommendations for JIA to be based on objective, validated methods, and have already been reviewed in this journal.7 The term ‘recommendations’ was used, instead of ‘guidelines’, to emphasize their nonprescriptive nature; the intended aim of the publi­ cation was to support, but not to dictate, the individual physician’s decision. The recommendations are based on a comprehensive list of clinical scenarios, in which hypothetical patients are categorized on the basis of different combinations of key clinical parameters rele­vant to the decision-making process, such as disease activity and potential prognostic features. The ACR recommendations are a very useful tool, which can guide the treatment of patients with JIA, but will soon require updating given the rapid evolution of this field. Indeed, tocilizumab—an antibody against the IL-6 receptor that has now been approved for the treatment of systemic JIA by both the FDA and the EMA—is not considered in the recommendations. More­over, trials are currently being performed in patients with systemic JIA that aim to investigate the efficacy of two IL‑1 inhibitors, canakinumab (a monoclonal anti-IL‑1 antibody) and rilonacept (the recombinant extracellular domain of the human IL‑1 receptor); the results of these studies will soon be available, and will presumably provide important new information re­garding treatment of this disease. Although the introduction of biologic therapies has represented a major advance in the treatment of JIA, the fact remains that the high costs associated with provision of these agents can be afforded only by the health­care systems of a limited number of countries.8 Around the world, most children with JIA have to rely on much less expensive drugs, such as methotrexate. Therefore, data regarding the efficacy of combination therapies comprising methotrexate and other synthetic DMARDs in compari­son with metho­trexate alone would be viewed with interest by rheuma­tologists worldwide. However, in contrast to rheumatoid arthritis—a dis­ease in which many trials have supported the over­all superiority of combination DMARD therapy over metho­ trexate monotherapy9—data on combi­nation DMARD therapy are lacking for JIA. Important findings supporting the potential efficacy of combination DMARD therapy in JIA were presented last year by Tynjälä et al.10 The authors randomly assigned 59 patients with early poly­a rticular JIA to three treatment cohorts: infliximab plus S68  |  JANUARY 2012



methotrexate; methotrexate alone; or metho­ trexate, sulfa­salazine and hydroxychloroquine in combination. The results of this trial showed that infliximab plus methotrexate was su­perior to combination therapy and strikingly superior to methotrexate alone. An interest­ing aspect of this study was, therefore, that synthetic DMARDs in combi­nation seemed to be superior to metho­t rexate treatment alone, although the difference in effi­cacy was not statistically significant. The study was, however, underpowered to show a signifi­cant difference and the trend in favor of combination therapy was consistent for all the endpoints tested. Thus, these results strongly suggest that combination therapies with inexpensive synthetic drugs could prove superior to methotrexate alone in future studies with appropriate sample sizes. The funding of these potentially very relevant investigator-initiated randomized studies should represent a future priority for in­ternational public funding bodies. 2011 has witnessed important new advances in the understanding and manage­ment of JIA, but much remains to be done. In the future, more accurate classification of patients with JIA will be possible and more effec­tive treatments will become avail­able, owing to the integration of clinical data with the results of research into dis­ease pathogenesis. University of Genoa, Pediatria II e Reumatologia, Istituto G. Gaslini, Largo G. Gaslini 5, 16147 Genoa, Italy. albertomartini@ospedale-gaslini.ge.it Competing interests The author declares no competing interests.

1.

Petty, R. E. et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J. Rheumatol. 31, 390–392 (2004). 2. Martini, A. Are the number of joints involved or the presence of psoriasis still useful tools to identify homogeneous disease entities in juvenile idiopathic arthritis? J. Rheumatol. 30, 1900–1903 (2003). 3. Ravelli, A. et al. Antinuclear antibody-positive patients should be grouped as a separate category in the classification of juvenile idiopathic arthritis. Arthritis Rheum. 63, 267–275 (2011). 4. Barnes, M. G. et al. Biologic similarities based on age at onset in oligoarticular and polyarticular subtypes of juvenile idiopathic arthritis. Arthritis Rheum. 62, 3249–3258 (2010). 5. Hirschfeld, S. & Saint-Raymond, A. Pediatric regulatory initiatives. Handb. Exp. Pharmacol. 205, 245–268 (2011). 6. Beukelman, T. et al. 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res. (Hoboken) 63, 465–482 (2011). 7. Hashkes, P. J. Pediatric rheumatology: strengths and challenges of a new guide for treating JIA. Nat. Rev. Rheumatol. 7, 377–378 (2011). 8. Sawhney, S. & Magalhães, C. S. Paediatric rheumatology—a global perspective. Best Pract. Res. Clin. Rheumatol. 20, 201–221 (2006). 9. Ma, M. H., Kingsley, G. H. & Scott, D. L. A systematic comparison of combination DMARD therapy and tumour necrosis inhibitor therapy with methotrexate in patients with early rheumatoid arthritis. Rheumatology (Oxford) 49, 91–98 (2010). 10. Tynjälä, P. et al. Aggressive combination drug therapy in very early polyarticular juvenile idiopathic arthritis (ACUTE-JIA): a multicentre randomised open-label clinical trial. Ann. Rheum. Dis. 70, 1605–1612 (2011).

SLE IN 2011

Deciphering the role of NETs and networks in SLE Thomas Dörner

From neutrophil extracellular traps to genetic networks that underlie the disease and new targeted therapies, important advances in 2011 improve our understanding of the pathogenesis of systemic lupus erythematosus and mark the beginning of our ability to treat it effectively. Dörner, T. Nat. Rev. Rheumatol. 8, 68–70 (2012); published online 10 January 2012; doi:10.1038/nrrheum.2011.200

2011 was a year of achievements in systemic lupus erythematosus (SLE)—for advances in basic and clinical research, and the translation of these findings into daily clinical practice. After a decade of failures of some biologic therapies in SLE, the recog­nition of

particular cellular and cytokine pathways as involved in the pathogenesis has initiated a promising period of progress in this complex disease. Many excellent contributions were published in 2011, but a few studies deserve emphasis for providing new perspectives. www.nature.com/reviews


RHEUMATOLOGY Inflammatory response Genetic predisposition

Epigenetic modulation

Abnormal activation of adaptive immunity with memory maintenance

Abnormal innate immune activation Neutrophil

Subphenotype 1 ■ HLA-DRB1*0301 (DR3) ■ Lupus nephritis

NETosis

Subphenotype 2 ■ Cumulative genetic risk factor and anti-dsDNA ■ Young age at onset, hematological disorders and absence of oral ulcers Subphenotype 3 ■ Lack of known SLE susceptibility genes ■ Malar or discoid rash, photosensitivity, serositis and neurologic disorders

■ ■ ■ ■ ■ ■

Plasmacytoid DC activation

HNP or LL37–NET DNA complex

IFN-α production APC

BAFF T cell

TLR

UV light Gender Smoking (Viral infections)

Nephritis Atherosclerosis Lung manifestations Scarring Vascular occlusions Dermatitis

Belimumab

B cell BAFF-R

la

timu

Macrophage

Co-s

tion Autoantibodies Immune complexes Complement consumption

CR Genetic risk score

End-organ damage

FcR

TH1 cell

Plasma cell

Myeloid DC

Figure 1 | From NETs to disease networks in SLE. A proposed pathogenic model of SLE incorporating key findings from 2011. Firstly, three genetic subphenotypes of SLE have been identified (left panel), which might be under different epigenetic control. Next, understanding of abnormal innate and adaptive immunity in SLE (middle panel) has increased, in particular with the finding that NETosis of neutrophils leads to IFN‑α production by pDCs. Finally, belimumab, which targets BAFF (a key cytokine in the adaptive immune response in SLE), has shown clinical efficacy. Abbreviations: APC, antigen-presenting cell; TH1 cell, type 1 T helper cell; NET, neutrophil extracellular trap; DC, dendritic cell; SLE, systemic lupus erythematosus.

Despite the accepted roles of auto­ reactive lymphocytes in adaptive immunity, re­searchers are only just beginning to understand the important early events of immune activation within innate immunity. Chronic activation of plasmacytoid dendritic cells (pDCs) leads to increased IFN‑α production, which stimulates autoreactive lympho­c ytes and reduces the activation threshold of auto­reactive B cells. Crucially, several recent papers have addressed neutrophil function in SLE. Increased neutrophil turnover corre­lates with interferon levels, suggesting a link between neutrophil activa­ tion and chronic pDC activation in SLE.1 Moreover, self nucleic acids (normally nonimmunogenic) incorporated within immune complexes can trigger Toll-like receptor (TLR)72 and TLR9 activation.3 In 2004, a cell-death process distinct from necrosis and apoptosis was identified,4 in which immunogenic self DNA–antimicrobial peptide complexes are released by dying neutrophils. This process, ‘NETosis’, involves extrusion into the extracellular space by activated neutro­phils of large amounts of nuclear DNA, in the form of web-like structures called neutrophil extracellular traps (NETs).4 NETs are abundantly released by neutrophils in patients with SLE. A key 2011 paper by Lande et al.5 has addressed a number of puzzling issues of KEY ADVANCES IN MEDICINE

NETosis in SLE. The researchers found that sera from patients with SLE (in contrast with control sera) contained immune complexes of self DNA and antimicrobial cationic peptides LL37 (also known as cathelicidin) and human neutrophil peptide (HNP). These immunogenic complexes were protected from nuclease degradation, and interaction with Fcγ receptor IIa (FcγRIIa, encoded by FCGR2A) on pDCs led to their internaliza­ tion and, ultimately, to pDC activation. More­over, autoantibodies against LL37 and HNP enhanced NET formation and facilitated further pDC activation.5 These data sup­port the notion that dysregulation of this neutrophil-dependent pathway drives chronic pDC activation and autoimmunity in SLE. An important finding was that the composition of the immune complexes—in particular LL37– double-stranded (ds)DNA and LL37–HNP– dsDNA complexes—determined their fate: FcRγIIa-mediated endo­cytosis. Thus, pDCs have a hitherto unknown ‘hidden’ receptor specificity that is not essentially related to speci­f ic immuno­receptor binding. These findings provide insights into early immune perturbations in SLE and deepen our understanding of SLE patho­genesis, as well as challenging a key concept in SLE: the selective specificity of the auto­immune response against certain self antigens.6

SLE is complex and heterogeneous. Rheuma­tologists have learned that finetuning diagnostic approaches and therapeutic decisions can substantially influence patient outcomes (exemplified by differentiating anti­phospholipid syndrome from SLE). Genetic loci identified as risk loci for SLE susceptibility (HLA-DRB1, FCGR2A, PTPN22, IRF5 and STAT4, among others) are mostly related to immunological pathways (such as antigen presentation and IFN signaling). Nevertheless, whether patterns of multiple risk alleles in patients with SLE constitute specific genotypes that relate to particular clinical manifestations has not been t­horoughly studied; the direct genetic and epigenetic networks that underlie SLE pathogenesis remain unclear (Figure 1). In the second 2011 paper highlighted here, Taylor et al.7 undertook a compre­hensive analysis of 22 genetic variants implicated in SLE pathogenesis. The most statistically significant individual risk alleles associated with SLE were HLA-DR3-IRF5 and FCGR2A-PXK (consistent with the findings by Lande et al.,5 which demonstrated the importance of FcγRIIa in pDC activation). Importantly, in addition to the characterization of SLE susceptibility loci, the researchers studied their relationship with disease charac­ teristics. An interesting categorization of SLE JANUARY 2012  |  S69


RHEUMATOLOGY Key advances ■■ Neutrophil extracellular traps induce innate immunity early in systemic lupus erythematosus (SLE) and possibly activate the adaptive immune response5 ■■ Genetic studies identify certain SLE subtypes and simultaneously indicate distinct roles of epigenetic modulation7 ■■ Approval of belimumab—the first targeted therapy in SLE—translates insights into abnormalities of the immune system in SLE into the clinic9

subphenotypes emerged, on the basis of the strength of association of each manifestation with known genetic susceptibility loci, and a genetic risk score. Thus, subphenotype 1 is closely associated with HLA-DRB1*0301 (DR3) and lupus nephritis, with ITGAM alleles protecting against arthritis; subphenotype 2 is closely associated with cumulative genetic risk factors and is characterized by anti-dsDNA autoantibodies, immunological abnormalities, young age at onset, hematological disorders and absence of oral ulcers; and subphenotype 3—not associated with any known SLE risk loci (perhaps reflecting susceptibility to environmental or epigenetic modulation)—is characterized by malar or discoid rash, photosensitivity, serositis and neurological disorders. These interesting data highlight two major aspects of SLE genetics: first, the existence of distinct phenotypes based on different ge­n­etics, each associated with particular morbid­ity and mortality risks; the other, that epi­genetic modification probably differs between the hypothetical subphenotypes. However, the data cannot be extrapolated to different ethnic backgrounds; the participants were almost exclusively of European ancestry. Finally, in 2011 Navarra et al.9 reported the phase III trial of belimumab, a new cytokinetargeted therapy for SLE—aimed, one could say, at disrupting the pathogenic ‘net­work’ of the disease. A number of cytokine perturbations have previously been iden­tified in patients with SLE, mainly comprising increased levels of B‑cell activating factor (BAFF; TNF superfamily member 13B, also known as BLyS) and type I interferons. Belimumab, which blocks soluble BAFF, is a welcome step in improving SLE therapy —now approved by the FDA and Euro­ pean Medical Agency, it is the first targeted therapy directed at B cells in SLE, in a disease known to involve hyper­active B lympho­cytes. Importantly, the 2011 BLISS‑52 trial9 did not study the efficacy of beli­mumab in only severe SLE; its success in a hetero­geneous S70  |  JANUARY 2012



SLE population needed a large effects size to differentiate the results from placebo. Nonetheless, the drug was of insufficient potency to show a strong effect early in disease. That response to beli­mumab might differ between the SLE sub­phenotypes discussed above is probable. As the frequency of ANA-positivity was 92–95% among phase III participants,9 compared with 66.7–74.3% in a previous phase II trial,10 the benefit of belimumab for ANA-negative patients remains unclear. Furthermore, identifying the specific profile of belimumab respon­ders could improve understanding of the dis­ tinct immuno­pathologies of SLE sub­pheno­ types and lead to more effective therapeutic de­cisions by tailoring therapy to each patient. Overall, from NETs to disease networks, studies published in 2011 collectively open new avenues of investigation in SLE, including early innate activation paths, delineation of subsets (with genetic profiles probably complemented by epigenetic modifications) and the identification of therapeutic responders to belimumab. Thus, basic and clinical research support re-evaluation SLE in terms of better defined subtypes. Department of Medicine, Rheumatology and Clinical Immunology, Charite Center 12, Charite Universitätsmedizin Berlin and Deutsches Rheumaforschungszentrum, Chariteplatz 01, 10098 Berlin, Germany. thomas.doerner@charite.de

Competing interests The author declares no competing interests. 1.

Craft, J. Dissecting the immune cell mayhem that drives lupus pathogenesis. Sci. Transl. Med. 3, 73ps9 (2011). 2. Rubtsov, A. V. Toll-like receptor 7 (TLR7)-driven accumulation of a novel CD11c+ B‑cell population is important for the development of autoimmunity. Blood 118, 1305–1315 (2011). 3. Leadbetter, E. A. et al. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416, 603–607 (2002). 4. Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535 (2004). 5. Lande, R. et al. Neutrophils activate plasmacytoid dendritic cells by releasing self‑DNA‑peptide complexes in systemic lupus erythematosus. Sci. Transl. Med. 3, 73ra19 (2011). 6. Dörner, T., Giesecke, C. & Lipsky, P. E. Mechanisms of B cell autoimmunity in SLE. Arthritis Res. Ther. 13, 243 (2011). 7. Taylor, K. E. et al. Risk alleles for systemic lupus erythematosus in a large case–control collection and associations with clinical subphenotypes. PLoS Genetics 7, e1001311 (2011). 8. Lindh, E. et al. AIRE regulates T‑cell‑independent B‑cell responses through BAFF. Proc. Natl Acad. Sci. USA 105, 18466–18471 (2008). 9. Navarra, S. V. et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebocontrolled, phase 3 trial. Lancet 377, 721–731 (2011). 10. Wallace, D. J. et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum. 61, 1168–1178 (2009).

OA IN 2011

Age-related OA—a concept emerging from infancy? Thomas Aigner and Wiltrud Richter

That primary osteoarthritis (OA) is an age-related disorder is undoubted, but how aging contributes to OA is poorly understood. New insights from 2011 offer potential explanations, novel models for study, and the suggestion that a deeper understanding of what ‘aging’ actually is might pave the way to everlasting joints. Aigner, T. & Richter, W. Nat. Rev. Rheumatol. 8, 70–72 (2012); published online 10 January 2012; doi:10.1038/nrrheum.2011.206

Aging is the most prominent risk factor for the initiation and progression of pri­mary OA. Many explanations for this phe-no­ menon have been suggested over time, 1 without conclusion. In fact—although the concepts underlying them might be largely correct—the details of these opposing theories might have obscured the true nature of what ‘aging’ is in relation to OA.

The most longstanding theory of the pathogenesis of primary OA (if one takes the articular cartilage as the starting point) involves the cumulative effects of continuous mechanical wear and tear on the articu­lar cartilage matrix during a lifetime of joint use (Box 1). A second theory is related to well known age-related intrinsic changes in the extracellular matrix of articular carti­lage, such as collagen network www.nature.com/reviews


RHEUMATOLOGY stiffen­ing and the formation of advanced glycation end products. A third, frequent explanation for OA cartilage degeneration is the mere loss of viable cells (due to apoptosis or any other mechanism of cell death), as cellular replenish­ment does not occur in articular cartilage. We and others have suggested that OA is a consequence of (premature) aging of chondrocytes in joint tissues (cell senescence theory, Box 1). Although not dead, senescent cells nevertheless lose their capac­ ity to sustain the cartilage matrix, which can trigger an osteoarthritic degeneration pathway.2–4 As we discuss below, chondrocyte behavior seems to change with increasing age: the cells respond less well to growth factors, and anabolic activity declines. In 2011, Loeser and colleagues5 went some way towards unpicking what OA‑related cellular aging actually looks like at the level of gene expression. Their interest­ing functional genomic study targeted gene expression alterations in a surgical meniscus destabilization mouse model of OA, and examined test animals of different ages. As well as disease-related changes, the investigators also observed substantial differences in the injury-induced patterns of expression between ‘young’ and ‘old’ mice, in chondrocytes, meniscal cells and other joint tissues.5 Genes involved in matrix production, immunity and defense were among those affected, but our current knowledge of chondrocyte cell biology—whether young or aging—is not detailed enough to explain the differences observed. Nonetheless, this finding clearly shows that cartilage cells react differently depending on their aging status, a phenomenon also documented for mesenchymal progenitor cells.6 Articular cartilage is especially vulnerable to the effects of cellular aging and senescence. At skeletal maturity, sub­chondral cal­c ification isolates the tissue from the vas­cular system such that no new cells can enter the articular cartilage. Chondrocytes become postmitotic—they cease proliferation and are thus among the oldest cells of the human body, able to survive for decades without replacement. Furthermore, they are constrained within the cartilage matrix, unable to move. Even when chondro­cytes start to divide again, as occurs in OA carti­ lage, cells from one site are, there­fore, unable to replace damaged or absent cells else­ where, except for those literally adjacent. One consequence of this postmitotic status is that oxidatively damaged molecules (proteins, DNA, lipids) accumulate in articular KEY ADVANCES IN MEDICINE

Box 1 | Aging theories in the pathogenesis of OA Continuous loading theory Osteoarthritis (OA) results from the cumulative effects of continuous mechanical wear and tear on cartilage; thus ‘aging’ is simply the accumulation of loading cycles over a lifetime of joint use. Matrix pathobiochemistry theory OA results from age-related changes in the extracellular matrix of articular cartilage: ■■ Collagen network stiffening due to increased covalent cross-linking ■■ Altered expression of aggrecan molecules that account for the enormous swelling capacity of articular cartilage and, thus, its resistance to compression ■■ The formation of advanced glycation end products affects matrix integrity and chondrocyte biology Progressive (apoptotic) cell loss theory OA results from the loss of viable cells, due to apoptosis or any other mechanism of cell death, at the beginning of and during the disease process. As chondrocytes are solely responsible for replenishing the articular matrix, substantial loss of these cells results in the loss and degeneration of the surrounding matrix. Mitochondrial degeneration theory OA results from the continuous degeneration of chondrocyte mitochondria that eventually leads to energy failure as well as high oxidative stress in the cells. Cell (pre)senescence theory OA results form the inability of the cells to maintain tissue homeostasis (in particular after insults of a mechanical or inflammatory nature) due to cellular degeneration and/or aging caused in part by the accumulation of oxidatively-damaged molecules.

chondrocytes with aging, as these molecules are not completely re-­synthesized within the cells, as would occur during cell division. This accumulation of damaged molecules impairs the ability of chondrocytes to remain functional and maintain tissue homeostasis. More importantly, the sene­ scent cellular phenotype alters how cells react to stimuli. Indeed, our conception of the laws of cellular organization and function in relation to age is evolving rapidly in the 21st century.7 Thus, the most important implications of this emerging aging concept in OA development might be that the biology of cellular degeneration is part of the basis for the initiation and progression of OA. Furthermore, this knowledge emphasizes that whatever treatment of OA we envisage, we must take into account that we are dealing with aged and senescent or pre-senescent cells that no longer have the abilities of their juvenile counterparts to counteract mechanical, inflammatory, and/or other insults to the tissue. This previously insufficiently appreciated requirement might be one core explanation why many promising therapeutic approaches, established and tested in ‘juvenile’ cell lines and animal models, have subsequently failed in aged human OA cartilage in vivo. Is the only way to investigate these agerelated effects to wait until individuals age—which is rather a long time in the con­text of most experiments—or can we find quicker, informative model systems?

Key advances ■■ Gene expression changes in joint tissue of older mice hint at how age and injury interact in OA5 ■■ Oxidative stress ages human chondrocytes in vitro,8 which might provide a model for studying age-related OA development ■■ Cartilage senescence is delayed by growth inhibition,10 indicating that cellular ‘aging’ might be uncoupled from time itself

Taking chondrocytes from the replaced joints of patients with OA is of limited practical use; isolating diseased chondrocytes is a difficult endeavor with low yields. More troublesome still is the suspicion that one might only sample the more healthy subpopulation of cells and not the really diseased ones, which would explain the low yields of isolated cells per gram of tissue (in fact, most OA chondrocytes are lost during the isolation procedure). Quicker in vitro model systems are clearly required. Poten­tially help­ful, therefore, is the 2011 report by Brandl and colleagues8 of an in vitro model of aging of chondrocytes. Chondrocytes are unique in their avascular setting, and the effect of oxidative stress on these cells is not well characterized. Brandl et al.8 found that oxidative stress accelerated cellular aging in chondrocytes—and can thus be used to artificially induce ‘age’ in cell culture—and that senescent chondrocytes are less resistant to oxidative stress. Similar strategies might be adapted to in vivo models, evading the JANUARY 2012  |  S71


RHEUMATOLOGY usually unfeasible requirement of waiting for the natural aging of test animals. Another potentially interesting in vivo study system was also advanced in 2011, and has furthered our understanding of aging in cartilage. Baron and colleagues have, 9 for several years now, studied senescence in fetal growth plate cartilage, previously finding it to be delayed as a consequence of hypothyroidism; once the deficiency is resolved, new, ‘catch-up’ growth results. In 2011, the group showed that cartilage senescence is delayed by general growth inhi­bition;10 thus, the onset of senescence is not governed by time, but rather by growth. These findings are further support for the notion that a time-­dependent wear process might be insufficient to explain the onset of OA. Nevertheless, whether growthplate cartilage reflects substantial aspects of OA chondrocyte senescence and, thus, can contribute substantially to OA and chondrocyte aging research remains to be examined. OA and OA research is increasingly leav­ ing behind the simple age-related fatalis­ tic concept of chronic wear and tear, that is, matrix and cell degeneration. The con­ cept of aging as a phenomenon with its own biology needs to be understood by the OA community as a new, innovative and excit­ing area of chondrocyte and carti­lage research. Though recent advances leave one with the impression that our understanding in this regard remains in its infancy, the emerging data might help to push OA research from a niche of orthopedic interests to a highly topical research area: what human aging means, in terms of biological processes, and what we can do about it. OA research might merge with the everexpanding search for the Holy Grail, or to speak with a German tongue, the ‘Jung­ brunnen’ (fountain of youth). In the case of OA research and patient management, the result would be ever-functioning, painless joints. Institute of Pathology, Medical Center Coburg, Ketschendorferstraße 33, 96450 Coburg, Germany (T. Aigner). Research Centre for Experimental Orthopedics, Heidelberg University Hospital, Schlierbacher Landstraße 200a, 69118 Heidelberg, Germany (W. Richter). Correspondence to: T. Aigner thomas.aigner@klinikum-coburg.de Acknowledgments We acknowledge the support of the DFG for our work (grant numbers Ai 20/7‑1,2 and Ri 707/7-1). Competing interests The authors declare no competing interests.

S72  |  JANUARY 2012



1.

2.

3.

4.

Aigner, T., Rose, J., Martin, J. & Buckwalter, J. Aging theories of primary osteoarthritis: from epidemiology to molecular biology. Rejuvenation Res. 7, 134–145 (2004). Aigner, T., Söder, S., Gebhard, P. M., McAlinden, A. & Haag, J. Mechanisms of disease: role of chondrocytes in the pathogenesis of osteoarthritis—structure, chaos and senescence. Nat. Clin. Pract. Rheumatol. 3, 391–399 (2007). Martin, J. A., Ellerbroek, S. M. & Buckwalter, J. A. Age-related decline in chondrocyte response to insulin-like growth factor‑I: the role of growth factor binding proteins. J. Orthop. Res. 15, 491–498 (1997). Loeser, R. F. Aging and osteoarthritis: the role of chondrocyte senescence and aging changes in the cartilage matrix. Osteoarthritis Cartilage 17, 971–979 (2009).

5.

Loeser, R. F. et al. Microarray analysis reveals agerelated differences in gene expression during the development of osteoarthritis in mice. Arthritis Rheum. http:dx.doi.org/10.1002/art.33388 6. Dexheimer, V., Mueller, S., Braatz, F. & Richter, W. Reduced reactivation from dormancy but maintained lineage choice of human mesenchymal stem cells with donor age. PLoS ONE 6, e22980 (2011). 7. Kirkwood, T. B. Understanding the odd science of aging. Cell 120, 437–447 (2005). 8. Brandl, A. et al. Oxidative stress induces senescence in chondrocytes. J. Orthop. Res. 29, 1114–1120 (2011). 9. Lui, J. C., Nilsson, O. & Baron, J. Growth plate senescence and catch-up growth. Endocr. Dev. 21, 23–29 (2011). 10. Forcinito, P. et al. Growth-inhibiting conditions slow growth plate senescence. J. Endocrinol. 208, 59–67 (2011).

SSC IN 2011

From mechanisms to medicines Luc Mouthon

Findings from ongoing studies of imatinib in systemic sclerosis (SSc) were eagerly awaited in 2011, but results from these clinical trials have so far been disappointing. However, progress in the understanding of the mechanisms that underlie SSc pathogenesis could provide clues to novel targets for 2012 and beyond. Mouthon, L. Nat. Rev. Rheumatol. 8, 72–74 (2012); published online 10 January 2012; doi.10.1038/ nrrheum.2011.203

Systemic sclerosis (SSc) is a connective tissue disorder characterized by excessive collagen deposition in the dermis and inter­nal organs, vascular hyper-reactivity and vascular obliteration. Tissue fibrosis results from the increased release of extracellular matrix from aberrantly activated fibroblasts.1 This accumulating extra­cellular matrix disrupts the physiological tissue structure, leading to organ dys­f unction, which contributes to the high morbidity and increased mortality in patients with SSc. However, the mechanisms under­ lying pathological fibroblast activation are incompletely understood. Transforming growth factor β (TGF‑β) seems, however, to be a master regulator of both physio­ logical and pathological matrix remodeling, and might be responsible for maintaining the activated fibroblast phenotype in SSc.1 Although a number of therapeutic trials have been conducted with antifibrotic agents (including d‑penicillamine, relaxin, IFN‑α and IFN‑γ) in patients with SSc, none had a major therapeutic effect. Here, I will highlight the results of recent clinical studies of imatinib (a new antifibrotic agent) in patients with SSc and the latest advances in understanding the mechanisms

of fibrosis in SSc. 2011 has been a year of progress, but will new mechanistic insights lead to new medicines for SSc? Understanding of fibrosis in SSc has already led to trials of new therapies that might control the disease. An example being imatinib mesylate, a tyrosine kinase inhibi­tor already approved for the treatment of chronic myelogenous leukemia. Imatinib binds to c‑Abl (an important down­stream signaling molecule of TGF‑β) and blocks its tyrosine kinase activity,2 as well as interfering with platelet-derived growth factor signaling. In an in  vitro model of bleomycin-­induced pulmonary fibrosis, c‑Abl inhibition by imatinib prevented TGF‑β-induced extracellular matrix component gene expression, transformation and proliferation of fibroblasts.3 Similar results were seen in mouse models of dermal fibrosis in SSc.4 These interesting results led a number of investigators to launch clinical studies to examine the effectiveness of imatinib as an SSc therapy, the findings of which were eagerly anticipated. Of the six trials testing the efficacy of imatinib registered on ClinicalTrials.gov, four have been completed; findings from three of these studies were published in 2011, while the results of www.nature.com/reviews


RHEUMATOLOGY the fourth are not yet available. Moreover, two other studies of different tyrosine kinase inhibitors are ongoing in patients with SSc: one open-label phase IIa study using nilotinib and another open-label phase I/II study using dasatinib.

‘‘

…will new mechanistic insights lead to new medicines for SSc?

’’

Results from the imatinib trials published in 2011 were somewhat disappointing in terms of the tolerance and efficacy of the drug. Spiera et al.5 conducted a phase IIa, open-label, single-arm clinical trial in 30 patients with diffuse SSc who were treated with imatinib (400 mg per day) over 12 months. Mean Rodnan skin score (MRSS) decreased by 6.6 points (or by 22.4%) at 12 months (P = 0.001).5 Pulmonary function was also tested, with forced vital capa­ city (FVC) improving by 6.4% predicted (P = 0.008), whereas the diffusion capacity remained stable.5 Six patients withdrew from the study, two because of non­compliance, four because of adverse events (including one who died after 11 months).5 In total, 171 adverse events of various grades were identified, the most common being edema, which was observed in 80% of patients. 24 serious adverse events were identified, two of which were attributed to the study medication.5 The authors concluded that imatinib has acceptable safety and toler­ability, and suggest it has potential efficacy for cutaneous and pulmonary manifestations of SSc.5 However, other studies did not replicate these findings. In their phase I/IIa pilot study, Khanna and colleagues6 recruited 20 patients with SSc-related interstitial lung disease (ILD) who had FVC <85% predicted, dyspnea on exertion and presence of ground glass appearance on high-resolution CT of the lung. Patients received imatinib therapy (up to 600 mg per day) for 1 year. 12 patients completed the study, seven discontinued due to adverse events and one was lost to follow-up. Although treatment with imatinib showed a trend towards an improvement of FVC (by 1.74%; P >0.05) and MRSS (of 3.9 units; P <0.001), use of high-dose daily (600 mg per day) imatinib was associated with a large number of adverse events (including edema and fatigue) in this study.6 Furthermore, Pope et al.7 performed a 6‑month double-blinded pilot study of imatinib in patients with active diffuse SSc KEY ADVANCES IN MEDICINE

who had at least one of: worsening skin score (measured by the MRSS); tendon fric­tion rubs; and/or increased erythrocyte sedi­mentation rate due to the active dis­ ease. The researchers planned to recruit 20 patients to their study and stratify them by cur­rent use of methotrexate. However, after enrolling only 10 patients (nine on imatinib, one placebo), the authors found poor tolerability and high numbers of adverse events with imatinib (200 mg twice a day) and enrollment was discontinued.7 Most adverse effects (such as fluid retention, weakness, nausea and vomiting) occurred within the first week of treatment and even reintroduction at a lower dose (200 mg daily) was poorly tolerated.7 Two participants were hospitalized due to these effects (one with syncope, and the other with nausea, edema and fatigue). The authors concluded that imatinib was poorly tolerated and the study was unfortunately insufficiently powered to give conclusions on drug efficacy.7 Taken together, the results of the above studies provide evidence that imatinib at doses of 400–600 mg per day is poorly tolerated in patients with SSc. No conclusion can, however, be made on drug efficacy because of the heterogeneity, limited power and nonrandomized nature of the above studies, although a trend towards an improvement of FVC and MRSS was observed in imatinibtreated patients. Because of poor tolerance, whether testing of imatinib for SSc will progress to large prospective randomized trials is unknown, as is whether imatinib warrants further study. Although the initial imatinib trial results were unsatisfying, recent advances in the understanding of fibrotic mechanisms have enabled the identification of a wide range of potential biologic agents with which to disrupt the development of fibrosis in SSc.1 These approaches include neutralizing the principal extracellular signals that activate Key advances ■■ The results of three studies show that imatinib is poorly tolerated in patients with SSc and do not enable clinicians to draw conclusions on drug efficacy5–7 ■■ Tissue factor—the primary in vivo initiator of coagulation—interacts with endothelin‑1 signaling in the activation of myofibroblasts from patients with SSc8 ■■ 5-HT–5-HT2B receptor signaling links vascular damage and platelet activation to tissue remodeling in SSc and could be a novel therapeutic target to treat fibrotic diseases9

fibroblasts and small molecules to disrupt intracellular signaling pathways linked to fibrosis.1 Progress in understanding fibrosis in SSc has been ongoing in 2011 and I will highlight the extrinsic coagulation system8 and platelet activation9 as potential new targets for reducing the risk of fibrotic complications in SSc. In 2011, Chrysanthopoulou et al.8 found that myofibroblasts cultured from the colon of patients with SSc and gastrointestinal symptoms expressed increased levels of tissue factor, the primary in vivo initia­tor of the coagulation system. Upregula­tion of tissue factor led to thrombin generation and subsequent production of connective tissue growth factor (CTGF) and collagen via protease-activated receptor 1 signaling.8 Further­more, thrombin induces endo­thelin 1 receptor A expression, while endo­thelin‑1 signaling is implicated in the enhanced expression of tissue factor in myo­fibroblasts from patients with SSc. 8 These findings suggest that blocking the extrinsic coagulation system could be a potentially novel approach to reduce the risk of fibrotic compli­cations in SSc. Moreover, the essential role of the tissue factor—­thrombin—CTGF pathway in the fibrotic manifestations of SSc has been demonstrated, as well as an interplay between the coagulation cascade and endothelin‑1 signaling in the activation of myofibroblasts in SSc.8

‘‘

Results from the imatinib trials published in 2011 were somewhat disappointing…

’’

Existing evidence indicates that platelets have a role in SSc. The levels of circulating platelet aggregates and of several platelet-derived molecules (such as β‑thrombomodulin and platelet-derived growth factor) are elevated in patients with SSc.10 However, the role of platelet activation in the pathogenesis of SSc and other fibro­ tic diseases has not yet been established. In 2011, Dees and colleagues9 showed that serotonin (5-­hydroxytryptamine [5-HT]) stored in platelets strongly induces synthesis of extracellular matrix components in inter­stitial fibroblasts via activation of 5‑HT2B receptors in a TGF‑β–dependent manner. Dermal fibrosis was reduced in 5‑Htr2b–/– mice using both inducible and genetic models of fibrosis.9 Pharmacological inactivation of 5‑HT2B receptors also effectively prevented the onset of experimental JANUARY 2012  |  S73


RHEUMATOLOGY fibrosis and ameliorated established fibrosis.9 Consistent with these findings, mice deficient in tryptophan hydroxylase 1—the rate-limiting enzyme for 5‑HT production outside the central nervous system—had reduced experimental skin fibrosis.9 These findings, together with recent results from 5‑HT receptor antagonists in experi­mental pulmonary or liver fibrosis, suggest that 5‑HT–5-HT2B receptor signaling links vascular damage and platelet activation to tissue remodeling, and highlight the 5‑HT2B receptor as a novel therapeutic target to treat fibrotic diseases. In summary, blocking extrinsic coagulation system and/or platelet activation might represent promising future strategies for SSc treatment. From mechanisms to new medicines, research in 2011 has made tenta­tive steps to providing an effective targeted therapy for SSc. Although the efficacy of imatinib has not yet been confirmed, mecha­n istic insights into the develop­ ment of fibrosis in SSc have provided vital clues for the development of new drugs for this challenging disease and trials of new therapies are ongoing. Université Paris Descartes, Faculté de Médecine, Service de Médecine Interne, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, 75014 Paris, France. luc.mouthon@cch.aphp.fr Competing interests The author declares associations with the following companies: Actelion, GlaxoSmithKline, Lilly, Pfizer. See the article online for full details of the relationships. 1.

2.

3.

4.

5.

6.

Bhattacharyya, S., Wei, J. & Varga, J. Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities. Nat. Rev. Rheumatol. http://dx.doi.org/ 10.1038/nrrheum.2011.149. Distler, J. H. & Distler, O. Imatinib as a novel therapeutic approach for fibrotic disorders. Rheumatology (Oxford) 48, 2–4 (2009). Aono, Y. et al. Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in mice. Am. J. Respir. Crit. Care Med. 171, 1279–1285 (2005). Distler, J. H. et al. Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis. Arthritis Rheum. 56, 311–322 (2007). Spiera, R. F. et al. Imatinib mesylate (Gleevec) in the treatment of diffuse cutaneous systemic sclerosis: results of a 1‑year, phase IIa, single-arm, open-label clinical trial. Ann. Rheum. Dis. 70, 1003–1009 (2011). Khanna, D. et al. A one-year, phase I/IIa, open-label pilot trial of imatinib mesylate in the treatment of systemic sclerosis-associated active interstitial lung disease. Arthritis Rheum. 63, 3540–3546 (2011).

S74  |  JANUARY 2012



7.

8.

Pope, J. et al. Imatinib in active diffuse cutaneous systemic sclerosis: results of a six-month, randomized, double-blind, placebocontrolled, proof‑of‑concept pilot study at a single center. Arthritis Rheum. 63, 3547–3551 (2011). Chrysanthopoulou, A. et al. Tissue factorthrombin signaling enhances the fibrotic activity of myofibroblasts in systemic sclerosis

through up-regulation of endothelin receptor A. Arthritis Rheum. 63, 3586–3597 (2011). 9. Dees, C. et al. Platelet-derived serotonin links vascular disease and tissue fibrosis. J. Exp. Med. 208, 961–972 (2011). 10. Postlethwaite, A. E. & Chiang, T. M. Platelet contributions to the pathogenesis of systemic sclerosis. Curr. Opin. Rheumatol. 19, 574–579 (2007).

VASCULITIS IN 2011

The renaissance of granulomatous inflammation in AAV Stephan D. Gadola and Wolfgang L. Gross

In 2011, the year that subtypes of ANCA-associated vasculitis (AAV) were officially renamed according to key pathological characteristics, important progress was made not only in differentiating these subtypes, but also in understanding—and treating—their eponymous manifestations. Gadola, S. D. & Gross, W. L. Nat. Rev. Rheumatol. 8, 74–76 (2012); published online 10 January 2012; corrected online 24 January 2012; doi:10.1038/nrrheum.2011.218

Granulomatosis with polyangiitis (GPA, formerly Wegener´s granulomatosis), ChurgStrauss syndrome (CSS) and microscopic polyangiitis (MPA) constitute the antineutrophil cytoplasmic antibody (ANCA)associated vasculitides (AAV), forms of primary small-vessel vasculitis associated with ANCA seropositivity. Owing to the rarity of their disease, patients with dif­ferent AAV are often pooled in clinical trials. Dis­ ease evolution, organ involvement, prog­ nosis, and other parameters , however, dif­fer substantially between GPA, CSS and MPA, although the mechanistic bases for these differences remain largely unexplored. To unravel them, effective classification of patients with AAV is essential, beginning with defining—and naming—the subtypes. 2011 saw the launch of an international effort among vasculitis experts, including rheumatologists, nephrologists, pathologists and others, to replace honorific eponyms of Key advances ■■ A new artificial neural network helps to differentiate subtypes of ANCAassociated vasculitis, including granulomatosis with polyangiitis (GPA)2 ■■ The effects of rituximab on granulomatous and vasculitic manifestations of GPA offer hope for patients with refractory disease, plus insights into the pathology of granulomatous lesions7 ■■ Autoantibodies with transmembrane protein targets are found—and generated—in GPA granulomas, but are undetectable in plasma9

diseases with names that highlight diseasespecific characteristics.1 GPA is in fact the test case for this initiative; its new name underlines the clinical and pathological similarities between GPA and MPA with regard to smallcaliber vessel involvement, while emphasizing the importance of granulomatous inflammation as a distinctive feature of GPA (Figure 1a). Indeed, since the introduction of effective immunosuppressive protocols that control vasculitic manifestations of GPA (and other AAV), clinicians have increasingly faced the challenges posed by granulomatous manifestations (for which effective treatments have lagged behind). Differentiating GPA and MPA, however, is sometimes difficult (biopsy proof of GPA is required, and established diagnostic criteria are lacking), especially when inter­disciplinary care cannot be provided. Surrogate markers of granulomatous inflammation have been proposed to dis­tinguish GPA, but are, as yet, unvalidated. Linder and colleagues2 stepped into this breach in 2011, applying an artificial neural net­work (ANN) approach to generate and validate improved criteria for distinguishing GPA and MPA. The ability of ANNs to find patterns in complex data sets has previously been used to differen­tiate GPA and CSS.3 In training the ANN, Linder et al.2 identified four potentially rele­vant parameters —involvement of the nose, sinuses, or ears, and presence of pulmonary nodules—to help in differen­tiating between GPA and MPA. Indeed, when these cri­teria were applied as the only input neurons, the ANN correctly differentiated cases of GPA and MPA with an www.nature.com/reviews


RHEUMATOLOGY accuracy of 94.3%,2 a substantial improvement over conventional classification criteria. Importantly, the authors validated the ANN in two independent cohorts of patients with GPA (n = 46) and MPA (n = 21) from a single center.2 This study, therefore, confirms that certain surrogate markers can be used in differential diagnosis of GPA, while also indica­ ting that ANNs might be useful to distinguish AAV subtypes in clinical trials. ANN-type approaches to the classification of AAV might be enhanced by the inclu­ sion of demographic and genetic markers. It is now known, for example, that MPA is much more common than GPA in Japan, whereas GPA is the predominant AAV in the UK.4 Further­more, a genetic associ­ation study in German and British patients with AAV found HLA-DPB1*0401 to be a strong risk factor for GPA, but not MPA or CSS,5 suggest­i ng that HLA-DPB1*0401 might contri­bute to the granulomatous aspect of GPA. The Euro­pean Vasculitis Study Group has defined two pheno­types of GPA—the rare, local­ized phenotype that presents with granuloma­tous tissue inflammation but without clinical signs of vasculitis, and the more frequent general­ized phenotype of GPA, which features granulo­matous tissue inflammation alongside systemic vasculitis. Localized disease was thought to be an essentially harmless variant of GPA, but recent studies have shown that granulomatous manifestations can indeed cause significant morbidity and even death. As these manifestations tend to be more refractory to treatment than vasculitic aspects of GPA, the need to understand and treat them is pressing.6,7 Now, Holle and colleagues7 have com­pared the efficacy of the B‑cell depleting anti­body rituximab for the treatment of granulo­ma­ tous and vasculitic manifestations of GPA. Their study, in 59 patients with refractory GPA, included a high proportion of patients with orbi­tal masses and pachymeningitis.7 Com­plete or partial remission was achieved for 90% of refractory vasculitic but only 58% of granulomatous manifestations, and, interest­ingly, rituximab was more effec­tive for pulmonary masses (83.4% responded, with 16.7% achieving complete remission) compared with either orbital masses (44.4% responded but none achieved complete remission) or pachymeningitis (50.0% and 8.3%, respectively). The rationale for using rituximab in AAV is to eliminate ANCAproducing B cells, and is based on a large body of evidence indicating a key role for ANCA in AAV small-vessel inflammation. Data published in 20108 added to this rationale by KEY ADVANCES IN MEDICINE

a

b Giant cells B

*

Fibrocyte rich pannus-like tissue

* Epitheloid cells B PMN

ELS

Destruction of bone and cartilage

Figure 1 | Clinical burden of granulomatous manifestations in GPA. a | Left panel: MRI showing retro-orbital ‘granuloma’ (arrowhead) leading to vision loss; middle panel: photograph and CT scan showing severe bone and cartilage destruction, with saddle nose, loss of inner nose, and fistula between the orbit and cavum nasi (arrowheads); right panel: large septal defect (circled) with granulomatous ‘pannus’ (arrowhead). b | Histopathology of GPA. Left panel: sinonasal mucosa (adjacent to area of geographic necrosis, not shown) showing giant cells (arrowheads), ELS (circled) and eroded bone (B) with palisading fibrocytes (crosses). Right panel: key pathological features. B‑cell-rich ELS resemble germinal centers, and B cells isolated from them can produce autoantibodies.9 Abbreviations: ELS, ectopic lymphoid structures; GPA, granulomatosis with polyangiitis; PMN, polymorphonuclear leukocytes. Permission to use her image was obtained from the patient depicted. Photograph and CT scan reproduced from Aries, P. M. & Both, M. N. Engl. J. Med. 352, 392 (2005), © Massachusetts Medical Society; histopathology slide reproduced from Mueller, A. et al. Rheumatology (Oxford) 47, 1111–1113 (2008), with permission.

showing that ANCAs stimulate neutro­phils to release B‑cell activating factor (BAFF, also known as BLyS and TNFSF13B), which might perpetu­ate ANCA production by increas­ing the survival of auto­reactive B cells. Never­ theless, ANCA and B-cell involvement in the granuloma­tous in­f lammation of GPA remains largely unexplored. Although consistent with a possible partial role for B cells in granulomatous inflammation, the findings of Holle et al.7 indicate that B‑cell-independent mechanisms are at the heart of granuloma formation. In fact, the granulomatous lesions of GPA har­bor B‑cell-rich germinal center-like lymp­ hoid structures, and have long been suspected to be the very sites where pathogenic ­auto­antibody-secreting B cells arise. In a tour de force, Thurner and colleagues9 provided in 2011 the first evidence for the existence of auto­antibody-secreting B cells in GPA granulomas. Using laser micro­dissection, they isolated single B cells from GPA granulo­ mata, cloned their immunoglobulin genes, reconstituted the corresponding antibodies

and, finally, tested their binding to human proteins. ‘Disappointingly’ none bound to proteinase 3 (one of the principle auto­ antigen targets of ANCAs), perhaps owing to the small number of antibodies tested. Two transmembrane proteins, the lysosomal protein TMEM9B and cell-surface expressed TM4SF2, were, however, identified as antigens for these auto­antibodies.9 Interestingly, two different anti­bodies from the same granuloma recognized TMEM9B, whereas no circulating antibodies against the protein could be detected in the corresponding patient plasma. Thus, this study9 not only helps to elucidate the role of the granuloma in autoantibody formation (Figure 1b), but also makes a strong point that the search for new autoantibodies in inflammatory diseases should encompass tertiary lymphoid structures in inflamed tissues, and not be restricted to plasma. Furthermore, the findings clearly suggest that ANCA-secreting B cells might well be present in granulomatous tissue even when they are not detectable in plasma (that is, in ANCA-negative patients with GPA). JANUARY 2012  |  S75


RHEUMATOLOGY Elucidating the role of B cells in granulomatous tissue injury would not only underpin the rationale for using B‑cell depletion in granulomatous complications of GPA, but also inspire new B‑cell directed drugs. Ulti­mately, however, we will need to understand why B‑cell-rich germinal center-like structures arise within GPA lesions, and how B cells are (dys)regulated by the local innate immune response. Promisingly, several genes involved in innate immunity have recently been implicated in GPA.10 Only with more such studies will we begin to get to grips with the complex pathophysiology of this fascinating disease—and the true meaning of its name… Department of Rheumatology, University Hospital of Southampton NHS Foundation Trust, University of Southampton, Southampton SO16 6YD, UK (S. D. Gadola). Department of Rheumatology, University Hospital of

Schleswig-Holstein, Campus Lübeck, D‑24576 Bad Bramstedt, Germany (W. L. Gross). Correspondence to: W. L. Gross w.gross@klinikumbb.de Competing interests The authors declare no competing interests. 1.

2.

3.

4.

Falk, R. J. et al. Granulomatosis with polyangiitis (Wegener’s): an alternative name for Wegener’s granulomatosis. Arthritis Rheum. 63, 863–864 (2011). Linder, R. et al. Differentiation between Wegener’s granulomatosis and microscopic polyangiitis by an artificial neural network and by traditional methods. J. Rheumatol 38, 1039–1047 (2011). Schmitt, W. H., Linder, R., Reinhold-Keller, E. & Gross, W. L. Improved differentiation between Churg-Strauss syndrome and Wegener’s granulomatosis by an artificial neural network. Arthritis Rheum. 44, 1887–1896 (2001). Fujimoto, S. et al. Comparison of the epidemiology of anti-neutrophil cytoplasmic antibody-associated vasculitis between Japan and the UK. Rheumatology (Oxford) 50, 1916–1920 (2011).

5.

Arning, L. et al. Are there specific genetic risk factors for the different forms of ANCAassociated vasculitis? Ann. Rheum. Dis. 70, 707–708 (2010). 6. Holle, J. U. et al. Prospective long-term follow-up of patients with localised Wegener’s granulomatosis: does it occur as persistent disease stage? Ann. Rheum. Dis. 69, 1934–1939 (2010). 7. Holle, J. U. et al. Rituximab for refractory granulomatosis with polyangiitis (Wegener’s granulomatosis): comparison of efficacy in granulomatous versus vasculitic manifestations. Ann. Rheum. Dis. http:// dx.doi.org/10.1136/ard.2011.153601 8. Holden, N. J. et al. ANCA-stimulated neutrophils release BLyS and promote B cell survival: a clinically relevant cellular process. Ann. Rheum. Dis. 70, 2229–2233 (2010). 9. Thurner, L. et al. Wegener’s granuloma harbour B lymphocytes with specificities against a proinflammatory transmembrane protein and a tetraspanin. J. Autoimmun. 36, 87–90 (2011). 10. Laudien, N. et al. Molecular signatures of a disturbed nasal barrier function in the primary tissue of Wegener’s granulomatosis. Mucosal Immunol. 4, 564–573 (2011).

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UROLOGY PROSTATE CANCER IN 2011

Redefining the therapeutic landscape for CRPC Carmel Pezaro and Gerhardt Attard

2011 was a breakthrough year for the treatment of castration-resistant prostate cancer. The encouraging results of two large clinical trials were reported, as well as data identifying a number of promising new therapeutic targets. Bone-modulating agents continued to show potential for the prevention of skeletal events.

A number of significant breakthroughs in the field of advanced prostate cancer were reported this year, both clinically and in translational and scientific research. Recently reported analy­ses of the phase III studies of abiraterone acetate and MDV3100 provide irrefutable evidence that the androgen receptor (AR) is a critical target in castration-­resistant prostate cancer (CRPC).1 These agents entered clinical development 5–6 years ago and proceeded to large (>1,000 patients) phase III trials in docetaxel-treated patients.2 MDV3100 is a novel potent AR antagonist, and abiraterone acetate specifically inhibits CYP17A1, a key enzyme in the testosterone bio­synthesis pathway that converts adrenal and potentially intratumoral steroid precursors into androgens. Interim analysis of the abiraterone acetate trial revealed that abiraterone acetate plus prednisone improved survival by 3.9 months compared to placebo plus prednisone (HR 0.65; P <0.001).1 Final analysis after 775 events showed an overall survival benefit of 4.6 months for abiraterone acetate (HR 0.74; P <0.0001).3 The drug was well tolerated, with most reported adverse effects relating to accumulation of steroid precursors with potent mineralocorticoid properties upstream of CYP17A1. 55% of patients who received abiraterone acetate experienced toxicity due to mineralo­ corticoid excess, and although few required a dose reduction, 3.8% of patients required increased doses of prednisone to suppress adrenocorticotropic hormone. 1.6% of patients treated with abiraterone acetate and 1.8% of those who received placebo were administered the mineralocorticoidreceptor antagonist eplerenone to manage adverse effects.1 The outcome of interim analysis of the MDV3100 phase III AFFIRM study was KEY ADVANCES IN MEDICINE

© Peto Zvonar | Dreamstime.com

Pezaro, C. & Attard, G. Nat. Rev. Urol. 9, 63–64 (2012); published online 17 January 2012; doi:10.1038/nrurol.2011.235

recently made public in a press release from the manufacturers. Administration of MDV3100 to docetaxel-treated patients improved survival by 4.8 months compared to placebo (HR 0.63; P <0.0001). Unblinding of the study in order to offer MDV3100 treatment to patients in the placebo group is expected in the near future. Both abiraterone acetate and MDV3100 are currently undergoing evalua­t ion in chemotherapy-naive patients (clinicaltrials.gov identifiers NCT00887198 and NCT01212991, respectively) and predictably, multiple new AR antagonists and CYP17A1 inhibitors are under clinical investigation.2 How best to select between new thera­p ies for individual patients is now the subject of further research. Combined treatment with AR antagonists and CYP17A1 inhibitors may offer greater benefit but requires clinical evaluation.

Unfortunately, resistance to drugs targeting the AR inevitably occurs. In the majority of patients, progression on abiraterone acetate or MDV3100 is associated with a rise in PSA (the product of an AR‑regulated gene), suggesting reactivation of steroid signaling.2 Bidirectional crosstalk between the serine/threonine protein kinase AKT and the AR has been suggested as a potential mechanism of this resistance. In two studies published back-to-back earlier this year genetically engineered mice with prostate-­conditional homo­zygous loss of PTEN (phosphatase and tensin homolog) were used to show that pharmacological blockade of the AR is associated with activation of AKT.4,5 One of the mechanisms responsible was the loss of AKT inhibition by the AKT-inactivating PH domain and leucine rich repeat protein phosphatases (PHLPP1 and PHLPP2). 4,5 Additionally, pharmacological inhibition of the PI3K pathway in these models caused activation of receptor tyrosine kinases HER2 and HER3, which in turn led to activation of the AR. Moreover, a separate study reported that the AR can inhibit PTEN transcription in cultured prostate cancer cells, which leads to activation of AKT signaling.6 These findings are particularly provocative because aberrations that result in activation of PI3K–AKT signaling are common in prostate cancer, and drugs targeting the PI3K–AKT cascade or HER signaling are in clinical development.5 Data reported over the past 6 years have prompted reclassification of prostate cancer into molecularly defined subtypes, based on, for example, the presence of underlying hormone-driven oncogene rearrangements, most commonly involving ETS genes such as ERG and ETV1.7 Hormone-dependent overexpression of ERG and ETV1 proteins JANUARY 2012  |  S77


UROLOGY Key advances ■■ Abiraterone acetate can now be considered standard of care for patients with CRPC who progress on docetaxel1 ■■ Dual blockade of the PI3K–AKT pathway and the androgen receptor has emerged as an important potential strategy for reversing castration resistance5 ■■ Preclinical validation of targeting of PARP in ETS-positive cancers introduces a potential new biologically rational approach for treating advanced prostate cancer7 ■■ Denosumab is superior to zoledronic acid in delaying skeletal-related events in men with bone metastasis9 ■■ Radium223 chloride improves survival in patients with advanced CRPC and symptomatic bone metastases10

owing to ETS gene rearrangements has been directly implicated in tumor invasion and metastasis in prostate cancer cell lines; therefore, the downregulation of these proteins could help explain the antitumor activity of therapeutics that disrupt AR signaling in nonselected patients. Accordingly, it has been suggested that direct targeting of ETS proteins could avoid the toxi­ city and AR‑related drug resistance of hormone therapies. In a study published this year, Brenner et al.7 screened for proteins that interact with ERG. They found that trans­cription regulated by both ERG and ETV1 was mediated by a protein complex comprising PARP1 (poly ADP-ribose polymerase 1) and DNAPKcs (DNA-dependent protein kinase, catalytic subunit), and that disruption of this complex using PARP1 inhibitors suppressed growth of ETS-driven cancers. Moreover, it has also been hypothesized that some sporadic prostate cancers (possibly those involving loss of PTEN) contain DNA repair defects, so PARP1 inhibition could function as an effective therapy either directly via synthetic lethality or indirectly through inhibition of the PARP1–ETS complex.8 Studies of PARP inhibitors, both alone and in combination with AR‑targeting drugs, are now planned. Targeting of bone metastases has long been a priority in CRPC, because of both its frequent occurrence and associated morbidity. The phase III double-blind study of denosumab, a humanized monoclonal antibody against receptor activator of nuclear factor κB ligand (RANKL; a stimulator of osteoclastic bone resorption) versus zoledronic acid was published earlier this year. 9 Although denosumab S78  |  JANUARY 2012



treatment resulted in a 3.6-month advantage in the composite end point of time to a skeletal-related event (SRE), there was no alteration in overall survival or disease progression. The clinically important adverse event of jaw osteonecrosis was rare, occurring in 22 patients in the denosumab group and 12 men who received zoledronate. These results suggest that denosumab is more effective at delaying SREs than the current standard. Denosumab also offers advantages in terms of its subcutaneous administration and a lesser requirement for renal monitoring; however, cost may limit its widespread use. The potential survival benefit of effective bone targeting was proven in the recently presented phase  III ALSYMPCA trial, testing the intravenously delivered alphaemitter radium223 chloride, which incorporates in place of calcium in replicating bone causing double-strand DNA damage in adjacent cells. ALSYMPCA compared radium 223 chloride with best supportive care in men with symptomatic bone-only meta­stases.10 The trial was unblinded after the preplanned interim analysis met efficacy criteria, demonstrating a 2.8-month improvement in the primary survival end point in the radium223 chloride group (HR 0.695; P = 0.00185). Secondary efficacy end points of time to SRE, time to PSA progression, and extent and duration of alkaline phosphatase response also favored the experimental arm. The rate of hemato­logical toxicity was low, but there was an increased rate of grade 1–2 diarrhea observed in patients who received active treatment. Radium223 chloride could therefore prove to be a highly effective treatment with low morbid­ity for men with bone metastases. In summary, significant milestones in prostate cancer research in 2011 included announcement of the results of two positive phase  III trials (ALSYMPCA and AFFIRM); granting of marketing approval for abiraterone acetate by the FDA and the EMA; and approval of cabazitaxel, already approved by the FDA in 2010, by the EMA. Furthermore, increased use of the autologous vaccine therapy sipuleucel‑T for the treatment of predominantly chemo­ therapy-naive patients was reported in the USA. Over the next 12 months physicians could therefore have at their disposal five new agents (abiraterone acetate, MDV3100, cabazitaxel, sipuleucel-T and radium 223 chloride) in addition to docetaxel that prolong the life of patients with CRPC, and

a second bone-modulating agent in addition to bisphosphonates (denosumab). Additionally, an unprecedented number of clinical trials are currently accruing patients with prostate cancer to test promising novel therapies. The therapeutic landscape of CRPC has certainly been redefined over the past 2 years. It is now anticipated that significant further advances will require biologically rational targeting of mol­ecularly defined subgroups. Section of Medicine, The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK (C. Pezaro, G. Attard). Correspondence to: G. Attard gerhardt.attard@icr.ac.uk Competing interests G. Attard declares associations with the following companies/organizations: AstraZeneca, The Institute of Cancer Research, Ipsen, Janssen-Cilag and Sanofi-Aventis. See the article online for full details of the relationships. C. Pezaro declares no competing interests. 1.

de Bono, J. S. et al. Abiraterone and increased survival in metastatic prostate cancer. N. Engl. J. Med. 364, 1995–2005 (2011). 2. Attard, G. & de Bono, J. S. Translating scientific advancement into clinical benefit for castrationresistant prostate cancer patients. Clin. Cancer Res. 17, 3867–3675 (2011). 3. Scher, H. I. et al. Evaluation of circulating tumor cell enumeration as an efficacy response biomarker of overall survival in metastatic castration-resistant prostate cancer (mCRPC): Planned final analysis of COU-AA-301, a randomized, double-blind, placebo-controlled, phase III study of abiraterone acetate plus lowdose prednisone post docetaxel [abstract]. J. Clin. Oncol. 29, LBA4517 (2011). 4. Mulholland, D. J. et al. Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth. Cancer Cell 19, 792–804 (2011). 5. Carver, B. S. et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 19, 575–586 (2011). 6. Wang, Y. et al. Differential regulation of PTEN expression by androgen receptor in prostate and breast cancers. Oncogene 30, 4327–4338 (2011). 7. Brenner, J. C. et al. Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell 19, 664–678 (2011). 8. de Bono, J., Sandhu, S. & Attard, G. Beyond hormone therapy for prostate cancer with PARP inhibitors. Cancer Cell 19, 573–574 (2011). 9. Fizazi, K. et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377, 813–822 (2011). 10. Parker, C. et al. Overall survival benefit of radium-223 chloride (Alpharadan) in the treatment of patients with symptomatic bone metastasis in castration-resistant prostate cancer: a phase III randomised trial (ALSYMPCA) [abstract LBA1]. Presented at the 16th ECCO–36th ESMO Annual Congress.

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UROLOGY BLADDER CANCER IN 2011

The dawn of personalized medicine Thomas W. Flaig and Dan Theodorescu

Long awaited data from the clinical investigation of bladder cancer in both the neoadjuvant and adjuvant settings were released in 2011, setting the stage for the next generation of work in this area. The findings of a number of studies provide the first steps towards a personalized approach to this disease. Flaig, T. W. & Theodorescu, D. Nat. Rev. Urol. 9, 65–66 (2012); published online 20 December 2011; doi:10.1038/nrurol.2011.220

2011 was a year of progress in the field of bladder cancer. Efforts to set the context for more definitive, practice-changing studies of targeted agents in bladder cancer were reported. Updated analysis of a large European phase III trial of neoadjuvant chemo­t herapy confirmed a significant survival advantage, and mutations that define potential drivers of disease, as well as a gene signature that predicts lymph node involvement before cystectomy, are now available. Taken together, these advances make signifi­cant strides in our understanding of bladder cancer and begin to pour the founda­t ion for a more personalized approach to the assessment and treatment of affected patients. Currently, no targeted therapies are utilized in the routine clinical care of advanced bladder cancer, and this is largely due to lack of study rather than negative results. Two notable studies published in 2011 addressed this dearth of evidence. The importance of angiogenesis in oncogenesis is widely accepted and several antiangiogenic agents have been approved for cancer treatment in recent years. Preclinical evidence indicates that the vascular end­othelial growth factor (VEGF) axis is important in urothelial carcinoma, but there has been little clinical investigation of vascular inhibition in patients with urothelial cancer. This year, the Hoosier Oncology Group published a single-arm, phase II study of a 21-day cisplatin–­gemcitabine regimen for advanced urothelial carcinoma with addition of the VEGF-directed antibody bevacizumab, in 43 patients.1 The overall radiographic response rate was 72% (19% were complete responses), with a median overall survival of 19.1 months. Both of these outcomes are encouraging and suggest improvement over historical series, in which overall survival has ranged from 14 to 18 months. Pulmonary embolism or deep vein thrombosis was observed in 21% of KEY ADVANCES IN MEDICINE

the study cohort, prompting a dose reduction of gemcitabine midway through the trial. The Cancer and Leukemia Group B is sponsoring a randomized, phase III study of this regimen in patients with advanced uro­t helial carcinoma (Clinical trials.gov identifier: NCT00942331). Adding to our insight of targeted therapy, a new understanding of the mechanism of pulmonary metastasis in bladder cancer was described in 2011. Endothelin‑1 (ET‑1) is a vasoconstrictor, expression levels of which correlate positively with muscle invasion and negatively with bladder cancer-­specific survival. In new preclinical findings, ET‑1 and its receptor were determined to be neces­s ary for lung metastasis in bladder cancer, and this process was shown to be dependent on macrophage activity in the lung.2 Importantly, pharmacologic inhibition of the ET‑1 axis, using orally bioavailable ET‑1 receptor inhibitors, prevented the development of lung metastases, but had little effect on established primary or metastatic tumors. Attempting to translate these findings into a clinical context suggests that the use of ET‑1 receptor inhibitors will be most efficacious in the adjuvant setting, not in the metastatic setting. This information may guide the future development of ET‑1 inhibitors for bladder cancer, given their availability and tolerability for chronic use. An important update to the large European phase III neoadjuvant chemotherapy trial was reported in 2011.3 This trial included patients with T2 grade 3, T3 or T4a bladder cancer (N0 M0) planning to undergo radical cystectomy or definitive radiation therapy. A total of 976 patients were randomized to either three cycles of a 21-day cisplatin, methotrexate and vinblastine (CMV) chemotherapy regimen or no chemotherapy before undergoing cyst­ectomy or radiation therapy. The initial reports of this study in 1999 revealed a trend toward chemotherapy benefit that did not reach significance. In the

© Orlando Florin Rosu | Dreamstime.com

updated report, there was a 16% reduction in the risk of death and an absolute increase in the 10-year survival (from 30% to 36%) with CMV chemotherapy. Of note, the reduction in the risk of death was 26% in patients treated with cyst­ectomy, which is compar­able to that reported in the neo­adjuvant findings with metho­trexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy reported by SWOG.4 Importantly, there is now evidence of a survival advantage with the use of neoadjuvant chemotherapy in two randomized, phase III studies, so a discussion of neo­adjuvant chemotherapy should take place in all fit patients with muscle-­ invasive disease preparing for definitive local bladder cancer therapy. Despite these positive findings, which are based on pathological risk stratification, it is clear that the majority of patients treated with neoadjuvant chemotherapy do not benefit. A robust prognostic test is needed that would facilitate the use of chemotherapy in those at highest risk of recurrence, with a predictive test to select the therapy most likely to elicit a response in each patient. We did see some progress in the search for better prognostic markers for bladder cancer in 2011. In one new study, gene expression was assessed in three separate cystectomy cohorts and evaluated in the context of pathologic lymph node status at the time of surgery.5 Two cohorts (including 90 and 66 patients) were used as training sets and a 20-gene signature was developed, which was validated in a larger group (n = 185). Patients in the valida­tion cohort were prospectively collected in an earlier clinical trial and analyzed retrospectively. The 20-gene expression model yielded an RR for the discovery of lymph node metastases of 1.74 in the desig­nated ‘high-risk’ group compared to an RR of 0.70 in ‘low-risk’ patients, and was independent of stage and lymphovascular JANUARY 2012  |  S79


UROLOGY Key advances ■■ Encouraging results have been obtained from studies of targeted therapies in bladder cancer,1 laying the groundwork for future investigation in this area ■■ The reporting of a second randomized phase III trial of neoadjuvant chemotherapy3 confirms a survival advantage for patients with muscleinvasive bladder cancer ■■ A 20-gene expression model has been developed5 that can identify patients, before cystectomy, at high risk of lymph node involvement ■■ Evidence suggests a number of chromatin remodeling genes are involved in bladder cancer,6 representing a novel area for future investigation ■■ The immunohistochemical assessment of p53 is not a useful marker of prognosis or predictive of response to chemotherapy9

invasion. Conceivably, with further validation, patients at high risk of node-positive disease could be identified using this algorithm and then strongly encouraged to undergo neoadjuvant chemotherapy before definitive treatment. Whole-exome sequencing of paired tumoral and peripheral blood samples was recently performed in a small set of patients with bladder cancer, in an attempt to identify prognostic biomarkers. 6 The initial findings from this cohort were then tested in a larger cohort of 88 patients. Several previously defined mutations were observed (in TP53, RB1 and HRAS), as well as a number of novel mutations. Of these, UTX was the most commonly mutated gene, identified in 21% of tested individuals, with 17 nonsense, 5 missense and 1 synonymous mutation noted when combining the discovery and validation screens. Of particular note, eight of the newly identified mutated genes were related to chromatin remodeling, suggesting a potential area for bladder cancer investigation. Interestingly, mutations in chromatin remodeling genes have been commonly found in several other cancer types, suggesting a fundamental contribution to carcinogenesis. Results of retrospective studies have suggested that p53 is both a marker of prog­ nosis7 and potentially predictive of response to cytotoxic chemotherapy.8 However, the results of a much anticipated phase III trial testing p53 as a biomarker in patients after radical cystectomy were somewhat dis­ appointing.9 Notably, these patients had early stage disease (pT1–2 N0 M0), and based on current pathologic risk stratification S80  |  JANUARY 2012



they would frequently not receive adjuvant chemo­therapy. Patients whose tumors were negative for p53 overexpression—with <10% nuclear reactivity on immuno­histochemical analysis—were observed, while those with p53-positive tumors were offered randomization to MVAC chemo­therapy or observation. A total of 521 patients were registered, 272 were positive for p53, and 42% of these consented to random­ization for chemo­ therapy. The findings of the trial were negative: the 5‑year rate of recurrence was 20% regardless of p53 status, and p53-positive patients randomized to chemo­therapy had a similar recurrence rate to p53-positive patients who did not receive chemotherapy. In other words, the immunohistochemical assessment of p53 is not useful in this setting. This study highlights both the challenge of successfully completing large-scale clinical trials in bladder cancer, with a trial accrual period of more than 8 years despite the participation of many academic institutions, and also the ongoing need for robust prognostic biomarkers for urothelial carcinoma. In summary, building on the findings described here should result in a better understanding of the underlying science of bladder cancer and possible clinical applications in the years to come. A future is approaching in which we can rationally and scientifically apply many of the targeted agents that are currently in development, based on a personalized assessment of patients with bladder cancer. University of Colorado Comprehensive Cancer Center, 1665 Aurora Court, Aurora, CO 80045, USA (T. W. Flaig, D. Theodorescu).

Correspondence to: D. Theodorescu dan.theodorescu@ucdenver.edu Competing interests D. Theodorescu declares an association with the following organization: University of Colorado. See the article online for full details of the relationship. T. W. Flaig declares no competing interests. 1.

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Hahn, N. M. et al. Phase II trial of cisplatin, gemcitabine, and bevacizumab as first-line therapy for metastatic urothelial carcinoma: Hoosier Oncology Group GU 04–75. J. Clin. Oncol. 29, 1525–1530 (2011). Said, N., Smith, S., Sanchez-Carbayo, M. & Theodorescu, D. Tumor endothelin‑1 enhances metastatic colonization of the lung in mouse xenograft models of bladder cancer. J. Clin. Invest. 121, 132–147 (2011). Griffiths, G., Hall, R., Sylvester, R., Raghavan, D. & Parmar, M. K. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscleinvasive bladder cancer: long-term results of the BA06 30894 trial. J. Clin. Oncol. 29, 2171–2177 (2011). Grossman, H. B. et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N. Engl. J. Med. 349, 859–866 (2003). Smith, S. C. et al. A 20-gene model for molecular nodal staging of bladder cancer: development and prospective assessment. Lancet Oncol. 12, 137–143 (2011). Gui, Y. et al. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat. Genet. 43, 875–878 (2011). Esrig, D. et al. Accumulation of nuclear p53 and tumor progression in bladder cancer. N. Engl. J. Med. 331, 1259–1264 (1994). Ferreira, C. G., Tolis, C. & Giaccone, G. p53 and chemosensitivity. Ann. Oncol. 10, 1011–1021 (1999). Stadler, W. M. et al. Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status. J. Clin. Oncol. 29, 3443–3449 (2011).

SEXUAL DYSFUNCTION IN 2011

Advances in epidemiology, pathophysiology and treatment Eric Chung and Gerald B. Brock

Research into sexual dysfunction is expanding rapidly; in 2011 alone more than 600 articles on sexual dysfunction were listed in PubMed. Increased understanding of pathophysiology, epidemiology, clinical diagnosis and therapeutic options has propelled clinicians and researchers alike to be more innovative and holistic in their approach to the management of sexual dysfunction. Chung, E. & Brock, G. B. Nat. Rev. Urol. 9, 66–68 (2012); published online 10 January 2012; doi:10.1038/nrurol.2011.223

Although evidence has previously indicated that erectile dysfunction (ED) might resolve spontaneously,1 the natural course

of ED had not been addressed in detail before 2011. Recent large-scale population analysis of the Massachusetts Male www.nature.com/reviews


UROLOGY Aging Study (MMAS) and the multi­ national Men’s Attitudes to Life Events and Sexuality (MALES), revealed that 21% and 25% of men reported improvement, over 7 and 3 years of follow-up, respectively.2 Worsening of ED was reported by 51% and 28% of men in MMAS and MALES, respectively. As might be expected, the proportion of men reporting progression increased with age, and men younger than 50 years were more likely to experience improvement than worsening. The age-specific rates of progression were higher in MMAS than in MALES, which might be explained by the fact that the MMAS population is older or that there was a longer period of follow-up in MMAS than MALES. Only a small proportion of men (14% in MMAS and 28% in MALES) reported use of phospho­diesterase type 5 (PDE5) inhibitors, which is not uncommon in population-­b ased studies. Furthermore, most patients were recruited before the commercialization of PDE5 inhibitors. Although this study reported several pertinent findings, there are problems associated with combining data from several longitudinal studies, including the difference in follow-­u p duration between studies. Moreover, self-reported outcomes might not represent formal diagnosis of a condition, and the lack of access to PDE5 inhibitors or other erectogenic agents may further restrict the generalization of this study. A novel treatment for men with vasculogenic ED was reported in 2011: extracorporeal shock wave therapy (ESWT). In contrast to high-intensity ESWT, which is commonly used to treat urolithiasis and orthopedic conditions, a low-intensity protocol (LI-ESWT) has previously been shown to improve the hemodynamics of many organs via an improvement in vascular supply and endothelial function. Neovascularization is mediated by the nonenzymatic production of physiologic levels of nitric oxide, activa­tion of intracellular signaling pathways, and increased expression of vascular endothelial growth factor and its receptor. This year, Gruenwald et al. 3 reported that penile LI‑ESWT (two treatment sessions per week for 3 weeks in 29 patients) can improve erectile function and penile hemodynamics. The mean IIEF-ED scores increased from 8.8 ± 1 at baseline to 12.3 ± 1 at 1‑month follow-up (P = 0.035). At 2 months, while patients were on active PDE5 inhibitor treatment, the IIEF-ED further increased to 18.8 ± 1 (P <0.0001), KEY ADVANCES IN MEDICINE

Key advances ■■ An attempt to describe the natural history of erectile dysfunction (ED) has revealed that 25–51% of men experience progression and 21–25% of men report improvement2 ■■ A new predictive algorithm5 can accurately predict erectile function after definitive prostate cancer treatment ■■ PDE5 inhibitors can increase erectile variables without sexual stimulation in a laboratory setting7 ■■ Shock wave therapy has been suggested as a novel treatment option for severe vasculogenic ED3 ■■ Data from a population-based study9 suggests a lack of association between sexual dysfunction and serum testosterone level

and 72.4% of patients reached an erection hardness score of ≥3 (P <0.0001), allowing full sexual intercourse. These encouraging results suggest that penile LI‑ESWT could be used to treat patients with severe vasculogenic ED. However, many questions—such as the long-term impact of ESWT on penile tissue—remain unanswered. In an animal model, Muller et al.4 have previously shown that ESWT results in time-­dependent and treatment-dependent reduction of intra­cavernosal pressure and alteration in smooth muscle cells, both of which are potentially deleterious to erectile function. Large-scale long-term doubleblind multicenter comparative studies, with specific patient selection criteria using standardized treatment protocols, are required before this novel therapeutic modality can be accepted as a mainstay treatment for ED. The association between ED and prostate cancer treatment is well established, and the loss of sexual function in previously potent men is closely related to outcome satisfaction. A longitudinal multicenter study by Alemozaffar et al.5 has reported that 37% of all patients (368 of 1,027) and 48% of men who had functional erections before treatment (335 of 694), reported functional erections 2 years after definitive prostate cancer therapy. Multivariate analysis revealed that younger age, lower PSA levels, better pretreatment sexual functioning score, and utilization of nerve-sparing surgery were associated with increased probability of functional erections after radical prostat­ ectomy (P <0.05 for each; area under curve [AUC] 0.7 [95% CI 0.72–0.82]). Similarly for men who received external beam radiotherapy, those who had a lower PSA level, better pretreatment sexual functioning

score and did not receive neoadjuvant hormone therapy, were more likely to report erectile function after treatment (P <0.05 for each; AUC 0.83 [95% CI 0.78–0.88]). Ethnicity and lower BMI, in addition to the risks mentioned above, were found to increase the log-odds of better erectile function after brachytherapy (P <0.05; AUC 0.89 [95% CI 0.85–0.94]). Investigators generated models based on the above data that could predict erectile function after primary prostate cancer treatment, and validated their performance using data from the Cancer of the Prostate Strategic Urologic Research Endeavor database. The multivariable logistic regression models could estimate probabilities of erectile function at 2 years after treatment, from as low as 10% to as high as 70%, depending on the patient’s pretreatment character­istics and treatment details. This important study demonstrates the use of predictive models to analyze practical and clinically relevant patient-reported outcomes for the first time. Consistent with existing knowledge, the benefit of nerve-sparing prostatectomy and the detri­ment associated with adjuvant hormone therapy during radiation were observed. Unfortunately, this study is limited by its observational design, possible selection bias, and absence of reported data on penile rehabilitation. Furthermore, the relatively short follow-up of patients did not take into account that some men continued to notice improvement or deterioration of sexual function beyond 2 years. These predictive models can be added to the growing list of nomograms and artificial neural networks for prostate cancer management, which will hopefully result in improved outcomes for patients. Penile rehabilitation after radical prostat­ectomy using PDE5 inhibitors has attracted considerable interest, and proofof-concept has been demonstrated. Nighttime use of PDE5 inhibitors is thought to increase the occurrence of nocturnal erections, which aid preservation of corporal smooth muscle.6 The absence of regular sexually stimulated erections or nocturnal erections may lead to insufficient oxygen tension causing increased fibrous tissue and decreased smooth muscle content, which further aggravates ED. In 2011, Gökçe et al.7 reported that penile erection can occur in the absence of sexual stimula­ tion in a laboratory-­b ased double-blind study. 80 men with lifelong premature ejacula­tion but not ED were divided equally into four groups to receive a single dose of JANUARY 2012  |  S81


UROLOGY either placebo, vardenafil (10 mg), sildenafil (50 mg) or tadalafil (20 mg), after 3 days of sexual abstinence. Despite the absence of any sexual stimulation, 10%, 41%, 26% and 55% of men in the placebo, sildenafil, tadalafil and vardenafil groups, respectively, were able to achieve ≥60% base or tip rigidities (P <0.05). The median time to first measured base rigidity was 58.0, 21.5, 54.5 and 57.0 min and the median total duration of recorded base rigidity was 4.0, 27.5, 10.0 and 11.5 min in patients who took placebo, sildenafil, tadalafil and vardenafil, respectively. This is the first study to show that substantial penile rigidity can be obtained with PDE5 inhibitors, with no sexual stimula­tion, in a laboratory setting. Evidence that PDE5 inhibitors can affect erectile variables supports the idea that dysfunctional endo­thelium can be rehabilitated, and suggests that men who require penile rehabilitation might benefit from PDE5 inhibitors. Finally, new research has assessed the complex relationship between metabolic syndrome, sexual dysfunction, and serum testosterone levels. Metabolic syndrome is often associated with male hypo­ gonadism and a recent meta-analysis 8 has confirmed that patients with metabolic syndrome have significantly lower total testo­sterone levels (about 3 nmol/l) than those without. Furthermore, after adjusting for age and BMI, both type 2 dia­b etes and metabolic syndrome independently predicted lower testosterone level (adjusted r = –0.752 [P <0.001] and –0.271 [P <0.05], respectively). In another study, Marberger et  al. 9 reported that age, International Prostate Symptom Score (IPSS), BMI and diabetes or glucose intolerance, but not serum testosterone or total prostate volume, were signifi­cant independent predictors of sexual dysfunction, based on baseline data in the REDUCE study population. On multi­ variate analysis, only age and IPSS were significant predictors of all four sexual function criteria assessed (sexual inactivity, impotence, decreased libido and Problem Assessment Scale of the Sexual Function Index score <9). Several criticisms can be leveled at this population-based study, including the varied timing of serum testosterone collection, the lack of reporting of other testosterone-related variables (such as free testosterone or sex hormone-binding globulin measurements) and the confounding factor that higher BMI is likely to result in metabolic syndrome, which contributes S82  |  JANUARY 2012



to the development of impaired glucose tolerance and decreased androgen levels. The lack of association between sexual dysfunction and serum testosterone reported here questions the value of using modestly reduced testosterone level as a criterion for testosterone replacement in older men with sexual dysfunction. Studies published in 2011 have improved and consolidated our understanding of sexual dysfunction. The large-scale population-­b ased studies of the natural history of ED, the proposed prediction models of ED after prostate cancer treatment and the various emerging and novel ED therapies have provided new management approaches for this sexually debilitating condition. The association between testosterone levels, metabolic syndrome and sexual dysfunction remains complex, contentious and poorly defined. There is no doubt that continued innovative research over the next few years will further enhance our understanding of the field. Department of Urology, Princess Alexandra Hospital, Ipswich Road, Brisbane, QLD 4102, Australia (E. Chung). Division of Urology, St Joseph Health Care, 268 Grosvenor Street, London, ON N6A4V2, Canada (G. B. Brock). Correspondence to: G. B. Brock gebrock@sympatico.ca Competing interests The authors declare no competing interests.

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8.

9.

Prins, J., Blanker, M. H., Bohnen, A. M., Thomas, S. & Bosch, J. L. Prevalence of erectile dysfunction: a systematic review of population-based studies. Int. J. Impot. Res. 14, 422–432 (2002). Travison, T. G. et al. The natural progression and regression of erectile dysfunction: follow-up results from the MMAS and MALES studies. J. Sex. Med. 8, 1917–1924 (2011). Gruenwald, I., Appel, B. & Yardi, Y. Low-intensity extracorporeal shock wave therapy‑A novel effective treatment for erectile dysfunction in severe ED patients who respond poorly to PDE5 inhibitor therapy. J. Sex. Med. http://dx.doi.org/10.1111/ j.1743–6109.2011.02498.x. Muller, A. et al. The impact of shock wave therapy at varied energy and dose levels on functional and structural changes in erectile tissue. Eur. Urol. 53, 635–642 (2008). Alemozaffar, M. et al. Prediction of erectile function following treatment for prostate cancer. JAMA 306, 1205–1214 (2011). Padma-Nathan, H. et al. Randomized, doubleblind, placebo-controlled study of postoperative nightly sildenafil citrate for the prevention of erectile dysfunction after bilateral nerve-sparing radical prostatectomy. Int. J. Impot. Res. 20, 479–486 (2008). Gökçe, A., Demirtas, A., Halis, F. & Ekmekcioglu, O. The effects of phosphodiesterase on penile rigidity variables during a period of no sexual stimulation: a laboratory setting double-blind study. BJU Int. 107, 264–267 (2011). Corona, G. et al. Testosterone and metabolic syndrome: a meta-analysis study. J. Sex. Med. 8, 272–283 (2011). Marberger, M., Wilson, T. H. & Rittmaster, R. S. Low serum testosterone levels are poor predictors of sexual dysfunction. BJU Int. 108, 256–262 (2011).

MALE FACTOR INFERTILITY IN 2011

Semen quality, sperm selection and hematospermia Amichai Kilchevsky and Stanton Honig

The past year has seen several new developments in the field of male reproductive health, including a major revision of how urologists should assess semen quality following the release of new WHO guidelines, novel approaches to sperm selection for intracytoplasmic sperm injection, and changes in how clinicians might evaluate and treat patients with hematospermia. Kilchevsky, A. & Honig, S. Nat. Rev. Urol. 9, 68–70 (2012); published online 17 January 2012; doi:10.1038/nrurol.2011.234

Updated reference values for human semen analysis from the WHO were reported by Cooper et al.1 in 2010, and much discussion followed in 2011. The new guidelines include significant changes from prior versions, and it is crucial that urologists understand them. Moreover, the 5th edition of this manual is the first to include

evidence-­based data as opposed to consensus-based recommendations. The authors derived the updated reference ranges from a collection of multicenter, multinational studies encompassing 1,953 men for whom the time to pregnancy was <12 months. However, it is important to note that the reported ranges are not ‘normal’ ranges but www.nature.com/reviews


UROLOGY rather information on the 95th percentile of semen analysis data. As such, they inform the reader that 95% of men who achieve pregnancy within 12 months of trying will have sperm concentrations of >15 million cells/ml, >40% of observed sperm demonstrating good movement, and >4% of sperm with normal morphology. Unfortunately, these criteria do not predict the likelihood of achieving a pregnancy in the following 12 months, which is typically when urologists first see these patients in consultation. Furthermore, the reference range must be viewed as a continuum, given that many patients at the low end of the range might still achieve pregnancy, and men at the high end might not. The nondefinitive nature of these guidelines confirms the need for further sophisticated testing—such as DNA fragmentation analy­ sis, oxidative stress analysis and sperm evaluation for genomic, proteomic and metabolic factors—in certain cases of male factor or unexplained infertility. For example, a patient whose semen parameters fall within the new reference ranges but has not achieved pregnancy might benefit from DNA fragmentation testing to identify subtle sperm abnormalities. Esteves et al.2 have analyzed the new reference values and highlight further issues that may face the urologist, including whether the referral of male partners will decrease, whether we were previously overtreating our male patients and how to better interpret these reference values by focusing on the 50 th percentile of data. Over the past decade, progress in the field of assisted reproduction has led to a change in the management of severe male factor infertility not amenable to medical or surgical correction. Currently, intracytoplasmic sperm injection (ICSI) is the treatment of choice for patients who suffer from either severe oligospermia or non­obstructive azoospermia (NOA). Historically, any motile sperm present in the ejaculate would be preferentially utilized for ICSI. Alternatively, if no sperm were found in the ejaculate, sperm surgically extracted from the testis were used instead. When very low numbers of sperm were present in the ejaculate and initial ICSI results with motile ejaculated sperm were poor, then testis sperm was considered. Evidence against this ejaculate-first approach was recently reported by Hauser et al.,3 who found that fertilization rates in patients with relative or virtual azoospermia were higher when fresh or frozen-thawed KEY ADVANCES IN MEDICINE

testicular sperm cells were used than when ejaculated sperm cells were used. This finding is particularly interesting considering that although more motile sperm cells were found in the ejaculated specimens than in the testicular samples, the quality of embryos from testicular sperm (fresh and frozen) was significantly higher than of those from ejaculated sperm. This observa­tion led the authors to conclude that it is the source of sperm cells, and not their motility, that plays a crucial role in fertility outcome. This pilot study suggests a possible role for testicular sperm extraction (TESE) coupled with ICSI in patients with severe oligo­asthenospermia or relative or virtual azoo­spermia. If testicular sperm leads to better fertility outcomes, does it matter if fresh or frozen-thawed testicular spermatozoa are retrieved? According to Hauser et al.,3 the answer is yes. While frozen-thawed spermatozoa may be more conveniently obtained, the researchers found that for patients with virtual or relative azoospermia, fresh testis sperm yielded better implantation rates than frozen testicular sperm. Although these results support the use of fresh testicular sperm for patients with relative or virtual azoospermia, there is still no consensus on the best approach for retrieving testis sperm from men with pure NOA. This year, the value of diagnostic testis biopsy in the era of ICSI was addressed by Kalsi et al., 4 who provide evidence that microsurgical TESE (m-TESE)— introduced by Schlegel and Li5 in 1998—is the optimum sperm retrieval method in patients with NOA, preferential to fine-needle aspira­tion and traditional TESE. Researchers were able to successfully retrieve spermatozoa from 50 of 100 men with NOA who underwent m‑TESE at their center, which includes a success rate of 57% in men with previously failed attempts at sperm retrieval. The only significant positive predictor of a successful retrieval was a previous histological diagnosis of hypospermatogenesis, and therefore the authors recommend against the common practice of performing isolated diagnostic testicular biopsies on men with NOA, and suggest instead that biopsy should always be combined with a TESE procedure. Therefore, the take home message for any urologist treating a patient with NOA is to either proceed with a combined diagnostic testis biopsy and send tissue to an andrology laboratory for processing and cryo­preservation, or to refer the patient to a reproductive

Key advances ■■ The updated 5th edition of the WHO semen guidelines includes significant changes from prior versions and is the first edition to include evidence-based data1 ■■ In certain cases, testicular sperm may be used for intracytoplasmic sperm injection, in preference to ejaculated sperm, for patients with relative or virtual azoospermia3 ■■ Diagnostic testis biopsy alone (without tissue processing) has limited value in the management of nonobstructive azoospermia4 ■■ The underlying cause of hematospermia can be evaluated using transrectal ultrasonography6 ■■ Finasteride is a feasible treatment option for men with recurrent idiopathic hematospermia7

urologist who has this capability. Our current approach is to begin with a standard TESE and if no sperm are observed to proceed with an immediate m‑TESE. Abnormal findings in ejaculate are not always related to male factor infertility. In fact, one of the most frequently encountered problems in general urology is hemato­ spermia, which can be a cause of great concern and anxiety for affected men. Until recently, hematospermia was assumed to be idiopathic and patients were reassured that their condition was benign. A recent study by Zhao et al.,6 however, may alter the urologist’s approach to hematospermia. In their study, researchers performed trans­ rectal ultrasonography on 270 men with hematospermia, and found abnormalities in 95% of the cohort. These abnormalities were universally benign in patients under 40 years of age, including prostatic calcifications, ejaculatory duct calculi, and benign prostatic hyperplasia. Patients over the age of 40 years, however, were significantly more likely to have a malignant disease; 8

Courtesy of A. Kilchevsky, Yale–New Haven Hospital, USA

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UROLOGY of 126 (6.3%) men over 40 years old were found to have prostate, seminal vesicle, or bladder cancer. So, although reassurance may be appropriate in a younger population, hematospermia in men over 40 years of age must be evaluated more closely. A small randomized study by Badawy et al.,7 published this year, evaluated the role of finasteride in the treatment of recurrent idiopathic hematospermia. This study reports the response of 24 patients to treatment with finasteride at 5 mg daily for 3 months. Men who received finasteride reported a statistically significant improvement in hematospermia compared to those in the placebo group (66% versus 25%; P = 0.05). Although this is a small study, it gives the general urologist an off-label option for the treatment of recurrent hemato­spermia after organic causes (such as infection and malignancy) have been ruled out. In summary, there have been several new developments in the fields of male factor infertility and andrology over the last year that are of great interest to the general urologist. The new WHO guidelines for semen quality provide updated reference ranges rooted in evidence-based data. New techniques for surgical sperm extraction have both clarified current approaches and provided novel treatment options for NOA and relative azoospermia. Finally, new information regarding the evaluation and treatment of hematospermia will help us better identify causality, reassure our patients, and provide treatment with better outcomes. Department of Urology, Yale–New Haven Hospital, Yale Physicians Building, 800 Howard Avenue, 3rd Floor, New Haven, CT 06519, USA (A. Kilchevsky). Division of Urology, University of Connecticut Health Sciences Center, 263 Farmington Avenue, Farmington, CT 06030, USA (S. Honig). Correspondence to: S. Honig shonig@srhs.org Competing interests The authors declare no competing interests. 1.

2.

3.

4.

Cooper, T. G. et al. World Health Organization reference values for human semen characteristics. Hum. Reprod. Update 16, 231–235 (2010). Esteves, S. C. et al. Critical appraisal of World Health Organization’s new reference values for human semen characteristics and effect on diagnosis and treatment of subfertile men. Urology http://dx.doi.org/10.1016/ j.urology.2011.08.003. Hauser, R. et al. Virtual azoospermia and cryptozoospermia—fresh/frozen testicular or ejaculate sperm for better IVF outcome? J. Androl. 32, 484–490 (2011). Kalsi, J., Thum, M. Y., Muneer, A., Abdullah, H. & Minhas, S. In the era of micro-dissection

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5.

sperm retrieval (m-TESE) is an isolated testicular biopsy necessary in the management of men with non-obstructive azoospermia? BJU Int. http://dx.doi.org/10.1111/ j.1464-410X.2011.10399.x. Schlegel, P. N. & Li, P. S. Microdissection TESE: sperm retrieval in non-obstructive azoospermia. Hum. Reprod. Update 4, 439 (1998).

6.

7.

Zhao, H. et al. The value of transrectal ultrasound in the diagnosis of hematospermia in a large cohort of patients. J. Androl. http:// dx.doi.org/10.2164/jandrol.111.013318. Badawy, A. A., Abdelhafez, A. A. & Abuzeid, A. M. Finasteride for treatment of refractory hemospermia: prospective placebocontrolled study. Int. Urol. Nephrol. http:// dx.doi.org/10.1007/s11255-011-0057-0.

KIDNEY CANCER IN 2011

Objectifying risk for localized renal masses Marc C. Smaldone and Robert G. Uzzo

Contemporary treatment guidelines for the localized renal mass are largely driven by expert opinion and retrospective observational data. Three articles published in 2011 add important information to the existing body of literature, enabling improved objectification of risk and individualization of clinical tradeoff decisions for patients presenting with localized renal tumors. Smaldone, M. C. & Uzzo, R. G. Nat. Rev. Urol. 9, 70–72 (2012); published online 13 December 2011; doi:10.1038/nrurol.2011.195

Increased utilization of abdominal imaging has led to a significant rise in the inci­ dental detection of clinically localized renal tumors. Although the gold standard treatment for clinically localized small renal masses remains surgical excision, contemporary practice patterns have evolved in an effort to match treatment strategy to tumor characteristics, as well as minimize the adverse effects associated with chronic kidney disease (CKD).1 The armamentarium of management options has expanded to include open and minimally-invasive radical nephrectomy, nephron-sparing surgical techniques, tumor ablation, and active surveillance with curative intent. In 2009, the American Urological Association Guidelines committee issued the following recommendation: “surgical excision by partial nephrectomy is the reference standard for the management of the clinical T1 renal mass, whether for imperative or elective indications, given the importance of preservation of renal parenchyma and avoidance of CKD.”2 However, when evaluating these guidelines it is important to bear in mind that the evidence quality of the contemporary body of literature is poor, and is limited primarily to retrospective observational studies. As a result, treatment decisions are driven primarily by expert opinion and surgeon experience, and a number of important questions regarding the safety and oncologic efficacy of current

management strategies remain unanswered. Three studies published in 2011 provide evidence that will improve the communication of risk and enable tradeoff decisions when counseling patients diagnosed with localized renal tumors. Until recently, level 1 evidence comparing the oncologic efficacy of radical and partial nephrectomy was lacking. In 2011, Van Poppel et al.3 reported the results of a European Organization for Research and Treatment of Cancer (EORTC) prospective, noninferiority, multicenter, phase III trial assessing oncologic outcomes in patients with a normal contralateral kidney randomized to either radical nephrectomy (n = 273) or nephron-­sparing surgery (n = 268) for solitary localized renal tumors ≤5cm in size.3 Oncologic efficacy was found to be equivalent between groups, with 10-year progression rates of 4.1% (95% CI 1.7–6.5%) and 3.3% (95% CI 1.2–5.4%) for partial and radical neph­rectomy, respectively (P = 0.48). Furthermore, only 12 renal-cancer-related deaths were noted in the study, with a median follow-up of 9.3 years, suggesting that the risk of cancer-­specific death in patients surgically treated for stage 1 tumors is extremely low. However, in the intentionto-treat analysis, the authors reported a significant 10-year overall survival benefit for patients undergoing radical surgery compared to partial nephrectomy (81.1% versus 75.7%; HR 1.50 [95% CI 1.03–2.16]; www.nature.com/reviews


P = 0.03). When the analysis was limited to patients with histologically confirmed renal cell carcinoma, these differences in overall survival were less pronounced. The findings of this study must be placed in context of its limitations. Designed to recruit 1,300 patients, the trial was closed early due to poor accrual, and did not achieve the target sample size chosen to identify a 3% difference in 5-year survival. In addition, there were differences in baseline comorbidities and considerable crossover between treatment arms (5.6% of patients randomized to radical neph­ rectomy underwent partial neph­rectomy, and 14.6% of patients randomized to partial nephrectomy underwent radical neph­ rectomy), which may have influenced the reported survival outcomes. Despite these limitations, the findings raise important questions regarding the relative contributions of preserved renal function and competing risks from pre-existing comorbidities to overall survival following surgical resection for localized renal tumors. Although these results are thought-provoking, further study is necessary to determine which patients stand to benefit the most from nephron-sparing surgery. The benefit of renal function preserva­ tion in nephron-sparing surgery must be weighed against the increased risk of postoperative complications compared with radical nephrectomy. 2 However, a lack of standardized reporting methods has resulted in a body of literature with limited generalizability that is challenging to interpret. In 2011, investigators at Fox Chase Cancer Center attempted to address these issues by rigorously evaluating the complica­t ions associated with partial neph­r ectomy in their institutional database4 using the Clavien-Dindo classifica­t ion system (CCS). 5 Aiming to provide a benchmark for comparative studies between institutions, patients were stratified using the nephrometry scoring system 6 to investigate the relationship between tumor complexity (low complexity score 4–6; intermediate complexity score 7–9; high complexity score 10–12) and risk of postoperative complications. The study cohort consisted of 390 patients with available imaging data for review, who underwent partial neph­rectomy between 2007 and 2010; 109 (28%), 217 (55.6%), and 64 (16.4%) patients underwent nephron-­ sparing surgery for low, intermediate, and high complexity lesions, respectively. The overall proportion of patients incurring KEY ADVANCES IN MEDICINE

© London_england | Dreamstime.com

UROLOGY

minor (CCS I–II) and major (CCS III–V) complications were 26.7% and 11.5%, respectively. No significant differences were observed in minor complications between complexity groups, but patients with highly complex lesions were more likely to develop a major complication requiring secondary intervention than intermediate and low complexity tumors (22% versus 11% versus 6%; P = 0.001). Controlling for demographic and clinical characteristics, patients with highly complex renal tumors were 5.4 times (95% CI 1.2–24.2) more likely to sustain a major complication compared to those with low complexity lesions. Although this study was limited by its retrospective methodology and lack of external validation, these findings highlight two important points: the rigorous reporting of complications using standardized reporting methodology is essential for comparing outcomes between institutions, and the benefit of nephron preserva­t ion in highly complex tumors comes with the attendant risk (>20%) of a major post­operative complication. Recent evidence suggests that a substantial proportion of the rapidly rising number of incidentally diagnosed small renal masses represents indolent disease Key advances ■■ In a recent phase III randomized trial,3 partial nephrectomy demonstrated equivalent cancer-specific survival to radical surgery for tumors ≤5 cm, but did not demonstrate the expected overall survival benefit ■■ The benefit of nephron preservation in highly complex tumors comes with the attendant risk (>20%) of a major postoperative complication4 ■■ A large proportion of small renal masses under observation grow slowly, and the short-term risks of progression or metastasis under active surveillance are low9

that may not require treatment. 7 As a result, much attention has been directed towards describing the natural history of untreated renal tumors in an effort to identify which lesions are safe to observe and which require early definitive intervention.8 In 2011, Jewett et al.9 reported the results of a multicenter prospective phase II trial investigating the growth kinetics and progression rates of 209 incidentally diagnosed cT1a lesions under observation in patients deemed unfit for surgery owing to advanced age, comorbidity, or refusal of other treatment.9 In this cohort of 178 patients (mean age 73 years, mean tumor size 2.3 cm), the authors defined tumor progression as growth to ≥4 cm, tumor volume doubling time ≤12 months, or progression to metastatic disease. Notably, 99 patients (56%) underwent renal biopsy and 127 patients (151 masses) were followed up for >12 months (mean 28 months). Important study findings include an average growth rate of 0.13 cm per year, documented progression (as defined above) in 27 patients (15%), and only two patients (1.1%) developing evidence of metastatic disease. Furthermore, there was no difference in growth rate between biopsy-proven malignant and benign disease (0.14 cm per year versus 0.17 cm per year; P = 0.8), and 36% of biopsy-proven renal cell carcinomas showed either no evidence of growth or a decrease in size. Although limited by lack of central pathology review, elevated nondiagnostic biopsy rate (33%), and short duration of follow-up, this study should be commended for its rigorous eligibility criteria, use of protocol renal mass biopsy, and strict definition of tumor progression. These findings add significantly to the growing body of literature documenting that a large proportion of small renal masses under observation grow slowly, and that short-term risks of progression or metastasis under active surveillance are low.8,10 In the absence of level 1 evidence, physi­ cians are increasingly challenged to manage risk on a patient by patient basis. Although the list of unanswered questions remains long, the studies described above each provide evidence to improve risk communication and enable tradeoff decisions when counseling patients diagnosed with localized renal tumors. Until the ability to match treatment to tumor biology has been achieved, urologists must continue to vigilantly evaluate and challenge contemporary management strategies, objectify tradeoff risks, and individualize treatment strategies. JANUARY 2012  |  S85


UROLOGY Division of Urologic Oncology, Department of Surgery, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA (M. C. Smaldone, R. G. Uzzo). Correspondence to: R. G. Uzzo r_uzzo@fccc.edu

3.

4.

Competing interests The authors declare no competing interests. 1.

2.

Go, A. S., Chertow, G. M., Fan, D., McCulloch, C. E. & Hsu, C. Y. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N. Engl. J. Med. 351, 1296–1305 (2004). Campbell, S. C. et al. Guideline for management of the clinical T1 renal mass. J. Urol. 182, 1271–1279 (2009).

5.

6.

Van Poppel, H. et al. A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur. Urol. 59, 543–552 (2011). Simhan, J. et al. Objective measures of renal mass anatomic complexity predict rates of major complications following partial nephrectomy. Eur. Urol. 60, 724–730 (2011). Dindo, D., Demartines, N. & Clavien, P. A. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann. Surg. 240, 205–213 (2004). Kutikov, A. & Uzzo, R. G. The R.E.N.A.L. nephrometry score: a comprehensive standardized system for quantitating renal

tumor size, location and depth. J. Urol. 182, 844–853 (2009). 7. Hollingsworth, J. M., Miller, D. C., Daignault, S. & Hollenbeck, B. K. Rising incidence of small renal masses: a need to reassess treatment effect. J. Natl Cancer Inst. 98, 1331–1334 (2006). 8. Chawla, S. N. et al. The natural history of observed enhancing renal masses: metaanalysis and review of the world literature. J. Urol. 175, 425–431 (2006). 9. Jewett, M. A. et al. Active surveillance of small renal masses: progression patterns of early stage kidney cancer. Eur. Urol. 60, 39–44 (2011). 10. Smaldone, M. C. et al. Small renal masses progressing to metastases under active surveillance: A systematic review and pooled analysis. Cancer http://dx.doi.org/10.1002/ cncr.26369.

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