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

June 2014 VOL 3 • NO 3

www.ValueBasedRheumatology.com

Subcutaneous Methotrexate More Effective Than Oral Administration By E. K. Charles

the Rheumatology nurse™

The Impact of Patient Education on Disease Outcomes By Deanna L. Owens, RN, MSN Director of Infusion & Clinical Services, Low Country Rheumatology, Charleston, SC; and Historian, Rheumatology Nurses Society

atients with rheumatic, immune- mediated, inflammatory diseases require extensive and ongoing assessments of their disease state in response to treatment, providing opportunities for nurse-patient education. Evolution of healthcare has led from treatment on an acute-care basis to patients receiving comprehensive

care of their chronic condition in a specialized clinic. The growth of rheumatology as a specialty led to the recent publication of Rheumatology Nursing: Scope and Standards of Practice in developed by the Rheumatology Nurses Society (RNS).1 The rheumatology registered nurse provides individualized care Continued on page 18

dult patients with rheumatoid arthritis (RA) may benefit from subcutaneous methotrexate (MTX) compared with oral

administration of the drug, recent study findings suggest (Schiff MH, et al. Ann Rheum Dis. April 2014. Epub ahead of print).

Continued on page 20

Hyperuricemia May Be a Marker for Cardiovascular Risk in Patients with Gout By E. K. Charles

revious research suggests that gouty arthritis (GA) is associated with an increased risk for certain disorders, such as cardiovascular (CV)

disease. Inger L. Meek, MD, and colleagues recently reported that hyperuricemia was associated with a 3.1-fold hazard of first CV event in patients

Continued on page 8

Pathway of Care Algorithms Feasible in RA And other news from ISPOR 2014 Montreal, Quebec—The healthcare costs associated with rheumatoid arthritis (RA) have been a growing cause of concern because of the chronic aspect of the disease, treatment costs, and variability in patterns of care, according to researchers. To address these costs, Bruce A. Feinberg, DO, Vice President and Chief Medical Officer, Cardinal Health Specialty Solutions,

Continued on page 9

inside VALUE PROPOSITIONS. . . . . . . . . . . Duloxetine Cost-Effective in Osteoarthritis Personalized Medicine in Rheumatology™. . . . . . . . . . . . . . . . . . . . . . Gene Expression Profiling Shows Potential in RA PSORIATIC ARTHRITIS. . . . . . . . . . . Diagnostic Codes Valid for Psoriatic Arthritis, Psoriasis OSTEOPOROSIS. . . . . . . . . . . . . . . . . . . . . FRAX Cost-Effective in Women ≥60 Years

Dublin, OH, and colleagues evaluated pathway programs as a way to reduce cost variability and improve the quality and cost of care. “High-level pathway program adoption suggests feasibility of this approach,” they found (Feinberg BA, et al. Rheumatoid arthritis pathway program impact on patterns of care. 2014. Poster PSH 170). “Opportunity exists

6 7

IN THE LITERATURE . . . . . . . . . . . 17 Patients with RA Tend to Accept Health State LUPUS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Neuropathy in Patients with Lupus Often Involves Small-Fiber Neuropathies

RHEUMATOID ARTHRITIS . . . . 21 Is a New Nomenclature for Classifying DMARDs Needed?

OSTEOARTHRITIS. . . . . . . . . . . . . . . 24 Experts Highlight Trends in Pain, Care in Different Patient Demographics

NOW

APPROVED!

First oral treatment FDA-approved for adults with active psoriatic arthritis Please see Important Safety Information on the adjacent page.

INDICATION Otezla® (apremilast) is indicated for the treatment of adult patients with active psoriatic arthritis.

IMPORTANT SAFETY INFORMATION Otezla is contraindicated in patients with hypersensitivity to apremilast or to components in its formulation. Depression was reported by patients taking Otezla, including serious depression. Some patients discontinued treatment due to depression. Weigh the risks and benefits of treatment with Otezla for patients with a history of depression and/or suicidal thoughts/behavior, and in patients who develop such symptoms while on Otezla. Weight loss was reported in patients taking Otezla. Monitor body weight regularly. Concomitant use of Otezla with CYP450 enzyme inducers (eg, rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended. The most common adverse reactions (≥5%) in clinical trials, and those most frequently leading to treatment discontinuation, were diarrhea, nausea, and headache. Otezla is Pregnancy Category C; it has not been studied in pregnant women. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. Caution should be exercised when Otezla is administered to a nursing woman. Otezla dosage should be reduced in patients with severe renal impairment (creatinine clearance less than 30 mL/min); for details, see Dosage and Administration, Section 2, in the Full Prescribing Information. Please see Brief Summary of Full Prescribing Information on the following page.

Get the latest news at www.otezla.com

Rx Only OTEZLA® (apremilast) tablets, for oral use The following is a Brief Summary of the Prescribing Information; see Full Prescribing Information for complete product information. INDICATIONS AND USAGE OTEZLA® (apremilast) is indicated for the treatment of adult patients with active psoriatic arthritis. CONTRAINDICATIONS OTEZLA is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients in the formulation [see Adverse Reactions (6.1)]. WARNINGS AND PRECAUTIONS Depression: Treatment with OTEZLA is associated with an increase in adverse reactions of depression. During the 0 to 16 weeks placebo-controlled period of the 3 controlled clinical trials, 1.0% (10/998) of patients treated with OTEZLA reported depression or depressed mood compared to 0.8% (4/495) treated with placebo. During the clinical trials, 0.3% (4/1441) of patients treated with OTEZLA discontinued treatment due to depression or depressed mood compared with none in placebo treated patients (0/495). Depression was reported as serious in 0.2% (3/1441) of patients exposed to OTEZLA, compared to none in placebo treated patients (0/495). Instances of suicidal ideation and behavior have been observed in 0.2% (3/1441) of patients while receiving OTEZLA, compared to none in placebo treated patients (0/495). In the clinical trials, two patients who received placebo committed suicide compared to none in OTEZLA treated patients. Before using OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior prescribers should carefully weigh the risks and benefits of treatment with OTEZLA in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with OTEZLA if such events occur. Weight Decrease: During the controlled period of the studies, weight decrease between 5-10% of body weight was reported in 10% (49/497) of patients treated with OTEZLA 30 mg twice daily compared to 3.3% (16/495) treated with placebo [see Adverse Reactions (6.1)]. Patients treated with OTEZLA should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of OTEZLA should be considered. Drug Interactions: Co-administration of strong cytochrome P450 enzyme inducer, rifampin, resulted in a reduction of systemic exposure of apremilast, which may result in a loss of efficacy of OTEZLA. Therefore, the use of cytochrome P450 enzyme inducers (e.g. rifampin, phenobarbital, carbamazepine, phenytoin) with OTEZLA is not recommended. [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. ADVERSE REACTIONS Clinical Trials Experience in Psoriatic Arthritis: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The majority of the most common adverse reactions presented in Table 2 occurred within the first two weeks of treatment and tended to resolve over time with continued dosing. Diarrhea, headache, and nausea were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for patients taking OTEZLA were nausea (1.8%), diarrhea (1.8%), and headache (1.2%). The proportion of patients with psoriatic arthritis who discontinued treatment due to any adverse reaction was 4.6% for patients taking OTEZLA 30 mg twice daily and 1.2% for placebo-treated patients.

Table 2: Adverse Reactions Reported in ≥ 2% of Patients on OTEZLA 30 mg Twice Daily and ≥ 1% Than That Observed in Patients on Placebo For Up To Day 112 ( Week 16) Placebo

Preferred Term

OTEZLA 30 mg BID

Day 1 to 5 Day 6 to Day 112 Day 1 to 5 Day 6 to Day 112 (N=495) (N=490) (N=497) (N=493) n (%)c n (%) n (%) n (%)

Diarrhea a

6 (1.2)

8 (1.6)

46 (9.3)

38 (7.7)

Nauseaa

7 (1.4)

15 (3.1)

37 (7.4)

44 (8.9)

Headachea

9 (1.8)

11 (2.2)

24 (4.8)

29 (5.9)

Upper respiratory tract infectionb

3 (0.6)

9 (1.8)

3 (0.6)

19 (3.9)

Vomitinga

2 (0.4)

4 (0.8)

16 (3.2)

Nasopharyngitisb

1 (0.2)

8 (1.6)

1 (0.2)

13 (2.6)

Abdominal pain upperb

0 (0.0)

1 (0.2)

3 (0.6)

10 (2.0)

Of the reported gastrointestinal adverse reactions, 1 subject experienced a serious adverse reaction of nausea and vomiting in OTEZLA 30 mg twice daily; 1 subject treated with OTEZLA 20 mg twice daily experienced a serious adverse reaction of diarrhea; 1 patient treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction of headache. b Of the reported adverse drug reactions none were serious. c n (%) indicates number of patients and percent.

Other adverse reactions reported in patients on OTEZLA were hypersensitivity, weight decrease, frequent bowel movement, gastroesophageal reflux disease, dyspepsia, decreased appetite*, migraine, cough, and rash. *1 patient treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction. DRUG INTERACTIONS Strong CYP 450 Inducers: Apremilast exposure is decreased when OTEZLA is co-administered with strong CYP450 inducers (such as rifampin) and may result in loss of efficacy [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C : OTEZLA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to OTEZLA during pregnancy. Information about the registry can be obtained by calling 1-877-311-8972. Nursing Mothers: It is not known whether OTEZLA or its metabolites are present in human milk. Because many drugs are present in human milk, caution should be exercised when OTEZLA is administered to a nursing woman. Pediatric use: The safety and effectiveness of OTEZLA in pediatric patients less than 18 years of age have not been established. Geriatric use: Of the 1493 patients who enrolled in Studies PsA-1, PsA-2, and PsA-3 a total of 146 psoriatic arthritis patients were 65 years of age and older, including 19 patients 75 years and older. No overall differences were observed in the safety profile of elderly patients ≥ 65 years of age and younger adult patients < 65 years of age in the clinical studies. Renal Impairment: OTEZLA pharmacokinetics were not characterized in subjects with mild (creatinine clearance of 60-89 mL per minute estimated by the Cockroft– Gault equation) or moderate (creatinine clearance of 30-59 mL per minute estimated by the Cockroft–Gault equation) renal impairment. The dose of OTEZLA should be reduced to 30 mg once daily in patients with severe renal impairment (creatinine clearance of less than 30 mL per minute estimated by the Cockroft– Gault equation) [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. Hepatic Impairment: Apremilast pharmacokinetics were characterized in subjects with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment. No dose adjustment is necessary in these patients. OVERDOSAGE In case of overdose, patients should seek immediate medical help. Patients should be managed by symptomatic and supportive care should there be an overdose. Manufactured for: Celgene Corporation, Summit, NJ 07901 OTEZLA® is a registered trademarks of Celgene Corporation. Pat. www.celgene.com ©2014 Celgene Corporation, All Rights Reserved.

OTZPBS.001 03/14

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 Editors Lara J. Lorton Lilly Ostroksky 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 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 Manager Jini Gopalaswamy Project Coordinators Deanna Martinez Jackie Luma IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski Administrative Coordinator Stephanie Ramadan 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 Health care 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 pho tocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Print ed 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 adver tisement 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.

VOL. 3

NO. 3

VALUE PROPOSITIONS

IN THE LITERATURE

Back pain and arthritis common Duloxetine cost-effective in osteoarthritis More…

Lack of control and rheumatoid arthritis linked to poor sleep More…

Personalized Medicine in Rheumatology™

LUPUS Neuropathies in patients with lupus commonly small-fiber neuropathies

Gene expression profiling shows potential in personalized medicine for RA

RHEUMATOID ARTHRITIS

Healthcare register diagnostic codes valid for psoriatic arthritis, psoriasis

Predicting tocilizumab response possible in patients with rheumatoid arthritis More…

GOUT

OSTEOARTHRITIS

PSORIATIC ARTHRITIS

Hyaluronic acid injection may be beneficial in delaying total knee replacement More…

Hyperuricemia may be a marker for cardiovascular risk in patients with gout

OSTEOPOROSIS Nurse intervention improves hospital-based osteoporosis care in elderly patients after a fall More…

FIBROMYALGIA Analysis of patients with fibromyalgia reveal 2 subclusters with pain and fatigue More…

DRUG UPDATE Otezla (apremilast), an oral PDE-4 inhibitor, receives FDA approval for the treatment of patients with active psoriatic arthritis

RHEUMATOLOGY UPDATE Ceasing all rheumatoid arthritis medications not optimal in patients trying to conceive

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.

JUNE 2014

www.ValueBasedRheumatology.com

Value Propositions European Data Show Biosimilars Cost-Effective

The introduction of a biosimilar of infliximab in several European countries was found to be cost-effective, research indicates. To assess the estimated budget impact of introducing a biosimilar of infliximab to patients with rheumatoid arthritis, investigators evaluated 6 Eastern European countries over the course of 3 years, including Bulgaria, the Czech Republic, Hungary, Poland, Romania, and Slovakia. Two scenarios were considered: (1) interchanging infliximab with its biosimilar was not allowed and only patients who start new biological therapy were allowed to use the infliximab biosimilar; (2) interchanging infliximab with its biosimilar was allowed and 80% of the patients treated with infliximab were interchanged to its biosimilar. In the reference scenario, no biosimilar infliximab was available. The net savings associated with the first and second scenarios were approximately 15.3 million euros and 20.8 million euros, respectively, compared with the reference scenario in which no biosimilars were available. The authors noted that if budget-savings were spent on reimbursement of additional biosimilar infliximab treatment, approximately 1200 or 1800 more patients could be treated in the 6 countries within 3 years in the 2 biosimilar scenarios, respectively. Brodsky V, et al. Eur J Health Econ. 2014 May 16 (Epub ahead of print)

Triple Therapy with DMARDs and Glucocorticosteroids Effective in Early Treatment of RA

Using data from the 2-year Combination Anti-Rheumatic Drugs in Early Rheumatoid Arthritis (CARDERA) trial, investigators found that intensive treatment of rheumatoid arthritis (RA) with 2 disease-modifying antirheumatic drugs (DMARDs) and short-term glucocorticosteroids was both clinically effective and cost-effective. The CARDERA study included 467 patients with active RA for less than 24 months; all of the patients received methotrexate. Overall, half of the patients received step-down prednisolone and half received ciclosporin in a placebo-controlled factorial trial. Patient-level data from a UK health service perspective and 2011-2102 costs were used to calculate differences in mean costs. The investigators found that the 2-year costs for each treatment strategy were negligible in all patient groups. Methotrexate/ciclosporin and triple therapy yielded the lowest drug costs and methotrexate/prednisolone and triple therapy had the lowest hospital costs. Triple therapy was the least costly and most effective. “Intensive treatment of early rheumatoid arthritis with triple (2 DMARDs and short-term glucocorticoids) is both clinically effective and cost effective,” the study authors found. Wailoo A, et al. Rheumatology (Oxford). 2014 April 25 (Epub ahead of print)

Duloxetine Cost-Effective in Osteoarthritis

A cohort of 55-year-old patients with osteoarthritis demonstrated that treatment with duloxetine was cost-effective, especially in patients who were older and patients at greater risk of adverse events. In a Quebec societal perspective study, the investigators sought to assess the cost-effectiveness of duloxetine compared with other oral post acetaminophen therapies for osteoarthritis in a cohort of patients with 12-month treatment followed by treatment from a selection of postdiscontinuation oral therapies until death. The investigators performed a cost-utility analysis and enhanced the Markov model from the 2008 osteoarthritis guidelines of the National Institute for Health and Care Excellence; the model was extended to include opioid and antidepressant comparators. In particular, comparators included duloxetine, celecoxib, diclofenac, naproxen, hydromorphone, and extended-release oxycodone. Adverse events associated with nonsteroidal anti-inflammatory drugs included gastrointestinal and cardiovascular events, as well as fractures,

value-based CARE in Rheumatology

JUNE 2014

opioid abuse, and constipation. The researchers found that naproxen and oxycodone were the least and most expensive treatments, respectively. Therapy with duloxetine yielded the highest number of quality-adjusted life-years (incremental cost-effectiveness ratio, $36,291) compared with celecoxib. Compared with celecoxib, duloxetine therapy yielded an incremental cost-effectiveness ratio of $15,619 (Canadian) in a subgroup analysis of patients at high risk of nonsteroidal anti-inflammatory drug-related adverse events and $20,463 (Canadian) in patients aged >65 years. Wielage RC et al. Arthritis Care Res (Hoboken). 2014;66:702-708

Ultrasonography Has Value in Synovitis-RA Diagnosis

To evaluate the value of ultrasonography for diagnosing synovitis associated with rheumatoid arthritis (RA), investigators looked at the bilateral metacarpophalangeal, proximal interphalangeal II-V, and the wrist joints of 46 patients with RA and 35 healthy individuals. In 20 of the 46 patients, magnetic resonance imaging was also used on wrists with more severely affected sides; results between magnetic resonance imaging and ultrasonography were compared. Overall, both magnetic resonance imaging and ultrasonography yielded consistent results in detecting synovitis in patients with RA. Ultrasonography sensitivity and specificity were 82.8% and 85.8%, when the cutoff for the bilateral metacarpophalangeal joints was 2.5 mm, and 98.2% and 84.8%, when the cutoff for the proximal interphalangeal joints was 2.6 mm. The investigators also observed that the average synovial membrane thickness was positively related to several biochemical biomarkers, including erythrocyte sedimentation rate, C-reactive protein, anticyclic citrullinated peptide antibody, and Disease Activity Index of 28 joints; however, it was poorly related to rheumatoid factor immunoglobulin (Ig) A, rheumatoid factor IgM, and rheumatoid factor IgG. “Ultrasonography is a valid method for diagnosing early-stage synovitis, with high-accuracy cut-offs for bilateral metacarpophalangeal, proximal interphalangeal, and wrist joint set at 2.5, 2.6, and 5.2 mm,” the investigators found. The mean synovial thicknesses of the bilateral wrist can be used to assess disease activity, they added. Xiao H, et al. Int J Rheum Dis. 2014 May 26 (Epub ahead of print)

Back Pain and Arthritis Common and Costly

Data suggest that back pain and arthritis, including osteoarthritis and rheumatoid arthritis, are the most common conditions requiring rehabilitation in the United States. As part of this study, the investigators performed a comprehensive bibliographic search using MEDLINE, Google Scholar, and UpToDate (June 2013) to determine the relative incidence, prevalence costs, and impact on disability of 8 common conditions treated by rehabilitation professionals. After screening the searches, 2 review authors were found, including 82 articles on conditions such as stroke, spinal cord injury, traumatic brain injury, multiple sclerosis, osteoarthritis, rheumatoid arthritis, limb loss, and back pain. Overall, they found that back pain and osteoarthritis/rheumatoid arthritis were the most common and costly conditions, affecting >100 million individuals, with a cost of $200 billion annually. Traumatic brain injury, they added, was less common than arthritis and back pain, and had significant per capita direct and indirect costs. Stroke was found to be the second most common disability because of its impact on functional limitations. “Of the common rehabilitation diagnoses we studied, musculoskeletal conditions such as back pain and arthritis have the most impact on the health care system because of their high prevalence and impact on disability,” the study authors concluded. Ma VY, et al. Arch Phys Med Rehabil. 2014;95(5):986-995

VOL. 3

NO. 3

Personalized Medicine in Rheumatology

™

Gene Expression Profiling Shows Potential in Personalized Medicine for RA By E. K. Charles

recent review evaluating currently available data on rheumatoid arthritis (RA) diagnosis, prognosis, and prediction of response to therapy, highlights the potential of gene expression profiling in understanding RA biology, patient management, and personalized care (Burska AN, et al. Pharmacogenomics J. 2014;14:93-106). Several genes were consistently associated with all diagnostics, indicating inflammation or autoimmunity rather than disease specificity, according to the authors. Other genes were associated with specific events in RA. The research reinforced the need for harmonization if gene expression is to become a useful clinical tool in personalized medicine for the patient’s benefit. However, the study authors acknowledged that adoption of gene expression tests into daily clinical practice will take time. “The rheumatology community is therefore facing a challenge to pool together the necessary resources and to use the available information already collected to reach appropriate conclusions and proceed with further validation, which is necessary to reach the next level,” according to Agata N. Burska, PhD, Leeds Institute of Rheumatic and Musculoskeletal Medicine, and Leeds Musculoskeletal Biomedical Research Unit, the University of Leeds, United Kingdom, and colleagues. Indicators for Diagnosis and Prognosis Burska and colleagues began their

review focusing on the use of gene expression as a tool to investigate pathogenesis in RA. In particular, they explain that genome-wide expression analysis has shown gene signatures that differentiate RA from osteoarthritis.

The rheumatology community is facing a challenge to pool together the necessary resources and to use the available information to reach appropriate conclusions and proceed with further validation needed to reach the next level. —Agata N. Burska, PhD, and colleagues The heterogeneity of RA has been associated with disease progression; evident differences have been observed in gene expression between early and late RA synovial tissue samples, indicating different pathophysiological mechanisms during the course of the disease. Furthermore, research has identified 3 different types of synovial tissue based on gene expression profiling: T- and B-cells, antigen-presenting cells, and major histocompatibility complex gene sig-

nature; stromal genes; and tissue with mixed information. Burska and colleagues then discussed diagnostic, prognostic, and preclinical signatures of RA. Early diagnosis and treatment of the disease is paramount, they emphasized, and recent changes to the EULAR (European League Against Rheumatism) diagnostic criteria stress the need for other diagnostic biomarkers for anti citrullinated protein antibody-negative disease. Genes—primarily those differentially expressed in T-cell synapse—have been identified whose expression is different in early inflammatory arthritis biopsies versus reactive arthritis. Other genes identified were apoptosis-related genes and calcium-signaling genes. “Recognition of the preclinical phase of RA has initiated a whole new field of research aimed at the discovery of predictive biomarkers for the development of arthritis,” the study authors explained. In particular, data suggest that systemic autoimmunity, such as the presence of anticitrullinated protein antibodies, occurs before disease onset and synovitis abnormalities, which are seen at the time of symptom onset. Other mechanisms that may suppress disease development and counter autoimmunity may exist, they noted. Researchers have also focused on identifying prognostic markers associated with disease progression. In one study, gene expression signatures were associated with severe disease at baseline and after 36 months of

follow-up in the peripheral blood cells of a population of patients with early RA; however, the study authors were not able to identify a clear expression profile (Reynolds RJ, et al. Rheumatol Int. 2012;33:129-137). The Value of Gene Expression Signatures The review authors went on to discuss gene expression signatures as predictors of treatment response to various therapies, including methotrexate, infliximab, rituximab, anakinra, and tocilizumab. “Not surprisingly, maybe gene expression signatures for a given clinical end point published to date do not always overlap and have not always been re-validated,” according to Burska and colleagues. Gene expression signatures for progression from the preclinical phase of RA and the prediction of response to rituximab were the only exceptions, they noted. Measuring microRNA in serum samples and cells is another area of research, although no study to date has investigated whether altered microRNA expression is associated with response to therapy in RA patients. Although there are ethical issues associated with the development of gene expression signature in RA, the identifiable data may be less sensitive because mRNA gene expression analysis is functionally close to any other biochemical biomarker or dynamic phenotype and is not a permanently affixed label to its carrier, according to the study authors. n

Psoriatic Arthritis

Healthcare Register Diagnostics Codes Valid for Psoriatic Arthritis, Psoriasis By E. K. Charles

imited data exist on the validity of diagnostic codes for psoriasis and psoriatic arthritis (PsA). A group of researcher from Sweden recently evaluated the validity of the International Classification of Diseases, Tenth Revision Systematisk Förtecking (ICD-10-SE) for both disorders in the Skåne Healthcare Register (SHR), and VOL. 3

NO. 3

found that SHR was a valid healthcare register for studies on psoriasis and PsA. The proportion of the diagnostic codes that could be verified varied with the frequency of diagnostic codes of care, the investigators noted (Löfvendahl S, et al. PLoS One. 2014 May 29. Epub ahead of print). The SHR includes continuously col-

lected data on all primary care and specialized outpatient and inpatient care of individuals living in the Skåne region in Sweden. The register also contains information on the patient’s age, sex, healthcare provider, date of visit, and diagnostic codes according to ICD-10. Using data from the register, the JUNE 2014

investigators identified patients with ≥1 physician consultations from January 2005 to December 2010, and whose ICD-10 codes indicated psoriasis; patients with PsA were also identified as part of the analysis. The medical rec ords of 100 randomly selected cases were reviewed to validate ICD-10 diagnostic codes. Prevalence estimates

Continued on page 8

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Gout

Hyperuricemia May Be a Marker for... with GA (Meek IL, et al. BMC Musculoskelet Disord. 2014;15:174). They conducted a prospective multivariate analysis to determine whether serum uric acid levels were a marker of future CV-event risk in patients with rheumatic diseases. Using data from the Arthritis Center Twente CardioVascular Disease database, which include both existing and new patients screened for traditional CV risk factors and followed for the occurrence of CV events, the investigators performed a cross-sectional analysis of the relationship between tertiles of serum uric acid and baseline traditional CV risk parameters. Systolic blood pressure, total cholesterol/ high-density lipoprotein ratio, glycated hemoglobin, body mass index, and first CV events were the traditional CV risk parameters evaluated. A cohort of 172 patients with GA, 480 patients with rheumatoid arthritis, and 206 patients with osteoarthritis, was included in the analysis. Baseline characteristics predominantly consisted of late middle-aged patients, women with rheumatoid arthritis and osteoarthritis, and men with GA. The study authors observed that previous CV events were significantly more frequent in patients with GA than in patients without GA. In addition, high-sensitivity C-reactive protein levels—a measure of systemic inflammation—were sig nificantly lower in patients with osteoarthritis. Baseline traditional CV risk parameters, including male sex,

systolic blood pressure, total cholesterol/high-density lipoprotein ratio, and body mass index, were significantly less favorable in patients with GA. Systolic blood pressure, total cholesterol/high-density lipoprotein ratio, and body mass index correlated with serum uric acid levels in patients

“The question remains if serum uric acid is only a potentially useful marker to improve the selection of high CV risk individuals for CV risk management, or if it casually related to the progression of CV disease.” —Inger L. Meek, MD, and colleagues with osteoarthritis and rheumatoid arthritis, and glycated hemoglobin in patients with osteoarthritis only. “In GA no association between serum uric acid and individual CV risk parameters was observed,” the study authors explained. Seventy-three percent of patients with gout used uric acid–lowering therapy (ULT); mean serum uric acid was significantly lower in patients using ULT. Prospective analysis indicated the occurrence of 64 CV events after a mean of 36 months. “In female patients, the frequency of CV events was unexpectedly high,” Dr Meek and col-

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leagues noted. In particular, 28% of women with GA versus 8.4% of the men had a CV event, 5.7% of women with non-GA compared with 9.7% of men. After taking into account confounders such as ULT, antihypertensive therapy, and statin therapy, the investigators found that the highest tertile of serum uric acid (≥0.34 mmol/L; hazard ratio [HR], 3.896) and N-terminal pro-brain natriuretic peptide level (HR, 1.012) were independent predictors of CV events in patients with non-GA versus age and glycated hemoglobin in patients with GA (HRs, 1.073 and 3.273, respectively). Both patients with GA and non-GA and serum uric acid levels ≥0.034 mmol/L had a significantly increased risk for first CV events compared with patients with non-GA and serum uric acid levels <0.27. The associations between individual traditional CV parameters such as systolic blood pressure and serum lipoprotein appeared to be relatively independent from chronic inflammation, the study authors noted in their discussion. In addition, they observed that although the frequency of first CV events was high in women with GA, it could be explained by the 10year age gap in that group of patients compared with the other patient groups. “The question remains if serum uric acid is only a potentially useful marker to improve the selection of high CV risk individuals for CV risk management, or if it casually related to the

at a glance ➤ Baseline characteristics predominantly consisted of late middle-aged patients, women with rheumatoid arthritis and osteoarthritis, and men with GA ➤ Previous CV events were significantly more frequent in patients with GA than in patients without GA ➤ Sixty-four CV events occurred in a median follow-up period of 36 months ➤ Increasing serum uric acid levels was associated with increased CV risk in patients with non-GA; CV risk was independent of serum uric acid levels in patients with GA

progression of CV disease,” Dr Meek and colleagues concluded. Further research is needed to determine the predictive value of pre-ULT uric acid levels for the occurrence of CV events in patients with GA. In addition, clarification is needed regarding the role of uric acid and xantine oxidase in pathophysiologic pathways that cause CV events in GA and hyperuricemia. The authors also noted that it is important to determine the optimal risk intervention strategy in high-CV risk patients, characterized by an upper range in their uric acid level. n

Psoriatic Arthritis

Healthcare Register Diagnostics Codes... of physician-diagnosed psoriasis and PsA were also performed. In total, 16,171 patients with psoriasis and/or PsA met criteria for inclusion. The investigators identified 13,185 patients with at least 1 diagnostic code consistent with psoriasis and 2986 patients with PsA diagnostic codes. Of the cases with psoriasis alone, nearly half consisted of women (49.2%), and the mean age was slightly lower in patients with psoriasis compared with patients with psoriasis and PsA. The most common diagnostic codes used were L40.9 “psoriasis, unspecified” (80%) and L40.1 “psoriasis vulgaris” (34.6%) in patients with psoriasis. In addition, 25.5% of the patients

received a diagnostic code for psoriasis on a single occasion in primary care and 11.2% on several occasions; 63.4% of the cases received a psoriasis diagnostic code at least once in specialized care. The validation assessment demonstrated that 81% of the 97 cases reviewed were registered with the correct diagnostic code in the SHR database. The positive predictive value of an ICD-10 code for psoriasis was between 81% and 100%, the investigators reported. In psoriasis with PsA, the most commonly used diagnostic code was L40.5 “arthropathic psoriasis” (98.7%). Overall, 4.6% of the cases received 1 diagnostic code for PsA on a single

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occasion, and 3.8% of cases received the diagnostic code on several occasions in primary care; 91.6% of the cases received a PsA code at least once in specialized care. The validation study indicated that 63% of the 93 cases reviewed were registered with the correct diagnostic code in the SHR database. The positive predictive value of an ICD-10 PsA diagnostic code was between 63% and 92%. The postvalidation prevalence was 1.23% for psoriasis, with or without PsA; 1.02% for psoriasis alone, and 0.21% for psoriasis with PsA. The postvalidation prevalence of PsA was 17.3% in the entire cohort. The number of confirmed diagnoses varied with the

level of care and how frequently the code appeared for the same patients, the study authors noted. The prevalence of PsA in the psoriasis population was approximately 18.5%. Data presented in this study were similar to previously published studies, according to the investigators. In particular, results from a UK study by Gelfand and colleagues found that the prevalence of psoriasis in the general population was 1.5% (Gelfand JM, et al. Arch Dermatol. 2005;141:1537–1541). The prevalence of PsA was similar to another study that reported a prevalence of 0.25% in a sample of the general US population (Gelfand JM, et al. J Am Acad Dermatol. 2005;53:573). n VOL. 3

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conference highlights

Pathway of Care Algorithms... to improve biologic use compliance.” Feinberg and colleagues evaluated the feasibility of a collaborative, evidence-based, consensus-driven RA pathway to determine levels of participation for network rheumatology providers and assess the adoption of an online decision-support tool. Provider compliance to an RA pathway was also evaluated. Together with CareFirst BlueCross BlueShield, Cardinal Health worked with rheumatologists in the CareFirst network to develop a payer-sponsored, collaborative RA pathway program, the investigators explained. Although participation was voluntary, reimbursement enhancements were offered to mitigate the cost of provider adoption and compliance. In addition, a preplanned consensus set the pathway compliance threshold to 70% and 80% for the first and second years, respectively. The RA pathway was created by a steering committee of 12 physicians. Several requirements were used to create it, including obligatory use of a real-time, decisionsupport, and data-capture tool; use of disease-modifying antirheumatic drugs (DMARDs) as first-line treatment for at least 12 weeks before use of a biologic agent; requirement that the dose, schedule, and adjustments for biologic agents follow package label prescribing guidelines; and requirement for a Clinical Disease Activity Index at each physician visit. Overall, 80 physicians from 37 Care First community network practices participated in the study, including 1800 unique patients with RA in the first year. The study authors found that the Clinical Disease Activity Index exceeded 70% of the visits, and

adherence to the pathway was without a consequent increase in the index scores. In addition, compliance to the DMARD rule yielded an 8% reduction in the use of biologic agents. Claims- validated compliance with the package label for the initial infused dose and schedule of the biologic agent increased from 40% to 53%. Evidence-based algorithms do not risk patient outcomes, Feinberg and colleagues found, as this analysis indicated that the use of label-based prescription of DMARDs and biologic agents do not increase the Clinical Disease Activity Index. Productivity Similar in Patients with RA, with and without Previous Anti-TNF Therapy Certolizumab pegol (CZP) improves workplace and household productivity, as well as social participation in patients with RA, with and without previous exposure to anti– tumor necrosis factors (TNF). “Limited data is available for the burden RA places on work and household productivity, comparing patients with and without prior anti-TNF exposure,” Arthur F. Kavanaugh, MD, Division of Rheumatology Allergy and Immunology, University of California, San Diego, and colleagues explained (Kavanaugh A, et al. Effect of tertolizumab pegol on workplace and household productivity in US patients with rheumatoid arthritis with or without prior anti-TNF exposure: results from the PREDICT study. 2014. Poster PMS66). “The data presented here [report], for the first time, the effect of CZP on work and household productivity in patients with prior anti-TNF exposure.”

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As part of the PREDICT trial, the investigators sought to determine the effect of CZP treatment on workplace and household productivity, as well as on social participation in US patients with RA who were and were not exposed to anti-TNF. The trial compared the effect of CZP in this patient population and evaluated Routine Assessment of Patient Index Data 3 (RAPID3) and the investigator-based Clinical Disease Activity Index tools.

Patients who were previously exposed to an anti-TNF therapy had a higher mean disease duration, higher disease activity based on RAPID3, and a greater proportion of the patients were rheumatoid factor positive.

The study design dictated that patients receive a loading dose of 400 mg CZP during weeks 0, 2, and 4 of the trial, followed by 200 mg of CZP every second weeks until week 50. The workplace and household productivity were assessed using the arthritis-specific Work Productivity Survey, which estimates productivity limitations associated with the disease on paid jobs outside of the home, on work within the home, as well as participation in social activities in the preceding month. Among 733 randomized patients,

55.5% were previously exposed to antiTNF; of these patients, 33.3% reported using 1 anti-TNF drug, 17.6% reported using 2 anti-TNF drugs, and 4.5% reported using >2 anti-TNF drugs. Patient demographics and disease characteristics were similar between the study groups, the study authors reported. Overall, patients who were previously exposed to an anti-TNF therapy had a higher mean disease duration, higher disease activity based on RAPID3, and a greater proportion of the patients were rheumatoid factor positive. At the start of the study, 43.5% of the patients were employed outside of the home—38.8% in the group of patients who took anti-TNF drugs and 49.3% in the group of patients who did not take anti-TNF drugs. Because of arthritis in patients with previous exposure to anti-TNF, a higher proportion of patients work disabled, the study investigators noted. In addition, both groups of patients reported high RA disease burden in workplace and household productivity, as well as social participation; the disease burden was slightly higher in patients who were previously exposed to anti-TNF drugs. The study authors observed improvements with CZP in both patients with and without previous anti-TNF exposure. By week 4, employed patients reported reductions in workplace absenteeism, presenteeism, and in the level of RA interference with work productivity; these improvements were sustained through the completion of the study at week 52. Both groups also had substantial improvements in household productivity and social participation. n

Osteoporosis

FRAX Cost-Effective in Women 60 Years and Older with Osteoporosis By Rosemary Frei, MSc Seville, Spain––Is it cost-effective to screen for osteoporosis using the prescreening Fracture Risk Assessment Tool (FRAX) scores in all women 60 years and older? In a presentation at the 2014 European Society for Clinical and Economic Aspects of OsteoporoVOL. 3

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sis meeting, a group of researchers from Belgium and Holland made the case that it is cost-effective. Using a simulation model of women living in the province of Liège, Belgium, the study investigators calculated that the incremental cost-effectiveness ratio

for population-wide screening is €73,050 (approximately $102,000) per quality-adjusted life-year gained. “This is less than the threshold for acceptable cost-effectiveness in the literature of 2 times the gross domestic product,” lead study investigator JUNE 2014

Mickaël Hiligsmann, PhD, Assistant Professor of Health Economics and Health Technology Assessment, Department of Health Services Research, Maastricht University, the Netherlands, told Value-Based Care in Rheumatology. He noted, however, that his Continued on page 10

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Osteoporosis

Nurse Intervention Improves Hospital-Based Osteoporosis Care in Elderly Patients After a Fall By Rosemary Frei, MSc Seville, Spain—A nurse-driven intervention appears to significantly improve osteoporosis care in older adults who present to the hospital after a fall, according to a preliminary study. In the Australian study, a nurse assessed osteoporosis and fracture risk in 30 people who had fallen (Shibu PK, et al. Seville, Spain: World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Disorders; 2014. Poster 132). The nurse liaised with the general physicians regarding further investigations and treatment for the patients, and also provided them with 1-on-1 counseling and other education. Patients’ rates of FRAX (Fracture Risk Assessment Tool) testing, vitamin D testing and use, and dual-energy x-ray absorpitometry (DEXA) scanning were much higher than among patients who had not received these interventions. As a result, lead investigator Pazhvoor Shibu, MD, told Value-Based Care in Rheumatology, they have appointed a nurse to perform these functions

with all patients presenting with fragility fractures to the orthopedic and medical areas.

“[Our] aim is to see if having a dedicated coordinator makes a significant difference in care.” —Pazhvoor Shibu, MD

“[Our] aim is to see if having a dedicated coordinator makes a significant difference in care,” said Dr Shibu, Consultant Geriatrician at the Queen Elizabeth Hospital, Woodville, South Australia, after the presentation of the results at the World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases. Dr Shibu and the other team members focused on people aged ≥65

years who were orthopedic and cardiology inpatients, and falls-clinic outpatients, who presented to the hospital after a fall. They compared 42 people who did not receive the 2-month intervention from the gerontology nurse to the 30 patients who did. The baseline demographics, comorbidities, and other characteristics were similar in both groups. The educational component of the intervention was 1-on-1 counseling and advice on lifestyle and dietary modification to improve bone health. The nurse also gave the patients information about osteoporosis and provided them with easy-to-understand information leaflets and handouts to reinforce the information and education. The FRAX testing rate was 5% in the group that did not receive the intervention and 100% in those who did. In addition, the rate of vitamin D testing increased from <50% to nearly 90%, and use of vitamin D increased

from approximately 60% to 100%. Antiresorptive use improved as well, from approximately 40% to >70%, and DEXA scanning increased from 11.60% to 60% (all parameters, P<.01 for no intervention vs intervention). “It was deemed necessary that the nurse ask patients whether they had an osteoporosis fragility fracture, and if they answered in the affirmative they would be treated as having osteo porosis and DEXA was not required to start treatment,” Dr Shibu noted, as he explained why DEXA testing did not rise to 100%. The osteoporosis diagnosis was conveyed to the general physician in 100% of the cases after the intervention, compared with just 62.8% in patients who did not receive the intervention. In addition, the 2-month postintervention rates of adherence and persistence were very high for drug therapy and vitamin D use. Dairy intake and sun exposure also increased appreciably, according to Dr Shibu. n

FRAX Cost-Effective in Women 60 Years and... Continued from page 9 team was not able to check whether these results hold true in clinical practice because that “would require decades of follow-up to capture the long-term benefits of preventing fractures.”

“This is less than the threshold for acceptable cost-effectiveness in the literature of 2 times the gross domestic product.” —Mickaël Hiligsmann, PhD The team’s model was based on data from 650 Belgian women who were screened for osteoporosis between January 2011 and May 2013 by healthcare personnel working in mobile units. FRAX was assessed in all the women. Bone densitometry was tested in women with a positive FRAX score and treatment with oral bisphosphonates was given for those with T-scores of ≤–2.5. Based on the

sample, researchers estimated that prescreening with the FRAX score has a specificity of 86% and a sensitivity of 71%. Information from administrative health databases in Liège showed that 21.8% of women in the province had a positive FRAX score. Approximately 85% of women with a positive FRAX score had a follow-up bone densitometry and 44.4% of those patients were found to have osteoporosis. Furthermore, 4.9% of women found not to have osteoporosis based on FRAX, had false negatives, and among the 15% of women with a positive FRAX score who did not receive densitometry, 44.4% had osteoporosis. Approximately 13% of those who were not screened, were diagnosed at some point with osteoporosis; this is the same percentage as women who were screened (Hiligsmann M, et al. Rev Med Liege. 2008;63:588-594). The per-person cost was €3.7 for FRAX assessment (approximately $5.16) and €58 for bone densitometry (approximately $80.45). This included the cost of the mobile screening units

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and the salary of the healthcare workers involved in the campaign, plus

To improve the efficiency of the screening strategy, women who have 1 or more clinical risk factors or women aged 65 years and older should be screened. other fixed and variable costs. The Markov microsimulation model yielded an incremental cost-effectiveness ratio of €73,050 per quality-adjusted life-year gained. In addition, the researchers found that cost effectiveness was even greater when generic was used instead of brand-name bisphosphonates, and when there was 100% adherence to treatment and follow-up. The researchers also determined that the screening strategy remained cost-effective even if there was only 70% follow-up among women with a pos-

at a glance ➤ The incremental costeffectiveness ratio for population-wide screening with FRAX is approximately $102,000 per quality-adjusted life-year gained ➤ Cost-effectiveness improved with adherence to treatment and follow-up, and use of generic instead of brand-name bisphosphonates ➤ Screening strategy is most efficient for women who have 1 or more clinical risk factors or women aged 65 years and older

itive FRAX score, or if the cost of FRAX assessment increased by 50%. To improve the efficiency of the screening strategy, the study investigators suggest screening women who have 1 or more clinical risk factors or women aged 65 years and older. n VOL. 3

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Fibromyalgia

Analysis of Patients with Fibromyalgia Reveal 2 Subclusters with Pain and Fatigue By Rosemary Frei, MSc Tampa, FL—Researchers have detected 2 different subclusters of patients with fibromyalgia, according to results presented at the American Pain Society's 2014 Annual Meeting. One group has widespread pain as one of their predominant characteristics and the other subcluster—which is far less common than the first—comprises patients with fatigue as their primary concern (Lukkahatai N, et al. Tampa, FL: American Pain Society; 2014. Abstract 157). Furthermore, patients with fatigue as their primary concern had a stronger relationship between pain intensity and pain interference, as well as between symptom-severity score and mental fatigue compared with patients in the other subcluster. The investigators believe that these findings underline the complexity of fibromyalgia and also point to possible individualization of treatment in the future. “It’s a human experience—it’s not like cancer where you can see the tumor and can treat it right away,” first author Nada Lukkahatai, RN, PhD, told Value-Based Care in Rheumatology. “How are you going to manage the patients who come to you and one day they say ‘the pain is here’ and the next day they say ‘the pain is there and the medication you gave them doesn’t work’? To better manage these patients we try to look for a pattern and then eventually this will enable

“How are you going to manage the patients who come to you and one day they say ‘the pain is here’ and the next day they say ‘the pain is there and the medication you gave them doesn’t work’?” —Nada Lukkahatai, RN, PhD clinicians to individualize treatment accordingly.” Dr Lukkahatai was a postdoctoral fellow at the National Institute of Nursing Research, National Institutes of Health, Bethesda, Maryland, during this study. Now she is an assistant professor in the Physiological Nursing Department at the University of Nevada, Las Vegas. The team analyzed the

initial-visit self-reported questionnaire responses of 120 patients diagnosed with fibromyalgia using the 1990 or 2010 American College of Rheumatology criteria. The study was part of a prospective, longitudinal, observational study from a MedStar Health Research Institute protocol at Georgetown University. Ninety percent of the patients were women and their mean age was 46.3 years. Just under one-third were African American and approximately twothirds were white non-Hispanic. They had a mean of 14.28 tender joints. The study consisted of the construction of a model in which the researchers mapped out the relationships of widespread pain and symptom severity, with pain, cognitive function, daytime sleepiness, fatigue, and psychological status. They also determined the strength of these relationships. The researchers demonstrated 2 distinct subclusters based on fibromyalgia syndrome diagnostic tools, Widespread Pain Index and Symptom Severity Score. One comprised 94 (78%) patients in whom widespread pain predominated, along with unrefreshed waking and somatic symptoms. In the other group, which consisted of 26 patients, fatigue and cognitive dysfunction were particularly strong. Overall, the symptoms of patients in the first subcluster were more intense than in the second. The investigators also detected dif-

at a glance ➤ Patients with fibromyalgia predominantly report pain as their primary concern ➤ Investigators observed that in another group of patients, fatigue is the primary concern; these patients had a stronger relationship between pain intensity and pain interference ➤ These data may underline the complexity of fibromyalgia and the need for individualization of treatment, according to the authors

ferences between the 2 groups in the strength of associations between different categories of symptoms. For example, the relationship between pain intensity and pain interference was stronger in the fatigue subcluster than in the widespread-pain subcluster, while the association between ca tastrophizing and total fatigue was stronger in the widespread-pain subcluster. “We intend to do a longitudinal study with a larger number of patients to see if the groupings remain the same or change over time and whether we can implement any interventions targeted at each of these subclusters,” said Dr Lukkahatai. n

In the Literature Patients with Rheumatoid Arthritis Tend to Accept Their Health State After a Certain Point

Data from a multicenter cross-sectional survey suggest that patients with rheumatoid arthritis consider less than perfect health states acceptable after a certain age. “Some health problems are considered by many individuals as a ‘normal’ part of ageing,” the study authors acknowledged (Péntek M, et al. Eur J Health Econ. 2014. Epub ahead of print). To assess whether patients with rheumatoid arthritis perceive that different types and levels of health losses are acceptable beyond a certain age, VOL. 3

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the investigators evaluated domain-specific health states at the time the first biological therapy was initiated. Domains evaluated included the EQ-5D and the Health Assessment Questionnaire Disability Index. Among the 77 patients with rheumatoid arthritis who completed the questionnaire, 86% were women, the mean age was 50.3 years, and the disease duration was 9.1 years. Most of the patients reported that ≥70 years was an acceptable age to have some health problems. In particular, EQ-5D: selfcare––42%; pain/discomfort––34%; usual activities––33%; mobility––33%; and anxiety and depression––27%. Ages ranging between 30 years and 40

years were considered unacceptable ages for these health problems. In addition, respondents indicated that severe health problems were for the most part considered never acceptable (57%-69%); the “usual activities” domain was an exception and was acceptable from age 80 years by 50.6% of the respondents. The study authors noted that 77% to 96% of the respondents were younger than what they indicated as the acceptability age limit.

Lack of Control in Rheumatoid Arthritis Linked to Poor Sleep

Patients with rheumatoid arthritis who do not have a good handle on JUNE 2014

their disease may have poor sleep, research suggests (Westhovens R, et al. J Rheumatol. 2014;41:31-40). As part of a cross-sectional, observational, multicenter study, investigators evaluated sleep problems, and potential links between sleep and disease activity in Belgian patients with established rheumatoid arthritis. Sleep quality was assessed using the Athens Insomnia Scale (AIS) and the Pittsburgh Sleep Quality Index (PSQI), and daytime sleepiness was assessed using the Epworth Sleepiness Scale. The authors performed analyses on the total population and on patients stratified by disease activity status. Overall, 305 patients were included Continued on page 18

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The Rheumatology Nurse

™

through in-depth health assessments, medication monitoring, and patient education related to rheumatic disease. Treatment for rheumatic disease is aimed at managing symptoms to prevent disease progression and damage while improving the patient’s overall quality of life. By identifying the needs of an individual patient, education from a rheumatology registered nurse increases patient compliance and improves disease outcomes. Patient Education Leads to Compliance With compliance in mind, developing a nursing plan focused on patients’ understanding of their disease is critical to foster participation and facilitate adherence to their treatment plan. It is necessary to properly assess the multiple learning needs of each individual to accurately balance what the patient wants to know versus what they need to know. Patients are typically concerned with treatment options, medication side effects, and quality of life, while healthcare providers often concentrate on safety, prevention of disease progression, and treatment plan adherence. The rheumatology registered nurse uses evidence-based knowledge to bridge the gap between patient concerns and provider focus, thus empowering patients to engage in individualized discussions, understand written materials, and participate in behavioral change counseling. To facilitate this dialogue, the varying levels of patient educational and cultural background must be taken into consideration, using both existing resources and developing new tools as necessary. A qualitative study revealed nurses providing medication information resulted in patients feeling in control and “described the importance of being involved in decisions about their medication,” leading to enhanced adherence.2 Tailoring in-

structions specifically to the individual creates a sense of security that contributes to the patient’s overall confidence and self-awareness necessary to comprehend disease management.

The level of education and counseling required to achieve Deanna L. Owens, improved RN, MSN patient outcomes highlights the importance of creating an organized team of healthcare providers dedicated to becoming a valuable resource. Patient Compliance Leads to Improved Outcomes Autoimmune diseases are often unpredictable, requiring continuous follow-up visits, and ongoing monitoring of various labs and disease activity scores. Recurring visits to an outpatient specialty clinic provide exposure to necessary resources, enhancing patients’ knowledge about their disease activity and treatment goals. Rheumatology registered nurses are integral in providing education during office visits, ensuring that pa-

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tients understand the value of their compliance in the effectiveness of their treatment plan. A systematic review of 63 studies that focused on the impact of educational intervention in the rheumatoid arthritis population revealed positive short-term effects of patient education targets for patients with rheumatoid arthritis.3 Although long-term effects of patient education were inconclusive, the short-term benefits demonstrated in the study provide a solid foundation to continue the development of quality patient resources. In another review, multiple studies involving nurse-led rheumatology clinics found that patient knowledge and satisfaction increased while pain and fatigue decreased.4 Furthermore, a 2013 study by Ndosi and colleagues showed that patients receiving nurse-led care achieved better disease activity scores compared with patients receiving rheumatologist-led care.5 In addition, nurseled care provided patient education more frequently than did rheumatology-led care.5 The authors’ findings further solidify the importance of the rheumatology registered nurse’s role in improving patient outcomes by providing valuable education. Benefits of Continued Education for the Healthcare Team Successful treatment of complex autoimmune disorders requires a multilayered approach that integrates the expert knowledge of the rheumatology registered nurse and a tailored

DO YOU SEE THE IMPACT OF PATIENT EDUCATION IN RA?

educational plan to increase patient compliance and improve outcomes. Although additional research is needed in this area, the benefits of nurse–patient educational interventions are clear. The goal of treatment is adequate disease management and patients experiencing symptomatic relief and increased quality of life will also result in additional referrals and recognition of the practice as a leader in the treatment of rheumatic disease. The level of education and counseling required to achieve improved patient outcomes highlights the importance of creating an organized team of healthcare providers dedicated to becoming a valuable resource. Through support from professional organizations like the RNS, rheumatology registered nurses are provided continued education opportunities to expand their evidence-based knowledge–– benefiting patients, their families, and the community. n References

1. The Rheumatology Nurses Society. Rheumatology Nursing: Scope and Standards of Practice. http:// rnsnurse.org/product/rheumatology-nursingscope-and-standards-practice. Accessed May 20, 2014. 2. Larsson I, Arvidsson S, Bergman S, Arvidsson B. Patients’ perceptions of drug information given by a rheumatology nurse: a phenomenographic study. Musculoskeletal Care. 2010;8:36-45. 3. Niedermann K, Fransen J, Knols R, Uebelhard D. Gap between short- and long-term effects of patient education in rheumatoid arthritis: a systematic review. Arthritis Rheum. 2004;51:388-398. 4. Hill J, Thorpe R, Bird H, et al. Outcomes for patients with RA: a rheumatology nurse practitioner clinic compared to standard outpatient care. Musculoskeletal Care. 2003;1:5-20. 5. Ndosi M, Lewis M, Hale C, et al. The outcome and cost-effectiveness of nurse-led care in people with rheumatoid arthritis: a multicentre randomised controlled trial. Ann Rheum Dis. 2013 Aug 27. Epub ahead of print.

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In the Literature Lack of Control in Rheumatoid Arthritis... Continued from page 17

in the study; the mean age was 57 years and the mean disease duration was 11.77 years. In addition, the mean

patient population AIS, PSQI, and ESS scores were 6.8, 7.8, and 7.3, respectively. The investigators found a significant positive relationship between the 28-joint Disease Activity Score (DAS28) using C-reactive protein

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(DAS28-CRP) and AIS/PSQI, and a significant negative relationship between DAS28-CRP and ESS. “Poor control of RA is associated with a reduction in sleep quality and decreased daytime sleepiness, which

is likely explained by pain-related alertness,” the authors concluded. “Future prospective studies are needed to confirm potential relationships between sleep quality, sleepiness, and RA treatment.” n VOL. 3

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Lupus

Peripheral Neuropathy in Patients with Lupus Frequently Involves Small-Fiber Neuropathies By E. K. Charles

limited number of studies have evaluated associations between peripheral neuropathies with autoantibody patterns and aspects of systemic lupus erythematosus (SLE) activity. “However, such studies have, importantly, begun to emphasize that peripheral neuropathies in SLE may occur with equal or greater frequency compared to some CNS syndromes, and therefore constitute an important although poorly understood cause of morbidity,” according to Amin Oomatia, MB BChir, University of Cambridge School of Clinical Medicine, United Kingdom, and colleagues (Oomatia A, et al. Arthritis Rheumatol. 2014;66:1000-1009). The Hopkins Lupus Cohort The investigators sought to characterize peripheral neuropathy subtypes, ancillary studies, and immunologic profiles associated with peripheral neuropathies in patients with SLE. As part of a 25-year Hopkins Lupus Cohort study, including 2097 patients with SLE, investigators characterized peripheral neuropathies associated with SLE, and compared clinical and SLE-related features in patients with neuropathy versus patients without neuropathy. The study authors collected various data from enrolled patients, including demographic features, presenting and cumulative clinical manifestations,

autoantibody and other immunologic features, SLE activity, SLE damage, and laboratory parameters. Patients were evaluated quarterly or more frequently if needed, and the SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment–SLE Disease Activity Index) activity index and the SDI (Systemic Lupus International Collaborating Clinics Damage Index) were updated at each visit, the study authors noted. Overall, 218 patients were initially diagnosed with SLE neuropathy, and 2 authors performed detailed chart reviews to identify alternate comorbid causes of neuropathy. Patients were eligible for study inclusion if they were diagnosed with SLE based on the American College of Rheumatology (ACR) classification criteria; satisfy definitions for peripheral neuropathy provided by task forces from the American Academy of Neurology and the American Academy of Physical Medicine and Rehabilitation; and have peripheral neuropathies specifically attributed to SLE. “We used these consensus definitions proposed by expert clinicians from these task forces instead of ACR NPSLE [neuropsychiatric SLE] case definitions,” the study authors acknowledged. These task force definitions are more up-todate than the ACR definitions, which date back to 1999, they added. The study authors enrolled 66 pa-

tients with the highest likelihood of having a peripheral neuropathy associated with abnormal electrophysiologic study or skin biopsies. In addition, 16 patients with a modest likelihood of a peripheral neuropathy (with neurologic evaluation revealing objective in symptomatic regions) were also included. Patients whose neuropathy could not be attributed to SLE were excluded from the analysis, including patients with diabetic neuropathies and infectious causes.

Punch-skin biopsies are a minimally invasive, valid, and reliable way to diagnose small-fiber neuropathies. —A. Oomatia, MD, and colleagues

A Closer Look at the Neuropathies Found Among the 2097 patients included in the lupus cohort, the prevalence of peripheral neuropathies was 5.9%, and 66.7% of these patients had peripheral neuropathies attributable to SLE. The investigators observed that 17.1% of the patients with SLE neuropathies had small-fiber neuropathy, “which is a painful neuropathy not

included in the ACR NPSLE case definitions,” the study authors added. Patients with SLE “with small-fiber neuropathies could present with unorthodox neuropathic pain patterns not consistent with a stocking-glove distribution and had associated skin biopsy results suggestive of dorsal root ganglion neuronal cell loss.” Patients with SLE and neuropathies had a lower mean disease activity (P = .01) and higher disease damage (P <.1) and were more likely to have a history of herpes zoster virus infection (P <.1), osteoporotic fractures (P <.1), and opportunistic infections (P <.1) compared with patients without peripheral neuropathies. The authors observed that patients with SLE with small-fiber neuropathy had skin biopsy findings that suggest that distinct mechanisms target the dorsal root ganglions and the distal axons. “The failure to include small-fiber neuropathies in the 1999 ACR NPSLE case definitions likely reflects the unfamiliarity with this sensory neuropathy at the time of publication,” Dr Oomatia and colleagues purported. Diagnostic strategies used to diagnose small-fiber neuropathies are different from those required to diagnose axonal neuropathies, they added. Punchskin biopsies are a minimally invasive, valid, and reliable way to diagnose small-fiber neuropathies. n

Rheumatology update

Rheumatologists May Lack Confidence in Their Knowledge of Cannabinoids By Rosemary Frei, MSc Quebec City, Quebec—The majority of Canadian rheumatologists who responded to a 19-item questionnaire about the use of medical marijuana for rheumatic conditions reported that they are not confident in this arena (Fitzcharles M, et al. Quebec City, Quebec: Canadian Pain Society; 2014. Poster P54). “As champions for the care of arthritis, rheumatologists should be knowledgeable about this treatment option,” the team of researchers noted in a poster presentation at the Canadian Pain Society’s 35th Annual Scientific Meeting. VOL. 3

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“More guidance is needed to better inform rheumatologists on the evidence for safe and effective use of cannabinoids in RA.” —Mary-Ann Fitzcharles, MD, and colleagues

Two-thirds of the 128 respondents said that they do not feel confident about their current knowledge of the

endocannabinoid system in health and disease. Furthermore, 90.6% said they are not confident enough to write JUNE 2014

a prescription for medical cannabis that includes the dosage, frequency of use, and method of administration. Lead investigator Mary-Ann Fitz charles, MD, told Value-Based Care in Rheumatology that “I believe this lack of confidence reflects absence of evidence in the rheumatic diseases for either efficacy or side effects.” There is a need for a proper evidence-based study, she added. Dr Fitzcharles, a rheumatologist at the McGill University Health Centre in Montreal, Quebec, and Daniel Clauw, MD, University of Michigan

Continued on page 20

www.ValueBasedRheumatology.com

Rheumatoid Arthritis

Subcutaneous Methotrexate More Effective... “Methotrexate is the cornerstone of treatment in RA,” study author Michael Schiff, MD, MACR, Department of Rheumatology, University of Colorado, Denver, told Value-Based Care in Rheumatology. “This data will help clinical rheumatologists optimize the dose and delivery of methotrexate for best patient care.” Previous Data Point to Limitations of Oral Administration Bioavailability of oral administration of MTX varies in patients and decreases with increasing dosages,

at a glance ➤ Bioavailability of oral administration of MTX varies in patients ➤ New data demonstrate consistently greater bioavailability of subcutaneous MTX compared with oral MTX ➤ Subcutaneous administration may allow for optimization of MTX in patients with RA ➤ Treatment was generally safe and well tolerated for both oral and subcutaneous administration ➤ No new treatment-related safety signals were identified

the study authors explained citing previously reported data. Oral MTX has also been associated with gastrointestinal adverse events, including nausea and vomiting, which limit optimal use. In addition, previous research that evaluated oral versus subcutaneous MTX indicated that limitations in systemic exposure of oral administration may affect efficacy. Clinical response was also better with subcutaneous MTX than with oral administration (Braun J. Arthritis Rheum. 2008;58:73-81). As part of an 8-week, open-label, randomized-sequence, 3-way crossover phase 2 study, the investigators sought to evaluate the relative bioavailability of oral MTX and subcutaneous MTX using an MTX auto-injector, which was recently approved by the US Food and Drug Administration, in patients with RA. The secondary objective was to compare the different methods of MTX administration in terms of the time of peak concentration, terminal rate constant, and terminal half-life of MTX. Pharmacokinetic parameters and safety of subcutaneous and oral MTX were evaluated. Challenging Common Practice Patients received MTX 10 mg, 15 mg, 20 mg, or 25 mg weekly in a random sequence of 3 regimens: oral, abdomen subcutaneous injection, and thigh subcutaneous injection. Blood

samples were collected for pharmacokinetic analysis and injection sites 24

“Methotrexate is the cornerstone of treatment in RA. This data will help clinical rheumatologists optimize the dose and delivery of methotrexate for best patient care.” —Michael Schiff, MD, MACR

hours after the administration of each treatment. Patients were eligible for inclusion if they were ≥18 years and received MTX for ≥3 months; concom-

Continued from page 1

itant medication had to be stable for ≥3 months. Patients with serious comorbid disease, as well as patients taking additional medications, including disease-modifying antirheumatic drugs, that could interfere with pharmacokinetic outcome measures were excluded from the study. Overall, 49 patients were randomized and received at least 1 dose of MTX; 47 patients completed the study. Pharmacokinetic assessments demonstrated a consistently greater bioavailability of subcutaneous MTX compared with oral MTX at all doses. Oral MTX plateaued at doses ≥15 mg compared with subcutaneous MTX, which increased in a dose-proportional manner. Treatments with both routes of administration were found to be generally safe and well tolerated with no new treatment-related safety signals identified, according to the study authors. “The current study is the first to compare bioavailability across commonly prescribed doses of oral and subcutaneous MTX and raise the possibility that there is no advantage to increasing the oral MTX dose above 15 mg/week, a common clinical practice,” Dr Schiff and colleagues concluded. These data also suggest that subcutaneous administration may allow for optimization of MTX in patients with RA in accordance with the treatment guidelines, they added. n

Rheumatology update Rheumatologists May Lack Confidence in Their... Continued from page 19

at a glance ➤ Rheumatologists should consider and be knowledgeable about other treatment options for rheumatoid arthritis, including cannabinoids ➤ Physicians who reported not being confident in their knowledge of the cannabinoids were much more likely to report that there is no role for either pharmaceutical cannabinoids or medical marijuana for rheumatic conditions ➤ More evidence-based research is needed on the use of these other treatment options

Medical Center, Ann Arbor, collaborated with other researchers from across Canada to survey members of the Canadian Rheumatology Association (CRA) regarding medical marijuana. Overall, 128 of 510 CRA members responded. Forty respondents reported that they were “confident” or “somewhat confident” in their current knowledge of the endocannabinoid system in health and disease. Eighty-six respondents reported that they were “not confident.” Thirty-three expressed being confident or somewhat confident in their current knowledge of the phyto-, syntheto-, and endocannabinoids and 95 said they were not confident. Among the 33 respondents who expressed some level of confidence in

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their cannabinoid-molecule knowledge, 16 (48%) said there is a role for medical cannabis for rheumatic conditions, and 10 (30%) said that there is a role for pharmaceutical cannabinoids only. The remaining 7 (21%) respondents reported that there is no role for either. In addition, 11 (33%) of the respondents said they had previously recommended a trial of pharmaceutical cannabinoids and 9 (27%) said they would recommend a trial of herbal/ medical cannabis. Fourteen (42%) said they would write a medical-cannabis prescription for a patient who did not respond to conventional treatments and 17 (52%) said they would not; the remaining 2 (6%) did not answer that question. However, only 3 (9%) said

they would write a medical-cannabis prescription based on a patient’s request regardless of previous treatments; 28 (85%) said they would not and 2 (6%) did not answer. The physicians who had expressed a lack of confidence in their knowledge of the cannabinoids were much more likely to report that there is no role for either pharmaceutical cannabinoids or medical marijuana for rheumatic conditions. They also were much less likely to have previously recommended a trial of one of these or have a patient try one. “[Further] guidance is required to better inform rheumatologists on the evidence for safe and effective use of cannabinoids to treat rheumatic complaints,” the team concluded. n VOL. 3

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Rheumatoid Arthritis

Is a New Nomenclature for Classifying DMARDs Needed? By Lianne Bennett

urrently, disease-modifying antirheumatic drugs (DMARDs) are classified as either biological or nonbiological. According to a recent study, however, this classification scheme is limiting and does not distinguish between the different types of DMARDs. The recent approvals of tofacitinib and biosimilars have prompted investigators to devise a new nomenclature structure that further groups DMARDs into more specific categories (Smolen JS, et al. Ann Rheum Dis. 2014;73:3-5). “In light of the recent emergence of new therapeutics for rheumatoid arthritis, such as kinase inhibitors and biosimilars, a new nomenclature for disease-modifying antirheumatic drugs…may be needed,” explained Josef S. Smolen, MD, Chairman of the Department of Rheumatology, Medical University of Vienna, Austria, and colleagues. The proposed nomenclature divides DMARDs into 2 overarching umbrellas: synthetic DMARDs and biological DMARDs Synthetic DMARDs are

further subdivided into conventional synthetic DMARDs (csDMARDs) and targeted synthetic DMARDs (tsDMARDs). Attributed to the histor-

that were specifically designed to interact with known structures. For example, tofacitinib is a synthetic compound that was developed to inhibit

“In light of the recent emergence of new therapeutics for rheumatoid arthritis, such as kinase inhibitors and biosimilars, a new nomenclature for diseasemodifying antirheumatic drugs… may be needed.” —Josef S. Smolen, MD, and colleagues

ical way in which they entered the treatment armamentarium for rheumatoid arthritis, csDMARDs comprise agents that were synthesized before their targets were known and include methotrexate, sulfasalazine, gold salts, antimalarials, and leflunomide. Conversely, tsDMARDs, include agents

Janus kinases and is therefore considered a tsDMARD. Under the proposed nomenclature, biological DMARDs consist of biosimilar DMARDs (bsDMARDs) and biological originator DMARDs. Defined as agents that copy the primary, secondary, and tertiary structure of a

parent compound, bsDMARDs (eg, an infliximab biosimilar) are gradually making their way onto the treatment landscape for rheumatoid arthritis. The authors noted that because different bsDMARDs may vary slightly in their composition, additional terminology may be warranted. Bruce N. Cronstein, MD, Division of Rheumatology, NYU Langone Medical Center, New York, told Value-Based Care in Rheumatology that this proposed nomenclature “is a classification of DMARDs based on the way they were discovered rather than either their mechanism of action or their use in the clinic, and it’s hard to see how this either will guide therapy or will improve the way we use these drugs.” The study authors believe that the proposed nomenclature will serve several purposes: provide mechanistic distinctions; help to better navigate the drug approval process; and improve future analyses of the different classes of agents in comparison with others. n

Predicting Tocilizumab Response Possible in Patients with Rheumatoid Arthritis By Rosemary Frei, MSc Seville, Spain—Using a panel of 4 biomarkers is effective in selecting patients with rheumatoid arthritis who are most likely to meet the American College of Rheumatology (ACR) criteria for 50% improvement (ACR50) to 4 mg/kg/day of tocilizumab, according to a study presented at the recent 2014 World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (Siebuhr AS. Seville, Spain: World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases; 2014. Abstract OC24). The 4 biomarkers are joint extracellular matrix proteins, matrix metalloproteinase-degraded types 1 and 3 collagen (C1M and C3M), and C-reactive protein. All 4 of these have been established by previous research to be markers of inflammation and tissue destruction in patients with rheumatoid arthritis. Anne-Christine Bay-Jensen, MBA, MSc, PhD, Principal Scientist and Head of Rheumatology, Nordic Bioscience, Biomarkers & Research, Herlev, Denmark, and colleagues analyzed results from the 200 patients in VOL. 3

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“Using a repeat of C1M helps to identify patients with fast progression— that is, those who are most in need of immediate treatment.” —Anne-Christine Bay-Jensen, MBA, MSc, PhD the 1-year, phase 3, Tocilizumab Safety and the Prevention of Structural Joint Damage (LITHE) clinical trial

(Semin Arthritis Rheum. 2013 Aug 6. Epub ahead of print) who received 4 mg/kg/day of tocilizumab. Overall, 54 of the patients had an ACR50 response to tocilizumab at 52 weeks and the remainder did not. LITHE is 1 of the 5 Genentech-sponsored phase 3 trials that led to the January 2010 US Food and Drug Administration approval of tocilizumab (Actemra) for the treatment of patients with rheumatoid arthritis. The investigators found that 53.5% of individuals with a positive result from the full biomarker panel at baseline had a response of at least ACR50 compared with 27% of the general study population. The specificity and sensitivity of the biomarkers panel were 86.3% and 42.6%, respectively. The results were even better for individuals who were tested with the biomarker panel at 4 weeks and who later had a retest of C1M: 64% of patients with positive results were tocilizumab responders. The team showed in a separate, as-yet unpublished study, that reduction in C1M early in the course of rheumatoid arthritis treatment is june 2014

at a glance ➤ A panel of 4 biomarkers may be effective in selecting patients with rheumatoid arthritis who are most likely to respond to tocilizumab therapy ➤ Joint extracellular matrix proteins, matrix metalloproteinase-degraded types 1 and 3 collagen, and C-reactive protein are biomarkers that have previously been shown to indicate inflammation and tissue destruction in patients with rheumatoid arthritis ➤ Using a repeat of C1M helps to identify patients who are most in need of immediate treatment predictive of treatment efficacy. “Using a repeat of C1M helps to identify patients with fast progression—that is, those who are most in need of immediate treatment,” noted Dr Bay-Jensen. n

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Osteoarthritis

Hyaluronic Acid Injection May Delay Total Knee Replacement By E. K. Charles Tampa, FL—Current guidelines for the management of knee osteoarthri-

at a glance ➤ Guidelines for the management of knee OA do not recommend IAHA for patients with symptomatic OA, because of the lack of data indicating that its use reduces pain ➤ More than 2000 patients were eligible for study inclusion, of which approximately 75% underwent TKR after 1 year of receiving their first IAHA injection and 37% of the patients within the first year of starting viscosupplementation ➤ Decreases in mean age and time-to-TKR were directy proportional, suggesting that younger patients may yield the most benefit from IAHA injections ➤ IAHA continues to be an option for patients with OA in the knee that do not respond to conventional treatment

tis (OA) from the American Academy of Orthopaedic Surgeons do not recommend intra-articular hyaluronic acid (IAHA) injection (ie, viscosupplementation) for patients with symptomatic OA because of the lack of data indicating that its use reduces pain. However, researchers at the 2014 Academy of Managed Care Pharmacy found that the mean timeto-total knee replacement (TKR) after starting IAHA was 2.5 years. “Today, a growing number of physicians and patients are utilizing viscosupplementation for OA as a means to delay or avoid knee replacement procedures (which are invasive and carry an average cost of $49,000$57,000),” according to study author Taha Khan, PharmD, Horizon Blue Cross Blue Shield of New Jersey, Newark, and colleagues. In a retrospective analysis of medical claims data, the investigators assessed the effectiveness of IAHA in managing OA and delaying TKR. Study participants were eligible for inclusion if they were Horizon Blue Cross Blue Shield of New Jersey members with both medical and pharmacy benefits between January 1, 2008, and October 30, 2013, and

aged ≥18 years. In addition, patients had to be diagnosed with OA based on the International Classification of Diseases, Ninth Revision (ICD-9) codes. Among approximately 30,000 patients, 2326 (7.8%) were eligible for study inclusion. Of these patients,

“Today, a growing number of physicians and patients are utilizing viscosupplementation for OA as a means to delay or avoid knee replacement procedures.” —Taha Khan, PharmD, and colleagues

approximately 75% underwent TKR after 1 year of receiving their first IAHA injection and 37% of the patients within the first year of starting viscosupplementation. The mean time-to-TKR in patients who received 1 through 9 courses of therapy (dura-

tion, ≤41.5 months) was 29.65 months; 58.1% of patients received only 1 course of IAHA therapy before undergoing TKR. Because the severity of OA most likely increased with courses of therapy, the investigators noted, the time from end of IAHA therapy to TKR trended downward from patients who received 1 course of therapy to those who received 9 courses of therapy. Synvisc-One and Synvisc had the highest utilization in both groups of patients (IAHA only and IAHA plus TKR) and the average cost for 1 hyaluronic acid injection, including administration fees, was $668. Data from the analysis indicated that decreases in mean age and timeto-TKR were directly proportional, suggesting that it might work best in younger patients. “Viscosupplementation continues to be an option for treatment of OA in the knee for patients who have failed or are intolerant to conventional treatment such as analgesics, but the benefit of IAHA must be weighed against possible adverse events and long-term cost implications in this growing popu lation,” according to Dr Khan and colleagues. n

Rheumatoid Arthritis

Nearly Half of Rheumatoid Arthritis Prescriptions Involve Copay Offset By Kurt Ullman, RN, MHA, BSPA

itter Health Insights (ZHI) recently released the latest edition of its Co-Pay Offset Monitor, a publication that serves as a research tool to help identify trends in copay assistance. The group surveyed 100 rheumatologists, 100 patients who had used copay offset programs (COPs) for their medications over the previous 6 months, and 25 specialty pharmacists. The report shows that COPs have been growing at a high rate. “The point of the survey was to get

a sense of what impacts co-pay offset programs were having on doctor’s prescribing behavior,” said Melinda C. Haren, RN, senior director of access strategies at Zitter. “We also were looking at whether the patients found one kind of program easier to use than others.” ZHI’s most recent publication has shown that there are 561 offset programs being run for more than 700 brand-name drugs. This is an increase of 34% across all therapeutic classes since the original survey was pub-

value-based CARE in Rheumatology

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lished in 2013. Only 12% of the copay programs were for products with an AB-rated generic equivalent. Half of RA Prescriptions Offset More than 1 of every 3 specialty pharmaceutical prescriptions were paid for using a copay program. There was a great deal of variation among specialty medication categories. However, more than half of rheumatoid arthritis (RA) medications were offset, the highest among the specialty areas.

This is in stark contrast to oral oncology medicines, where there was some kind of assistance for only 7% of prescriptions. In the sample reviewed by Zitter, RA accounted for about half of specialty pharmacy scripts. The average copay prior to any offset was $60; this often was reduced to $5 or less following the payment assistance. “Specialty medications are highly utilized, and there are dynamics that are different from one to another,” noted Ms Haren. “You would instincContinued on page 24

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Time to Get on TRACK and RACE to Excellence Together!

o National O r ganizat ion of R heumatolo g y Mana gers Racing to Rheumatology Excellence Friday, September 12, 2014 and Saturday, September 13, 2014 Increase your odds of “being in the winner’s circle” by joining us for the 2014 NORM Conference where nationally known speakers will help NORM members race on the fast track rather than the sloppy track. Presentations and breakouts on topics such as MU2, OSHA, Customer Service, Physician and Team Engagement, and Financial Management of your practice will help your practice win the race. The conference will end with a presentation on Understanding the Impact of ICD-10 and an ICD-10 workshop stocked with take-aways for your practice. This year NORM has added 6 product theatres offering attendees the opportunity to be hands-on with some products. NORM membership also provides access to the NORM listserv and education portal. The listserv allows NORM members to seek answers to their practice and nationwide issues from members across the country. The educational portal provides access to training and informational presentations as well as sample documents. Conference Registration is Now Open | 2014 Dues and Conference Registration $250

For more information contact NORM at info@normgroup.org or visit our website www.normgroup.org

“Of all the practice management resources out there, none are as relevant and as valuable to me as my NORM membership. With benefits like the member listserv and an affordable annual conference, the NORM group provides a forum for mentorship, education, professional feedback, cutting edge ideas and inspiration.” Jay Salliotte

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Osteoarthritis

Experts Highlight Trends in Pain, Care in Different Patient Demographics with Osteoarthritis By Rosemary Frei, MSc Tampa, FL—The grey wave that is washing over the United States will mean many more people will need help coping with their osteoarthritis pain, according to presenters at a symposium during the American Pain Society’s 2014 Annual Meeting. Ann L. Horgas, RN, PhD, described the preliminary results of a 10-year, 2774-person study, which showed that as people with osteoarthritis age, they have increased pain interference. This, in turn, affects their ability to perform daily activities (Horgas AL, et al. Tampa, FL: American Pain Society. Symposium 802). Exploring the Options Dr Horgas said she and her colleagues are now exploring the best ways to stem this tide. “We are considering all options at this point, including mindfulness and other resilience-enhancing strategies, that might be useful in facilitating coping with pain in later life,” Dr Horgas told Value-Based Care in Rheumatology. Dr Horgas, Associate Professor, College of Nursing, University of Florida, Gainesville, performed the analysis with Michael Marsiske, PhD, Associate Professor, College of Clinical and Health Psychology, University of Florida, Gainesville. The community-dwelling study participants had an average age of 73.6 years, 75.9% were women, 73.8% were white, and 57.1% had arthritis. The 1578 study participants with

arthritis were more likely to be women, to be older, and to have clinically significant pain compared with study participants without arthritis. In addition, the group of 487 African Americans with arthritis included a higher proportion of women and a higher average age compared with the 1111 white patients with arthritis.

“We found significantly more self-reported functional limitations and perceived difficulty performing activities among people with clinically significant self-reported pain interference.” —Ann L. Horgas, RN, PhD

The patients had a significant rise in both pain and pain interference during the 10 years of the study, based on their scores on the bodily pain section of Short Form-36. Average pain intensity increased from a score of 32 at baseline to 40.5 at year 10 (P <.01); average pain interference scores increased from 25 to 34 (P <.01). The researchers also performed mixed-effects modeling with covariates that included age, sex, baseline pain, and baseline functioning. Simi-

lar to previous data, physical functioning worsened significantly over time in older patients with osteoarthritis. Scores increased on both the performance and difficulty subscales of the Lawton Instrumental Activities of Daily Living (IADL) Scale, with the most significant increase observed in patients starting at approximately 85 years of age. The investigators also found race did not influence these trajectories; similar patterns were observed in both whites and African Americans. However, people with more pain interference had higher IADL performance and difficulty scores. Increased pain intensity was not associated with higher IADL subscale scores, the investigators noted.“We found significantly more self-reported functional limitations and perceived difficulty performing activities among people with clinically significant self-reported pain interference,” said Dr Horgas. UPLOAD Study Results Another presenter in the same symposium described results from the Understanding Pain and Limitations in Osteoarthritic Disease (UPLOAD) study, which was funded by the National Institutes of Health’s National Institute on Aging and the University of Florida Clinical and Translational Science Institute (Glover TL, et al. Tampa, FL: American Pain Society. Symposium 802). Toni L. Glover, PhD, GNP-BC, As-

sistant Professor in the Department of Adult and Elderly Nursing, College of Nursing, University of Florida, Gainesville, and colleagues found widespread use of prescription and over-the-counter medications among patients, most of whom had symptomatic knee pain from osteoarthritis. A higher proportion of African Americans than non-Hispanic whites used topical pain-relief agents; white patients used alternative/complementary medicine and supplements more frequently than African Americans. A third presenter, Tamara Baker, PhD, Associate Professor in the School of Aging Studies at the University of South Florida, Tampa, discussed results from an older study showing that increased pain intensity, more pain locations, depression, and lower educational attainment are significantly associated with poorer physical functioning among community-dwelling African Americans with osteoarthritis (Baker TA, Whitfield KE. J Natl Med Assoc. 2006;98:1114-1120). “Pervasive disparities persist, including pain-related disparities,” said symposium chair Robert R. Edwards, PhD, Associate Professor of Anesthesia, Brigham and Women’s Hospital, Boston. He noted this is something clinicians should pay attention to, since “steady demographic changes in the United States suggest that non-Latino whites will cease to be an absolute majority in the not-so-distant future.” n

Rheumatology update

Nearly Half of Rheumatoid Arthritis Prescriptions Involve... Continued from page 22 tively think that oncology has to be the group where COPs are used most often, but that isn’t the case. RA biologics have much more use of these programs than other specialty therapies.” Differences Between Medications This may be related to a number of factors, Ms Haren said. Most cancer therapies do not have direct competitors, so payers often cover them with

minimal patient cost-sharing required. Even when a patient has a high level of cost-sharing required for coverage, oncologists may waive copayments because of the life-threatening nature of the disease. Further, cancer patients may have a higher price point they are willing to pay than RA patients. From a recent 2014 ZHI report, cancer patients were willing to stay on therapy and were likely to start looking for savings only when their out-of-pocket expenses

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were greater than $240. RA patients would start looking for savings if their out-of-pocket expenses were more than $90. “RA tips into this space of an extremely serious disease that isn’t life-threatening in the short-term,” said Ms Haren. “This creates a difference in the threshold above which people decide they can’t afford the drug.” Other rheumatologic drugs saw relatively high levels of prescriptions

with offset. Psoriasis patients had their medications offset 39% of the time, growth hormone and related disorders costs were reduced in 28% of the scripts, and patients receiving medications for systemic lupus erythematous had their copayments cut at a 3% rate. The weighted average for the entire sample suggested that 37% of patients had assistance with their medication payments. The average patient received $427 in assistance from copay programs. n VOL. 3

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Drug Update

Otezla (Apremilast), an Oral PDE-4 Inhibitor, Receives FDA Approval for the Treatment of Patients with Active Psoriatic Arthritis By Loretta Fala, Medical Writer

soriatic arthritis, a progressive, potentially debilitating type of arthritic inflammation, affects approximately 7 million people in the United States.1,2 An estimated 15% to 30% of patients with psoriasis will develop psoriatic arthritis.1,3 Psoriasis, a chronic, relapsing disease characterized by thick patches of inflamed, scaly skin resulting from excessive proliferation of skin cells, affects up to 2.6% of people in the United States.2 Both psoriatic arthritis and psoriasis are chronic autoimmune diseases.1 The symptoms of psoriatic arthritis, like the symptoms of psoriasis, may flare and subside, varying from person to person.3 In some cases, the arthritis precedes skin disorders. Psoriatic arthritis can affect any joint in the body; it may affect 1 or more joints (eg, 1 or both knees), and it may affect fingers and toes.3 Some patients also develop dactylitis, a condition in which the fingers and toes swell profusely.3 Many patients with psoriatic arthritis are affected by the joint disease and the psoriasis that often accompanies it.4 Psoriatic arthritis affects women and men equally.5 Although it generally develops between the ages of 30 years and 50 years, psoriatic arthritis can also start in childhood.3 An estimated 40% of patients with psoriatic arthritis have a family member with the disease, suggesting that heredity may play a key role. Psoriatic arthritis may also be triggered by an infection, including a streptococcal throat infection.3 The chronic pain, fatigue, limitations in physical function, and work disability associated with psoriatic arthritis can have a profound effect on the patient’s health-related quality of life.6 Furthermore, the risk for cardiovascular disease and other comorbidities is greater in patients with psoriatic arthritis and other inflammatory diseases than in individuals without these diseases.2,4 Psoriatic arthritis can also have a substantial impact on a patient’s psychological well-being, because of the itching, pain, and potential for social rejection encountered by many patients.2,4 Psoriatic arthritis imposes a considerable economic burden on patients and society. Based on a 2010 review of Copyright © 2014 American Health & Drug Benefits. All rights reserved.

Table 1 Apremilast Dosage Titration Schedule for Patients with Psoriatic Arthritis Day 1

Day 2

am 10 mg

Day 3

Day 4

Day 5

Day 6 and thereafter

10 mg

20 mg

30 mg

Source: Otezla (apremilast) tablets prescribing information; March 2014.

the literature, in the United States, direct annual medical costs associated with psoriatic arthritis total nearly $1.9 billion.4 In this review of 49 studies, patients with psoriatic arthritis

“Relief of pain and inflammation and improving physical function are important treatment goals for patients with active psoriatic arthritis. Otezla provides a new treatment option for patients suffering from this disease.” —Curtis Rosebraugh, MD, MPH

had a lower health-related quality of life compared with the general population.4 Moreover, the direct and indirect costs associated with psoriatic arthritis, including lost productivity and disability, increase with worsening disease activity (ie, joint involvement and psoriatic skin lesions) and worsening physical function.4 Evidence shows that persistent inflammation associated with psoriatic arthritis causes joint damage over time. Consequently, early diagnosis of psoriatic arthritis is essential, because early detection and treatment may prevent further damage to the joints.3 The therapeutic goals for patients with psoriatic arthritis are to alleviate symptoms, control inflammation in affected joints, and prevent joint pain and disability.7 Treatment depends on the severity of the disease, the number of joints involved, and the associated skin symptoms.1 During the early stages of psoriatic arthritis, nonsteroidal anti-inflammatory drugs (NSAIDs) and cortisone may be used to manage mild inflammation. For patients with erosive disease or for those in whom NSAIDs fail

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to work, the disease-modifying antirheumatic drugs (DMARDs), including methotrexate, sulfasalazine, leflunomide, and a number of biologic agents may be used to slow the progression of psoriatic arthritis and spare the joints and other tissues from permanent damage.1,7 Until recently, the US Food and Drug Administration (FDA)-approved treatments for psoriatic arthritis included corticosteroids, several tumor necrosis factor blockers, and an interleukin-12/interleukin-23 inhibitor.8

be taken orally starting on day 6. The recommended initial dosage titration of apremilast from day 1 to day 5 is shown in Table 1.9 Coadministration of apremilast with food does not alter the extent of absorption of this drug.9 The recommended dose for patients with severe renal impairment is 30 mg once daily. For initial dose titration in these patients, titration should follow the morning schedule in Table 1; the afternoon doses should be skipped.9 Apremilast is available in 10-mg, 20-mg, and 30-mg tablets.9

A Novel Oral Therapeutic Option for Psoriatic Arthritis On March 21, 2014, the FDA approved apremilast (Otezla; Celgene) for the treatment of adults with active psoriatic arthritis. An oral inhibitor of phosphodiesterase (PDE)-4, apremilast is the first oral therapy to receive FDA approval for the treatment of adult patients with active psoriatic arthritis.8 According to Curtis Rosebraugh, MD, MPH, Director of the Office of Drug Evaluation II at the FDA Center for Drug Evaluation and Research, “Relief of pain and inflammation and improving physical function are important treatment goals for patients with active psoriatic arthritis. Otezla provides a new treatment option for patients suffering from this disease.”8

Clinical Trials The safety and efficacy of apremilast were demonstrated in 3 multicenter, randomized, double-blind, placebocontrolled trials of similar design.9 In these studies (ie, PsA-1, PsA-2, PsA-3), a total of 1493 adult patients with active psoriatic arthritis (≥3 swollen joints and ≥3 tender joints) despite previous or current treatment with DMARD therapy were randomized to receive placebo, apremilast 20 mg twice daily, or apremilast 30 mg twice daily.9 Enrolled patients had a diagnosis of psoriatic arthritis for at least 6 months. The primary end point was the percentage of patients who achieved American College of Rheumatology (ACR)20 response at week 16.9 An ACR20 is defined as a 20% improvement in tender and swollen joint counts and a 20% improvement in 3 of the 5 remaining ACR core set measures (ie, patient and physician global assessments, pain, disability, others.)10 An ACR50 represents a 50% improvement in both measures; an ACR70, a 70% improvement in both measures.10 In these studies, placebo-controlled efficacy data were also collected and analyzed through week 24. If patients’ tender and swollen joint counts had not improved by at least 20%, they were considered nonresponders at week 16. Placebo nonresponders were rerandomized 1:1 in a blind fashion to either apremilast 20 mg twice daily or

Mechanism of Action Apremilast is a small-molecule inhibitor of PDE-4 specific for cyclic aden osine monophosphate (cAMP). Inhibition of PDE-4 results in increased intracellular cAMP levels. The specific mechanism by which apremilast exerts its therapeutic effect in patients with psoriatic arthritis is not well defined.9 Dosing and Administration To reduce the risk of gastrointestinal symptoms, it is recommended that apremilast is titrated to the recommended dose of 30 mg twice daily, to

Continued on page 28

VOL. 3

NO. 3

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Drug Update Continued from page 26

30 mg twice daily, after titration. Patients receiving apremilast continued their initial treatment. At week 24, all remaining patients receiving placebo were rerandomized to either 20 mg twice daily or to 30 mg twice daily.9 Patients enrolled across the 3 clinical studies had a median duration of psoriatic arthritis disease of 5 years, with a variety of psoriatic arthritis subtypes, including symmetric polyarthritis (62%), asymmetric oligoarthritis (27%), distal interphalangeal joint arthritis (6%), arthritis mutilans (3%), and predominant spondylitis (2.1%). Patients received concomitant therapy with at least 1 DMARD (65%), methotrexate (55%), sulfasalazine (9%), leflunomide (7%), low-dose oral corticosteroids (14%), and NSAIDs (71%). Previous treatment with small-molecule DMARDs was reported in only 76% of patients, and previous treatment with biologic DMARDs was reported in 22% of patients, including 9% who failed previous biologic DMARD treatment.9 The proportion of patients who achieved a clinical response (ie, ACR20, ACR50, or ACR70 responses) in studies PsA-1, PsA-2, and PsA-3 are shown in Table 2. Patients receiving apremilast ± DMARDs showed greater reductions in signs and symptoms of psoriatic arthritis compared with placebo ± DMARDs as demonstrated by the proportion of patients who achieved an ACR20 response at week 16.9 Apremilast 30 mg twice daily also demonstrated improvement for each ACR component versus placebo at week 16 in study PsA-1, as shown in Table 3. These results from study PsA-1 were consistent with those observed in studies PsA-2 and PsA-3. In study PsA-1, apremilast 30 mg twice daily also showed a greater improvement in mean change from baseline for the health assessment questionnaire disability index (HAQ-DI) score at week 16 compared with the placebo group. The proportions of HAQ-DI responders (≥0.3 improvement from baseline) at week 16 were 38% for the apremilast (30 mg twice daily) group compared with 27% for the placebo group. Consistent results were observed in studies PsA-2 and PsA-3.9 Safety The most common adverse reactions associated with apremilast occurring in ≥5% of patients were nausea (8.3%), diarrhea (7.7%), and headache (5.9%). In addition, upper respiratory tract infections were reported in 3.9% of patients and vomiting in 3.2%.9 Similarly, the most common reasons leading to treatment discontinuation

Table 2 Apremilast versus Placebo: Proportion of Patients with Psoriatic Arthritis and ACR Response at Week 16 PsA-1 study

PsA-2 study

Placebo ± DMARDs (N = 168)

Apremilast 30 mg twice daily ± DMARDs (N = 168)

ACR20, %

ACR50, % ACR70, %

Patients with ACR response at week 16

PsA-3 study

Placebo ± DMARDs (N = 159)

Apremilast 30 mg twice daily ± DMARDs (N = 162)

Placebo ± DMARDs (N = 169)

Apremilast 30 mg twice daily ± DMARDs (N = 167)

38a

32a

41a

Significantly different from placebo (P <.05). ACR indicates American College of Rheumatology; DMARD, disease-modifying antirheumatic drug; PsA, psoriatic arthritis. Source: Otezla (apremilast) tablets prescribing information; March 2014.

with apremilast were diarrhea (1.8%), nausea (1.8%), and headache (1.2%). In clinical trials, the proportion of patients with psoriatic arthritis who discontinued treatment because of any adverse reaction was 4.6% for patients taking apremilast 30 mg twice daily and 1.2% for patients receiving placebo.9 Warnings and Precautions Contraindications. Apremilast is contraindicated in patients with a known hypersensitivity to apremilast or any of the excipients in the formulation.9 Drug interactions. Use of apremilast with strong cytochrome P450 enzyme inducers (eg, rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended, because it may result in a loss of efficacy of apremilast.9 Depression. Patients should be advised of the potential emergence or worsening of depression, suicidal thoughts, or other mood changes. The risks and benefits of treatment with apremilast should be weighed carefully in patients with a history of depression and/or suicidal thoughts or behavior.9 Weight decrease. The patient’s weight should be monitored regularly. If unexplained or clinically significant weight loss occurs, discontinuation of apremilast should be considered.9 Use in Specific Populations Pregnancy. Adequate and well-controlled studies with apremilast have not been conducted in pregnant women. Apremilast should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.9 Nursing mothers. It is not known whether apremilast or its metabolites are present in human milk. However, because many drugs are present in human milk, caution should be exercised when apremilast is administered to a nursing woman.9 Severe renal impairment. Increased systemic exposure of apremilast has been observed in patients with severe renal impairment; a reduction in dose to 30 mg once daily is recommended.9

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JUNE 2014

Table 3 Study PsA-1 of Patients with Psoriatic Arthritis: Mean Change in ACR Components from Baseline with Apremilast, at Week 16 Placebo Apremilast 30 mg ACR component (N = 168) twice daily (N = 168) Number of tender jointsa Sample size, N 166 164 a 23 23 Baseline b –2 –7 Mean change at week 16 Number of swollen jointsc Sample size, N 166 164 c 13 13 Baseline –2 –5 Mean change at week 16b d Patient’s assessment of pain (VAS) Sample size, N 165 159 61 58 Baselined b –6 –14 Mean change at week 16 d Patient’s global assessment of disease activity (VAS) Sample size, N 165 159 d 59 56 Baseline b –3 –10 Mean change at week 16 Physician’s global assessment of disease activityd Sample size, N 158 159 d 55 56 Baseline –8 –19 Mean change at week 16b HAQ-DI scoree Sample size, N 165 159 1.2 1.2 Baselinee b –0.09 –0.2 Mean change at week 16 f CRP Sample size, N 166 167 f 1.1 0.8 Baseline a 0.1 –0.1 Mean change at week 16 Scale, 0-78. Mean changes from baseline are least square means from analyses of covariance. c Scale, 0-76. d 0 = best; 100 = worst. e 0 = best; 3 = worst; the HAQ-DI measures the subject’s ability to perform daily activities, including dressing, eating, walking, griping, maintaining hygiene. f Reference range, 0-0.5 mg/dL. ACR indicates American College of Rheumatology; CRP, C-reactive protein; HAQ-DI, health assessment questionnaire disability index; PsA, psoriatic arthritis; VAS, visual analog scale. Source: Otezla (apremilast) tablets prescribing information; March 2014. a

Conclusion The FDA approval of apremilast marks the availability of the first oral treatment option for patients with active psoriatic arthritis. Having an oral

option can be important for patients who are unable or unwilling to use other therapeutic options. The safety and efficacy of apremilast, a novel PDE-4 inhibitor, were VOL. 3

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Rheumatology Update

Ceasing All RA Medications Not Optimal in Patients Trying to Conceive How to manage your pregnant patients with inflammatory RA By E. K. Charles Charlotte, NC—Although managing rheumatoid arthritis (RA) in patients who are pregnant or trying to conceive may be challenging, rheumatologists should aim to improve disease activity and pregnancy outcomes, according to Megan E. B. Clowse, MD, MPH, Associate Professor of Medicine, Director, Duke Autoimmunity in Pregnancy Registry, Duke University Medical Center, at the North Carolina Regional Association 2014 annual meeting. “I really have seen from both data and personal experience that stopping all medications in a rheumatoid arthritis patient when she wants to conceive is really the wrong thing to do,” Dr Clowse emphasized at the beginning of her talk. “What we see are patients flaring, not getting pregnant, and having a lot of difficulty during their pregnancies.” Treating these patients with prednisone when they flare after all medication has been stopped is not the best approach, she added. Most patients with RA get better, Dr Clowse explained, citing previous research, with 77% of patients going into remission during pregnancy and 81% of patients relapsing during the first 3 months after delivery. “Patients who are on TNF [tumor necrosis factor]-inhibitors, stop them, and then get pregnant, are never doing as well as they did when they were on their TNF-inhibitor,” Dr Clowse added.

Does RA Activity Impact Pregnancy Outcomes? Pregnancy outcomes in patients with RA are good overall, Dr Clowse stated, citing previously published data. In particular, the risk of preterm delivery increases approximately 30% in patients with RA, and preeclampsia is increased by approximately 75% in patients with RA compared with the general population. “But I think that what we need to determine is who is actually going to have those problems, as opposed to what the overall rates are,” Dr Clowse noted. Growing evidence indicates that RA impacts pregnancy outcomes, she continued. In the Pregnancy-Induced Amelioration of Rheumatoid Arthritis study, 81 prospective pregnancies were evaluated. The investigators found that increased disease activity was associated with lower birth weight, and increased prednisone use was associated with shorter gestational age. Results from another study by Chakravarty and colleagues, which evaluated 42 retrospective pregnancies, found that there was no change in pregnancy outcomes with RA activity; patients who stopped taking their RA medication tended to have earlier delivery. The Duke Autoimmunity in Pregnancy Registry, which was started in 2008, has approximately 230 patients with various rheumatic disorders. Overall, approximately half of the

Otezla (Apremilast)... demonstrated in 3 randomized, double-blind, placebo-controlled trials that involved 1493 patients. In all 3 studies, a statistically significant proportion of patients receiving apremilast achieved an ACR20 response at week 16 compared with placebo. Treatment with apremilast 30 mg twice daily also resulted in improvement for each ACR component, including tender joints, swollen joints, and physical function. n References

1. Cleveland Clinic Foundation. Psoriatic arthritis. http://my.clevelandclinic.org/orthopaedics-rheu matology/diseases-conditions/hic-psoriatic-arthritis. aspx. Accessed May 1, 2014. 2. National Institutes of Health. Psoriasis. Fact sheet. Updated October 2010. http://report.nih.gov/ NIHfactsheets/Pdfs/Psoriasis%28NIAMS%29.pdf. Accessed April 28, 2014.

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3. Emery P, Ash Z. American College of Rheumatology. Psoriatic arthritis. Updated September 2012. www. rheumatology.org/Practice/Clinical/Patients/ Diseases_And_Conditions/Psoriatic_Arthritis/. Accessed May 1, 2014. 4. Lee S, Mendelsohn A, Sarnes E. The burden of psoriatic arthritis: a literature review from a global health systems perspective. P T. 2010;35:680-689. 5. Gelfand JM, Gladman DD, Mease PJ, et al. Epidemiology of psoriatic arthritis in the population of the United States. J Am Acad Dermatol. 2005;53:573-577. 6. Armstrong AW, Schupp C, Wu J, Bebo B. Quality of life and work productivity impairment among psoriasis patients: findings from the National Psoriasis Foundation survey data 2003-2011. PLoS One. 2012; 7:e52935. 7. Mayo Clinic staff. Psoriatic arthritis: treatment and drugs. January 29, 2014. Accessed May 1, 2014. 8. US Food and Drug Administration. FDA approves Otezla to treat psoriatic arthritis. Press release. March 21, 2014. www.fda.gov/newsevents/newsroom/pressan nounce ments/ucm390091.htm. Accessed April 23, 2014. 9. Otezla (apremilast) tablets [prescribing information]. Summit, NJ: Celgene Corporation; March 2014. 10. Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995;38:727-735.

women included in the registry were diagnosed with systemic lupus erythematosus; other diagnoses included RA, other inflammatory arthritis, and Ro antibody-positive. “What we found was that disease activity in the early part of pregnancy correlated highly with pregnancy outcomes,” Dr Clowse explained, citing results from the prospective cohort study. “In particular, with timing of the delivery.” All of the patients with preterm births had moderate-to-severe disease activity in the first and second trimesters compared with patients who delivered full-term. Only 1 patient who delivered full-term had moderate-to-severe disease activity, she noted. Treating Pregnant Patients with RA The goal is to improve RA activity and improve pregnancy outcomes, Dr Clowse stated. Unfortunately, prednisone therapy has adverse events associated with its use, she explained. In particular, data have shown that prednisone is associated with a 3-fold increase in the occurrence of cleft lip or palate and long-term neurocognitive changes in the offspring of patients taking the drug. Increased preterm birth, preeclampsia, gestational diabetes, maternal hypertension, and excessive weight gain have also been observed. “There are other really good options that I really want you to think about when a patient comes in and is sitting in front of you,” Dr Clowse continued. These include hydroxychloroquine and sulfasalazine. The former has some effect on mild arthritis and is a pregnancy Category C drug, with no human toxicity reports. The latter has shown good efficacy for peripheral arthritis and is a pregnancy Category B drug with a good safety profile in pregnancy. Both methotrexate and leflunomide are classified as pregnancy Category X and are not good options for pregnant patients with RA. Data indicate a 25% to 50% risk for pregnancy loss and a 10% risk for congenital anomalies associated with methotrexate. Although human data are reassuring for the use of leflunomide, the pregnancy profile is terrible in animals. “I would certainly not recommend that anybody get pregnant on leflunomide, JUNE 2014

but I also would never recommend a termination, particularly without any evidence of anomalies,” she stated. If the patient’s obstetrician insists on a pregnancy termination, Dr Clowse suggested recommending the patient get a second opinion. TNF inhibitors, as well as all antibodies, can transfer across the placenta and that transfer increases as patients get closer to term. If the patient is taking immunoglobulin-based med ications, there will be a significant amount of transfer during the time of delivery, she explained. Taking a closer look at specific TNF inhibitors, infliximab and adalimumab levels are higher in the cord blood serum than in maternal serum levels, while etanercept and certolizumab levels are lower in the infant than they are in the mother. Overall, the pregnancy outcomes of patients taking TNF inhibitors are not worrisome for the most part, according to Dr Clowse. Results from a 2009 review by Vinet and colleagues indicated that pregnancy outcomes are similar among pregnant patients taking TNF inhibitors and the general US population: live-birth rates (76%), miscarriage rate (13%), termination rate (11%), and rate of congenital abnormalities (3%). “Infants who are exposed to TNF-inhibitors, particularly toward the end of term, may have immunosuppression,” Dr Clowse emphasized. “These babies should not get live vaccines in the first 5 months of life.” The only live vaccine given to infants before 1 year of age in the United States is rotavirus. Investigators using data from the Duke Autoimmunity in Pregnancy Registry evaluated whether TNF-inhibitors may improve pregnancy outcomes in RA. Patients were divided based on the medication they were taking during the first trimester. Overall, 11 patients were taking prednisone, 7 were taking anti-TNF inhibitors, and 11 were taking neither drugs. Patients taking prednisone had a high level of disease activity, with 54.4% resulting in abnormal outcomes, and patients taking anti-TNF inhibitors also had a high level of disease activity, with 14.3% resulting in abnormal outcomes. Patients who did not take either drug, however, had a low level of disease activity and no abnormal outcomes. n

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OTREXUP™ (methotrexate) injection, for subcutaneous use. Brief Summary of Prescribing Information WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY AND DEATH Otrexup should be used only by physicians whose knowledge and experience include the use of antimetabolite therapy. Because of the possibility of serious toxic reactions (which can be fatal), Otrexup should be used only in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy. Deaths have been reported with the use of methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis. Patients should be closely monitored for bone marrow, liver, lung, skin, and kidney toxicities. Patients should be informed by their physician of the risks involved and be under a physician’s care throughout therapy [see Warnings and Precautions (5.1)]. 1. Methotrexate has been reported to cause fetal death and/or congenital anomalies. Therefore, Otrexup is not recommended for females of childbearing potential unless there is clear medical evidence that the benefits can be expected to outweigh the considered risks [see Warnings and Precautions (5.2)]. Otrexup is contraindicated in pregnant women [see Contraindications (4)]. 2. Methotrexate elimination is reduced in patients with impaired renal functions, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of Otrexup administration [see Warnings and Precautions (5.6)]. 3. Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs) [see Warnings and Precautions (5.1) and Drug Interactions (7.1)]. 4. Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen. These are usually transient and asymptomatic, and also do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions may not be preceded by symptoms or abnormal liver function tests in the psoriasis population. For this reason, periodic liver biopsies are usually recommended for psoriatic patients who are under long-term treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population [see Warnings and Precautions (5.1)]. 5. Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation [see Warnings and Precautions (5.1)]. 6. Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death from intestinal perforation may occur [see Warnings and Precautions (5.1)]. 7. Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue Otrexup first and, if the lymphoma does not regress, appropriate treatment should be instituted [see Warnings and Precautions (5.8)]. 8. Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors [see Warnings and Precautions (5.9)]. 9. Severe, occasionally fatal, skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy [see Warnings and Precautions (5.1)]. 10. Potentially fatal opportunistic infections, especially Pneumocystis jiroveci pneumonia, may occur with methotrexate therapy [see Warnings and Precautions (5.1)]. 11. Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis [see Warnings and Precautions (5.10)]. 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosing Information Otrexup is a single-dose auto-injector for once-weekly subcutaneous use only [see Warnings and Precautions (5.5)]. Administer Otrexup in the abdomen or the thigh. Otrexup is only available in doses between 10 to 25 mg in 5 mg increments. Use another formulation of methotrexate for alternative dosing in patients who require oral, intramuscular, intravenous, intra-arterial, or intrathecal dosing, doses less than 10 mg per week, doses more than 25 mg per week, high-dose regimens, or dose adjustments of less than 5 mg increments. 2.2 Rheumatoid Arthritis including Polyarticular Juvenile Idiopathic Arthritis Recommended starting dose of methotrexate: Adult RA: single oral doses of 7.5 mg weekly using an oral formulation of methotrexate. pJIA: 10 mg/m2 once weekly. For patients switching from oral methotrexate to Otrexup, consider any differences in bioavailability between oral and subcutaneously administered methotrexate [see Clinical Pharmacology (12.3)]. Dosages may be adjusted gradually to achieve an optimal response. Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg/wk in adults. Although there is experience with doses up to 30 mg/m2/wk in children, there are too few published data to assess how doses over 20 mg/m2/wk might affect the risk of serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m2/wk (0.65 to 1.0 mg/kg/wk) may have better absorption and fewer gastrointestinal side effects if methotrexate is administered either intramuscularly or subcutaneously. Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more. The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least two years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks. The patient should be fully informed of the risks involved and should be under constant supervision of the physician. Assessment of hematologic, hepatic, renal, and pulmonary function should be made by history, physical examination, and laboratory tests before beginning, periodically during, and before reinstituting Otrexup therapy [see Warnings and Precautions (5.4)]. Females of childbearing potential should not be started on Otrexup until pregnancy is excluded [see Contraindications (4) and Warnings and Precautions (5.2)] All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects. Maximal myelosuppression usually occurs in seven to ten days. 2.3 Psoriasis Recommended starting dose of methotrexate: Psoriasis: single weekly oral, intramuscular, subcutaneous, or intravenous doses of 10-25 mg. For patients switching from oral methotrexate to Otrexup, consider any differences in bioavailability between oral and subcutaneously administered methotrexate [see Clinical Pharmacology (12.3)]. Dosage may be gradually adjusted to achieve optimal clinical response; 30 mg/week should not ordinarily be exceeded. Once optimal clinical response has been achieved, the dosage should be reduced to the lowest possible amount of drug and to the longest possible rest period. The use of Otrexup may permit the return to conventional topical therapy, which should be encouraged. 2.4 Administration and Handling Otrexup is an auto-injector intended for subcutaneous use under the guidance and supervision of a physician. Patients may self-inject with Otrexup if a physician determines that it is appropriate, if they have received proper training in how to prepare and administer the correct dose, and if they receive medical follow-up, as necessary. A trainer device is available for training purposes. Visually inspect Otrexup for particulate matter and discoloration prior to administration. Do not use Otrexup if the seal is broken. Handle and dispose of Otrexup consistent with recommendations for handling and disposal of cytotoxic drugs1. 3 DOSAGE FORMS AND STRENGTHS Otrexup is an injection available as an autoinjector that administers a single 0.4 mL dose of methotrexate solution in the following dosage strengths: • 10 mg/0.4 mL methotrexate • 15 mg/0.4 mL methotrexate • 20 mg/0.4 mL methotrexate • 25 mg/0.4 mL methotrexate 4 CONTRAINDICATIONS Otrexup is contraindicated in the following: • Pregnancy Otrexup can cause fetal death or teratogenic effects when administered to a pregnant woman. Otrexup is contraindicated in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1)]. • Nursing Mothers Because of the potential for serious adverse reactions from methotrexate in breast fed infants, Otrexup is contraindicated in nursing mothers [see Use in Specific Populations (8.3)]. • Alcoholism or Liver Disease Patients with alcoholism, alcoholic liver disease or other chronic liver disease [see Warnings and Precautions (5.1)]. • Immunodeficiency Syndromes Patients who have overt or laboratory evidence of immunodeficiency syndromes [see Warnings and Precautions (5.1)]. • Preexisting Blood Dyscrasias Patients who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia [see Warnings and Precautions (5.1)]. • Hypersensitivity Patients with a known hypersensitivity to methotrexate. Severe hypersensitivity reactions have been observed with methotrexate use [see Warnings and Precautions (5.1) and Adverse Reactions (6.1 and 6.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Organ System Toxicity Otrexup should be used only by physicians whose knowledge and experience include the use of antimetabolite therapy. Because of the possibility of serious toxic reactions (which can be fatal), Otrexup should be used only in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy. Deaths have been reported with the use of methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis. Patients should be closely monitored for bone marrow, liver, lung and kidney toxicities.

Otrexup has the potential for serious toxicity. Toxic effects may be related in frequency and severity to dose or frequency of administration but have been seen at all doses. Because they can occur at any time during therapy, it is necessary to follow patients on Otrexup closely. Most adverse reactions are reversible if detected early. When such reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. If necessary, this could include the use of leucovorin calcium and/or acute, intermittent hemodialysis with a high-flux dialyzer [see Overdosage (10)]. If Otrexup therapy is reinstituted, it should be carried out with caution, with adequate consideration of further need for the drug and increased alertness as to possible recurrence of toxicity. The clinical pharmacology of methotrexate has not been well studied in older individuals. Due to diminished hepatic and renal function as well as decreased folate stores in this population, relatively low doses should be considered, and these patients should be closely monitored for early signs of toxicity [see Use in Specific Populations (8.5)]. Gastrointestinal: Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death from intestinal perforation may occur. If vomiting, diarrhea, or stomatitis occur, which may result in dehydration, Otrexup should be discontinued until recovery occurs. Otrexup should be used with extreme caution in the presence of peptic ulcer disease or ulcerative colitis. Unexpectedly severe (sometimes fatal) gastrointestinal toxicity has been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.1)] Hematologic: Otrexup can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. In patients with preexisting hematopoietic impairment, Otrexup should be used with caution, if at all. In controlled clinical trials conducted with another formulation of methotrexate in rheumatoid arthritis (n=128), leukopenia (WBC <3000/mm3) was seen in 2 patients, thrombocytopenia (platelets <100,000/mm3) in 6 patients, and pancytopenia in 2 patients. Otrexup should be stopped immediately if there is a significant drop in blood counts. Patients with profound granulocytopenia and fever should be evaluated immediately and usually require parenteral broad-spectrum antibiotic therapy. Unexpectedly severe (sometimes fatal) bone marrow suppression and aplastic anemia have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.1)]. Hepatic: Otrexup has the potential for acute (elevated transaminases) and chronic (fibrosis and cirrhosis) hepatotoxicity. Chronic toxicity is potentially fatal; it generally has occurred after prolonged use (generally two years or more) and after a total dose of at least 1.5 grams. In studies in psoriatic patients, hepatotoxicity appeared to be a function of total cumulative dose and appeared to be enhanced by alcoholism, obesity, diabetes and advanced age. An accurate incidence rate has not been determined; the rate of progression and reversibility of lesions is not known. Special caution is indicated in the presence of preexisting liver damage or impaired hepatic function. In psoriasis, liver function tests, including serum albumin, should be performed periodically prior to dosing but are often normal in the face of developing fibrosis or cirrhosis. These lesions may be detectable only by biopsy. The usual recommendation is to obtain a liver biopsy at 1) pretherapy or shortly after initiation of therapy (2 to 4 months), 2) a total cumulative dose of 1.5 grams, and 3) after each additional 1.0 to 1.5 grams. Moderate fibrosis or any cirrhosis normally leads to discontinuation of the drug; mild fibrosis normally suggests a repeat biopsy in 6 months. Milder histologic findings such as fatty change and low grade portal inflammation, are relatively common pretherapy. Although these mild changes are usually not a reason to avoid or discontinue Otrexup therapy, the drug should be used with caution. In rheumatoid arthritis, age at first use of methotrexate and duration of therapy have been reported as risk factors for hepatotoxicity; other risk factors, similar to those observed in psoriasis, may be present in rheumatoid arthritis but have not been confirmed to date. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in this population. There is a combined reported experience in 217 rheumatoid arthritis patients with liver biopsies both before and during treatment (after a cumulative dose of at least 1.5 g) and in 714 patients with a biopsy only during treatment. There are 64 (7%) cases of fibrosis and 1 (0.1%) case of cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The reticulin stain is more sensitive for early fibrosis and its use may increase these figures. It is unknown whether even longer use will increase these risks. Liver function tests should be performed at baseline at 4 to 8 week intervals in patients receiving Otrexup for rheumatoid arthritis. Pretreatment liver biopsy should be performed for patients with a history of excessive alcohol consumption, persistently abnormal baseline liver function test values or chronic hepatitis B or C infection. During therapy, liver biopsy should be performed if there are persistent liver function test abnormalities or there is a decrease in serum albumin below the normal range (in the setting of well controlled rheumatoid arthritis). If the results of a liver biopsy show mild changes (Roenigk, grades I, II, IIIa), Otrexup may be continued and the patient monitored as per recommendations listed above. Otrexup should be discontinued in any patient who displays persistently abnormal liver function tests and refuses liver biopsy or in any patient whose liver biopsy shows moderate to severe changes (Roenigk grade IIIb or IV). Infection or Immunologic States: Otrexup should be used with extreme caution in the presence of active infection, and is contraindicated in patients with overt or laboratory evidence of immunodeficiency syndromes. Immunization may be ineffective when given during Otrexup therapy. Immunization with live virus vaccines is generally not recommended. There have been reports of disseminated vaccinia infections after smallpox immunizations in patients receiving methotrexate therapy. Hypogammaglobulinemia has been reported rarely. Potentially fatal opportunistic infections, especially Pneumocystis jiroveci pneumonia, may occur with Otrexup therapy. When a patient presents with pulmonary symptoms, the possibility of Pneumocystis jiroveci pneumonia should be considered. Neurologic: There have been reports of leukoencephalopathy following intravenous administration of methotrexate to patients who have had craniospinal irradiation. Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 gm/m2). Symptomatic patients were commonly noted to have leukoencephalopathy and/or microangiopathic calcifications on diagnostic imaging studies. Chronic leukoencephalopathy has also been reported in patients who received repeated doses of high-dose methotrexate with leucovorin rescue even without cranial irradiation. Discontinuation of methotrexate does not always result in complete recovery. A transient acute neurologic syndrome has been observed in patients treated with high dose regimens. Manifestations of this stroke-like encephalopathy may include confusion, hemiparesis, transient blindness, seizures and coma. The exact cause is unknown. After the intrathecal use of methotrexate, the central nervous system toxicity which may occur can be classified as follows: acute chemical arachnoiditis manifested by such symptoms as headache, back pain, nuchal rigidity, and fever; sub-acute myelopathy characterized by paraparesis/paraplegia associated with involvement with one or more spinal nerve roots; chronic leukoencephalopathy manifested by confusion, irritability, somnolence, ataxia, dementia, seizures and coma. This condition can be progressive and even fatal. Pulmonary: Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially a dry nonproductive cough) or a non-specific pneumonitis occurring during Otrexup therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Although clinically variable, the typical patient with methotrexate induced lung disease presents with fever, cough, dyspnea, hypoxemia, and an infiltrate on chest X-ray; infection (including pneumonia) needs to be excluded. This lesion can occur at all dosages. Renal: Otrexup may cause renal damage that may lead to acute renal failure. High doses of methotrexate used in the treatment of osteosarcoma may cause renal damage leading to acute renal failure. Nephrotoxicity is due primarily to the precipitation of methotrexate and 7-hydroxymethotrexate in the renal tubules. Close attention to renal function including adequate hydration, urine alkalinization and measurement of serum methotrexate and creatinine levels are essential for safe administration. Skin: Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Reactions were noted after single or multiple low, intermediate, or high doses of methotrexate in patients with neoplastic and non-neoplastic diseases. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Radiation dermatitis and sunburn may be “recalled” by the use of methotrexate. Other precautions: Otrexup should be used with extreme caution in the presence of debility. Methotrexate exits slowly from third space compartments (e.g., pleural effusions or ascites). This results in a prolonged terminal plasma half-life and unexpected toxicity. In patients with significant third space accumulations, it is advisable to evacuate the fluid before treatment and to monitor plasma methotrexate levels. 5.2 Embryo-Fetal Toxicity Methotrexate has been reported to cause fetal death and/or congenital anomalies. Therefore, Otrexup is not recommended for females of childbearing potential unless there is clear medical evidence that the benefits can be expected to outweigh the considered risks. Otrexup is contraindicated in pregnant women with psoriasis or rheumatoid arthritis. Females of childbearing potential should not be started on Otrexup until pregnancy is excluded and should be fully counseled on the serious risk to the fetus should they become pregnant while undergoing treatment. Appropriate steps should be taken to avoid conception during Otrexup therapy. Pregnancy should be avoided if either partner is receiving Otrexup; during and for a minimum of three months after therapy for male patients, and during and for at least one ovulatory cycle after therapy for female patients. 5.3 Effects on Reproduction Methotrexate has been reported to cause impairment of fertility, oligospermia and menstrual dysfunction in humans, during and for a short period after cessation of therapy. The risk of effects of reproduction should be discussed with both male and female patients taking Otrexup. 5.4 Laboratory Tests Patients undergoing Otrexup therapy should be closely monitored so that toxic effects are detected promptly. Baseline assessment should include a complete blood count with differential and platelet counts, hepatic enzymes, renal function tests and a chest X-ray. During therapy, monitoring of these parameters is recommended: hematology at least monthly, renal function and liver function every 1 to 2 months [see Warnings and Precautions (5.1)]. During initial or changing doses, or during periods of increased risk of elevated methotrexate blood levels (e.g., dehydration), more frequent monitoring may also be indicated. Liver Function Tests Transient liver function test abnormalities are observed frequently after methotrexate administration and are usually not cause for modification of methotrexate therapy. Persistent liver function test abnormalities, and/or depression of serum albumin may be indicators of serious liver toxicity and require evaluation [see Warnings and Precautions (5.1)]. A relationship between abnormal liver function tests and fibrosis or cirrhosis of the liver has not been established for patients with psoriasis. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population. Pulmonary Function Tests Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially if baseline measurements are available [see Warnings and Precautions (5.1)]. 5.5 Risks from Improper Dosing Both the physician and pharmacist should emphasize to the patient that Otrexup is administered weekly and that mistaken daily use has led to fatal toxicity [see Dosage and Administration (2)]. 5.6 Patients with Impaired Renal Function, Ascites, or Pleural Effusions Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity and require dose reduction or, in some cases, discontinuation of Otrexup administration. 5.7 Dizziness and Fatigue Adverse reactions, such as dizziness and fatigue, may affect the ability to drive or operate machinery.

5.8 Malignant Lymphomas Non-Hodgkin’s lymphoma and other tumors have been reported in patients receiving low-dose oral methotrexate. However, there have been instances of malignant lymphoma arising during treatment with low-dose oral methotrexate, which have regressed completely following withdrawal of methotrexate, without requiring active anti-lymphoma treatment. Discontinue Otrexup first and, if the lymphoma does not regress, appropriate treatment should be instituted. 5.9 Tumor Lysis Syndrome Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors. 5.10 Concomitant Radiation Therapy Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis. 6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling. • Organ System Toxicity [see Warnings and Precautions (5.1)] • Embryo-Fetal Toxicity [see Warnings and Precautions (5.2)] • Effects on Reproduction [see Warnings and Precautions (5.3)] • Malignant Lymphomas [see Warnings and Precautions (5.8)] The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection. 6.1 Clinical Trials Experience This section provides a summary of adverse reactions reported in subjects in clinical studies conducted with Otrexup as well as with methotrexate injection and oral methotrexate. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates observed in practice. Rheumatoid Arthritis The approximate incidences of methotrexate-attributed (i.e. placebo rate subtracted) adverse reactions in 12 to 18 week double-blind studies of patients (n=128) with rheumatoid arthritis treated with low-dose oral (7.5 to 15 mg/week) pulse methotrexate, are listed below. Virtually all of these patients were on concomitant nonsteroidal anti-inflammatory drugs and some were also taking low dosages of corticosteroids. Hepatic histology was not examined in these short-term studies. Incidence greater than 10%: Elevated liver function tests 15%, nausea/vomiting 10%. Incidence 3% to 10%: Stomatitis, thrombocytopenia (platelet count less than 100,000/mm3). Incidence 1% to 3%: Rash/pruritis/dermatitis, diarrhea, alopecia, leukopenia (WBC less than 3000/mm3), pancytopenia, dizziness. Two other controlled trials of patients (n=680) with Rheumatoid Arthritis on 7.5 mg to 15 mg/wk oral doses showed an incidence of interstitial pneumonitis of 1%. Other less common reactions included decreased hematocrit, headache, upper respiratory infection, anorexia, arthralgias, chest pain, coughing, dysuria, eye discomfort, epistaxis, fever, infection, sweating, tinnitus, and vaginal discharge. Polyarticular Juvenile Idiopathic Arthritis The approximate incidences of adverse reactions reported in pediatric patients with pJIA treated with oral, weekly doses of methotrexate (5 to 20 mg/m2/wk or 0.1 to 0.65 mg/kg/wk) were as follows (virtually all patients were receiving concomitant nonsteroidal anti-inflammatory drugs, and some also were taking low doses of corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; and rash, 0.2%. Although there is experience with dosing up to 30 mg/m2/wk in pJIA, the published data for doses above 20 mg/m2/wk are too limited to provide reliable estimates of adverse reaction rates. Psoriasis There are two literature reports (Roenigk, 1969, and Nyfors, 1978) describing large series (n=204, 248) of psoriasis patients treated with methotrexate. Dosages ranged up to 25 mg per week and treatment was administered for up to four years. With the exception of alopecia, photosensitivity, and “burning of skin lesions” (each 3% to 10%), the adverse reaction rates in these reports were very similar to those in the rheumatoid arthritis studies. Rarely, painful plaque erosions may appear (Pearce, HP and Wilson, BB: J Am Acad Dermatol 35: 835-838, 1996).

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Contraindications (4)] Methotrexate has been reported to cause embryotoxicity, fetal death, congenital anomalies, and abortion in humans and is contraindicated in pregnant women. 8.3 Nursing Mothers Because of the potential for serious adverse reactions from methotrexate in breast fed infants, methotrexate is contraindicated in nursing mothers. Therefore, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Methotrexate has been detected in human breast milk. The highest breast milk to plasma concentration ratio reached was 0.08:1. 8.4 Pediatric Use The safety and effectiveness of methotrexate, including Otrexup, have not been established in pediatric patients with psoriasis. The safety and effectiveness of Otrexup have not been established in pediatric patients with neoplastic diseases. The safety and effectiveness of methotrexate have been established in pediatric patients with polyarticular juvenile idiopathic arthritis [see Clinical Studies (14.2)]. Published clinical studies evaluating the use of methotrexate in children and adolescents (i.e., patients 2 to 16 years of age) with pJIA demonstrated safety comparable to that observed in adults with rheumatoid arthritis [see Adverse Reactions (6.1)]. Otrexup does not contain a preservative. However, methotrexate injectable formulations containing the preservative benzyl alcohol are not recommended for use in neonates. There have been reports of fatal ‘gasping syndrome’ in neonates (children less than one month of age) following the administrations of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse. Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 gm/m2) [see Warnings and Precautions (5.1)]. 8.5 Geriatric Use Clinical studies of methotrexate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic and renal function, decreased folate stores, concomitant disease or other drug therapy (i.e., that interfere with renal function, methotrexate or folate metabolism) in this population [see Warnings and Precautions (5.1) Drug Interactions (7.7) and Use in Specific Populations (8.7)]. Since decline in renal function may be associated with increases in adverse reactions and serum creatinine measurements may over estimate renal function in the elderly, more accurate methods (i.e., creatinine clearance) should be considered. Serum methotrexate levels may also be helpful. Elderly patients should be closely monitored for early signs of hepatic, bone marrow and renal toxicity. In chronic use situations, certain toxicities may be reduced by folate supplementation. Post-marketing experience suggests that the occurrence of bone marrow suppression, thrombocytopenia, and pneumonitis may increase with age [see Warnings and Precautions (5.1)]. 8.6 Females and Males of Reproductive Potential Otrexup is not recommended for females of childbearing potential unless there is clear medical evidence that the benefits can be expected to outweigh the considered risks. Females of childbearing potential should not be started on methotrexate until pregnancy is excluded and should be fully counseled on the serious risk to the fetus should they become pregnant while undergoing treatment [see Use in Specific Populations (8.1)]. Appropriate steps should be taken to avoid conception during Otrexup therapy. Pregnancy should be avoided if either partner is receiving methotrexate; during and for a minimum of three months after therapy for male patients, and during and for at least one ovulatory cycle after therapy for female patients. Methotrexate has been reported to cause impairment of fertility, oligospermia and menstrual dysfunction in humans, during and for a short period after cessation of therapy. 8.7 Renal Impairment Methotrexate elimination is reduced in patients with impaired renal function. Such patients require especially careful monitoring for toxicity and require dose reduction or, in some cases, discontinuation of Otrexup administration. 8.8 Hepatic Impairment The effect of hepatic impairment on methotrexate pharmacokinetics has not been studied. Otrexup is contraindicated in patients with alcoholic liver disease or other chronic liver disease. Patients with obesity, diabetes, hepatic fibrosis or steatohepatitis are at increased risk for hepatic injury and fibrosis secondary to methotrexate, and should be monitored closely [see Warnings and Precautions (5.1)].

6.2 Other Adverse Reactions Other adverse reactions that have been reported with methotrexate in oncology, RA, pJIA, and psoriasis patients are listed below by organ system. Alimentary System: gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis. Blood and Lymphatic System Disorders: suppressed hematopoiesis, anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, agranulocytosis, eosinophilia, lymphadenopathy and lymphoproliferative disorders (including reversible). Hypogammaglobulinemia has been reported rarely. Cardiovascular: pericarditis, pericardial effusion, hypotension, and thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus). Central Nervous System: headaches, drowsiness, blurred vision, transient blindness, speech impairment including dysarthria and aphasia, hemiparesis, paresis and convulsions have also occurred following administration of methotrexate. Following low doses, there have been occasional reports of transient subtle cognitive dysfunction, mood alteration or unusual cranial sensations, leukoencephalopathy, or encephalopathy. Hepatobiliary Disorders: hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, hepatic failure, decrease in serum albumin, liver enzyme elevations. Infection: There have been case reports of sometimes fatal opportunistic infections in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases. Pneumocystis jiroveci pneumonia was the most common opportunistic infection. There have also been reports of infections, pneumonia, Cytomegalovirus infection, including cytomegaloviral pneumonia, sepsis, fatal sepsis, nocardiosis; histoplasmosis, cryptococcosis, Herpes zoster, Herpes simplex hepatitis, and disseminated Herpes simplex. Musculoskeletal System: stress fracture. Ophthalmic: conjunctivitis, serious visual changes of unknown etiology. Pulmonary System: respiratory fibrosis, respiratory failure, alveolitis, interstitial pneumonitis deaths have been reported, and chronic interstitial obstructive pulmonary disease has occasionally occurred. Skin: erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis, skin ulceration and exfoliative dermatitis. Urogenital System: severe nephropathy or renal failure, azotemia, cystitis, hematuria, proteinuria; defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, vaginal discharge, and gynecomastia; infertility, abortion, fetal death, fetal defects. Other rarer reactions related to or attributed to the use of methotrexate such as nodulosis, vasculitis, arthralgia/myalgia, loss of libido/ impotence, diabetes, osteoporosis, sudden death, lymphoma, including reversible lymphomas, tumor lysis syndrome, soft tissue necrosis and osteonecrosis. Anaphylactoid reactions have been reported.

10 OVERDOSAGE Leucovorin is indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate. Leucovorin administration should begin as promptly as possible. As the time interval between methotrexate administration and leucovorin initiation increases, the effectiveness of leucovorin in counteracting toxicity decreases. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin. In cases of massive overdosage, hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Generally speaking, neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high-flux dialyzer (Wall, SM et al: Am J Kidney Dis 28 (6): 846-854, 1996). Accidental intrathecal overdosage may require intensive systemic support, high-dose systemic leucovorin, alkaline diuresis and rapid CSF drainage and ventriculolumbar perfusion. In postmarketing experience, overdose with methotrexate has generally occurred with oral and intrathecal administration, although intravenous and intramuscular overdose have also been reported. Reports of oral overdose often indicate accidental daily administration instead of weekly (single or divided doses). Symptoms commonly reported following oral overdose include those symptoms and signs reported at pharmacologic doses, particularly hematologic and gastrointestinal reaction. For example, leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding. In some cases, no symptoms were reported. There have been reports of death following overdose. In these cases, events such as sepsis or septic shock, renal failure, and aplastic anemia were also reported. Symptoms of intrathecal overdose are generally central nervous system (CNS) symptoms, including headache, nausea and vomiting, seizure or convulsion, and acute toxic encephalopathy. In some cases, no symptoms were reported. There have been reports of death following intrathecal overdose. In these cases, cerebellar herniation associated with increased intracranial pressure, and acute toxic encephalopathy have also been reported. There are published case reports of intravenous and intrathecal carboxypeptidase G2 treatment to hasten clearance of methotrexate in cases of overdose.

7 DRUG INTERACTIONS 7.1 Aspirin, Nonsteroidal Anti-Inflammatory Drugs, and Steroids Nonsteroidal anti-inflammatory drugs (NSAIDs) should not be administered prior to or concomitantly with the high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity [see Warnings and Precautions (5.1)]. Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate, including Otrexup. These drugs have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite the potential interactions, studies of methotrexate in patients with rheumatoid arthritis have usually included concurrent use of constant dosage regimens of NSAIDs, without apparent problems. It should be appreciated, however, that the doses used in rheumatoid arthritis (7.5 to 15 mg/week) are somewhat lower than those used in psoriasis and that larger doses could lead to unexpected toxicity. Aspirin, NSAIDs, and/or low dose steroids may be continued, although the possibility of increased toxicity with concomitant use of NSAIDs including salicylates has not been fully explored. Steroids may be reduced gradually in patients who respond to methotrexate. 7.2 Proton Pump Inhibitors (PPIs) Use caution if high-dose methotrexate is administered to patients receiving proton pump inhibitor (PPI) therapy. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs, such as omeprazole, esomeprazole, and pantoprazole, with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was co-administered with PPIs, but was not observed when methotrexate was co-administered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted. 7.3 Oral Antibiotics Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics, may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria. Penicillins may reduce the renal clearance of methotrexate; increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with high and low dose methotrexate. Use of Otrexup with penicillins should be carefully monitored. Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by decreased tubular secretion and/or an additive antifolate effect. 7.4 Hepatotoxins The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore, patients receiving concomitant therapy with Otrexup and other potential hepatotoxins (e.g., azathioprine, retinoids, and sulfasalazine) should be closely monitored for possible increased risk of hepatotoxicity. 7.5 Theophylline Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with Otrexup. 7.6 Folic Acid and Antifolates Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate. Preliminary animal and human studies have shown that small quantities of intravenously administered leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1 to 3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate. Folate deficiency states may increase methotrexate toxicity. Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by decreased tubular secretion and/or an additive antifolate effect. 7.7 Mercaptopurine Methotrexate increases the plasma levels of mercaptopurine. The combination of Otrexup and mercaptopurine may therefore require dose adjustment. 7.8 Other Drugs Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides. Renal tubular transport is also diminished by probenecid; use of Otrexup with this drug should be carefully monitored. Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, or cytotoxic agents, has not been studied and may increase the incidence of adverse effects.

15 REFERENCES 1. “Hazardous Drugs”. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results. Although there is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells, the clinical significance remains uncertain. Data are available regarding the risks for pregnancy and for fertility in humans [see Use in Specific Populations (8.1 and 8.6)].

16 HOW SUPPLIED/STORAGE AND HANDLING Otrexup contains methotrexate in a preservative-free sterile solution for a single subcutaneous injection. Otrexup is available in the following strengths and configurations. Otrexup (methotrexate) injection 10 mg/0.4 mL • Carton of 1 NDC 54436-010-01 • Carton of 4 NDC 54436-010-04 • Otrexup NDC 54436-010-02 Otrexup (methotrexate) injection 15 mg/0.4 mL • Carton of 1 NDC 54436-015-01 • Carton of 4 NDC 54436-015-04 • Otrexup NDC 54436-015-02 Otrexup (methotrexate) injection 20 mg/0.4 mL • Carton of 1 NDC 54436-020-01 • Carton of 4 NDC 54436-020-04 • Otrexup NDC 54436-020-02 Otrexup (methotrexate) injection 25 mg/0.4 mL • Carton of 1 NDC 54436-025-01 • Carton of 4 NDC 54436-025-04 • Otrexup NDC 54436-025-02 Store at controlled room temperature, 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). PROTECT FROM LIGHT. Handling and Disposal Handle and dispose of Otrexup consistent with recommendations for handling and disposal of cytotoxic drugs.1 Address Medical Inquiries to: Antares Pharma, Inc. Medical Communications 100 Princeton South, Suite 300 Ewing, NJ 08628 1-855-Otrexup (1-855-687-3987) Manufactured for: Antares Pharma, Inc. 100 Princeton South, Suite 300 Ewing, NJ 08628 USA Otrexup™ is subject of US Patent Nos. 7,776,015, 8,021,335, 6,746,429, 7,744,582 and 8,480,631. ©2013 Antares Pharma, Inc., Ewing, NJ 08628

To manage selected adults with severe, active rheumatoid arthritis (ACR criteria), or children with active polyarticular juvenile idiopathic arthritis, who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full-dose NSAIDs

greater methotrexate …made easy! *Compared with oral methotrexate.1 • Bioavailability of oral methotrexate plateaus at 15 mg. OtrexupTM (methotrexate) injection, for subcutaneous use, provides greater systemic exposure than oral methotrexate1 • Otrexup may provide benefits to patients experiencing an inadequate response to, or who cannot tolerate, methotrexate tablets1 • In a study of Otrexup, most patients found Otrexup easy to use and experienced minimal injection-related pain2 Indications • Otrexup is indicated in the management of selected adults with severe, active rheumatoid arthritis (RA) (ACR criteria), or children with active polyarticular juvenile idiopathic arthritis (pJIA), who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs). Otrexup should not be used for the treatment of cancer.

Important Safety Information (ABBREVIATED) WARNING: SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY AND DEATH • Serious toxic reactions and deaths have been reported with the use of methotrexate. Patients should be closely monitored for bone marrow, liver, lung, skin, and kidney toxicities. • Methotrexate has been reported to cause fetal death and/or congenital anomalies, and is contraindicated in pregnancy. • Methotrexate elimination is reduced in patients with impaired renal functions, ascites, or pleural effusions. • Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate along with some NSAIDs. • Hepatotoxicity, fibrosis and cirrhosis may occur after prolonged use. • Methotrexate may cause interstitial pneumonitis at any time during therapy and has been reported at low doses. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation. • Diarrhea, ulcerative stomatitis, hemorrhagic enteritis and death from intestinal perforation may occur. • Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur. • Severe, occasionally fatal, skin reactions have been reported. • Potentially fatal opportunistic infections may occur. Contraindications • Pregnancy • Nursing mothers • Alcoholism or liver disease • Immunodeficiency syndromes • Preexisting blood dyscrasias • Hypersensitivity to methotrexate Warnings and Precautions: Organ system toxicity: Potential for serious toxicity. Only for use by physicians experienced in antimetabolite therapy. Embryo-fetal toxicity: Exclude pregnancy before treatment. Avoid pregnancy if either partner is receiving Otrexup. Advise males to avoid pregnancy for at least 3 months after therapy and females to avoid pregnancy for at least 1 ovulatory cycle after therapy. Effects on reproduction: May cause impairment of fertility, oligospermia and menstrual dysfunction. Laboratory tests: Monitor complete blood counts, renal function and liver function tests. Risks from improper dosing: Mistaken daily use has led to fatal toxicity Patients with impaired renal function, ascites, or pleural effusions: Elimination is reduced Dizziness and fatigue: May impair ability to drive or operate machinery. Adverse Reactions Common adverse reactions are: nausea, abdominal pain, dyspepsia, stomatitis/mouth sores, rash, nasopharyngitis, diarrhea, liver function test abnormalities, vomiting, headache, bronchitis, thrombocytopenia, alopecia, leucopenia, pancytopenia, Otrexup.com dizziness, photosensitivity, and “burning of skin lesions.” Please see adjacent pages for Brief Summary, including Boxed Warning. References: 1. Otrexup [prescribing information]. Ewing, NJ: Antares Pharma Inc.; 2013. 2. Kivitz A, McLain D, Hill J, et al. Nearly pain-free self-administration of methotrexate using an investigational auto-injector: results from a phase 2 clinical trial in rheumatoid arthritis patients with mild-to-severe functional limitations. Poster presented at: American College of Rheumatology Annual Meeting; October 26-30, 2013; San Diego, California. Poster 1337.