VBCR February 2014, Vol 3, No 1 by Value-Based Cancer Care

FEBRUARY 2014 VOL 3 • NO 1

www.ValueBasedRheumatology.com the Rheumatology nurse™

Rheumatology Nursing Is Evolving Rapidly, Prominent Role Already Assumed By Wayne Kuznar

San Diego, CA—Rheumatology nurs ing is in its infancy but is evolving rapidly as demand increases for modern services and new complex medications require skilled providers to administer and manage them, said Kori A. Dewing, DNP, ARNP, Rheumatology Nurse Practitioner, Virginia Mason Medical Center, Seattle, WA, at the 2013 American College of Rheumatology meeting. The additional millions of Americans that are acquiring healthcare coverage and the rapid increase in Medicare-eligible patients will strain specialty services, creating shortages in rheumatology providers. As such, rheumatology nurses will assume a more prominent role as part of an

By Wayne Kuznar San Diego, CA—Subcutaneous claz akizumab, an investigational monoclonal antibody against interleukin (IL)-6, was found to be effective with or without methotrexate in adults with moderate-to-severe active rheumatoid arthritis (RA) who have an inadequate response to methotrexate at key end points, according to a phase 2b study presented at the 2013 American College of Rheumatology (ACR) meeting.

Kori A. Dewing, DNP, ARNP interdisciplinary team of providers. “With the Affordable Care Act,

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By Alice Goodman

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the first study to quantify the effect of a knee brace on pain and joint damage in patients with OA, according to the authors. The effect on joint damage was assessed using change in volume of Continued on page 21

Rheumatology

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Future Therapies May Come from Modulation of Cell Signaling in Rheumatic Disease By Phoebe Starr San Diego, CA—“This is an exciting time for treatment of rheumatoid arthritis [RA], with many new therapies. But the question is where do we go from here for future therapies, and what have we learned from past failures,” Arthur F. Kavanaugh, MD, Di-

rector, Center for Innovative Therapy, University of California, San Diego, La Jolla, told listeners at the 2013 American College of Rheumatology meeting. Rheumatic diseases are considered auto immune conditions as a conseContinued on page 7

inside VALUE PROPOSITIONS. . . . . . . . . . . 4 Medical test results now accessible to patients directly from laboratory IN THE LITERATURE . . . . . . . . . . . . . Long-term belimumad use safe and effective in patients with SLE

HEALTH ECONOMICS. . . . . . . . . . . . . 6 Step-therapy drug policies rarely limit high-cost specialty pharmaceuticals RHEUMATOID ARTHRITIS . . . . . . JAK inhibitors, other biologics the future of RA treatment © 2014 Engage Healthcare Communications, LLC

Clazakizumab binds the IL-6 cytokine, but not the receptor, which is an important distinction from tocilizu mab, said Michael E. Weinblatt, MD, Codirector, Clinical Rheumatology, Brigham and Women’s Hospital, Boston, MA. Clazakizumab does not mediate antibody-dependent cell toxicity and has a 30-day half-life. In the phase 2b double-blind study, patients were randomly assigned to 24 weeks of placebo and methotrexate;

Personalized Medicine in

Inexpensive Knee Brace Helps Reduce Pain and Joint Damage in Patients with Osteoarthritis San Diego, CA—A low-tech, inexpensive, slip-on knee brace reduces pain and joint damage associated with osteoarthritis (OA), according to a study presented at the 2013 American College of Rheumatology meeting. This is

Investigational Anti–IL-6 Monoclonal Antibody Shows Promising Response Rates in RA

PSORIATIC ARTHRITIS. . . . . . . . . 10 IL-17 inhibitor induces clinical response GOUT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 More aggressive treatment needed LUPUS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Glucocorticoid dose linked to adverse events and overall costs DRUG UPDATE. . . . . . . . . . . . . . . . . . . 22 Otrexup injection for rheumatoid arthritis CONTINUING EDUCATION . . . 26 Optimal use of biologics in delivering value-based care

Join Our Editorial Advisory Board Value-Based Care in RheumatologyTM is looking for practicing rheumatologists with a wide range of experience who are interested in joining our Editorial Advisory Board. Now in its second year of publication, Value-Based Care in RheumatologyTM covers key developments from rheumatology literature and from national and international rheumatology meetings. Editorial Advisory Board members provide expert commentaries and perspectives on value-based care in all rheumatic diseases and offer expert opinion on relevant topics and new developments in the field, including new and emerging drug therapies, managing patients with rheumatic diseases, practice management, as well as payers and policy issues affecting rheumatology practices.

Mission Statement Value-Based Care in RheumatologyTM provides a forum for payers, providers, and the entire rheumatology team to consider the cost-value issues particular to rheumatology treatments. This unique focus is achieved through news coverage from major rheumatology meetings and the rheumatic diseases literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care.

I would like to join the Editorial Advisory Board of Value-Based Care in RheumatologyTM. Fax to: 732-992-1881

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In This Issue Value-Based Care in Integrating Rheumatologists, NPs/PAs, Practice Managers & Payers

Publishing Staff

Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Director, Client Services Zach Ceretelle zceretelle@the-lynx-group.com Editorial Directors Dalia Buffery dbuffery@the-lynx-group.com Frederique H. Evans fevans@the-lynx-group.com Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Senior Production Manager Lynn Hamilton Production Manager Melissa Lawlor

The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Associate Director, Content Strategy & Development John Welz Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Managers Andrea Boylston Jini Gopalaswamy Project Coordinators Deanna Martinez Jackie Luma IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Engage Healthcare Communications, LLC 1249 South River Road, Ste 202A Cranbury, NJ 08512 Telephone: 732-992-1882 Fax: 732-992-1881 Value-Based Care in Rheumatology, ISSN (applied), is published 6 times a year by Engage Healthcare Com munications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2014 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Care in Rheumatology is a trademark of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America. The ideas and opinions expressed in Value-Based Care in Rheumatology do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Value-Based Care in Rheumatology should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

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VALUE PROPOSITIONS

RHEUMATOID ARTHRITIS

PET useful for prevention, early detection of inflammatory arthritic disease More…

CP-P13 a potential biosimilar of infliximab More…

THE Rheumatology NURSE™

Investigational IL-17 inhibitor induces response

Rheumatology nursing is rapidly evolving, prominent role already assumed

PSORIATRIC ARTHRITIS GOUT More aggressive treatment needed for patients

IN THE LITERATURE PAH screening should be performed in patients with systemic sclerosis Chronic kidney disease in top 3 risk factors for gout More…

HEALTH ECONOMICS

LUPUS Glucocorticoid dose linked to adverse events and overall costs More…

RHEUMATOLOGY UPDATE

Biologics may not be cost savers in RA More…

Personalized Medicine in Rheumatology™

More…

ACR committee identifies rheumatologist workforce shortages

DRUG UPDATE

Future therapies may come from modulating cell signaling in rheumatic disease

Otrexup injection for rheumatoid arthritis

CONTINUING EDUCATION Optimal use of biologics in value-based care

VBCR Editorial Advisory Board Howard B. Blumstein, MD Rheumatology Associates of Long Island, Smithtown, NY Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield New York, NY Gary R. Feldman, MD, FACR Private Practice, Pacific Rheumatology, Los Angeles, CA Gary L. Johnson, MD, MS, MBA Regional Medical Director Humana, Inc., Madison, WI Atheer A. Kaddis, PharmD Vice President, Managed Markets Diplomat Specialty Pharmacy Swartz Creek, MI Shelly P. Kafka, MD, FACR Rheumatologist, Mountain State Rheumatology, Medical Director, Mountain State Clinical Research, Clarksburg, WV Clinical Assistant Professor West Virginia University School of Medicine, Morgantown, WV James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA

Gary M. Owens, MD President, Gary Owens Associates Philadelphia, PA

Muhammad Asim Khan, MD Professor of Medicine Case Western Reserve University Cleveland, OH

Kim A. Papp, MD, PhD Founder and President Probity Medical Research Waterloo, Ontario, Canada

John Kolstoe, MD Kolstoe Rheumatology: Musculoskeletal Medicine East Lansing, MI Randall Krakauer, MD, FACP, FACR National Medical Director Medicare, Aetna, Princeton, NJ

Edmund J. Pezalla, MD, MPH National Medical Director for Pharmacy Policy and Strategy Aetna, Hartford, CT

Joel M. Kremer, MD Pfaff Family Professor of Medicine Albany Medical College Director of Research, Center for Rheumatology, Albany, NY Alan Menter, MD Director, Baylor Psoriasis Research Center Dallas, TX Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Murray, UT Lynn Nishida, RPh Director, Clinical Services Catamaran Center of Excellence Northwest Region, Portland, OR

Jeffrey S. Peller, MD Practicing Rheumatologist Harbin Clinic/Rheumatology Rome, GA

William A. Sunshine, MD, FACR Rheumatology Practice Boca Raton & Delray Beach, FL Ronald van Vollenhoven, MD, PhD Associate Professor Karlinska University Hospital Solna Stockholm, Sweden F. Randy Vogenberg, RPh, PhD Principal, Institute of Integrated Healthcare, Greenville, SC

Mission Statement

Value-Based Care in Rheumatology provides a forum for payers, providers, and the entire rheumatology team to consider the cost-value issues particular to rheumatology treatments. This unique focus is achieved through news coverage from major rheumatology meetings and the rheumatic diseases literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care. Contact Information: For subscription information please contact: Telephone: 732-992-1880 Fax: 732-992-1881. Permission requests to reprint all or part of any article published in this publication should be addressed to editorial@engagehc.com. Address all editorial queries to: editorial@engagehc.com. Telephone: 732-992-1882 Fax: 732-992-1881. Postmaster: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Care in Rheumatology, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

february 2014

www.ValueBasedRheumatology.com

Value Propositions PET Useful for Prevention, Early Detection, and Monitoring of Inflammatory Arthritic Disease

Positron emission tomography (PET) is a useful tool to monitor rheumatic disease activity, including rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, and reactive arthritis, according to a systematic review of the current literature. The analysis included 18 studies encompassing 276 patients with an inflammatory disease; 79% of the patients were diagnosed with rheumatoid arthritis. The results showed that PET visualized inflammatory arthritis with a high sensitivity corresponding with clinical assessments. In addition, PET was found to be similar to ultrasound and magnetic resonance imaging in monitoring disease activity in patients with clinically active disease. PET can also detect subclinical disease activity. The authors acknowledged that PET will not be useful in clinical practice for the imaging of active disease in patients with inflammatory arthritis that can be easily determined by clinical assessment, because of the high costs and radiation burden associated with this modality. However, PET may be used to detect the preclinical phase of the disease, to monitor disease activity, and/or to predict therapeutic efficacy. Bruijnen ST, et al. Arthritis Care Res (Hoboken). 2014;66(1):120-130

First Biosimilar Monoclonal Antibody Approved in Europe

The European Commission has approved the first biosimilar monoclonal antibody in Europe, Remsima (by Celltrion) and Inflectra (by Hospira), a biosimilar version of Remicade (infliximab). Although biosimilars are available in other drug classes, especially drugs for the treatment of cancer, this is the first drug class for the treatment of rheumatic diseases to be approved as a biosimilar. The approval of a biosimilar for rheumatic diseases is a positive step toward providing lowercost therapies for patients with these conditions. This will also have implications for drug development in Europe and in the United States. Although the US Food and Drug Administration (FDA) has yet to approve any biosimilar drugs, the FDA does have a path for biosimilars, but it has not reached a consensus on the proper regulations and guidances needed for these new drugs. The cost of biosimilars is expected to be lower than biologics, but it is widely expected that the cost difference in the United States between the original biologic and its biosimilars will be much less than the cost difference between small-molecule brand name and their generic alternatives. Nevertheless, the availability of biosimilars as alternatives to the original biologic agents is expected to save patients, insurers, and the federal government billions of dollars annually in treatment costs. However, the US patent for Remicade does not expire until September 2018; therefore, a biosimilar for the treatment of rheumatic diseases may not become available for quite a while longer. Decision Resources; December 5, 2013

Medical Test Results Now Accessible to Patients Directly from the Laboratory

Patients, or individuals designated by patients, may have direct access to their laboratory test results, according to the US Department of Health and Human Services (HHS). “The right to access personal health information is a cornerstone of the Health Insurance Portability and Accountability Act Privacy Rule,” said HHS Secretary Kathleen Sebelius. “Information like lab results can empower patients to track their health progress, make decisions with healthcare professionals, and adhere to important treatment plans.” This rule amends the Clinical Laboratory

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Improvement Amendments of 1988 to allow laboratories to give a patient, or a person designated by a patient, access to the patient’s completed test reports on the patient or his/her representative’s request. Although patients can continue to receive their laboratory test results directly from their physicians, they now have the ability to access the information directly from the laboratory and maintain strong protections for their privacy. This rule is being issued by the Centers for Medicare & Medicaid Services, the Centers for Disease Control and Prevention, and the Office for Civil Rights. Health & Human Services Press Release; February 3, 2014

Protein Linked to Bone Growth in Mice

WNT7B—a protein associated with cell proliferation, fate decision, polarity, and migration—may also promote bone formation, according to a recent study from Washington University School of Medicine, St Louis. The mechanism of action is partly mediated through the mammalian target rapamycin complex 1 (mTORC1). “We have been looking for new ways to stimulate bone formation,” said principal investigator Fanxin Long, PhD. “The tools we already have are very good at slowing the breakdown of the bone, but we need better ways to stimulate new bone growth.” In addition to enhancing increasing osteoblast number and activity, they found that WNT7B stimulates bone acquisition in the embryo, enhances bone accrual in postnatal cells, and stimulates bone formation in part through mTORC1; WNT7B and WNT3A activated mTORC1 signaling. Specifically, the WNT proteins activated mTORC1 through phosphoinositide 3-kinase (PI3K)-AKT signaling, the authors explained. Furthermore, mTORC1 appeared to increase osteoblast activity in response to the WNT7B protein. These results may lead to new therapies for patients with osteoporosis. Chen J, et al. PLoS Genet. 2014;10:e1004145

Bipartisan Proposal to Repeal Medicare’s SRG and Implement Value-Based Physician Payment

A bipartisan group of House and Senate lawmakers proposed the SRG Repeal and Medicare Payment Modernization Act, which intends to permanently repeal Medicare’s sustainable growth rate (SRG) formula for physician payments and replace it with annual increases of 0.5% between 2014 and 2018. These increases would be maintained through 2023 so that physicians have time to receive additional payments through a merit-based incentive payment system. The proposed act would apply to clinical nurse specialists, nurse practitioners, and physicians of medicine or osteopathy. The summary of the legislation suggests that the new payment system would encourage care coordination initiatives for patients with chronic illnesses. In addition, the legislation would require the US Department of Health and Human Services to make public a list of clinical decision support tools, which would be used in a program that would require clinicians ordering scans for their patients to consult with one of the listed qualified systems and ensure the scans follow “appropriate use criteria” before Medicare coverage. Clinicians found to be noncompliant with these criteria would require prior authorization before using applicable imaging services. It would also require electronic health records to be interoperable by 2017. “Congress has been debating the shortcoming of the SRG policy for more than a decade,” American Medical Association President Ardis Dee Hoven, MD, said in a statement. “Continuing the cycle of short-term patches by merely addressing the 2014 cut that is imminent on April 1 without solving the underlying problem would be fiscally irresponsible and further undermine the Medicare program.” California Healthline; February 7, 2014

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Rheumatology Nursing Is Evolving Rapidly... there’s a lot of push legislatively to increase the scope of nurse practitioners to help provide care to a growing number of patients who were previously uninsured who will be seeking care,” Dr Dewing said. Complex Medicines Require Complex Skills Few licensed nurses were working in rheumatology a decade ago, but the complexity of modern treatment options has created a need for skilled nurses in this specialty. The newer rheumatologic therapies that came to market in the 1990s demanded that nurses learn about them, and effectively communicate their risks and benefits to patients. “Nurses at this time needed help understanding these complex issues—the immune system and understanding how it worked, the diseases in intricate detail, and the treatments available,” said Dr Dewing. Administration of infusible medications in particular requires the expertise of a rheumatology nurse who is competent in intravenous (IV) infusion techniques, specific drug infusion criteria, and management of adverse and serious infusion reactions, as well as to identify insufficient therapeutic effects, according to the 2013 Rheumatology Nursing: Scope and Standards of Practice. “We need to be familiar with multiple drug combinations and the protocols to treat rheumatic diseases, how we measure outcomes, the side effects of these medications, the comorbidities associated with these diseases, how to monitor these medications, and the interactions between different drugs,” she said. One of the most important duties

is patient education. “I believe that it is one of the best things rheumatology nurses do for our patients,” she said. “I think it’s truly what they appreciate.”

“With the Affordable Care Act, there’s a lot of push legislatively to increase the scope of nurse practitioners to help provide care to a growing number of patients who were previously uninsured who will be seeking care.” —Kori A. Dewing, DNP, ARNP

Scope of Practice In November 2012, the American Nurses’ Association Board of Directors recognized rheumatology nursing as a new specialty, and approved the rheumatology nursing scope of practice statement (Table). This scope includes the outpatient setting, said Dr Dewing. Patient education and injection teaching is the core of duties. Physical assessment, medication monitoring, knowledge of insurance, coordination of care, and psychosocial support and assistance, are other core duties. “Advance practice nurses may have other roles in the clinical setting in the

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US,” she said. “The scope of practice of an APRN varies from state to state. In Washington…my practice is fully autonomous. I have full prescriptive authority. I can work independently if I choose. I choose to work with a group of rheumatologists as part of an interdisciplinary team but it’s not required that anybody reviews my notes or signs off on what I do. However, we remain a team and we work together.” Rheumatology nurses may also participate in infusion suites in a clinical and management capacity. They prepare medication for IV infusion; access the IV site; assess the patients before, after, or during the infusions; manage infusion site reactions—often independently—provide patient education, manage inventory, and develop infusion suite protocols. Many nurses in rheumatology work in research facilities, possibly as trial coordinators. “In the advanced practice role, I have served as a subinvestigator and a primary investigator in some clinical trials,” she said. “Nurses are also responsible for maintaining records and administering medications…what’s needed to make the trial happen. They obtain blood tests or other measurements according to study protocols. Nurses can be involved in study recruitment and assist in providing consent and educating study participants.” Rheumatology nurses can be involved in a rehabilitation setting, long-term care, home health, hospice, palliative care, faith community, and as school nurses. A rheumatology nursing core curriculum has been developed. It is the core knowledge that must be in a nurse’s armamen-

Table Rheumatology Nursing Standards of Practice 1. Assessment 2. Diagnosis 3. Outcomes identification 4. Planning 5. Implementation 5A. Coordination of care 5B. Health teaching and health promotion 5C. Consultation 5D. Prescriptive authority and treatment 6. Evaluation Standards of Professional Performance 7. Ethics 8. Education 9. Evidence-based practice and research 10. Quality of practice 11. Communication 12. Leadership 13. Collaboration 14. Professional practice evaluation 15. Resource utilization 16. Environmental health tarium to practice in a specialty. It is the basis on which a certification examination is being developed, written, and submitted to the American Nurses Association. The test should be available by the summer of 2015, and should eventually separate into 2 tracks: registered nurses and advanced practice nurses. n

In the Literature Long-Term Belimumab Safe and Effective in Patients with Systemic Lupus Erythematosus

Although patient survival has improved, systemic lupus erythematosus (SLE) remains associated with significant morbidity and mortality. As part of a continuation study of a phase 2 clinical trial, investigators sought to determine the disease control and safety profile of belimumab with standard therapy in patients with SLE and found that when administered with standard therapy, it was safe and maintained disease control (Ginzler EM, et al. J Rheumatol. 2014;41:300-309). VOL. 3

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Patients were eligible for inclusion in the continuation study if they completed the double-blind, placebo-controlled, 52-week trial of belimumab (1, 4, and 10 mg/kg) and the 24-week extension study (placebo switched to 10 mg/kg; belimumab same dose or switched to 10 mg/kg). Overall, 296 patients met the criteria for inclusion and were enrolled in the open-label continuation trial (belimumab 10 mg/ kg). Data pertaining to disease activity, biomarkers, and medication changes were evaluated. This study had the longest reporting period for an ongoing trial of a biologic agent in patients with SLE. The SLE Flare Index response in-

creased from 57% by year 2 to 65% in patients who were autoantibody positive during the continuation study. In addition, the annual rate of decline of severe flares was 2% to 9% during the continuation study. Between year 2 and year 7, there was a progressive decline in anti–double-stranded DNA in patients who were autoantibody positive at baseline. Median dose of corticosteroid use decreased over time between year 5 and year 7, and serious and overall annual rates of adverse events were stable or decreased by the conclusion of the continuation study. The mortality rate was below previously reported data for SLE (0.4 vs february 2014

1.63/100 patient-years), and no increase in mortality associated with belimumab was reported. In addition, corticosteroid use decreased by 55% among patients who participated for the length of the study. Autoantibody-positive patients had sustained disease control, as well as decreased and stabilized disease frequency of all flares and severe flares. The pool of patients who participated in the continuation trial may have been enriched with patients who responded to or tolerated belimumab. Another limitation was the lack of a matched-control group to directly compare the long-term safety and efficacy data. Continued on page 21

www.ValueBasedRheumatology.com

Health Economics

Biologics May Not Be the Cost Savers They Are Assumed to Be in RA By Wayne Kuznar San Diego, CA—Biologic response modifiers for the treatment of patients with rheumatoid arthritis (RA) do not appear to offset healthcare costs over 3 years, according to an econometric analysis presented at the 2013 American College of Rheumatology meeting. The finding comes from a population-based cohort of more than 700 patients with RA in British Columbia, Canada, identified from an administrative database. Despite more than a decade of routine use, there is no direct evidence to support an association between biologic use and subsequent reductions in healthcare utilization, said lead investigator Nick Bansback, PhD, a health economist, Centre for Health Evaluation and Outcome Sciences, and Assistant Professor, University of British Columbia, Vancouver. “We

at a glance ➤ Biologics may not provide cost-savings beyond 3 years ➤ Total cumulative cost was $12,274 in the biologic group and $9576 in the DMARD group

were interested in the hypothesis that biologics have reduced hospitalizations. That’s the premise we were trying to test,” Dr Bansback said. “Nobody has ever shown whether that’s true or not, but they assume it’s true.” The impact of biologic treatment compared with disease-modifying antirheumatic drugs (DMARDs) on other healthcare utilization was assessed in patients with RA based on their eligibility for biologic agents between 2003 and 2007. “We used instrumental variables to overcome issues of confounding because we were concerned that patients with biologics have more severe disease, and so would have higher costs,” said Dr Bansback. There were 314 patients in the biologic group and 486 in the DMARD group. The primary outcome was the cumulative direct cost of RA-related hospitalizations, physician services, and prescription medications other than biologics and DMARDs incurred per patient over 3 years. The biologic group was more likely to have had an RA-related surgery at baseline, and had higher RA-related and total resource utilization 1 year before baseline. During the 3 years, the biologic group continued to incur

higher costs. The total cost per patient was $4670 in the biologic group and $3566 in the DMARD group. The

“There’s no signal after 3 years that biologics have reduced costs, but we suspect that might be because conventional DMARDs have been used more aggressively in that time period, so there’s not much difference between the biologic and the DMARD arm. Perhaps the biologics have an impact beyond 3 years, but we don’t know.” —Nick Bansback, PhD

mean number of physician visits was 39 in the biologic group versus 31 in the DMARD group. Hospitalization for any cause occurred in 92 patients in the biologic group and in 114 in

the DMARD group. The cumulative RA-related cost was $1839 in the biologic group and $1287 in the DMARD group. The total cumulative cost was $12,274 in the biologic group and $9576 in the DMARD group. Without controlling for confounders (ie, disease severity), costs were 17.7% higher in the biologic group compared with the DMARD group. Results from the instrumental variable estimation showed that costs increased when controlling for confounders: 60.4% and 28.6% more in RA-related expenditures in the 3-year and 2-year follow-up, respectively. “There’s no signal after 3 years that biologics have reduced costs, but we suspect that might be because conventional DMARDs have been used more aggressively in that time period, so there’s not much difference between the biologic and the DMARD arm,” said Dr Bansback. “Perhaps the biologics have an impact beyond 3 years, but we don’t know.” He added, “Of course, with any administrative data you worry about confounding bias, so we still can’t be completely confident, although we believe that this technique has overcome a number of the potential observed differences.” n

Step-Therapy Drug Policies Rarely Limit Utilization of High-Cost Specialty Pharmaceuticals San Diego, CA—Although health insurance benefit plans often include “step-therapy” policies that aim at limiting the use of specialty pharmaceuticals (eg, infused biologics), which often are costly, such policies often do not achieve this goal, according to a study presented at the 2013 American College of Rheumatology meeting by Michael P. Ingham, MSc, Department of Health Economics & Outcomes Research–Immunology, Janssen Scientific Affairs, Horsham, PA, and colleagues. Currently, more than 12 million medical lives are affected by steptherapy policies, with an additional 60 million possible in the near future, estimates Mr Ingham. These step-therapy policies for specialty drugs, including many drugs used for rheumatic diseases, are instituted by many managed care organizations and assume cost-savings on

the basis of reduced utilization of infused biologics, but whether they have the desired effect had not been demonstrated.

“Because there are so many patients already on any of the biologics, and switching is happening in a dynamic way, the policy will still only impact a small proportion of possible users.” —Michael P. Ingham, MSc Mr Ingham and colleagues evaluated the utilization patterns of biologic therapies under plans with step-therapy policies using 3 different method-

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ologies. Two analyses included data from health insurance plans with step-therapy policies through 2010. In the first analysis, the percentage of patients who had claims for biologic drugs covered by plans with step-therapy formularies was compared with all other drug plans in the database during the same time period (ie, “all other”). The second analysis compared the percentage of patients with claims for biologics covered by plans with step-therapy policies and claims from a set of plans matched on the basis of region and relative size (ie, “matched”). The third analysis included plans that had step-therapy policy changes at a known implementation date between January 1, 2006, and April 30, 2011, for plans with data for biologic drug claims within 365 days before

and after the step-therapy policy implementation date, which allowed for 1-year pre- and postmeasurement periods (ie, “pre-/postanalysis”). The investigators identified 16 plans in the database that had a step-therapy policy. Only 1 analysis showed fewer claims for infused biologics in plans with step-therapy policies—the “all other” comparison— which found 5.1% fewer claims for infused biologics. This analysis was the least controlled of the 3 analyses, noted Mr Ingham. “Because there are so many patients already on any of the biologics, and switching is happening in a dynamic way, the policy will still only impact a small proportion of possible users,” Mr Ingham told Value-Based Care in Rheumatology. In the pre-/postanalysis, most of the patients were already receiving Continued on page 7

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Future Therapies May Come from Modulation... quence of a dysregulated immune system that attacks the body’s own tissues. Potential therapeutic targets, including T-cells, B-cells, and macrophages, are thought to drive immune response and inflammatory mediators that sustain the ongoing dynamic autoimmune process, he said. Immunotherapeutic approaches can help dissect out various rheumatic diseases, because some therapies work better in one disease, for example, psoriatic arthritis than in RA. Autoimmune diseases are multigenetic, heterogeneous, and complex, and developing new therapies is therefore also complex. “As we think about responders and nonresponders, we have to consider different layers of response. This speaks to the difficulty of picking a single target that will work across all patients. We would like to have personalized medicine, but we need to learn which patients need to have a specific pathway blocked versus a different pathway,” Dr Kavanaugh said. Large- and Small-Molecule Inhibitors Currently, 5 tumor necrosis factor (TNF) inhibitors are approved by the US Food and Drug Administration; these agents have revolutionized the treatment of RA and other rheumatic diseases. But they are composed of large molecules, which means they are administered either parenterally or subcutaneously, they are expen sive to produce, and are difficult to replicate. “Maybe there is another way to inhibit kinases. One alternative is to look into individual cells, to allow the use of smaller and potentially more precise molecules,” he noted. “This involves transcription, translation, and the protein. Small molecules would be orally available, less expensive to make, and different in selectivity.”

Several small-molecule inhibitors are currently available, and others are in late-phase development for various rheumatic diseases. Kinases that regulate signaling pathways that modulate transcription, translation, and mRNA stability have emerged as the next generation of therapeutic targets. A decade ago, sights were set on developing a P38 MAP kinase inhibitor, based on promising experimental data. “A decade later, we found that they don’t work. Clinical trials showed significant toxicity due to lack of specificity,” Dr Kavanaugh said. “There are many possible reasons for this failure, including lack of inhibition of cytokines, affecting counter-regulatory pathways, and other complex and chaotic undefined interactions.”

Several small-molecule inhibitors are currently available, and others are in late-phase development for various rheumatic diseases.

Experience has shown that a small molecule can inhibit one pathway, and then downstream can inhibit other unintended pathways, giving rise to toxicity. Cyclooxygenase-2 inhibitors are such an example. “This is not a simple question. The more questions you ask, the more answers you get. Mainly, these studies reveal lack of specificity,” he said. A Closer Look at More Complex Pathways Affecting counterregulation pathways is a major hurdle in the treatment of patients with autoimmune disease. Proinflammatory cytokines drive autoimmune diseases, but they

Step-Therapy Drug Policies... a biologic when they entered the analysis, thereby limiting the potential impact of the step-therapy policy. In fact, there was a 2.8% net increase in the percentage of patients with claims for infused biologics in the postmeasurement versus the premeasurement phase. In the “matched analysis,” the use of infused biologics increased by 7% among patients in plans with steptherapy policies. “These data suggest that policies VOL. 3

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also drive anti-inflammatory processes. Anti-inflammatory cytokines drive anti-inflammatory and proinflammatory pathways to achieve homeostasis, which is the ultimate goal for regulatory processes. “Clearly we need more complex approaches, and more complex approaches are being tried,” he said. The signaling protein Janus kinase (JAK), one such approach, has 4 isoforms, including JAK1, JAK2, JAK3, and TYK2. Different JAK inhibitors target separate pathways. Tofacitinib targets JAK1 and JAK2. This agent has exerted faster and more effective disease control compared with methotrexate in clinical trials thus far, but it also has more safety concerns, including changes in cholesterol, liver enzymes, hemoglobin, and serum creatinine, and like many biologics, tofacitinib increases the risk of serious infection. “We will need to monitor carefully for side effects with tofacitinib and other JAK inhibitors,” Dr Kavanaugh commented. Another potential approach in RA and other rheumatic diseases is targeting the B-cell receptor pathway downstream. Rituximab is effective in some of these diseases, and drugs that target the downstream B-cell receptor pathway, such as the Bruton’s tyrosine kinase inhibitor idelalisib and the spleen tyrosine kinase (STK) fostamatinib, are under study. Early data suggested that fostamatinib has good activity in patients with RA receiving background methotrexate, but studies to date are equivocal, and hypertension is a big issue with this drug. “It is not clear if STK is still a viable target, but studies of more specific STK inhibitors may have better results. The debate is ongoing. STK inhibitors are still in development, but the P38 story is still fresh in our

Continued from page 1

at a glance ➤ Autoimmune diseases are multigenetic, heterogeneous, and complex, and developing new therapies is therefore also complex ➤ Experience has shown that a small molecule can inhibit one pathway, and then downstream can inhibit other unintended pathways, giving rise to toxicity ➤ Rheumatologists should follow the example in cancer care, where inhibitors are available for specific mutations

minds,” Dr Kavanaugh noted. Although TNF inhibitors are effective across the spectrum of rheumatic diseases, separate pathways are of research interest in specific rheumatic diseases. For psoriatic arthritis, there is interest in interleukin (IL)-12/23 and IL-17 inhibitors, phosphodiesterase (PDE)-4 inhibitors, and JAK/signal transducer and activator of transcription inhibitors. A PDE-4 inhibitor was also found effective in Behçet’s disease in a paper presented at this meeting. “Personalized medicine has always been our goal. We have 12 therapies to offer a patient, but it is not clear which one is the best for which patient. The hope is that personal omics profiles will pay off in this regard, but this is still expensive and not feasible in every patient,” Dr Kavanaugh said. “We need to replicate the successes in oncology, where inhibitors are available for specific mutations. There are many questions to address in rheumatology. Maybe in 6 to 8 years we will have more to talk about.” n

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“These data suggest that policies intended to restrict product choice for patients requiring a biologic therapy have relatively little impact on the proportion of patients receiving a particular biologic.” —Michael P. Ingham and colleagues intended to restrict product choice for patients requiring a biologic therapy have relatively little impact on the proportion of patients receiving a particular biologic,” Mr Ingham and col-

leagues concluded. The cost of implementing and maintaining these drug benefit policies needs to be balanced against any potential for cost-savings, they noted. february 2014

“In the near term, the intended effects of implementing step-therapy policies may be mitigated, in the bestcase scenario, by relatively small numbers of patients that are affected relative to the total number of users,” according to Mr Ingham. “We did not look at the requirement to use 2 subcutaneous products prior to infusion versus only 1, so we do not know exactly how those plans, if analyzed separately, might compare,” he added.—WK n

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Rheumatoid Arthritis

Investigational Anti–IL-6 Monoclonal Antibody... clazakizumab 25 mg, 100 mg, or 200 mg and methotrexate; clazakiz umab 100 mg or 200 mg without methotrexate; and adalimumab 40 mg every other week plus methotrexate (active reference arm). The primary end point was week 12 ACR 20% improvement (ACR20) response rate. The week 24 secondary end points included ACR20, ACR50, and ACR70 response rates, as well as performance on the Health Assessment Questionnaire Disability Index (HAQ-DI). Remission was defined as Disease Activity Score in 28 joints (DAS28) C-reactive protein (CRP) <2.6, Clinical Disease Activity Index (CDAI) <2.8, and Simplified Disease Activity Index (SDAI) <3.3. Of the 373 patients (mean age, 50 years), 82% were women, mean duration of RA was 5.9 years, mean DAS28CRP was 5.94, and 80% were rheumatoid-factor positive. All clazakizumab groups showed an improvement in ACR20, ACR50, and ACR70 response rates, HAQ-DI, and remission compared with the placebo and the methotrexate groups, through week 24. Approximately 40% of the placebo group met the ACR20 response rate

Subcutaneous clazakizumab was found to be effective with or without methotrexate in adults with moderateto-severe active rheumatoid arthritis who have an inadequate response to methotrexate at key end points. —Michael E. Weinblatt, MD

primary end point, which is consistent with other placebo response rates in emerging countries, said Dr Weinblatt. At week 12, the ACR20 response rates were 78% with clazakizumab 25 mg plus methotrexate (P <.001 vs placebo plus methotrexate), 71.7% with clazakizumab 100 mg plus methotrexate (P <.001), 60% with clazakizumab 200 mg plus methotrexate (P = .015), 55% with claza kizumab 100 mg alone (P = .042), 61% with clazakizumab 200 mg alone (P = .015), and 39.3% with metho trexate plus placebo. The ACR20 response rate for ada limumab 40 mg plus methotrexate

was 76.3%. The week 24 ACR20 response rates ranged from 58% to 83% with clazakizumab, 39% with placebo, and 68% in the reference arm. Remission per DAS28-CRP <2.6, SDAI <3.3, and CDAI <2.8 was higher in the clazakizumab plus methotrexate arms versus in the adalimumab plus methotrexate arm. Clazakizumab and methotrexate responded better than monotherapy. Although the low dose was expected to have a limited dose effect, the 5-mg dose was “surprising,” said Dr Weinblatt, but no clear dose response was noted. Serious adverse events affected 8.3% to 13.3% of the patients in the clazakizumab arms (3.3% for placebo

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and methotrexate, and 5.1% for ada limumab plus methotrexate). One patient had reversible liver transaminases, and the second had neutropenia normalized off drug. Two patients had pulmonary tuberculosis, and 1 pneumocystitis. Mild injection-site reactions, increased transaminases, adverse changes in lipids (including increases in low-density lipoprotein cholesterol in more than 50%) and hemoglobin, and decreased polymorphonuclear

Further research should evaluate clazakizumab dosing and monotherapy. neutrophils and platelets were observed in clazakizumab recipients. The most frequent serious adverse events were serious infections, with comparable rates in the clazakizumab and adalimumab arms. Further research should evaluate clazakizumab dosing and monotherapy, said Dr Weinblatt. n

Positive Results for CP-P13, Potential Biosimilar of Infliximab By Phoebe Starr San Diego, CA—CT-P13 showed 2year efficacy and safety equivalent to that of infliximab (Remicade) in patients with rheumatoid arthritis (RA) on assessments of disease activity and safety, according to a study presented at the 2013 American College of Rheumatology (ACR) meeting. “CT-P13 was effective and well tolerated over 2 years. Switching from infliximab to CT-P13 was feasible, and was safe and effective,” stated lead investigator Dae-Hyun Yoo, MD, PhD, of Hanyang University, Seoul, South Korea. CT-P13 is being developed as a biosimilar of infliximab, one of several biosimilars under study in rheumatic diseases. If this drug and other biosimilars clear the hurdles for approval set by the US Food and Drug Administration, they will be poised to replace costly biologic therapies. Remicade will go off patent in 2018 in the United States. CT-P13 was recently approved by the European Medicines Agency, but the lengthy

approval process in the United States means that biosimilars may not be available for some time. The parent Program Evaluating the Autoimmune Disease Investigational Drug CT-P13 in RA Patients trial was a 54-week randomized, double-blind, parallel-group study that showed that CT-P13 was equivalent to infliximab given with methotrexate and folic acid every 8 weeks in patients with RA; 302 of the patients who participated in the parent study were entered into an open-label 48-week extension study on CT-P13 (maintenance group), and 144 patients were switched from infliximab to CT-P13 (switch group). The rates of disease control were similar between the 2 groups, as measured by the ACR 20% improvement (ACR20), ACR50, and ACR70 response rates. At week 53, the rate of ACR20 was 76.8% for maintenance therapy and 77.5% for the switch arm; the rate of ACR50 was 45.7% and 50%, respectively; and the rate

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of ACR70 was 21.9% and 23.9%, respectively. At week 78, ACR20 response rates were 71.5% for the maintenance arm

“CT-P13 was effective and well tolerated over 2 years. Switching from infliximab to CT-P13 was feasible, and was safe and effective.” —Dae-Hyun Yoo, MD, PhD

and 78.2% for the switch arm. The rate of ACR50 was 48.3% and 47.9%, respectively, and the rate of ACR70 was 24.5% and 29.6%, respectively. ACR20, ACR50, and ACR70 response rates were maintained through

week 102 and were similar in each group: 72.2%, 48.3%, and 24.5%, respectively, in the maintenance arm, and 71.8%, 51.4%, and 26.1%, respectively, in the switch arm. Changes in Disease Activity Score–C-reactive protein from baseline were also comparable between the 2 groups. Antidrug antibodies were documented in approximately 50% of patients in each group by year 2. Antidrug antibodies positivity did not increase significantly during year 2 when both groups were receiving CTP13, Dr Yoo told listeners. At 2 years, the proportion of patients with ≥1 treatment-emergent adverse events was similar in both groups: 53.5% in the maintenance group and 53.8% in the switch group. Infusion-related reactions were reported in 10 (6.3%) patients in the maintenance group, and in 4 (2.8%) patients in the switch group. No reports of tuberculosis occurred. Cancers were reported in 1 patient in the maintenance group and in 4 patients in the switch group. n VOL. 3

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Rheumatoid Arthritis

JAK Inhibitors and Other Biologics Are the Future of RA Treatment By Wayne Kuznar San Diego, CA—Developments in therapeutics for rheumatoid arthritis (RA) have been taking place at breathtaking speed. Biologic agents have greatly increased the ability to improve the lives of patients with RA, and integrating their use with conventional agents will lead to optimal patient outcomes, said Ronald van Vollenhoven, MD, PhD, at the Rational Approach to Treating RA symposium presented during the 2013 American College of Rheumatology (ACR) meeting. Expect additional biologic agents, biosimilars, and oral agents with efficacies comparable to biologics, he said. Nine biologic agents, acting at various receptor sites and with different targets, are currently approved for the treatment of patients with RA. Targets include tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, T-cells, and B-cells. “By using the biologics, we are very specifically interfering with immune inflammatory mechanisms, and we’re doing that at several different levels,” said Dr van Vollenhoven, Professor and Chief of the Unit for Clinical Therapy Research, Inflammatory Diseases, Karolinska Institute, Stockholm, Sweden. In the treatment of patients with RA, dual goals are symptom relief and, in the long run, prevention of structural damage, he said. The combination of methotrexate with an anti-TNF drug or other biologic agent in early RA is superior to monotherapy in achieving an ACR 20% symptom improvement (ACR20) response (approximately 70% vs 50%, respectively). Furthermore, ACR70 responses are more frequent and remission is achieved about twice as often with combination therapy compared with single-agent strategy. Radiographic joint damage is also less progressive with combination strategy. Significantly fewer patients in a TNF-only arm have new erosions

compared with methotrexate monotherapy, and the best radiographic result is achieved with the combination strategy, which is evidence of prevention of structural damage. Methotrexate acts as the cornerstone

“By using the biologics, we are very specifically interfering with immune inflammatory mechanisms, and we’re doing that at several different levels.” —Ronald van Vollenhoven, MD, PhD

of RA therapy, said Dr van Vollenhoven. Adding injections of a corticosteroid every 2 weeks to methotrexate has shown to be an effective, although inconvenient, strategy to improve response rates. This observation led to the design of a study known as OPERA, in which 180 patients at 14 Danish hospitals were treated with adalimumab (Humira) plus methotrexate and intra-articular triamcinolone or methotrexate and triamcinolone as first-line therapy (H�rslev-Petersen K, et al. Ann Rheum Dis. 2013 Mar 7. Epub ahead of print). The addition of adalimumab significantly improved the Disease Activity Score in 28 joints (DAS28) C-reac-

Table 1 OPERA: Investigator-Initiated Trial 12 months outcomes

MTX + placebo

MTX + adalimumab

P value

DAS28(CRP) ≤2.6

49%

74%

.001

CDAI ≤2.8

41%

61%

.011

SDAI ≤3.3

40%

63%

.003

ACR/EULAR (28 joints) remission

31%

48%

.024

Adapted from Hørslev-Petersen K, et al. EULAR 2012, Abstract FRI0148. ACR indicates American College of Rheumatology; CDAI, Clinical Disease Activity Index; Disease Activity Score in 28 joints c-reactive protein combined with C-reactive protein (CRP); DAS28(CRP), Disease Activity Score in 28 joints (DAS28); EULAR, European League Against Rheumatism; SDAI, Simplified Disease Activity Index.

tive protein (CRP), the remission rate, function, and quality of life (Table 1). The 2001 Swefot (Swedish Pharmacotherapy) trial included patients with early RA, who were given methotrexate up to 20 mg weekly (van Vollenhoven RF, et al. Lancet. 2009;374:459466). At 3 to 4 months, patients who did not achieve a DAS28 <3.2 were randomized to receive either sulfasalazine (Azulfidine) and hydroxychloroquine (Plaquenil) or the anti-TNF agent infliximab (Remicade). Compared with the conventional therapy, infliximab added to methotrexate improved the rate of a good response based on the European League Against Rheumatism (EULAR) criteria at 12 months, from 25% to 39% (P = .016). At 2 years, anti-TNF therapy combined with methotrexate was still superior to conventional therapy on this measure, but the difference was no longer significant (P = .26). The difference between the 2 groups narrowed because the rate of good response in patients receiving conventional therapy increased to 31%; the response to infliximab also improved to 43%, noted Dr van Vollenhoven. On an intent-to-treat basis, 2-year radiographic data of patients in the Swefot trial showed significantly less disease progression in patients taking infliximab compared with patients taking conventional therapy (P <.02). “In the direct comparison of an antiTNF therapy against a very well-established and good combination of disease-modifying antirheumatic drugs, we see a clinical benefit that is proven after 1 year, and a radiological benefit that is proven after 2 years,” said Dr van Vollenhoven. Predicting which patients require aggressive therapy versus moderate therapy would enable individuali zation of treatment. Baseline serum samples of 235 patients enrolled in the Swefot trial were tested with the

Table 2 Oral JAK Inhibitors Being Developed for RA Agent

Main target(s)

Tofacitinib

VX-509

JAK1 and JAK3 JAK3

Baricitinib

JAK1 and JAK2

GLPG0634

JAK1

US Food and Drug Administration approved (late 2013). JAK indicates Janus Kinase; RA, rheumatoid arthritis.

at a glance ➤ Predicting which patients require aggressive therapy versus moderate therapy would enable individualization of treatment ➤ Oral JAK inhibitors being developed are tofacitinib, VX-509, baricitinib, and GLPG0634 ➤ Patients taking biologics will probably need to provide blood counts, because they can cause elevations in liver enzymes as well as cytopenias

12 biomarker disease-activity assay called Vectra DA. None of the 5 patients with a low baseline multibiomarker disease activity (MBDA) score and only 1 of 29 with a moderate MBDA score at baseline had radiographic disease progression compared with 42 of 201 with a high baseline MBDA score. CRP did not predict disease progression. Future Developments “In the coming 2 or 3 years, we’re going to learn a lot about IL-17 as a target,” said Dr van Vollenhoven. IL 17 is intricately involved in the regulatory mechanism for T lymphocytes. Clinical and experimental evidence with IL-17 blockade indicates improved ACR responses, DAS28 and DAS28-erythrocyte sedimentation rate (ESR) scores, and CRP levels compared with placebo in patients with active RA. Promising results have also been achieved in patients with psoriatic arthritis treated with IL-17–targeted therapy. Janus kinase (JAK) is a family of intracellular non–receptor tyrosine kinases that transduce cytokine-mediated signals. “If you block the JAK enzymes, you downregulate the inflammation pathways, because it ends up not being able to stimulate the inflammatory gene expression,” he said. Oral JAK inhibitors being developed for the treatment of patients with RA are tofacitinib (Xeljanz)—approved in the United States—VX-509, baricitinib, and GLPG0634 (Table 2). Each blocks a different JAK enzyme, which could potentially result in differential efficacy and safety. In a phase 2b study, the percentage of patients achieving ACR20, ACR50, Continued on page 10

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Psoriatic Arthritis

Investigational IL-17 Inhibitor Induces Clinical Response in Patients with Psoriatic Arthritis By Wayne Kuznar San Diego, CA—Brodalumab, a mono clonal antibody to the interleukin (IL)-17 receptor A, is associated with significant clinical response and an acceptable safety profile in patients with psoriatic arthritis (PsA), said Mark C. Genovese, MD, Professor of Medicine, Immunology and Rheumatology, Stanford University, Palo Alto, CA, at the 2013 American College of Rheumatology (ACR) meeting. “IL-17 is implicated in the pathogenesis of both psoriasis and PsA,” said Dr Genovese. “Brodalumab is a human Ig [immunoglobulin]G2 monoclonal antibody that is designed to block the IL-17 receptor subtype. By engaging in blocking the IL-17 receptor, it interferes with the engagement of IL-17A with the receptor, as well as the engagement of other members of the IL-17 family, including IL-17A/F heterodimers and IL-17F proper.” Blockade of IL-17 is paired with the ability to block the engagement of IL25, he noted. Because IL-17 biology is mediated by a family of proinflammatory cytokines, brodalumab is being assessed in a variety of inflammatory diseases, such as psoriasis, asthma, rheumatoid arthritis, and Crohn’s disease. The phase 2b study presented by Dr Genovese included 168 adults with active PsA for at least 6 months who

were randomized in a 1:1:1 ratio to 1 of 2 dosages of brodalumab (140 mg or 280 mg subcutaneously every other week, with an additional injection at week 1) or to placebo. At week 12, 156 patients enrolled in an open-label extension in which all subjects received

“Brodalumab is a human IgG2 monoclonal antibody that is designed to block the IL-17 receptor subtype. By engaging in blocking the IL-17 receptor, it interferes with the engagement of IL-17A with the receptor.” —Mark C. Genovese, MD 280 mg of brodalumab; blinding was maintained through 24 weeks. “More than 50% of patients were prior biologic exposures; they had tried and failed a tumor necrosis factor inhibitor,” Dr Genovese pointed out. Stable-dose methotrexate, leflunomide, corticosteroids, or nonsteroidal anti-inflammatory drugs were allowed as concomitant medications. The primary response end point was ACR 20% improvement (ACR20

JAK Inhibitors... and ACR70 responses, a DAS28-CRP <2.6, and a CDAI ≤2.8 were superior with baricitinib in a dose-dependent manner, compared with placebo at 12 and 24 weeks. Baricitinib, which has JAK1 and JAK2 as its main targets, has since progressed to a phase 3 study. Tofacitinib’s targets are JAK1 and JAK3. In the ORAL Standard trial, 717 patients with RA who did not respond to methotrexate were randomized to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, 40 mg of ada limumab once every 2 weeks, or placebo with continuation of methotrexate (van Vollenhoven R, et al. N Engl J Med. 2012;367:508-519). At 6 months, the ACR20 response rates were superior with 5 mg or 10 mg of tofacitinib (51.5% and 52.6%, respectively) and with adalimumab (47.2%) compared with placebo (28.3%; P <.001 for all). The active-treatment groups also had greater reductions in the

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Health Assessment Questionnaire Disability Index score at month 3 and higher percentages with a DAS284(ESR) <2.6 at month 6 compared with placebo. “It was not a head-to-head trial, but side-by-side, it looks like we’re getting the same kind of efficacy with [the JAK inhibitor] tofacitinib versus adalimu mab, the anti-TNF agent,” said Dr van Vollenhoven. In terms of safety, there were more treatment-emergent adverse events, especially gastrointestinal events and infections, with tofacitinib and adalimumab compared with placebo. Tofacitinib was also associated with a reduction in neutrophil counts. “What is different with tofacitinib, and probably other JAK inhibitors, is that we will probably have to monitor them, by taking blood counts,” he said. “They can cause elevations in liver enzymes and they can also cause cytopenias.” n

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response). This end point was achieved at week 12 by 37% and 39% of patients in the groups receiving 140 mg and 280 mg of brodalumab, respectively, compared with 18% of patients receiving placebo (P <.05). In an observational analysis, the percent of ACR20 responders increased at week 24 (after being given the option to receive open-label brodalumab) to 44% in the group that was initially randomized to placebo, 51% in the group previously receiving 140 mg of bro dalumab, and 64% in the group previous ly receiving 280 mg of brodalumab. The percent of ACR50 responders (observed) across all groups also increased from week 12 to week 24. Improvements were achieved in other secondary end points, including Disease Activity Score in 28 joints and several components of the ACR criteria, from baseline to week 12, and continued through week 24 in all treatment groups. Dose-related improvement in the levels of C-reactive protein (CRP) from baseline to week 12 was also obtained with brodalumab relative to placebo. “It appears that the CRP change was predominantly driven during the first 12 weeks, and [with] very little occurring between weeks 12 and 24,” Dr Genovese noted. An improvement in dactylitis from

baseline to week 12 occurred with both dosages of brodalumab compared with placebo, with further improvement from weeks 12 to 24. The group that switched from placebo to 280 mg of brodalumab at week 12 also experienced an improvement in dactylitis during the extension phase. There was very little change in enthesitis in the groups receiving brodal umab relative to the group receiving placebo. In an observational analysis of patients with ≥3% body surface involvement of psoriasis, improvements in the Psoriasis Symptom Inventory total score occurred with brodalumab in a dose-dependent manner compared with patients receiving placebo from baseline to week 12, with additional improvement from weeks 12 to 24. The rates of adverse events and serious adverse events were similar between the treatment groups and placebo group, with 85% of patients reporting an adverse event during the open-label extension. The most frequently reported adverse events were nasopharyngitis, arthralgia, psoriatic arthropathy, upper respiratory tract infection, and oropharyngeal pain. The benefit:risk profile supports the continued evaluation of brodalumab for the treatment of patients with PsA, said Dr Genovese. n

Makers of the Only RA Biomarker Test May Be Switching Hands

he manufacturers of the first and only multibiomarkerbased blood test validated to monitor disease activity in patients with rheumatoid arthritis (RA), Crescendo Bioscience, Inc, is in the process of being acquired by Myriad Genetics, Inc. Vectra DA is a quantitative, protein-based test that allows for routine monitoring of disease activity and allows rheumatologists to more effectively treat their patients. The test can determine whether patients are responding to a drug as quickly as 4 weeks, which can allow them to switch to a new, better therapy sooner, William Hagstrom, Crescendo’s President and Chief Executive stated. A quick evaluation of

disease activity is especially impor tant in the early stages of RA, in which joint destruction occurs rapidly if not successfully treated. According to the study validating the tests’ efficacy, which measured levels of 12 biomarkers in serum samples from several cohorts and generated a composite multibiomarker disease activity score in seropositive and seronegative patients, the composite score was significantly associated with Disease Activity Score in 28 joints using the C-reactive protein level in both groups of patients (P <.001). The test is reimbursed by the Centers for Medicare & Medicaid Services. The Wall Street Journal; February 4, 2014

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Gout

Patients with Gout Often Do Not Meet Target Uric Acid Levels, Even with Treatment By Phoebe Starr San Diego, CA—Patients with gout and elevated serum uric acid levels are not receiving optimal urate-lowering therapy (ULT), according to the results of an international prospective study reported at the 2013 American College of Rheumatology meeting. In this study, less than 50% of the patients with gout who received allopurinol did not reach target serum uric acid levels (<6 mg/dL). Optimal allopurinol dose escalation occurred only infrequently in patients with gout who were receiving allopurinol. The majority of the patients with a baseline dose of allopurinol of 200 mg to 300 mg daily were not dose-escalated. These findings, similar to other published studies, suggest that a significant proportion of real-world patients with gout do not reach serum uric acid targets with allopurinol as currently used, said lead investigator Scott Baumgartner, MD, Vice President, Clinical Research and Development, Ardea Biosciences, San Diego, CA. The open-label study—carried out

in 186 sites in North America, Europe, Australia, New Zealand, and South Africa—included 1735 patients who met the American Rheumatism Association criteria for acute arthritis of primary gout, and had at least 2 gout disease flares in the preceding year.

Based on these findings, a significant proportion of real-world patients with gout do not reach serum uric acid targets with allopurinol as currently used. —Scott Baumgartner, MD

Participants were required to have a serum uric acid level of ≥6.5 mg/dL if they were receiving ULT at screening, or ≥8 mg/dL if they were not receiving ULT. During the screening period,

patients receiving a ULT other than allopurinol undertook a 7-day washout period, whereas those already receiving allopurinol continued treatment. Almost all (93.2%) of the patients were male, almost 75% were white, and the mean age was 51.4±11.9 years. At baseline, allopurinol was prescribed for all patients according to standard of care and local product labels. The study protocol called for an upward titration of allopurinol to an optimal dose as determined by the investigator. The investigators were allowed to see patients more frequently than the regular monthly visit if they deemed that continued titration was appropriate. Patients also received gout flare prophylaxis with colchicine (0.5 mg or 0.6 mg daily) or a nonsteroidal anti-inflammatory drug for patients intolerant to colchicine or in whom it was contraindicated. The study cohort was divided into 3 groups, based on the maximum daily dose of allopurinol achieved for analysis, <300 mg daily, 300 mg

daily, and >300 mg daily. Of the patients receiving allopurinol, 43% reached the primary end point of a serum uric acid level <6 mg/dL at the end of the 6-month study. Even at doses >300 mg daily, approximately 46% of the patients did not reach target serum uric acid levels <6 mg/dL. In the group of patients who received at least 1 dose of allopurinol, 328 patients (18.9%) exceeded the 300mg daily dose. Only 15.8% of the patients who completed the study received >300 mg of allopurinol daily. The study was completed by 71.4% (1238 of 1735) of the initial enrollees. Overall, 54.1% of the patients ended treatment at a higher allopurinol dose than at baseline. The researchers concluded that optimal allopurinol dose escalation occurs infrequently in the treatment of patients with gout. Although the investigators were instructed to titrate up to the medically appropriate dose, the most common dose used was 300 mg daily. n

National Survey Results: Rheumatologists Not Treating Patients with Gout Aggressively Enough By Wayne Kuznar San Diego, CA—A high percentage of patients with gout treated by rheumatologists are not at treatment goals as recognized by the American College of Rheumatology (ACR), even after 6 months or more of higher-dose urate-lowering therapy (ULT), according to the results from a national survey. Patients with more severe disease were less likely to be at treatment goal. New ACR guidelines recommend that these patients should be considered for an increase in ULT dose or other treatment change, but no change was made in nearly half of encounters, said Max I. Hamburger, MD, Managing Partner, Rheumatology Associates of Long Island, Melville, NY, at the 2013 ACR meeting. “These findings suggest that even amongst rheumatologists,…management may not be optimal, in particular for the most severe patients,” Dr Hamburger said. In 2012, the ACR issued guidelines for the management of gout that recVOL. 3

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ommended treating serum uric acid to a target of <6 mg/dL (or <5 mg/dL in selected patients), in an effort to durably improve the signs and symptoms of gout, including palpable and visible tophi.

“These findings suggest that even amongst rheumatologists,… management may not be optimal, in particular for the most severe patients.” —Max I. Hamburger, MD

Dr Hamburger and colleagues recruited a national sample of 127 rheumatologists to report encounters with patients with gout. The data collected included patient demographics, histo-

ry with the rheumatologist’s practice, gout symptoms, rheumatologist assessment of disease control, gout medications, and treatment changes at the time of each visit. Approximately 2380 patient encounter forms were submitted. The patients (mean age, 61 years; 79% male) were grouped by increasing disease severity using the following ACR grouping scenarios: • Scenarios 1 to 3 (intermittent symptoms, no tophi) • Scenarios 4 to 6 (intermittent symptoms, ≥1 tophus) • Scenarios 7 to 9 (chronic tophaceous gouty arthropathy). Higher-dose ULT was defined as >300 mg daily of allopurinol or ≥80 mg daily of febuxostat. Of the patients, 72% were seen by a rheumatologist for at least 6 months. More than two thirds (68%) of encounters were ACR scenarios 1 to 3, 4% were 4 to 6, and 28% were 7 to 9. february 2014

at a glance ➤ New ACR guidelines recommend that patients who do not meet target serum uric acid levels (<6 mg/dL) should be considered for an increase in ULT dose or other treatment change ➤ 81% of patients considered to have the most severe forms of gout were judged by the rheumatologist to be controlled ➤ Gout management is suboptimal and inadequately aggressive for many patients

A total of 93% of the patients in scenarios 1 to 3, and 91% in scenarios 4 to 6 were deemed to have controlled disease. “Even 81% of patients con-

Continued on page 12

www.ValueBasedRheumatology.com

Gout

Health, Economic Advantages Linked to UrateLowering Therapy in Patients with Hyperuricemia By Alice Goodman levels ≥7 mg/dL between December 1, 2002, and December 31, 2010. Patients were excluded if they had a history of dialysis, chronic kidney disease, organ transplant, proteinuria, kidney stones, human immunodeficiency virus, nonremission cancer, and had no urate-lowering therapy (ULT) in the previous year.

“Achieving serum uric acid <6 mg/dL was protective and associated with a 37% improvement in renal outcomes. These patients represented the real world.” —Gerald D. Levy, MD, MBA

The study population comprised 16,186 patients with at least 1 serum uric acid level and 1 glomerular filtration rate (GFR) measurement within 6 months before study entry, and at least 1 of each assay in the follow-up period. All patients were followed from the first index date, doc-

umenting high serum uric acid levels for 36 months. There were 3 groups of patients: • 11,192 who were never treated with ULT (ie, never treated) • 3902 who received ULT <80% of the time when their serum uric acid level was >7 mg/dL (ie, <80% of the time group) • 1092 who received ULT ≥80% of the time when their serum uric acid level was high (ie, ≥80% of the time group). Almost all (98.3%) of the patients who received ULT during the trial took allopurinol. The patients who received ULT ≥80% of the time experienced a 37% reduction in any of 3 events included in the composite primary outcome measure: at least a 30% reduction in GFR, the initiation of dialysis, or a GFR of ≤15 mL/min. Patients with high serum uric acid levels who took ULT <80% of the time had an 8% increased risk for 1 of the 3 outcomes, but this difference was not significant compared with the other 2 groups. Patients who stayed on therapy ≥80% of the time were older and had more comorbidities, including gout. They also initiated therapy earlier

compared with the other 2 groups: 43.5% started ULT within 2 weeks of the study compared with 16.9% of the patients who received ULT <80% of the time; 91% and 41%, respectively, started therapy within 6 months.

“This study gives rheumatologists reasons to tell patients to stay on uratelowering therapy.” —Christie M. Bartels, MD

Predictors of worse outcomes included age, female sex, hypertension, diabetes, congestive heart failure, previous hospitalizations, higher serum uric acid levels at entry, and rheumatoid arthritis. “This study gives rheumatologists reasons to tell patients to stay on urate-lowering therapy,” said Christie M. Bartels, MD, Assistant Professor, Division of Rheumatology, University of Wisconsin, Madison, who moderated a press conference where these data were discussed. n

National Survey Results: Rheumatologists Not Treating Patients with Gout Aggressively... sidered to have the most severe forms of gout were judged by the rheumatologist to be controlled,” said Dr Hamburger. Only 14% of the patients in the scenarios 1 to 3 group received higherdose ULT compared with 28% in scenarios 4 to 6, and 40% in scenarios 7 to 9. Approximately 20% of the patients were receiving higher-dose ULT. Half of the patients receiving higher-dose ULT had a serum uric acid level above target based on their latest serum uric acid, said Dr Hamburger. Goal attainment was lower among patients with more severe disease; the serum uric acid level remained >6 mg/dL in 61% of the patients in scenarios 7 to 9. Despite elevated serum

uric acid, 45% of encounters did not result in an increased ULT dose or a treatment change at this visit. Even with ≥6 months at higher-dose ULT, only 55% of patients overall, and only 40% in scenarios 7 to 9, had a serum uric acid level at or below

READER POLL

value-based CARE in Rheumatology

guideline recommendations. Sixteen percent of patients had a serum uric acid level between 6.0 mg/dL and 6.8 mg/dL, despite ≥6 months of highdose ULT. Approximately 29% of the patients receiving long-term higher-dose ULT had a serum uric acid

Continued from page 11

level >6.8 mg/dL, including 23% of the patients in scenarios 7 to 9 with a serum uric acid level >8.0 mg/dL. “Gout management is currently suboptimal and inadequately aggressive for many patients,” Dr Hamburger said. n

DO YOU TREAT YOUR PATIENTS £ Yes WITH GOUT AGGRESSIVELY? £ No

VBCR_ReaderPoll021814

San Diego, CA—Patients with hyperuricemia who comply with the recommended serum uric acid levels ≤6 mg/dL set by the American College of Rheumatology (ACR) are less likely to develop progressive kidney damage, chronic kidney disease, or to need dialysis compared with patients who do not comply with the guidelines. These were the implications of a large retrospective study presented at the 2013 ACR meeting. “Achieving serum uric acid <6 mg/dL was protective and associated with a 37% improvement in renal outcomes,” said lead investigator Gerald D. Levy, MD, MBA, Rheumatologist, Kaiser Permanente Medical Group, Downey, CA. “These patients represented the real world.” Dr Levy and colleagues sought to determine whether reversing uricemia could have an impact on renal disease in patients with gout. “People with renal disease can develop hyperuricemia, and some will also develop gout. Since the direct and indirect costs of gout currently total $1 billion per year, there was an economic incentive to conduct this study.” The investigators used the Kaiser Permanente database to identify 111,992 patients with serum uric acid

Send us feedback about how you manage your patients and submit your vote to this poll online. Results will be published in print in the upcoming issue.

february 2014

www.ValueBasedRheumatology.com VOL. 3

NO. 1

Now this is novel. Janus kinase inhibitor

IMPORTANT SAFETY INFORMATION Patients treated with XELJANZ速 (tofacitinib citrate) are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Lymphoma and other malignancies have also been observed in patients treated with XELJANZ. Please see Indication, Important Safety Information, and brief summary of full Prescribing Information, including boxed warning, on the following pages.

First in a New Class Oral JAK Inhibitor

1,2

XELJANZ — Powerful Efficacy XELJANZ significantly reduces RA signs and symptoms alone or with MTX2 In 2 separate studies, XELJANZ achieved similar ACR response rates as monotherapy and in combination with DMARDs at 6 months1,2 MONOTHERAPY Oral Solo (Study I) 1,2 6 months

*P<0.001 vs. placebo † P<0.05 vs. placebo NRI‡

69 50

100

Patient Response Rates (%)

100

COMBINATION THERAPY Oral Sync (Study II)2 6 months

*P<0.0001 vs. placebo NRI‡

34*

22 0

(167/241)

ACR20

(101/241)

ACR50

(53/241)

ACR70

XELJANZ 5 mg BID results at 3 months: 59%*, 31%*, 15%† Placebo results at 3 months: 26%, 12%, 6% ACR20 was a secondary end point at 6 months and a primary end point at 3 months. Results of a 6-month, randomized, double-blind, controlled, multicenter monotherapy study of 610 moderate to severe RA patients with lack of efficacy or toxicity on a biologic or nonbiologic DMARD who received XELJANZ 5 mg twice daily (N=241) or placebo (N=120). At month 3, all placebo patients advanced blindly to a predetermined XELJANZ dose. ‡ NRI: Nonresponder imputation.

100

13* 0

(164/311)

ACR20

(105/311)

ACR50

(41/311)

ACR70

Placebo results at 6 months: 31%, 13%, 3% ACR20 at 6 months was a primary end point. Results of a 12-month, randomized, double-blind, controlled, multicenter study of 792 moderate to severe active RA patients with lack of efficacy or toxicity on a biologic or nonbiologic DMARD who received XELJANZ 5 mg twice daily (N=311) or placebo (N=157) added to background nonbiologic DMARD therapy. At month 3 nonresponding placebo patients advanced blindly to a predetermined XELJANZ dose; at 6 months all remaining placebo patients advanced.

INDICATION • XELJANZ (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). • XELJANZ should not be used in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine. • Active tuberculosis, which may present with pulmonary IMPORTANT SAFETY INFORMATION or extrapulmonary disease. Patients should be tested for WARNING: SERIOUS INFECTIONS AND latent tuberculosis before XELJANZ use and during therapy. MALIGNANCY Treatment for latent infection should be initiated prior to XELJANZ use. SERIOUS INFECTIONS • Invasive fungal infections, including cryptococcosis and Patients treated with XELJANZ are at increased risk for developing serious infections that may lead to hospitalization or pneumocystosis. Patients with invasive fungal infections may death. Most patients who developed these infections were taking present with disseminated, rather than localized, disease. concomitant immunosuppressants such as methotrexate or • Bacterial, viral, and other infections due to opportunistic corticosteroids. pathogens. If a serious infection develops, interrupt XELJANZ until the The risks and benefits of treatment with XELJANZ should be infection is controlled. carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Reported infections include:

Please see additional Important Safety Information and brief summary of full Prescribing Information, including boxed warning, on the following pages.

For adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to methotrexate (MTX)1 1

Alone or in Combination

In your MTX-IR patients, discover powerful efficacy with XELJANZ IMPORTANT SAFETY INFORMATION continued Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. MALIGNANCIES Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virus-associated posttransplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications. SERIOUS INFECTIONS The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster and urinary tract infection. XELJANZ should not be initiated in patients with an active infection, including localized infections. Consider the risks and benefits of treatment before initiating XELJANZ in patients: References: 1. XELJANZ® (tofacitinib) Prescribing Information. New York, NY: Pfizer Inc. 2. Data on file. Pfizer Inc, New York, NY.

• with chronic or recurrent infection; • who have been exposed to tuberculosis (TB); • with a history of a serious or an opportunistic infection; • who have lived or traveled in areas of endemic TB or mycoses; or • with underlying conditions that may predispose them to infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ. XELJANZ should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis.

Learn more at XeljanzHCP.com

IMPORTANT SAFETY INFORMATION WARNING: SERIOUS INFECTIONS AND MALIGNANCY

SERIOUS INFECTIONS Patients treated with XELJANZ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. If a serious infection develops, interrupt XELJANZ until the infection is controlled. Reported infections include: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before XELJANZ use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ use. • Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease. • Bacterial, viral, and other infections due to opportunistic pathogens. The risks and benefits of treatment with XELJANZ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. MALIGNANCIES Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications. SERIOUS INFECTIONS The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster and urinary tract infection. XELJANZ should not be initiated in patients with an active infection, including localized infections. Consider the risks and benefits of treatment before initiating XELJANZ in patients: • with chronic or recurrent infection; • who have been exposed to tuberculosis (TB); • with a history of a serious or an opportunistic infection; • who have lived or traveled in areas of endemic TB or mycoses; or • with underlying conditions that may predispose them to infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ. XELJANZ should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. Tuberculosis Evaluate and test patients for latent or active infection before administration of XELJANZ. Consider anti-TB therapy prior to administration of XELJANZ in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection. Treat patients with latent TB with standard therapy before administrating XELJANZ. Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster) were observed in clinical studies with XELJANZ. MALIGNANCY and LYMPHOPROLIFERATIVE DISORDER Consider the risks and benefits of XELJANZ treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ in patients who develop a malignancy. In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one lymphoma were diagnosed in 3328 patients receiving XELJANZ with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure. Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with XELJANZ. In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high dose corticosteroids, and mycophenolic acid products, Epstein Barr Virusassociated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of 111 patients treated with cyclosporine.

TRA595505-02

GASTROINTESTINAL PERFORATIONS Gastrointestinal perforations have been reported in rheumatoid arthritis clinical trials, although the role of JAK inhibition is not known. XELJANZ should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). LABORATORY PARAMETERS Lymphocytes Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean lymphocyte counts of approximately 10% during 12 months of therapy. Counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections. Avoid initiation of XELJANZ treatment in patients with a count less than 500 cells/mm3. In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3 treatment with XELJANZ is not recommended. Monitor lymphocyte counts at baseline and every 3 months thereafter. Neutrophils Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo. Avoid initiation of XELJANZ treatment in patients with an ANC less than 1000 cells/mm3. For patients who develop a persistent ANC of 5001000 cells/mm3, interrupt XELJANZ dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with XELJANZ is not recommended. Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter. Hemoglobin Avoid initiation of XELJANZ treatment in patients with a hemoglobin level less than 9 g/dL. Treatment with XELJANZ should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment. Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter. Liver Enzymes Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy. Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury. If drug-induced liver injury is suspected, the administration of XELJANZ should be interrupted until this diagnosis has been excluded. Lipids Treatment with XELJANZ was associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. Assess lipid parameters approximately 4-8 weeks following initiation of XELJANZ therapy, and manage patients according to clinical guidelines for the management of hyperlipidemia. VACCINATIONS Live vaccines should not be given concurrently with XELJANZ. Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ therapy. HEPATIC IMPAIRMENT Treatment with XELJANZ is not recommended in patients with severe hepatic impairment. ADVERSE REACTIONS The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions during the first 3 months in controlled clinical trials with XELJANZ 5 mg twice daily and placebo, respectively, (occurring in greater than or equal to 2% of patients treated with XELJANZ with or without DMARDs ) were upper respiratory tract infections (4.5%, 3.3%), headache (4.3%, 2.1%), diarrhea (4.0%, 2.3%), and nasopharyngitis (3.8%, 2.8%). USE IN PREGNANCY There are no adequate and well-controlled studies in pregnant women. XELJANZ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Please see brief summary of full Prescribing Information, including boxed warning, on the following pages.

Printed in USA/October 2013

XELJANZ® (tofacitinib) BRIEF SUMMARY OF PRESCRIBING INFORMATION. SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION. WARNING: SERIOUS INFECTIONS AND MALIGNANCY SERIOUS INFECTIONS Patients treated with XELJANZ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. If a serious infection develops, interrupt XELJANZ until the infection is controlled. Reported infections include: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before XELJANZ use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ use. • Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease. • Bacterial, viral, and other infections due to opportunistic pathogens. The risks and benefits of treatment with XELJANZ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. MALIGNANCIES Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications. INDICATIONS AND USAGE • XELJANZ (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). • XELJANZ should not be used in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Serious Infections Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving XELJANZ. The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster and urinary tract infection. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcus, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus, and BK virus were reported with XELJANZ. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids. Other serious infections that were not reported in clinical studies may also occur (e.g., histoplasmosis, coccidioidomycosis, and listeriosis). XELJANZ should not be initiated in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating XELJANZ in patients: • with chronic or recurrent infection • who have been exposed to tuberculosis • with a history of a serious or an opportunistic infection • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or • with underlying conditions that may predispose them to infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ. XELJANZ should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with XELJANZ should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.

Tuberculosis Patients should be evaluated and tested for latent or active infection prior to administration of XELJANZ. Anti-tuberculosis therapy should also be considered prior to administration of XELJANZ in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Patients should be closely monitored for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy. Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering XELJANZ. Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with XELJANZ. The impact of XELJANZ on chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or C were excluded from clinical trials. Malignancy and Lymphoproliferative Disorder Consider the risks and benefits of XELJANZ treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ in patients who develop a malignancy. Malignancies were observed in clinical studies of XELJANZ. In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one lymphoma were diagnosed in 3328 patients receiving XELJANZ with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure. Lymphomas and solid cancers have also been observed in the long-term extensions studies in rheumatoid arthritis patients treated with XELJANZ. In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high dose corticosteroids, and mycophenolic acid products, Epstein Barr Virus-associated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of 111 patients treated with cyclosporine. Gastrointestinal Perforations Events of gastrointestinal perforation have been reported in clinical studies with XELJANZ in rheumatoid arthritis patients, although the role of JAK inhibition in these events is not known. XELJANZ should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation. Laboratory Parameters Lymphocytes Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean lymphocyte counts below the baseline of approximately 10% during 12 months of therapy. Lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections. Avoid initiation of XELJANZ treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm3). In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3 treatment with XELJANZ is not recommended. Monitor lymphocyte counts at baseline and every 3 months thereafter. Neutrophils Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo. Avoid initiation of XELJANZ treatment in patients with a low neutrophil count (i.e., ANC less than 1000 cells/mm3). For patients who develop a persistent ANC of 500-1000 cells/mm3, interrupt XELJANZ dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with XELJANZ is not recommended. Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter. Hemoglobin Avoid initiation of XELJANZ treatment in patients with a low hemoglobin level (i.e. less than 9 g/dL). Treatment with XELJANZ should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment. Monitor hemoglobin at baseline and after 4–8 weeks of treatment and every 3 months thereafter. Liver Enzymes Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy. Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury. If drug-induced liver injury is suspected, the administration of

XELJANZ should be interrupted until this diagnosis has been excluded. Lipids Treatment with XELJANZ was associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined. Assessment of lipid parameters should be performed approximately 4-8 weeks following initiation of XELJANZ therapy. Manage patients according to clinical guidelines [e.g., National Cholesterol Education Program (NCEP)] for the management of hyperlipidemia. Vaccinations No data are available on the response to vaccination or on the secondary transmission of infection by live vaccines to patients receiving XELJANZ. Live vaccines should not be given concurrently with XELJANZ. Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ therapy. Hepatic Impairment Treatment with XELJANZ is not recommended in patients with severe hepatic impairment. ADVERSE REACTIONS Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. The following data includes two Phase 2 and five Phase 3 double-blind, controlled, multicenter trials. In these trials, patients were randomized to doses of XELJANZ 5 mg twice daily (292 patients) and 10 mg twice daily (306 patients) monotherapy, XELJANZ 5 mg twice daily (1044 patients) and 10 mg twice daily (1043 patients) in combination with DMARDs (including methotrexate) and placebo (809 patients). All seven protocols included provisions for patients taking placebo to receive treatment with XELJANZ at Month 3 or Month 6 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Therefore some analyses that follow include patients who changed treatment by design or by patient response from placebo to XELJANZ in both the placebo and XELJANZ group of a given interval. Comparisons between placebo and XELJANZ were based on the first 3 months of exposure, and comparisons between XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily were based on the first 12 months of exposure. The long-term safety population includes all patients who participated in a double-blind, controlled trial (including earlier development phase studies) and then participated in one of two long-term safety studies. The design of the long-term safety studies allowed for modification of XELJANZ doses according to clinical judgment. This limits the interpretation of the long-term safety data with respect to dose. Clinical Trial Experience The most common serious adverse reactions were serious infections. The proportion of patients who discontinued treatment due to any adverse reaction during the 0 to 3 months exposure in the double-blind, placebo-controlled trials was 4% for patients taking XELJANZ and 3% for placebo-treated patients. Overall Infections In the seven controlled trials, during the 0 to 3 months exposure, the overall frequency of infections was 20% and 22% in the 5 mg twice daily and 10 mg twice daily groups, respectively, and 18% in the placebo group. The most commonly reported infections with XELJANZ were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively). Serious Infections In the seven controlled trials, during the 0 to 3 months exposure, serious infections were reported in 1 patient (0.5 events per 100 patient-years) who received placebo and 11 patients (1.7 events per 100 patient-years) who received XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 1.1 (-0.4, 2.5) events per 100 patient-years for the combined 5 mg twice daily and 10 mg twice daily XELJANZ group minus placebo. In the seven controlled trials, during the 0 to 12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 33 patients (2.7 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection. Tuberculosis In the seven controlled trials, during the 0 to 3 months exposure, tuberculosis was not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ. In the seven controlled trials, during the 0 to 12 months exposure, tuberculosis was reported in 0 patients who received 5 mg twice daily of XELJANZ and 6 patients (0.5 events per 100 patient-years) who received 10 mg twice daily

of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% conďŹ dence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. Cases of disseminated tuberculosis were also reported. The median XELJANZ exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days).

cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the ďŹ rst 3 months of exposure in the controlled clinical trials are summarized below: s -EAN ,$, CHOLESTEROL INCREASED BY IN THE 8%,*!.: 5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm.

Opportunistic Infections (excluding tuberculosis) In the seven controlled trials, during the 0 to 3 months exposure, opportunistic infections were not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ.

s -EAN ($, CHOLESTEROL INCREASED BY IN THE 8%,*!.: 5 mg twice daily arm and 12% in the XELJANZ 10 mg twice daily arm.

In the seven controlled trials, during the 0 to 12 months exposure, opportunistic infections were reported in 4 patients (0.3 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 4 patients (0.3 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% conďŹ dence interval) was 0 (-0.5, 0.5) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ.

In a controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy.

The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days). Malignancy In the seven controlled trials, during the 0 to 3 months exposure, malignancies excluding NMSC were reported in 0 patients who received placebo and 2 patients (0.3 events per 100 patient-years) who received either XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% conďŹ dence interval) was 0.3 (-0.1, 0.7) events per 100 patient-years for the combined 5 mg and 10 mg twice daily XELJANZ group minus placebo. In the seven controlled trials, during the 0 to 12 months exposure, malignancies excluding NMSC were reported in 5 patients (0.4 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 7 patients (0.6 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% conďŹ dence interval) was 0.2 (-0.4, 0.7) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. One of these malignancies was a case of lymphoma that occurred during the 0 to 12 month period in a patient treated with XELJANZ 10 mg twice daily. The most common types of malignancy, including malignancies observed during the long-term extension, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma, and malignant melanoma. Laboratory Tests Lymphocytes In the controlled clinical trials, conďŹ rmed decreases in lymphocyte counts below 500 cells/mm3 occurred in 0.04% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the ďŹ rst 3 months of exposure. ConďŹ rmed lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections. Neutrophils In the controlled clinical trials, conďŹ rmed decreases in ANC below 1000 cells/mm3 occurred in 0.07% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the ďŹ rst 3 months of exposure. There were no conďŹ rmed decreases in ANC below 500 cells/mm3 observed in any treatment group. There was no clear relationship between neutropenia and the occurrence of serious infections. In the long-term safety population, the pattern and incidence of conďŹ rmed decreases in ANC remained consistent with what was seen in the controlled clinical trials. Liver Enzyme Tests ConďŹ rmed increases in liver enzymes greater than 3 times the upper limit of normal (3x ULN) were observed in patients treated with XELJANZ. In patients experiencing liver enzyme elevation, modiďŹ cation of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of XELJANZ, or reduction in XELJANZ dose, resulted in decrease or normalization of liver enzymes. In the controlled monotherapy trials (0-3 months), no differences in the incidence of ALT or AST elevations were observed between the placebo, and XELJANZ 5 mg, and 10 mg twice daily groups. In the controlled background DMARD trials (0-3 months), ALT elevations greater than 3x ULN were observed in 1.0%, 1.3% and 1.2% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3x ULN were observed in 0.6%, 0.5% and 0.4% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively. One case of drug-induced liver injury was reported in a patient treated with XELJANZ 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3x ULN and bilirubin elevations greater than 2x ULN, which required hospitalizations and a liver biopsy. Lipids In the controlled clinical trials, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL

s -EAN ,$, ($, RATIOS WERE ESSENTIALLY UNCHANGED IN XELJANZ-treated patients.

In the long-term safety population, elevations in lipid parameters remained consistent with what was seen in the controlled clinical trials. Serum Creatinine In the controlled clinical trials, dose-related elevations in serum creatinine were observed with XELJANZ treatment. The mean increase in serum creatinine was <0.1 mg/dL in the 12-month pooled safety analysis; however with increasing duration of exposure in the long-term extensions, up to 2% of patients were discontinued from XELJANZ treatment due to the protocol-speciďŹ ed discontinuation criterion of an increase in creatinine by more than 50% of baseline. The clinical signiďŹ cance of the observed serum creatinine elevations is unknown. Other Adverse Reactions Adverse reactions occurring in 2% or more of patients on 5 mg twice daily or 10 mg twice daily XELJANZ and at least 1% greater than that observed in patients on placebo with or without DMARD are summarized in the table below. Adverse Reactions Occurring in at Least 2% or More of Patients on 5 or 10 mg Twice Daily XELJANZ With or Without DMARD (0-3 months) and at Least 1% Greater Than That Observed in Patients on Placebo

XELJANZ XELJANZ 5 mg 10 mg Twice Daily Twice Daily N = 1336 N = 1349 Preferred Term (%) (%) Diarrhea 4.0 2.9 Nasopharyngitis 3.8 2.8 Upper respiratory tract 4.5 3.8 infection

Placebo N = 809 (%) 2.3 2.8 3.3

Headache

4.3

3.4

2.1

Hypertension

1.6

2.3

1.1

N reďŹ&#x201A;ects randomized and treated patients from the seven clinical trials Other adverse reactions occurring in controlled and open-label extension studies included: Blood and lymphatic system disorders: Anemia Metabolism and nutrition disorders: Dehydration Psychiatric disorders: Insomnia Nervous system disorders: Paresthesia Respiratory, thoracic and mediastinal disorders: Dyspnea, cough, sinus congestion Gastrointestinal disorders: Abdominal pain, dyspepsia, vomiting, gastritis, nausea Hepatobiliary disorders: Hepatic steatosis Skin and subcutaneous tissue disorders: Rash, erythema, pruritus Musculoskeletal, connective tissue and bone disorders: Musculoskeletal pain, arthralgia, tendonitis, joint swelling General disorders and administration site conditions: Pyrexia, fatigue, peripheral edema DRUG INTERACTIONS Potent CYP3A4 Inhibitors Tofacitinib exposure is increased when XELJANZ is coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 (e.g., ketoconazole). Moderate CYP3A4 and Potent CYP2C19 Inhibitors Tofacitinib exposure is increased when XELJANZ is coadministered with medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., ďŹ&#x201A;uconazole). Potent CYP3A4 Inducers Tofacitinib exposure is decreased when XELJANZ is coadministered with potent CYP3A4 inducers (e.g., rifampin). Immunosuppressive Drugs There is a risk of added immunosuppression when XELJANZ is coadministered with potent immunosuppressive drugs (e.g., azathioprine, tacrolimus, cyclosporine). Combined use of multiple-dose XELJANZ with potent immunosuppressives has not been studied in rheumatoid arthritis. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic effects: Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. XELJANZ

TRA476916-01

should be used during pregnancy only if the potential beneďŹ t justiďŹ es the potential risk to the fetus. Tofacitinib has been shown to be fetocidal and teratogenic in rats and rabbits when given at exposures 146 times and 13 times, respectively, the maximum recommended human dose (MRHD). In a rat embryofetal developmental study, tofacitinib was teratogenic at exposure levels approximately 146 times the MRHD (on an AUC basis at oral doses of 100 mg/kg/day). Teratogenic effects consisted of external and soft tissue malformations of anasarca, and membranous ventricular septal defects, respectively, and skeletal malformations or variations (absent cervical arch; bent femur, ďŹ bula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day). In the rabbit embryofetal development study, tofacitinib was teratogenic at exposure levels approximately 13 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day). Nonteratogenic effects: In a peri- and postnatal rat study, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the MRHD (on an AUC basis at oral doses of 50 mg/kg/day). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day). Pregnancy Registry: To monitor the outcomes of pregnant women exposed to XELJANZ, a pregnancy registry has been established. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972. Nursing Mothers Tofacitinib was secreted in milk of lactating rats. It is not known whether tofacitinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from tofacitinib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug for the mother. Pediatric Use The safety and effectiveness of XELJANZ in pediatric patients have not been established. Geriatric Use Of the 3315 patients who enrolled in Studies I to V, a total of 505 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older. The frequency of serious infection among XELJANZ-treated subjects 65 years of age and older was higher than among those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly. Hepatic Impairment No dose adjustment is required in patients with mild hepatic impairment. XELJANZ dose should be reduced to 5 mg once daily in patients with moderate hepatic impairment. The safety and efďŹ cacy of XELJANZ have not been studied in patients with severe hepatic impairment or in patients with positive hepatitis B virus or hepatitis C virus serology. Renal Impairment No dose adjustment is required in patients with mild renal impairment. XELJANZ dose should be reduced to 5 mg once daily in patients with moderate and severe renal impairment. In clinical trials, XELJANZ was not evaluated in rheumatoid arthritis patients with baseline creatinine clearance values (estimated by the Cockroft-Gault equation) less than 40 mL/min. OVERDOSAGE Signs, Symptoms, and Laboratory Findings of Acute Overdosage in Humans There is no experience with overdose of XELJANZ. Treatment or Management of Overdose Pharmacokinetic data up to and including a single dose of 100 mg in healthy volunteers indicate that more than 95% of the administered dose is expected to be eliminated within 24 hours. There is no speciďŹ c antidote for overdose with XELJANZ. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate treatment. This brief summary is based on XELJANZÂŽ (tofacitinib) Prescribing Information LAB-0445-1.0 Issued: November 2012

ÂŠ 2012 PďŹ zer Inc.

November 2012

Lupus

In Systemic Lupus Erythematosus, Glucocorticoid Dose Linked to Adverse Events and Overall Costs By Wayne Kuznar San Diego, CA—High doses patients with of glucocorticoids in the treatment of patients with systemic lupus erythematosus (SLE) are associated with a greater incidence of adverse events (AEs) and greater healthcare resource utilization compared with low doses or no use of glucocorticoids, found Wei-Shi Yeh, PhD, Associate Director, Global Market Access, Biogen Idec, Weston, MA, and colleagues. Their study examined the relationship between the dose of glucocorticoids, the risk of AEs, and healthcare

at a glance ➤ The proportion of patients with emergency department visits increased from 29.7% in lowdose users of glucocorticoid to 47% in high-dose users ➤ The annual average costs increased with an increasing daily dose of glucocorticoids ➤ The study results highlight the value of future effective SLE treatments with a steroidtapering effect

resource utilization associated with SLE, using a US commercial insurance claims database of approximately 60,000 patients with SLE. “Ideally, we would like to have longitudinal data, but in the US, the average patient enrolls in a health plan for 2 to 3 years,” said Dr Yeh. “We don’t have this type of data, so we looked at a commercial dataset cross sectionally, from the first diagnosis, and then at 1 year from diagnosis to see whether there’s a dose trend for glucocorticoids and adverse events and resource utilization.” The investigators categorized patients receiving ≥60 days of glucocorticoids based on their average daily oral dose of prednisolone, or equivalent. Low dose was considered a daily dose ≤7.5 mg, medium dose from >7.5 mg to ≤15 mg, and high dose >15 mg. Patients with SLE who did not take oral glucocorticoids were used as the reference group. Health resource utilization included outpatient/emergency department visits, hospitalizations, prescriptions, and total health costs for the 12 months postdiagnosis. There were 46,785 patients with SLE with no glucocorticoid use, 5221

low-dose users, 4965 medium-dose users, and 4136 high-dose users. “Some but not all steroid-related AEs were observed at a higher frequency among GC [glucocorticosteroid] users than non-users,” noted Dr Yeh and colleagues. A positive dose-relationship was observed for myopathy, atherosclerosis, hypertension, heart failure, Cushing syndrome, and bacterial infection (P <.05 for all).

“Some but not all steroid-related AEs were observed at a higher frequency among GC users than non-users.” —Wei-Shi Yeh, PhD, and colleagues

High-dose users had 5 times the rate of myopathy as nonusers, 3 times the rate of heart failure, and almost a 4-fold increase in the rate of Cushing syndrome and bacterial infections. The proportion of patients with emergency department visits increased from 29.7% among low-dose

users to 47% among high-dose users (P <.01) compared with 31% among nonusers. Similarly, significantly more high-dose users (42.8%) were hospitalized than medium-dose users (24.8%) and low-dose users (18.3%). The number of inpatient stays, total hospital days, and outpatient visits increased significantly with increasing glucocorticoid dose. The annual average total health costs increased significantly with an increasing daily dose. These costs were $21,815 for the low-dose glucocorticoid users; $27,635 for the medium-dose users; and $45,339 for the highdose users. The total annual healthcare cost for nonusers was $17,291. The association between glucocorticoid dose, AEs, and resource utilization may be confounded by disease severity, admits Dr Yeh. “The biggest challenge is that many potential adverse events from steroids are also related to disease progression of lupus. The patients may have been on high doses because they have more severe lupus,” he said. The study results highlight the value of future effective SLE treatments with a steroid-tapering effect, Dr Yeh said. n

Consideration of Pathogenesis Leads to Appropriate Therapy in Patients with Severe Thrombocytopenia and Lupus San Diego, CA—The selection of treatment for patients with systemic lupus erythematosus and thrombocytopenia should hinge on the differential diagnosis and the pathogenic mechanisms involved. Three possible options include splenectomy, B-cell depletion, and platelet augmentation, said Brady L. Stein, MD, MHS, Assistant Professor of Medicine, Northwestern University, Chicago, IL, at the 2013 American College of Rheumatology meeting. A broad differential diagnosis of suspected immune thrombocytopenia purpura (ITP) includes consumptive processes; blood loss; reversible causes, such as vitamin or mineral deficiencies; the use of marrow-suppressive medications; typical and atypical infections; and other immune-mediated processes. Evans syndrome, thrombotic thrombocytopenic purpura, and VOL. 3

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macrophage activation syndrome may be suspected. If these diagnoses are excluded, ITP may be considered.

“It is the B-cell that results in the autoantibodies that coat platelets or bind to thrombopoietin or to its receptor. It would be very logical to deplete the B-cell with an anti-CD20 antibody rituximab.” —Brady L. Stein, MD, MHS

A diagnosis of ITP may predate an official diagnosis of lupus in 15% to 16% of patients, said Dr Stein. “This is

particularly true in women with high titer antinuclear antibodies or other autoantibodies at presentation.” Treatment strategies need to take into account age, comorbidity, the cost of the drug, and bleeding history. In ITP, a platelet count ≤30 × 109/L is a threshold for treatment, so an asymptomatic patient with a platelet count >30 × 109/L may not require treatment. “But in the patient with lupus with antiphospholipid antibodies syndrome who may have had a thrombosis and requires anticoagulation, then the threshold platelet count must be higher,” Dr Stein said. “We need to target a platelet count of 50 × 109/L in this case.” Splenectomy Splenectomy is an option, especially in patients who may need a second-line approach. “The rationale for february 2014

at a glance ➤ The overall response rate with laparoscopic splenectomy is 85%, and is also associated with decreased disease activity and steroid dosing ➤ In 4 phase 3 studies, oral eltrombopag and subcutaneous romiplostim have shown efficacy in primary ITP to augment platelet production, with responses reported in splenectomized and nonsplenectomized patients splenectomy is both in decreasing antibody production—the spleen is a major site of lymphoid organ—and also removing the site of autoantiContinued on page 20

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Rheumatology Update

ACR Committee Identifies Rheumatologist Workforce Shortages By Frederique H. Evans, MBS

he American College of Rheumatology (ACR) Committee on Rheumatology Training and Workforce Issues found ongoing regional shortages in the rheumatology workforce and highlighted potential target communities that may benefit the most from the addition of a local rheumatologist, according to a recent report in the December 2013 issue of Arthritis & Rheumatism (American College of Rheumatology Committee on Rheumatology Training and Workforce Issues. 2013;65:3017-3025). In an effort to better understand the regional number of rheumatologists, the investigators used the ACR membership database to map all adult practicing rheumatologist office addresses and calculate the number of rheumatologists per Core Based Statistical Area (CBSA) and their density. Data pertaining to age, sex, race/ethnicity, and median household income were collected from the 2010 US Census to determine whether sociodemographic factors impacted rheumatologist clusters. Regional areas were defined as metropolitan if they included a population of 50,000 or more, and micropolitan if the population was 10,000 or more and less than 50,000. Potentially underserved areas were defined using a modified Lewin

report–defined threshold of 1.67 rheumatologists per 100,000 persons to include travel distances to the nearest rheumatologist.

“Simply providing up-todate information about the local supply of rheumatologists could attract more rheumatologists to underserved regions through migration, expansion, or attraction of new rheumatologists.” —ACR Committee on Rheumatology Training and Workforce Issues

Overall, 3920 practicing rheumatologists from 48 states and the District of Columbia were identified from the ACR database. Ninety percent of rheumatologists practiced in metropolitan areas, 3% in micropolitan areas, and 7% in rural areas. A greater proportion of rheumatologists practiced in metropolitan areas than would be expected based on population distribution alone (P <.001), the

committee observed. Nine percent of metropolitan areas did not have a practicing rheumatologist, compared with 84% of micropolitan areas. In addition, they found that some large CBSAs (population >200,000) were without a practicing rheumatologist, and some had a travel distance of 94 miles to the nearest rheumatologist. Some smaller micropolitans, however, had a travel distance of more than 200 miles to the nearest rheumatologist. Taking a closer look at regional characteristics associated with the distribution of rheumatologists, the committee found that rheumatologists were more likely to practice in areas with higher population densities and median incomes. Rheumatologists were also more likely to practice in CBSAs with training programs. “Simply providing up-to-date information about the local supply of rheumatologists could attract more rheumatologists to underserved regions through migration, expansion, or attraction of new rheumatologists,” they suggested. Additional funds to training programs in these areas may also increase the number of rheumatologists, the committee added. Other solutions included traveling clinics, e-mail, as well as videoconsultation

at a glance ➤ Many CBSAs, especially micropolitan areas, did not have a practicing rheumatologist ➤ In some smaller micropolitan areas, the travel distance to the nearest rheumatologist was more than 200 miles ➤ Rheumatologists were likely to practice in areas with higher population densities and income

via direct care rheumatologist-topatient interview or peer-to-peer consultation. The committee also briefly touched upon the Affordable Care Act, which provides funds for primary care training as well as a loan forgiveness program, noting that rheumatologists are not eligible for these programs. This research is critical for identifying underserved areas, the ACR Committee on Rheumatology Training and Workforce Issues concluded. Additional research is warranted before the implementation of policies and reallocation of resources are considered. n

Lupus

Consideration of Pathogenesis Leads to Appropriate... body coated platelets,” said Dr Stein. The response rate of splenectomy at 6 years is comparable to splenectomy for primary ITP. The overall response rate with laparoscopic splenectomy is 85%, and is also associated with decreased disease activity and steroid dosing. B-Cell Depletion Another consideration is the major role of the B-cell in disease pathogenesis, not only in lupus but also in ITP. “It is the B-cell that results in the autoantibodies that coat platelets or bind to thrombopoietin or to its receptor,” said Dr Stein. “It would be very logical to deplete the B-cell with an antiCD20 antibody rituximab.”

In primary ITP, rituximab (Rituxan) is effective as a single agent or in combination with other agents. Rituximab is also effective after splenectomy, but this is still an unlabeled use for primary ITP, and is without a clear optimal dosing regimen. “Considering the mechanism of action of rituximab, this treatment would need to be repeated, since B-cell depletion is a transient effect of rituximab,” said Dr Stein. In randomized controlled trials, ri tuximab had an unclear impact on underlying disease activity in lupus. Adverse reactions have included 2 cases of progressive multifocal leukoencephalopathy. More common adverse reactions include infu-

value-based CARE in Rheumatology

february 2014

sion-related reactions, typically with the first dose, and reactivation of hepatitis B. Thrombopoietin Receptor Agonists The final strategy is augmenting platelet production. “We know there are antibodies against thrombopoietin and its receptor,” said Dr Stein. In 4 phase 3 studies, oral eltrombopag (Promacta) and subcutaneous romiplostim (Nplate) have shown efficacy in primary ITP to augment platelet production, with responses reported in splenectomized and non splenectomized patients. Patients receiving treatment have been able to discontinue or taper immunosuppres-

Continued from page 19

sive medications, Dr Stein said. For primary ITP, eltrombopag is typically used as a second- or thirdline therapy, but long-term therapy is required, because platelet levels will decline, often within 2 weeks, upon termination. The risk of thrombosis with eltrombopag is 5% to 6.5% in long-term follow-up, and it occurred in those who were otherwise at risk, such as in those with antiphospholipid antibodies. In 2 case reports, patients with lupus and Evans syndrome showed improvement in platelet count with eltrombopag and romiplostim. Conversely, 2 other case reports cited thrombotic microangiopathy after using these thrombopoietin receptor agonists.—WK n VOL. 3

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Osteoarthritis

Inexpensive Knee Brace Helps Reduce Pain... bone marrow lesions. The volume of the bone marrow lesions can serve as a marker for effectiveness of treatments, noted lead author David Felson, MD, Boston University, MA. Bone marrow lesions are thought to represent areas of bone trauma caused by increased focal stress across the knee. Bone marrow lesions fluctuate in volume in as little time as 6 weeks, he added. “There is a pressing need for nonsurgical interventions for knee OA, but there are no currently approved structure-modifying treatments. Bone marrow lesion change offers a tremendous opportunity for drug development in osteoarthritis. Unlike cartilage loss, a bone marrow lesion is associated with pain. Bone marrow lesions could be a structural treatment target if we can demonstrate repeatedly that treatments affect bone marrow lesion,” Dr Felson stated. The authors sought to assess change in bone marrow lesions as a treatment target and the effect of the knee brace

on OA-related pain using the BioSkin patellar tracking Q brace (Össur Inc, Foothill Ranch, CA).

“There is a pressing need for nonsurgical interventions for knee OA, but there are no currently approved structuremodifying treatments. Bone marrow lesions change offers a tremendous opportunity for drug development in osteoarthritis.” —David Felson, MD

Overall, 126 patients with painful knee OA were randomized to wear the brace or no brace. The brace was worn for a median of 7.35 hours daily for 6 weeks. Patients did not partici-

pate in any exercise program over the course of the study. All of the patients included in the study had x-ray evidence of knee joint damage and tender knee joints on physical examination. The mean age was approximately 55 years, slightly more than 50% of the patients were women, and the median body mass index was >30 kg/m2. At baseline, all patients reported knee pain during daily activities that put stress on the knee, including climbing stairs, kneeling, and prolonged sitting or squatting. Impressive Results The primary outcome measure was change in visual analog scale (VAS) pain score (range, 0-100: 0 = least pain, 100 = most severe pain) during physical activity. Patients in the brace group had a substantial reduction in VAS of approximately 18 points during physical activity, while those in the nobrace group had almost no change in VAS during activity (P <.001). The

Continued from page 1

knee OA outcome score pain subscale showed substantial pain reduction in the treatment group, but not in the control group. At baseline, bone marrow lesion volumes in the patellofemoral joint, which is the joint targeted by the brace, were almost identical in the 2 groups on contrast magnetic resonance imaging. At 6 weeks, contrast magnetic resonance imaging revealed a significant 25% decrease in bone marrow lesion volume of the patellofemoral joint in patients randomized to the brace versus no brace (P = .02). No difference in bone marrow lesion volume change was observed from baseline to 6 weeks in the control group. The study was 6 weeks long, and Dr Felson acknowledged that OA is a chronic condition that would require long-term use of the brace. After an additional 3 months, 75% of the patients were still wearing the brace. “The brace appears to be feasible as a longer-term strategy,” he noted. n

In the Literature Continued from page 5

PAH Screening Should Be Performed in Patients with Systemic Sclerosis

Although pulmonary arterial hypertension (PAH) is becoming more recognized in patients with systemic sclerosis, early detection is still lagging. Therefore, a group of experts developed new recommendations for screening and early diagnosis of connective tissue disease (CTD)-associated PAH. These first consensus-based and evidence-driven recommendations for the screening and early detection of CTD-associated PAH suggest that all patients with systemic sclerosis should undergo screening for PAH (Khanna D, et al. Arthritis Rheum. 2013;65:3194-3201). The key recommendations suggest that all patients with systemic sclerosis should be screened for PAH, because it is prevalent in that patient population (moderate quality of evidence), and diagnosed using right-sided heart catheterization (high quality evidence). Patients with mixed CTD or other CTDs with scleroderma features should also be screened for PAH, because they are at high risk (very low quality evidence). For this population, the panel recommends pulmonary function tests with sinVOL. 3

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gle-breath diffusing capacity for carbon monoxide (high quality evidence), transthoracic echocardiogram (high quality evidence), and measurement of N-terminal pro–brain natriuretic peptide (moderate quality evidence). Annual screenings, including transthoracic echocardiogram and pulmonary function tests, should be done for all patients with systemic sclerosis (low quality evidence) and scleroderma spectrum disorders (very low quality evidence). All patients with a tricuspid regurgitation jet velocity of >2.8 m/s and those with right atrial or right ventricular enlargement regardless of tricuspid regurgitation jet velocity should be referred for right-sided heart catheterization (high quality evidence). Similarly, patients with systemic sclerosis and scleroderma spectrum disorders who have signs and/or symptoms of pulmonary hypertension and tricuspid regurgitation velocity of 2.5 m/s to 2.8 m/s should also be referred for right-sided heart catheterization (high quality evidence). The investigators hope that these recommendations will ultimately improve patient outcomes, noting that they should be updated as more evi-

dence becomes available. They emphasized that the recommendations are not meant to be substituted for individualized direct assessment of patients, coupled with clinical decision-making, nor are they meant to limit or deny third-party payer coverage of healthcare costs.

Chronic Kidney Disease in Top 3 Risk Factors for Gout

Although kidneys are a major route for the excretion of urate, data evaluating the link between reduced glomerular filtration rate and kidney damage, and its role in gout are lacking. Common risk factors for gout include obesity and hypertension, and should now include chronic kidney disease (CKD), results from an epidemiologic study suggest (Krishnan E. Arthritis Rheum. 2013;65:3271-3278). Using data from the Multiple Risk Factor Intervention Trial—a primary prevention trial for cardiovascular disease with a 7-year follow-up—the researcher evaluated whether symptoms indicative of CKD (ie, reduction in glomerular filtration rate, and/or presence of proteinuria and hematuria) were predictors of increased risk of incident gout. Evaluation of baseline data from february 2014

the original trial (N = 12,866 men; 35-57 years of age) demonstrated that patients with poor renal function had a higher prevalence for several known risk factors, including elevated blood pressure and obesity. From this group, there were 722 cases of physician-diagnosed gout during a follow-up of 76,602 person-years. The incidence of gout was 9.4 per 1000 person-years with similar rates seen between the usual care group and the intervention group. In addition, as glomerular function decreased, the cumulative incidence of gout increased. In addition, the investigators observed that proteinuria and hematuria, which are indicative of kidney damage, were associated with an elevated risk for gout, independent of estimated glomerular filtration rate. While the researcher acknowledges that this is the first study to report these data, he also notes that an inherent limitation includes gender bias, because the original study comprised an all male population. The study definition of CKD was also based on measures of glomerular outcomes instead of measures of tubular function. Safe and effective treatment of gout patients with CKD is needed, the investigator concluded. n

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Drug Update

Otrexup Injection: Novel Methotrexate Delivery System for Patients with Rheumatoid Arthritis By Lisa A. Raedler, PhD, RPh, Medical Writer

heumatoid arthritis (RA) is a chronic, systemic autoimmune disease that affects at least 1.3 million adults in the United States.1 Symptoms include pain, stiffness, swelling, and limited motion and function of many joints, particularly the small joints in the hands and feet.1 A diagnosis of RA is made on the basis of symptoms, physical examination results, and blood tests that are positive for anemia, rheumatoid factor, antibodies, and elevated erythrocyte sedimentation rate.1 Continued inflammation of the synovium can lead to cartilage and bone damage.1,2 Although the etiology of RA is unknown, there is an association with genetic factors and environmental exposures.2 Risk factors include smoking, reproductive hormone exposures, dietary factors, and microbial exposure, as well as having human leukocyte antigen class II genotypes (eg, DR4 and DRB1 molecules).2 In addition to affecting the functioning and quality of life of patients, RA exacts a heavy economic toll on patients, employers, and payers. A recent study highlights the significant cost borne by American workers who live with RA and their employers.3 The research was conducted using a database of US employees’ administrative healthcare and payroll data for individuals enrolled in an employer-sponsored insurance plan for at least 1 year.3 Compared with employees who do not have RA, an employee with RA incurs approximately $5200 more in annual healthcare costs.3 Workers with RA also pay an average of $1500 more per person for prescription medications annually, and are absent from work approximately 3.5 more days annually.3 On the whole, patients with RA cost their employers across the United States approximately $5.8 billion annually.3 Today’s treatment of RA is symptom-based and often requires a combination of agents.1 Typically, therapy begins with disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, leflunomide, hydroxychloroquine, or sulfasalazine.1 DMARDs are administered along with nonsteroidal anti-inflammatory drugs (NSAIDs) and/or low-dose corticosteroids to reduce swelling, pain, and fever.1 The treatment course for more seri-

ous cases of RA includes biologic agents, which are also considered DMARDs, that target specific aspects of the immune system.1 These drugs include abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), certolizumab (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade), rituximab (Rituxan), and toclizumab (Actemra). The most recently approved agent for RA in adults, tofacitinib (Xeljanz), is an oral inhibitor of Janus kinase–mediated cell signaling.4 As unique biomarkers, genetic defects, and drug targets are identified, the development of novel RA agents continues. A recent genome-wide association study identified 42 new genes that confer the risk for RA at a genome-wide level of significance, bringing the total of known RA risk genes to 101.5 Although many current RA therapies target these genes, these findings suggest that drugs that are currently approved for other indications may be repurposed for use in patients with RA.5 Other novel targeting agents, including inhibitors of granulocyte-macrophage colony-stimulating factor receptors, have been shown to suppress cytokine responses in patients with RA.6 Otrexup: Novel Delivery of Methotrexate In October 2013, the US Food and Drug Administration (FDA) approved the first methotrexate injection (MTXI) for subcutaneous (SC) use (Otrexup; Antares Pharma).7 This once-weekly self-administered injection is indicated for adults with severe active RA who have had inadequate response to or are intolerant of first-line therapy.7 MTXI was also approved for use in children with active polyarticular juvenile idiopathic arthritis.7 The approval of MTXI was based on the demonstration of bioavailability in a 12-week, open-label, crossover study comparing the relative bioavailability of MTXI with oral methotrexate.8 Data from this study were presented at the 2013 annual meeting of the American College of Rheumatology. Originally developed as an oncology drug, methotrexate has become a cornerstone in the treatment of RA.9 In a recent interview regarding his experience in the study of MTXI, Michael Schiff, MD, Clinical Professor of Medicine in the Division of Rheumatology

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Table 1 Relative Bioavailability of Subcutaneous Methotrexate versus Oral Methotrexate MTXI dose, mg Relative bioavailability, % 10

121

114

131

141

MTXI indicates methotrexate injection. Source: Schiff MH, et al. Arthritis Rheum. 2013;65(10 suppl):S337-S338. at the University of Colorado, stated, “This new delivery system for methotrexate provides a welcome option for physicians and their patients to continue effective use of methotrexate…. The availability of an easy and safe way to administer subcutaneous methotrexate may…enable more patients to realize the possibility of continued disease control.”7 The use of parenteral methotrexate for the treatment of RA is less popular as a result of the challenges related to self-administration. Patients with RA may have compromised manual dexterity, needle phobia, and/or a lack of confidence in safely self-injecting with a vial, a needle, or a syringe, which can be barriers to use.7 Kevin Deane, MD, of the Division of Rheumatology at the University of Colorado stated, “Injectable [methotrexate] to date has come in a large vial, and [the] patient draws up medication and injects it.... Drawing up and administering this medication may be somewhat difficult for some patients to do, especially with arthritic conditions.”10 Mechanism of Action Methotrexate, an inhibitor of dihydrofolic acid reductase, interferes with DNA synthesis, repair, and cellular replication.11 Cells that are actively proliferating are particularly susceptible to these effects. The mechanism of action of methotrexate in RA is unknown. It may work by altering immune function.11 Dosing and Administration MTXI is a single-dose, easy-to-use autoinjector for once-weekly SC use.11 It is available in doses ranging from 10 mg to 25 mg in 5-mg increments and is administered in the abdomen or thigh.11 The MTXI dose can be adjusted gradually for optimal outcomes. Therapeutic response to methotrexate is usually seen within 3 to 6 weeks

and continues for 12 weeks or more.11 The optimal duration of MTXI therapy is unknown.11 Healthcare professionals should ensure that patients understand that MTXI is administered once weekly. The daily use of methotrexate has resulted in fatal toxicity.11 Clinical Trials

Bioavailability Study

The bioavailability of MTXI was assessed in an open-label, crossover study in which 49 adults with RA who had been receiving methotrexate for 3 months or more were given 10 mg, 15 mg, 20 mg, or 25 mg of methotrexate.8 They were randomized to receive either oral methotrexate, MTXI injected in the abdomen, or MTXI injected in the thigh.8 Blood samples were collected for analysis before the drug’s administration and at 13 time points of 15 minutes to 12 hours after drug administration.8 The average age of patients with RA who enrolled in the bioavailability study was 61 years and they had been diagnosed with RA for an average of 13 years.8 Their mean body mass index was 30.7 kg/m2.8 Pharmacokinetic parameters of interest included the area under the plasma concentration time curve (AUC), the maximum drug concentration, and the time of occurrence for maximum drug concentration. Safety was determined using the incidence of treatment-emergent adverse events (AEs), including injection-site reactions, as well as by monitoring laboratory parameters and vital signs.8 The analysis of pharmacokinetic parameters demonstrated that 4 hours after administration, the bioavailability of MTXI (administered in the thigh) was consistently greater than oral methotrexate at all dose levels (10-25 mg).8 At doses of 10 mg, 15 mg, 20 mg, and 25 mg, the relative bioavailability calculations (AUC of MTXI vs oral VOL. 3

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Table 2 Additional Warnings and Precautions for Subcutaneous Methotrexate Risk category

Description of potential risk

Guidance

Organ-system toxicity

• MTXI has the potential for serious toxicity; patients using MTXI should be closely monitored for bone marrow, liver, lung, and kidney toxicities. Toxic effects may be related to dose or frequency at any dose

• If adverse reactions occur, MTXI should be discontinued or the dose reduced; correction with leuco vorin calcium and/or acute intermittent hemodialysis with a high-flux dialyzer may be warranted. If MTXI therapy is reinstituted, it should be done cautiously • Because methotrexate has not been well studied in older individuals, relatively low doses should be considered in elderly patients and they should be closely monitored

Gastrointestinal

• MTXI should be used with extreme caution in patients with peptic ulcer disease or ulcerative colitis • Unexpectedly severe and at times fatal gastrointestinal toxicity have been documented in patients taking methotrexate (usually high dose) in combination with some NSAIDs

• Interruption of MTXI therapy is necessary if diarrhea and ulcerative stomatitis occur • Dehydration resulting from vomiting, diarrhea, or stomatitis warrants discontinuation of MTXI until recovery

Hematologic

• Because MTXI can suppress hematopoiesis, anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia can occur. In controlled clinical trials conducted with a different formulation of methotrexate in 128 patients with RA, 2 patients had leukopenia, 6 had thrombocytopenia, and 2 had pancytopenia • When administered with some NSAIDs, high doses of MTXI may cause severe and sometimes fatal bone marrow suppression and aplastic anemia • Patients with severe granulocytopenia and fever should be evaluated as soon as possible. Such patients usually require parenteral broad-spectrum antibiotic therapy

• MTXI should be used with extreme caution in patients with preexisting hematopoietic impairment. The drug should be stopped immediately if a significant drop in blood counts is observed

Hepatic

• MTXI can cause hepatotoxicity in patients with RA, ranging from elevated transaminases to fibrosis and cirrhosis • In RA, methotrexate hepatotoxicity may be associated with age at first use and duration of therapy. Other risk factors, such as total cumulative dose, diabetes, and advanced age, as well as lifestyle factors including alcoholism and obesity may be associated, but have not been confirmed • Liver function tests should be performed at baseline and at 4- to 8-week intervals in patients receiving MTXI for RA • Patients with a history of excessive alcohol use, abnormal baseline liver function test values, or chronic hepatitis B or C infection should undergo liver biopsy before MTXI treatment • During treatment, liver biopsy should be performed if liver function test abnormalities are persistent or if serum album in levels fall below the normal range • MTXI should be discontinued in patients who show persistent abnormal liver function tests, those who do not consent to liver biopsy, and in any patient whose liver biopsy exhibits moderate-to-severe changes

• Special caution should be taken in patients with preexisting liver damage and impaired hepatic function

Infection

• Patients with an active infection should use MTXI with extreme caution • Opportunistic infections, especially Pneumocystis pneumonia, may occur with MTXI

• Live virus vaccines are not recommended and may be ineffective when given during MTXI therapy

Neurologic

• Leukoencephalopathy after intravenous methotrexate administration has been reported in patients who have had craniospinal irradiation. Discontinuation of methotrexate does not always resolve neurotoxicity • Transient acute neurologic syndrome has been reported in patients treated with high-dose methotrexate. This stroke-like encephalopathy can manifest as confusion, hemiparesis, transient blindness, seizures, and coma. Its exact cause is unknown

Pulmonary

• Use of methotrexate may result in lung disease, including acute or chronic interstitial pneumonitis. This may occur at any time during therapy and has occurred at low doses of methotrexate. Lung disease may not be fully reversible and can be fatal • Symptoms of pulmonary distress, especially a dry nonproductive cough, and nonspecific pneumonitis occurring during MTXI therapy may indicate a dangerous lesion • Other symptoms can include fever, cough, dyspnea, hypoxemia, and an infiltrate on chest x-ray. Infection (pneumonia) must be excluded

• If pulmonary symptoms are observed, MTXI treatment should be interrupted and the patient should be closely monitored

Renal

• High doses of methotrexate used in the treatment of osteosarcoma can cause renal damage that may lead to acute renal failure

• Renal function, adequate hydration, urine alkalini zation, and levels of serum methotrexate and creatinine should be monitored

Skin

• Dermatologic reactions, including severe reactions and fatalities, have been reported in children and adults within days of taking oral, intramuscular, intravenous, or intrathecal methotrexate administration at any dose

Dizziness and fatigue

• MTXI use may lead to dizziness and fatigue

• Patients should be cautious when driving or using machinery

MTXI indicates methotrexate injection; NSAIDs, nonsteroidal anti-inflammatory drugs; RA, rheumatoid arthritis. Source: Otrexup (methotrexate) injection [prescribing information]; October 2013. Continued on page 24 VOL. 3

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Otrexup Injection: Novel Methotrexate Delivery System... methotrexate) were 121%, 114%, 131%, and 141%, respectively, as summarized in Table 1.8 No bioavailability plateau was seen for MTXI, whereas the bioavailability of oral methotrexate plateaued at a dose of 15 mg.8

Phase 2 Clinical Trial

A phase 2, multicenter, openlabel, single-dose, single-arm, inclinic study enrolled 101 adults with RA to evaluate the ease of use of MTXI.12 The autoinjected product was tested with the intention of addressing the concerns of patients with RA regarding self-administering methotrexate using a conventional vial and syringe.12 The patients in the trial received MTXI at a dose of 10 mg, 15 mg, 20 mg, or 25 mg weekly.12 Dosing was determined by investigators based on each patient’s previous methotrexate regimen and disease status (ie, controlled or uncontrolled) at the time of study enrollment. Of the 101 patients enrolled, 99 patients were evaluable.12 Most patients (79%) were female, with an average age of 61 years.12 These patients had been diagnosed with RA for an average of 13 years.12 All patients had received methotrexate for at least 3 months before enrolling in the study.12 Overall, 20% of patients had received SC methotrexate, and their functional status ranged from mild to severe; 89% were in American College of Rheumatology Functional Class II or III.12 The primary outcome measure in this phase 2 trial of MTXI was pain associated with SC administration as measured using a 100-mm visual analog scale (VAS).12 The administration sites were evaluated before administration and at 15 minutes, 1 hour, 6 hours, and 24 hours after self-ad ministration.12 The mean administration-site pain ratings for all enrolled patients (N = 101) were 3.6 on day 1 and 1.4 on day 2 (standard deviations, ±9.1 and ±3.2, respectively).12 Of the 99 evaluable patients, 94% reported VAS scores of ≤10 on day 1, and 87% had scores of ≤5 on day 1.12 All 99 patients handled the autoinjector successfully.12 Of 404 skin sites that were evaluat-

ed after MTXI administration, 92% reported no erythema, with the balance showing “very slight, barely perceptible” erythema.12 Three patients experienced AEs while taking MTXI, including sick sinus syndrome, exostosis, and headache.12 None of these was considered to be related to the study drug.12 Safety Methotrexate and MTXI were safe and well tolerated in the bioavailability study.8 The few AEs that were observed with MTXI were deemed transient and manageable. None required medical treatment.8 Two serious AEs were deemed unrelated to treatment, including 1 death from myocardial infarction in a 79-year-old man with a history of heart disease.8 Contraindications MTXI is contraindicated in pregnant women, nursing mothers, patients with alcoholism or liver disease, patients with immunodeficiency syndromes, patients with preexisting blood dyscrasias, and patients with hypersensitivity to methotrexate.11 Warnings and Precautions Boxed warning. Like the oral formulation of methotrexate, MTXI labeling includes a boxed warning for multiple safety risks, including embryo-fetal toxicity and death.11 These warnings include11: • Serious toxic reactions and death; patients taking methotrexate should be closely monitored for bone marrow, liver, lung, skin, and kidney toxicities • Fetal death and congenital anomalies; methotrexate is contraindicated in pregnancy • Unexpectedly severe and sometimes fatal bone marrow suppression, aplastic anemia, and gastrointestinal toxicity; these events were reported when methotrexate and some NSAIDs were administered concurrently • Hepatotoxicity, fibrosis, and cirrhosis after prolonged use • Interstitial pneumonitis • Diarrhea, ulcerative stomatitis, hemorrhagic enteritis, and death from intestinal perforation

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• Severe and occasionally fatal skin reactions • Potentially fatal opportunistic infections. Laboratory tests needed. Patients who are candidates for MTXI should undergo a complete blood count with differential and platelet counts, hepatic enzymes, renal function tests, and a chest x-ray before initiating therapy. During MTXI therapy, clinicians should monitor hematology parameters at least monthly, and monitor renal and liver function parameters every 1 to 2 months.

Although the literature documents the clinical utility of SC methotrexate in patients with active RA, this dosing alternative is often overlooked by clinicians. Embryo-fetal toxicity. Fetal death and congenital anomalies have been reported with methotrexate use. MTXI is not recommended for women of childbearing age unless its benefits outweigh risks. Steps to avoid conception should be taken if either partner is receiving MTXI therapy. Malignant lymphomas. Non-Hodg kin lymphoma and other tumors have been observed in patients taking lowdose oral methotrexate. In some cases, however, malignancies that arose during treatment regressed completely after methotrexate withdrawal. Before initiating antilymphoma treatment, MTXI should be discontinued. Additional warnings. Additional warnings and precautions related to MTXI include organ-system toxicity, infection, skin reactions, dizziness and fatigue, malignant lymphomas, as well as gastrointestinal, hematologic, hepatic, neurologic, pulmonary, and renal complications. Additional information regarding these warnings and precautions is listed in Table 2. Conclusion The FDA approval of a new delivery system for the administration of

Continued from page 23

methotrexate adds a new and convenient treatment option for patients with RA. Although the literature documents the clinical utility of SC methotrexate in patients with active RA, this dosing alternative is often overlooked by clinicians. Methotrexate administered subcutaneously using an autoinjector is a well-tolerated, effective, and nearly pain-free alternative for patients with severe RA who have had inadequate response to or who are intolerant of first-line therapy. In addition to higher drug exposure levels with MTXI, easy self-administration of the medication with this first-in-class autoinjector may help to improve patient adherence and overall clinical outcomes. n References

1. Ruderman E, Tambar S. Rheumatoid arthritis. Updated August 2012. www.rheumatology.org/ practice/clinical/patients/diseases_and_conditions/ ra.asp. Accessed January 4, 2014. 2. Centers for Disease Control and Prevention. Rheumatoid arthritis. Updated November 19, 2012. www.cdc.gov/arthritis/basics/rheumatoid.htm. Accessed January 4, 2014. 3. Kleinman NL, Cifaldi MA, Smeeding JE, et al. Annual incremental health benefit costs and absenteeism among employees with and without rheumatoid arthritis. J Occup Environ Med. 2013;55:240-244. 4. Xeljanz (tofacitinib) tablets [prescribing information]. New York, NY: Pfizer Inc; November 2013. 5. Okada Y, Wu D, Trynka G, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2013 Dec 25 [Epub ahead of print]. 6. Burmester GR, Feist E, Sleeman MA, et al. Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor-α, in subjects with rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase I, first-in-human study. Ann Rheum Dis. 2011;70:1542-1549. 7. Antares Pharma, Inc. Otrexup (methotrexate) injection approved by FDA: a new treatment for adults with rheumatoid arthritis, children with polyarticular idiopathic arthritis, and adults with psoriasis. Press release. October 14, 2013. www.antarespharma.com/ files/8613/8175/5363/OTREXUP_FDA_Approval. pdf. Accessed January 4, 2014. 8. Schiff MH, Simon LS, Freundlich B, et al. Drug exposure limitations of oral methotrexate (MTX) at doses >15 mgs may be overcome by using a subcutaneous MTX auto-injector in patients with rheumatoid arthritis (RA). Arthritis Rheum. 2013;65(10 suppl):S337-S338. 9. Gower T. Understanding methotrexate, a cornerstone in RA treatment: how did a cancer drug become a staple in rheumatoid arthritis treatment? www.arthritistoday.org/about-arthritis/types-of-ar thritis/rheumatoid-arthritis/treatment-plan/treat ment-choices/understanding-methotrexate.php. Accessed January 5, 2014. 10. Brooks M. FDA OKs Methotrexate Autoinjector (Otrexup). Medscape. October 18, 2013. www.med scape.com/viewarticle/812821. Accessed January 28, 2014. 11. Otrexup (methotrexate) injection [prescribing information]. Ewing, NJ: Antares Pharma, Inc; October 2013. 12. Kivitz AJ, McLain D, Hill J, et al. Nearly pain free self-administration of methotrexate using an investigational auto-injector: results of a phase-2 clinical trial in rheumatoid arthritis patients with mild-to-severe functional limitations. Arthritis Rheum. 2013;65(10 suppl):S565.

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Continuing Education

Optimal Use of Biologics in Delivering Value-Based Care: Challenges for Managed Care Pharmacy Faculty Douglas Burgoyne, PharmD

John Fox, MD, MHA

President VRx Pharmacy Services, LLC Salt Lake City, UT

Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Commercial Support Acknowledgment This activity is supported by an educational grant from Genentech/ Biogen Idec. Target Audience This activity was developed for managed care pharmacists and professionals who are involved in the care of patients with cancer or autoimmune disorders, and who manage insurance designs. Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 1.0 contact hour (0.1 CEU) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-13-028-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Describe the current trends in the use of biologic therapies in oncology, rheumatology, inflammatory bowel disease, and multiple sclerosis • Discuss the challenges facing all stakeholders in optimizing value in the use of biologic therapies • Analyze issues around cost, quality, and access to care in the use of biologic therapies • Formulate biologic treatment options that maximize value by improving clinical outcomes and reducing disease burden on patients, families, and the healthcare system

Senior Medical Director Vice President of Medical Affairs Priority Health Associate Professor of Medicine Michigan State University College of Human Medicine Grand Rapids, MI

Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute Inc for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations. The associates of Medical Learning Institute Inc, the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CPE activity for any amount during the past 12 months. Planners’ and Managers’ Disclosures Sabeeha Muneer, PhD, Medical Writer, has nothing to disclose. She does not intend to discuss any non–FDA-approved or investigational use of any products/devices. Patricia Ensor, RPh, MBA, MLI Reviewer, has nothing to disclose. Faculty Disclosures Douglas Burgoyne, PharmD, has received consulting fees from Biogen Idec, Eli Lilly, Novo Nordisk, and Purdue. He does not intend to discuss any non–FDA-approved or investigational use of any products/devices. John Fox, MD, MHA, has nothing to disclose. He does not intend to discuss any non–FDA-approved or investigational use of any products/devices. Jeffrey D. Dunn, PharmD, MBA, has received honorarium from AbbVie, Biogen Idec, and Janssen. He does not intend to discuss any non–FDA-approved or investigational use of any products/devices.

Jeffrey D. Dunn, PharmD, MBA Senior Vice President VRx Pharmacy Services, LLC Salt Lake City, UT

Disclaimer The information provided in this CPE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias toward or promotion for any agent discussed in this program should be inferred. Instructions for Credit There is no fee for this activity. To receive credit after reading this CPE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P13031E.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records. For questions regarding the accreditation of this activity, please contact Medical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org. For pharmacists, Medical Learning Institute Inc will report your participation in this educational activity to the NABP only if you provide your NABP e-Profile number and date of birth. For more information regarding this process or to get your NABP e-Profile number, go to www.mycpemonitor.net. Estimated time to complete activity: 1 hour Date of initial release: February 11, 2014 Valid for CPE credit through: February 11, 2015.

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Supported by an educational grant from Genentech/Biogen Idec.

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Continuing Education

he advent of biologic therapies has revolutionized the management of patients with cancer and autoimmune diseases across the therapeutic spectrum. These advances reflect improved understanding of the pathobiology of different malignancies and immunologically mediated disorders, and identification of rational targets for therapeutic development. Current projections, however, indicate that spending related to specialty drugs, including biologic agents, will reach astronomical levels by the year 2018—amounting to an increase per member per year (PMPY) from $290 in 2012 to $845 PMPY in 2018 (Figure).1 Although the clinical drug pipeline historically has been dominated by biologic agents directed toward cancer-relevant antigens, a majority of biologic therapies are increasingly being developed for noncancerous indications, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and multiple sclerosis (MS). Consistent with this trend, inflammatory diseases, such as RA and MS, show the highest PMPY spending of specialty drugs (23.3% and 18.0%, respectively), followed by oncology at 14.3%.2 The concept of Triple Aim, which was first proposed in 2008, defines the simultaneous improvement of population health, patient experience of care, and per-capita cost reduction as the 3 dimensions needed to achieve optimal outcomes.3 Outcome measures for achieving these lofty goals have since been developed by the Institute for Healthcare Improvement, and they serve as the central tenet for public and private health organizations.4 As novel biologic agents are entering clinical practice, and the considerable cost burden associated with these agents is increasingly being realized, important questions regarding their clinical utility and value are being raised, including whether they can help achieve the Triple Aim goal. A live symposium was held on October 16, 2013, during meetings of the Academy of Managed Care Pharmacy, to educate managed care pharmacists, who are uniquely positioned to evaluate the value of biologic therapies, on recent treatment advances and practice management strategies. This review provides a synthesis of the proceedings of this meeting, including current trends in personalized biologic therapy–based management approaches in oncology and chronic inflammatory diseases, and cost-effective strategies for improving overall outcomes from the perspective of managed care pharmacists.

Review of Current and Emerging Biologic Agents for the Treatment of Cancer and Autoimmune Diseases Biologics in Oncology According to the most recent estimates from the Centers for Disease Control and Prevention, cancer is the second leading cause of death in the United States, Figure Exponential Growth of Specialty Drug Spending Traditional

surpassed only by cardiovascular diseases.5 Historically, standard treatment modalities in oncology have included a combination of surgery, radiation, and/or chemotherapy. Immunotherapy with biologic agents, however, is now considered an integral and indispensable component of the treatment arsenal for many different types of cancer.6,7 Cancer immunotherapy strategies are aimed at exploiting the therapeutic potential of tumor-specific antibodies and cellular immune effector mechanisms, and include monoclonal antibodies (mAbs), cytokines and growth factors, and vaccines.6,7 Indeed, the oncology arena has witnessed an unprecedented upswing in the use of biologic therapies. Currently, the US Food and Drug Administration (FDA) lists more than 50 medications with accompanying pharmacogenomic biomarkers that have been approved for clinical use.8 In many cancer types, antibody-based treatment has dramatically improved disease response while reducing the major concomitant toxicities typically associated with the use of chemotherapy. In the field of oncology, mAbs include the anti–human epidermal growth factor receptor 2 (HER2) mAb trastuzumab for breast cancer, the anti-CD20

As novel biologic agents are entering clinical practice, and the considerable cost burden associated with these agents is increasingly being realized, important questions regarding their clinical utility and value are being raised, including whether they can help achieve the Triple Aim goal. mAb rituximab for non-Hodgkin’s lymphoma, the anti–vascular endothelial growth factor (VEGF) mAb bevacizumab for several different cancer types, the anti–epidermal growth factor receptor (EGFR) mAb panitumumab for colon cancer, and the anti-EGFR mAb cetuximab for colorectal cancer and head and neck cancer.9 These mAbs directly target the cancer antigen, resulting in blockade of growth factor–mediated signaling and inhibition of angiogenesis, which regulate key processes involved in cancer growth and progression. Other types of biologic immunotherapy used in oncology include cytokines such as interleukin (IL)-2 and interferon (IFN)-alpha for various forms of cancer, and vaccines9 such as Bacillus Calmette-Guérin for the treatment of bladder cancer. In addition, biologic agents are used as supportive care in oncology, for the mitigation of treatment-related side effects. These treatments include the use of such hematopoietic growth factors as granulocyte colony-stimulating factor following cytotoxic chemotherapy, in order to promote neutrophil production and thus reduce the risk for infection.9

Biologics for Autoimmune Diseases Multiple sclerosis MS is a chronic autoimmune disease that is defined by the progressive destruction of axonal myelin sheaths in the central nervous system.10,11 The symptoms associated with MS are interrelated, having a major impact on quality of life

Specialty

$1800 $1600 $1400

Table 1 Biologics Currently Approved for the Treatment of Multiple Sclerosis

$1200 $612

$1000 $800

$290

$348

$425

$722

$845

$514

$600 $400

$665

$675

$694

$722

$751

$789

$836

$200 $0

2012

2013

2014

2015

2016

2017

2018

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Generic name

Mechanism of action

Approval date

Interferon beta-1b

Immunomodulator

1993

Interferon beta-1a

Immunomodulator

1996

Glatiramer acetate

Immunomodulator

1996

Natalizumab

Adhesion molecule blocker (anti-integrin α-4)

2006

Fingolimod

Immunomodulator

2010

Teriflunomide

Immunomodulator

2012

Dimethyl fumarate

Immunomodulator

2013

Source: Reference 12.

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Continuing Education

Table 2 Biologic Disease-Modifying Antirheumatic Drugs for Rheumatoid Arthritis Name of agent

Mechanism of action

Approval date

Infliximab

Anti–TNF-α

1998

Etanercept

Anti–TNF-α

1998

Anakinra

IL-1 receptor

2001

Adalimumab

Anti–TNF-α

2002

Abatacept

CD28

2005

Rituximab

CD20

2006

Certolizumab pegol

Anti–TNF-α

2008

Golimumab

Anti–TNF-α

2009

Tocilizumab

IL-6 receptor

2010

IL indicates interleukin; TNF, tumor necrosis factor. Sources: References 18, 19.

Table 3 Expanding Therapeutic Pipeline for Inflammatory Bowel Disease Name of agent

Mechanism of action

Approval date

Adalimumab

Anti–TNF-α

2007

Natalizumab

Adhesion molecule blocker (anti-integrin α-4)

2008

Certolizumab pegol

Anti–TNF-α

2008

Golimumab

Anti–TNF-α

2013

Tofacitinib

JAK inhibitor

2012

Vedolizumab

Adhesion molecule blocker (anti-integrin α-4/β-7)

In FDA review

PF-00547659

Mucosal adhesion blocker

In clinical testing

GSK-1605786

Oral chemokine antagonist

In clinical testing

Ustekinumab

Cytokine blocker

In clinical testing

FDA indicates US Food and Drug Administration; JAK, Janus kinase; TNF, tumor necrosis factor. Source: Reference 25.

(QOL) and carrying a considerable economic burden.11 The current treatment armamentarium for MS includes IFN beta-1a, IFN beta-1b, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, and dimethyl fumarate— all of which are able to reduce relapse rates and the accumulated disability scores in patients with relapsing-remitting MS (RRMS) (Table 1).12 The overwhelming majority of these treatments, however, have been unable to prevent disease progression or demonstrate curative potential. Therefore, several novel therapies, including alemtuzumab, daclizumab, laquinimod, and neuroprotective agents, are currently under investigation for the treatment of MS.13 In the near future, biosimilars, generics, and novel formulations of current agents (eg, low-dose and generic fingolimod, glatiramer acetate injections 3 times weekly, and first-line intravenous natalizumab) should be available in the biologic MS space, which is expected to have a favorable impact on the treatment paradigm, as well as on the cost of therapy.14 Rheumatoid arthritis RA is a chronic, debilitating, systemic autoimmune disorder that is often characterized by swollen joints, pain, and decreased functional mobility.15,16 Little is understood about the many extraarticular manifestations of RA, including cardio-

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vascular disease, infections, depression, and gastrointestinal ulcers.16 Consequently, RA frequently leads to an increased risk for premature mortality, hospitalization, work disability, increased medical costs, and poor QOL.16 Historically, RA has been managed primarily with corticosteroids and nonsteroidal anti-inflammatory agents, followed by the use of conventional, nonbiologic disease-modifying antirheumatic drugs (DMARDs). These agents have been able to prevent or delay erosive changes that lead to disability, have demonstrated efficacy in reducing synovitis and systemic inflammation, and have improved functionality.16 Recently, the use of biologic agents has significantly altered the natural history of the disease. The latest RA treatment guidelines from the European League Against Rheumatism advocate that the key to optimizing patient outcomes is early diagnosis and early aggressive therapy with optimal doses of conventional DMARDs and, if active disease persists, early introduction of biologic agents.17 Biologic approaches include such tumor necrosis factor (TNF) alpha inhibitors as etanercept, infliximab, adalimumab, golimumab, and certolizumab; the anti–IL-6 agent tocilizumab; the anti–CD20-directed mAb rituximab; the small-molecule Janus kinase (JAK) 1/3 inhibitor tofacitinib; and the antiCTLA-4 fusion protein abatacept (Table 2).18,19 These agents all have demonstrated efficacy in limiting both symptomatic manifestations and radiographic progression of disease.18,19 Inflammatory bowel disease IBD broadly refers to conditions that are believed to be the result of immune dysregulation, impaired mucosal integrity, enteric bacterial dysbiosis, and genetic susceptibility factors.20 These debilitating diseases are characterized by intestinal inflammation, and are associated with such symptoms as persistent diarrhea, cramping abdominal pain, fever, rectal bleeding, loss of appetite, and weight loss.21-23 The 2 most common types of IBD are Crohn’s disease and ulcerative colitis.23-25 The expanding pipeline of drugs for IBD include the anti–TNF-alpha agents adalimumab and golimumab; the adhesion molecule blockers natalizumab, vedolizumab, and certolizumab; the mucosal adhesion blocker PF-00547659; the oral chemokine antagonist GSK-1605786; the JAK inhibitor tofacitinib; and the cytokine blocker ustekinumab (Table 3).25 Increased understanding of the pathogenesis of IBD has identified several other biologic targets for the disorder, including growth factors such as platelet-activating factor and transforming growth factor beta; inflammatory cytokines such as IL-1; immunoregulatory cytokines such as IL-2, IL-4, and IL-12; and chemokines such as intercellular adhesion molecule-1, all of which might further expand the biologic armamentarium for IBD.26

Personalized Management Approaches with Biologic Agents Our expanding knowledge regarding the role of genetic and molecular drivers of disease pathogenesis heralds an era of molecular disease classification and personalized treatment strategies. In basic terms, personalized medicine refers to tailoring treatment to address patient- and disease-related characteristics that are unique to each individual. At the core of practicing personalized medicine is the identification and validation of biomarkers that may be useful for diagnostic purposes, along with the prediction of disease course, prognosis, treatment response, and risk for adverse events associated with a particular therapy. Personalized Medicine in Oncology The use of trastuzumab in breast cancer serves as a prototype for the successful application of personalized medicine.27 Trastuzumab, first approved in 1998 for the treatment of patients with HER2-positive breast cancer, relied on a molecular diagnostic test to identify individuals who overexpress HER2 and would therefore benefit from trastuzumab therapy.27 Prior to the approval of trastuzumab, patients with HER2-positive disease were resigned to a particularly poor prognosis.28 In addition to trastuzumab, several other HER2-targeted therapies are now available for this patient population, including pertuzumab, trastuzumab-DM1, and lapatinib, all with proven efficacy in significantly improving outcomes in both early and metastatic HER2-positive breast cancer settings.28 In a subset of lung adenocarcinomas, the identification of driver mutations in the EGFR gene is associated with response to the tyrosine kinase inhibitor (TKI) erlotinib, leading to the successful application of genetic profiling and rational use of targeted therapies directed toward these common mutations.29 Similarly, recent data demonstrate that response to the anti-EGFR mAb cetuximab in EGFR-

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expressing tumors in metastatic colorectal carcinoma is predicted not by EGFR expression, but rather by KRAS mutation status.30 In a non–small-cell lung cancer subset, the presence of mutations in the anaplastic lymphoma kinase (ALK) receptor has provided the opportunity for successful use of the ALK/Met TKI crizotinib in these patients.31 Therefore, current National Comprehensive Cancer Network (NCCN) guidelines recommend the first-line use of erlotinib and crizotinib in patients with EGFR and ALK mutations, respectively, and doublet chemotherapy or cisplatin plus pemetrexed in those without mutations.31 Unfortunately, acquired resistance to TKI therapy is a clinical challenge; a clearer understanding of drug-resistance mechanisms is critical to developing more effective personalized therapeutics. Along the same line, activating mutations in BRAF, such as V600E and V600K, have been identified in metastatic melanoma. The selective BRAF V600E inhibitor vemurafenib has been FDA approved in this patient subset, and is associated with improved outcomes with respect to overall survival, progression-free survival, and clinical response rates.32 In patients with colorectal cancer, the same BRAF V600E mutation is also present in 5% to 15% of all tumors and in up to 80% of tumors with high microsatellite instability, and is associated with a poor prognosis.33 Unexpectedly, patients with colorectal cancer who harbor BRAF V600E mutations and are treated with vemurafenib exhibit suboptimal responses, highlighting the importance of disease-specific studies.33 These conflicting data emphasize the heterogeneous biology and pathogenesis underlying different malignancies, and caution against extrapolating results among different cancer types. Although whole-genome sequencing is an attractive prospect in oncology, contradictory data, such as with the BRAF V600E mutation, undermine its universal applicability. Moreover, considerable intratumor heterogeneity exists, rendering biomarker assessment challenging. Gerlinger and colleagues found significant mutational microheterogeneity and corresponding protein expression, with discrepancies detected in different regions of the same tumor, and among molecular profiles of primary and metastatic lesions.34 Despite such limitations, however, it is clear that identification of genetic or molecular tumor abnormality profiles in oncology will allow more rational use of targeted agents and biologic therapies, leading to improved health outcomes, improved patient experience, better use of resources, and reduced costs through avoidance of ineffective therapies.

Personalized Medicine in Chronic Inflammatory Diseases Unlike in oncology, personalized management approaches are still in their infancy in chronic inflammatory diseases, with few biomarkers having made their way into clinical practice. Increasing evidence, however, suggests that this will be the way in which inflammatory or immunologically mediated diseases will be treated in the future.

Emerging data suggest that assessment of unique markers of gene expression in the peripheral blood of persons with RA may prove useful in monitoring disease progression and response to therapy, including combination of a conventional DMARD and an anti–TNF-alpha agent. MS is a highly heterogeneous disorder with diverse etiology, pathologic features, clinical course, disease severity, and response to therapy, which presents obvious challenges when making treatment decisions.35 Treatment selection for MS has been largely empirical and not guided by validated molecular or genetic biomarkers. Existing treatments for RRMS have demonstrated limited efficacy, with disease activity persisting in the majority of patients despite therapy. Treatment response has been based on preventing clinical relapses and progression of disability, and monitoring for new lesions on magnetic resonance imaging after 1 year of treatment.36 Established predictive biomarkers include neutralizing antibodies against such immunotherapies as IFN-beta and natalizumab.37 Detection of pathologic immune responses, primarily antibody responses, against putative autoantigens has also shown some promise in predicting patient response.35

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In RA, several matrices have been developed to predict the risk for rapid radiologic progression following treatment with either DMARD monotherapy or combination therapy.38 Predictive biomarkers have also been identified for response to biologic agents and for their successful discontinuation upon achievement of treatment goals. Moreover, emerging data suggest that assessment of unique markers of gene expression in the peripheral blood of persons with RA may prove useful in monitoring disease progression and response to therapy, including combination of a conventional DMARD and an anti–TNFalpha agent.39 In IBD, genomic assessments have identified approximately 100 loci whose gene products function as key transcription factors or are involved in several critical pathways, such as the IL-23 pathway, and in modulating functions that affect IBD pathogenesis, including microbe recognition, lymphocyte activation, cytokine signaling, and intestinal epithelial defense.40 Such profiles also reveal association patterns that are similar between Crohn’s disease and ulcerative colitis, such as those involving Th17 pathways, indicating significant overlap in pathophysiology, as well as distinct disease-specific pathways (eg, NOD2 and autophagy in Crohn’s disease; major histocompatibility complex and epithelial barrier genes in ulcerative colitis).41,42

Although biologic agents have transformed the treatment paradigm of several malignancies and of autoimmune diseases as well, their high cost and the potential for patient nonadherence to therapy have become significant impediments to their use, raising questions regarding their clinical utility and “value.” Despite these promising new avenues of research, only clinical markers of treatment response are being applied at the current time. Other tools, however, such as disease activity measures, are being used to assess remission and state of disease activity in patients with MS, RA, and IBD.43-46 In RA, the Simplified Disease Activity Index is a validated composite score of the tender joint count, swollen joint count, patient global assessment, physician global assessment, and C-reactive protein (CRP) level, which is associated with the highest sensitivity and specificity for treatment decisions.43,44 In spite of its limitations, the Kurtzke Expanded Disability Status Scale, which combines disability and neurologic impairment, remains the most widely used activity score in MS.45 Similar indices are available for patients with IBD, such as the Crohn’s Disease Activity Index and the HarveyBradshaw Index, as well as such surrogate markers as CRP and fecal calprotectin.46 Their reliability and sensitivity remain questionable, however. Taken together, these data suggest that a combination of clinical markers, response biomarkers, and disease activity or disability indices holds great promise for the use of personalized medicine in patients with chronic inflammatory diseases.

Cost-Effective Strategies for Improving Overall Outcomes from the Managed Care Perspective: Meeting the Challenges and Barriers to the Use of Biologic Agents Although biologic agents have transformed the treatment paradigm of several malignancies and of autoimmune diseases as well, their high cost and the potential for patient nonadherence to therapy have become significant impediments to their use, raising questions regarding their clinical utility and “value.”2,47 Given that the “pursuit of the Triple Aim is an exercise in balance,”3 it is imperative that the clinical utility and “value” of biologic agents be balanced, and that appropriate utilization occurs—that is, the biologic is used in the right patient with the right disease at the right time. In this regard, numerous examples abound in clinical practice in which significantly less expensive, nonbiologic therapy can be used to obtain good clinical outcomes prior to the use of biologic agents.48 For example, a recent 2-year, randomized, double-blind study demonstrated that initial methotrexate monotherapy with the option to step up to combination therapy is associated with similar outcomes to the use of immediate combination therapy in patients with early, poor-prognosis RA.48 Managed care pharmacy, in particular, plays a key role in incorporating diagnosis, cost, and treatment information with pharmacy data. These efforts also

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Table 4 Clinical Pathways in Oncology Clinical pathways: Are an evidence-based approach to care Use the framework of tumor-specific guidelines Specify which interventions are performed and in what sequence Are intended to reduce practice variation, improve outcomes, and reduce costs Are typically developed by an individual provider team or national organization Source: References 50, 51.

improve appropriate utilization and optimal leveraging of pharmacy resources, thereby affecting benefit design, implementing management approaches for diseases that can be treated with biologic agents, and ensuring cost-effectiveness. From a managed care perspective, cost-effectiveness of an intervention equates with “value” in terms of efficacy and cost. A survey by The Zitter Group showed that most stakeholders are concerned about the inappropriate utilization of specialty drugs in oncology and consider waste reduction to be a primary cost-control strategy. The participants in this survey differed significantly, however, with respect to their estimation of the percentage of excess cost that could be eliminated from cancer treatment without negatively impacting overall outcomes.49 Payers were of the opinion that there was a 22.7% wastage in oncology, whereas oncologists and practice managers believed the wastage to be approximately 18% and 15.9%, respectively.49 Excessive end-of-life care, inappropriate drug use, and unwarranted diagnostic testing were considered to be key contributors to excess costs by payers and by oncologists.49 The costs of biologic agents and waste drive many of the value-based control mechanisms currently in place. Potential solutions, such as comparative effectiveness research (CER) and drug benefit designs, have been implemented by many managed care organizations.50 An important value initiative has been the recent efforts to define limited clinical pathways or evidence-based algorithms that describe the treatment selection, sequence, and timing of biologic therapies, and typically drive formulary decisions (Table 4).50,51

When making healthcare decisions, key stakeholders, including pharmacists, physicians, payers, policymakers, and patients, are often faced with incomplete or unavailable data—particularly comparative data—thus impeding the ability to deliver and pay for high-value, optimal care. In oncology, clinical pathways typically use tumor-specific guidelines from the NCCN and the American Society of Clinical Oncology, which are systematically developed, evidence-based best practices. The primary purposes of clinical pathways are to ensure proper utilization, reduce practice variation or standardize care, improve outcomes, and reduce cost variation. Preferred pathway options are often developed by individual teams or national organizations in collaboration with participating physicians. Oncologists may receive incentives to achieve a certain level of pathway compliance, whereas potential manufacturer rebates received for use of specific drugs in the preferred pathways can further lower net costs to payers.51 Additional data related to clinical pathways are warranted to substantiate improved outcomes and cost-savings, not only for oncology, but for inflammatory diseases as well. In addition, a patient-focused, value-based benefit design has been developed that offers plan-based incentives, such as reduction or elimination of patient cost-sharing, to encourage patients to use preferred treatment pathways and fol-

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low healthy behaviors, in order to improve health outcomes and control costs.52 Alternatively, patients may be penalized with increased cost-sharing for services that are not associated with clinical benefit or that have marginal benefit improvements with significant price increases. In inflammatory diseases, optimization of the use of specialty pharmaceuticals in a cost-effective manner is of primary interest. Several cost-containment management strategies for biologic agents are being implemented, including pharmacy prior authorization, clinical care management, 30-day supply limits, preferred products and formulary, pharmacy step therapies, cost-sharing tiers, restricted medical benefit coverage and closed pharmacy benefits, and tracking outcomes.53 Moreover, improving medication adherence in these chronic diseases is a major priority; increased out-of-pocket costs and adverse effects associated with biologic agents can limit patient adherence and result in reduced drug efficacy.54 Essentially, health plans want to realize the clinical benefits of their financial investment in biologics. When making healthcare decisions, key stakeholders, including pharmacists, physicians, payers, policymakers, and patients, are often faced with incomplete or unavailable data—particularly comparative data—thus impeding the ability to deliver and pay for high-value, optimal care.55 Rising healthcare costs and the introduction of novel, efficacious, and expensive biologic therapies have led to renewed emphasis on comparing the relative merits of one intervention versus competing interventions, particularly in the absence of head-to-head comparison data, in order to bridge knowledge gaps and drive informed clinical decisions and outcomes. Such efforts are known as CER, which is defined as “the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition, or to improve the delivery of care.”56 CER consolidates evidence from multiple sources, including prospective observational studies and peer-reviewed, published, retrospective analyses of healthcare data, such as medical or pharmacy claims, electronic health records, registries, and systematic literature reviews or meta-analyses.

Conclusion Biologic agents have become the mainstay of treatment for several disease states, including several cancer types, MS, RA, and IBD, and are the cornerstone of personalized medicine in these disorders. In the face of ongoing innovation, rising utilization, and increased costs, important considerations related to cost, value, patient access, and clinical utility are warranted. Cost-effectiveness may be optimized by implementation of value-based initiatives, including the use of CER and clinical pathways to inform treatment decisions for payers and physicians. Moreover, managed care pharmacists play a critical role in managing the use of biologics and in improving healthcare outcomes in their plan members. In this context, managed care pharmacists find themselves in the unique position of evaluating the clinical utility of biologic agents, affecting benefit design, optimizing current standards of personalized care, and helping providers and patients achieve optimal clinical outcomes. ◆ Acknowledgment Sabeeha Muneer, PhD, contributed to the development of this article. References

1. Artemetrx. Specialty drug trend across the pharmacy and medical benefit. 2013. www.artemetrx. com/docs/ARTEMETRX_Specialty_Trend_Rpt.pdf. Accessed December 17, 2013. 2. CVS/Caremark. Insights 2011. http://info.cvscaremark.com/files/reports/Insights2011.pdf. Accessed December 19, 2013. 3. Berwick DM, Nolan TW, Whittington J. The triple aim: care, health, and cost. Health Aff (Millwood). 2008;27(3):759-769. 4. Stiefel M, Nolan K. A Guide to Measuring the Triple Aim: Population Health, Experience of Care, and Per Capita Cost. IHI Innovation Series white paper. Cambridge, MA: Institute for Healthcare Improvement; 2012. www.IHI.org. Accessed December 18, 2013. 5. Hoyert DL, Xu J. Deaths: preliminary data for 2011. National Vital Statistics Reports. 2012; 61(6). www.cdc.gov/nchs/data/nvsr/nvsr61/nvsr61_06.pdf. Accessed December 18, 2013. 6. Schuster M, Nechansky A, Kircheis R. Cancer immunotherapy. Biotechnol J. 2006;1(2):138-147. 7. Huber CH, Wölfel T. Immunotherapy of cancer: from vision to standard clinical practice. J Cancer Res Clin Oncol. 2004;130(7):367-374. 8. US Food and Drug Administration. www.fda.gov/drugs/scienceresearch/researchareas/pharma cogenetics/ucm083378.htm. Accessed January 10, 2014. 9. Boyle RM. The use of biologics in cancer therapy. US Pharm. 2010;35(3)(Oncology suppl):4-7. www.uspharmacist.com/content/s/115/c/19768/. Accessed December 18, 2013.

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10. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372(9648):1502-1517. 11. Williams R, Rigby AS, Airey M, et al. Multiple sclerosis: its epidemiological, genetic, and health care impact. J Epidemiol Community Health. 1995;49(6):563-569. 12. Damal K, Stoker E, Foley JF. Optimizing therapeutics in the management of patients with multiple sclerosis: a review of drug efficacy, dosing, and mechanisms of action. Biologics. 2013;7:247-258. 13. Curtin F, Hartung HP. Novel therapeutic options for multiple sclerosis. Expert Rev Clin Pharmacol. 2014;7(1):91-104. 14. Reingold SC, Steiner JP, Polman CH, et al. The challenge of follow-on biologics for treatment of multiple sclerosis. Neurology. 2009;73(7):552-559. 15. Pablos JL, Cañete JD. Immunopathology of rheumatoid arthritis. Curr Top Med Chem. 2013; 13(6):705-711. 16. Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet. 2010;376(9746):1094-1108. 17. Kremer JM. Rheumatoid arthritis: new EULAR guidelines for RA: a job well done. Nat Rev Rheumatol. 2014;10(1):6-8. 18. Scher JU. Monotherapy in rheumatoid arthritis. Bull Hosp Jt Dis (2013). 2013;71(3):204-207. 19. Kumar P, Banik S. Pharmacotherapy options in rheumatoid arthritis. Clin Med Insights Arthritis Musculoskelet Disord. 2013;6:35-43. 20. Speight RA, Mansfield JC. Drug advances in inflammatory bowel disease. Clin Med. 2013;13(4): 378-382. 21. Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet. 2007; 369(9573):1627-1640. 22. Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet. 2007;369(9573):1641-1657. 23. Centers for Disease Control and Prevention. Inflammatory bowel disease (IBD). www.cdc.gov/ ibd/. Accessed December 18, 2013. 24. Ordás I, Eckmann L, Talamini M, et al. Ulcerative colitis. Lancet. 2012;380(9853):1606-1619. 25. Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet. 2012;380(9853):1590-1605. 26. Perrier C, Rutgeerts P. New drug therapies on the horizon for IBD. Dig Dis. 2012;30(suppl 1): 100-105. 27. Chen TW, Bedard PL. Personalized medicine for metastatic breast cancer. Curr Opin Oncol. 2013;25(6):615-624. 28. Jelovac D, Emens LA. HER2-directed therapy for metastatic breast cancer. Oncology (Williston Park). 2013;27(3):166-175. 29. Rosell R, Bivona TG, Karachaliou N. Genetics and biomarkers in personalisation of lung cancer treatment. Lancet. 2013;382(9893):720-731. 30. Karapetis CS, Khambata-Ford K, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359(17):1757-1765. 31. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Non-Small Cell Lung Cancer. Version 2.1014. www.nccn. org/professionals/physician_gls/pdf/nscl.pdf. Accessed January 23, 2014. 32. Jang S, Atkins MB. Treatment of BRAF-mutant melanoma: the role of vemurafenib and other therapies. Clin Pharmacol Ther. 2013;95(1):24-31. 33. Thiel A, Ristimäki A. Toward a molecular classification of colorectal cancer: the role of BRAF. Front Oncol. 2013;3:281. 34. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883-892. 35. Derfuss T. Personalized medicine in multiple sclerosis: hope or reality? BMC Med. 2012;10:116. 36. Rio J, Comabella M, Montalban X. Predicting responders to therapies for multiple sclerosis. Nat Rev Neurol. 2009;5(10):553-560. 37. Polman CH, Bertolotto A, Deisenhammer F, et al. Recommendations for clinical use of data on neutralising antibodies to interferon-beta therapy in multiple sclerosis. Lancet Neurol. 2010; 9(7):740-750.

38. van den Broek M, Visser K, Allaart CF, Huizinga TW. Personalized medicine: predicting responses to therapy in patients with RA. Curr Opin Pharmacol. 2013;13(3):463-469. 39. Edwards CK III, Green JS, Volk H-D, et al. Combined anti-tumor necrosis factor-α therapy and DMARD therapy in rheumatoid arthritis patients reduces inflammatory gene expression in whole blood compared to DMARD therapy alone. Front Immunol. 2012;3:366. 40. Cho JH, Brant SR. Recent insights into the genetics of inflammatory bowel disease. Gastro enterology. 2011;140(6):1704-1712. 41. Parkes M. The genetics universe of Crohn’s disease and ulcerative colitis. Dig Dis. 2012;30(suppl 1):78-81. 42. Gerich ME, McGovern DP. Towards personalized care in IBD. Nat Rev Gastroenterol Hepatol. 2013 Dec 17 [Epub ahead of print]. 43. Anderson JK, Zimmerman L, Caplan L, Michaud K. Measures of rheumatoid arthritis disease activity: Patient (PtGA) and Provider (PrGA) Global Assessment of Disease Activity, Disease Activity Score (DAS) and Disease Activity Score with 28-Joint Counts (DAS28), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), Patient Activity Score (PAS) and Patient Activity Score-II (PASII), Routine Assessment of Patient Index Data (RAPID), Rheumatoid Arthritis Disease Activity Index (RADAI) and Rheumatoid Arthritis Disease Activity Index-5 (RADAI-5), Chronic Arthritis Systemic Index (CASI), Patient-Based Disease Activity Score With ESR (PDAS1) and Patient-Based Disease Activity Score Without ESR (PDAS2), and Mean Overall Index for Rheumatoid Arthritis (MOI-RA). Arthritis Care Res (Hoboken). 2011;63(suppl 11):S14-S36. 44. Bentley MJ, Reed GW. Simplified composite disease activity measures in rheumatoid arthritis: should they be used in standard care? Clin Exp Rheumatol. 2008;26(2):358-366. 45. Kurtzke JF. Disability rating scales in multiple sclerosis. Ann N Y Acad Sci. 1984;436:347-360. 46. Burri E, Beglinger C, Lehmann FS. Monitoring of therapy for inflammatory bowel disease. Digestion. 2012;86(suppl 1):1-5. 47. Goldman DP, Joyce GF, Zheng Y. Prescription drug cost sharing: associations with medication and medical utilization and spending and health. JAMA. 2007;298(1):61-69. 48. O’Dell JR, Curtis JR, Mikuls TR, et al; TEAR Trial Investigators. Validation of the methotrexate-first strategy in patients with early, poor-prognosis rheumatoid arthritis: results from a two-year randomized, double-blind trial. Arthritis Rheum. 2013;65(8):1985-1994. 49. The Zitter Group. The Managed Care Oncology Index. Summer 2011. Data on file at The Zitter Group. 50. Holcombe D. Oncology management programs for payers and physicians: evaluating current models and diagnosing successful strategies for payers and physicians. J Oncol Pract. 2011;7(3 suppl):e46s-e49s. 51. Danielson E, Demartino J, Mullen JA. Managed care & medical oncology: the focus is on value. J Natl Compr Canc Netw. 2010;8(suppl 7):S28-S37. 52. Fendrick AM, Smith DG, Chernew ME. Applying value-based insurance design to low-value health services. Health Aff (Millwood). 2010;29(11):2017-2021. 53. Greenapple R. Trends in biologic therapies for rheumatoid arthritis: results from a survey of payers and providers. Am Health Drug Benefits. 2012;5(2):83-92. www.reimbursementintelligence. com/wp-content/uploads/2012/05/Trends-in-Biologic-Therapies-for-Rheumatoid-Arthritis-Resultsfrom-a-Survey-of-Payers-and-Providers.pdf. Accesssed January 23, 2014. 54. Goldberg EL, DeKoven M, Schabert VF, Coyle K. Patient medication adherence: the forgotten aspect of biologics. Biotechnol Healthc. 2009;6(2):39-42. 55. Brixner DI, Oderda G. It is important to distinguish CER from patient-centered outcomes research. Introduction. J Manag Care Pharm. 2012;18(4 suppl A):S3-S4. 56. Institute of Medicine of the National Academies. Initial National Priorities for Comparative Effectiveness Research. Washington, DC: The National Academies Press; 2009. www.iom.edu/~/ media/Files/Report%20Files/2009/ComparativeEffectivenessResearchPriorities/CER%20 report%20brief%2008-13-09.ashx. Accessed January 23, 2013.

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