VBCR December Vol 1, No 6 by Value-Based Cancer Care

Value-Based Care in Rheumatology

December 2012 VOL 1 • NO 6

F r o m t h e p u b l i s h e r s of A m e r i c a n H e a l t h & d r u g b e n e f i t s

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Year in Review: Clinical Perspectives, Part 1 By Wayne Kuznar

Latest Treatment Options for Lupus By Phoebe Starr

Washington, DC—The goal of treating lupus is to induce improvement and maintain it, said Bevra Hahn, MD, Chief, Department of Rheumatology and Arthritis, University of California at Los Angeles. Improvement can be induced in 75% of patients with currently available therapies, some of them off-label, she told listeners at the 2012 meeting of the American College of Rheumatology. “New agents for lupus hold the promise of effective treatment for patients who are not doing well on

Washington, DC—Over the past year, several publications in the peer-reviewed literature were worthy of influencing clinical practice. At the 2012 meeting of the Ameri-

can College of Rheumatology (ACR), David A. Isenberg, MD, FRCP, FAMS, Arthritis Research Campaign’s Diamond Jubilee Professor of Rheumatology, University College London, Continued on page 5

Patients Who Fail Other Biologics Respond to Tofacitinib By Phoebe Starr Washington, DC—Tofacitinib (Xeljanz), an oral Janus kinase (JAK) inhibitor, is effective in the treatment of patients with rheumatoid arthritis (RA) whose disease has an inadequate response to previous treatment with biologic therapies, and the response

with tofacitinib is maintained for 24 months. These were the findings of an analysis of data from randomized trials in the development program for tofacitinib and were presented at the 2012 meeting of the American College of Rheumatology (ACR). Continued on page 14

their current therapy or have a lot of side effects,” she stated. Antimalarials plus nonsteroidal anti-inflammatory drugs are the main stays of treatment, Dr Hahn said, but most patients will have a suboptimal response and require additional treatments. Off-Label Options Anecdotal evidence supports the use of low-dose corticosteroids for patients who do not respond to initial therapy. Two small trials suggested that the addition of methotrexate may Continued on page 6

Treat-to-Target Strategy for Rheumatoid Arthritis Does Not Increase Total Medical Costs By Wayne Kuznar Washington, DC—Compliance with treat-to-target guidelines for rheumatoid arthritis (RA) results in fewer inpatient visits, shorter lengths of stay, and lower utilization of emergency department services without additional medical service costs despite more frequent follow-up with a rheumatologist, found Martin J. Bergman, MD, FACR, FACP, Chief, Division of Rheumatology, Taylor Hospital, Ridley Park, PA,

and colleagues. They presented their data at the 2012 meeting of the American College of Rheumatology. Treat-to-target principles include the frequent monitoring of RA disease activity and corresponding drug therapy adjustment at least every 3 months to prevent structural damage and to maximize health-related quality of life through abrogation of inflammation. Although frequent Continued on page 13

inside FDA UPDATE. . . . . . . . . . . . . . . . . . . . . . Tofacitinib approved for RA

Personalized Medicine in

HEALTH ECONOMICS. . . . . . . . . . 13 Cell phone monitoring can help reduce office visits for patients with RA

Rheumatology™ . . . . . . . . 9 ARTHRITIS UPDATE. . . . . . . . . . .

Biomarker panel measures RA disease activity, treatment response OSTEOARTHRITIS. . . . . . . . . . . . . . Strontium ranelate shows positive effects on knee OA

Rheumatology PRACTICE

Management™ . . . . . . . . . . . . . . . . .

Streamline your clinical practice to increase efficiency

10 12

Patients who fail other therapies respond to tofacitinib

FIBROMYALGIA. . . . . . . . . . . . . . . . . Impact on physical, cognitive, and emotional functioning

14 17

JUVENILE IDIOPATHIC ARTHRITIS . . . . . . . . . . . . . . . . . . . . . . 18 Treatment is shifting toward biologics

In This Issue

Value-Based Carein Rheumatology FROM THE PUBLISHERS OF AMERICAN HEALTH & DRUG BENEFITS

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889 Associate Publisher American Health & Drug Benefits Maurice Nogueira maurice@engagehc.com 732-992-1895 Associate Editor Lara J. Lorton lara@engagehc.com 732-992-1892 Editorial Assistant Jennifer Brandt jbrandt@the-lynx-group.com 732-992-1536 Director, Client Services Zach Ceretelle Senior Production Manager Lynn Hamilton Quality Control Director Barbara Marino Business Manager Blanche Marchitto

Rheumatology PRACTICE

FDA UPDATE Tofacitinib approved for RA

MANAGEMENT™

Streamlining your clinical practice

VALUE PROPOSITIONS Rheumatologists connect with patients on Facebook More…

HEALTH ECONOMICS Treat-to-target strategies include frequent monitoring of disease activity Cell phone monitoring can help reduce office visits for patients with RA

RHEUMATOLOGY UPDATE Clinical perspectives from ACR 2012

ARTHRITIS UPDATE

LUPUS New agents hold promise for patients not responding to current therapy Biomarker may help predict lupus flares

Patients who fail on other therapies respond to tofacitinib IV golimumab delays radiographic progression of RA

IN THE LITERATURE

GOUT

Vitamin D may not increase risk for lupus, RA

Patients considered controlled on uratelowering therapy continue to flare A head-to-head comparison of abatacept and adalimumab More…

More…

Personalized Medicine in

Rheumatology™

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.

Biomarker panel measures disease activity, treatment response Microbiome may affect patients with RA

Contact Information: For subscription information please contact: Telephone: 732-992-1880 Fax: 732-992-1881

Strontium ranelate shows positive effects on knee osteoarthritis

Permission requests to reprint all or part of any article published in this magazine should be addressed to editorial@engagehc.com. Address all editorial queries to: editorial@engagehc.com Telephone: 732-992-1536 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 © 2013 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Care in Rheumatology is a registered trademark of Engage Health care Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America. The ideas and opinions expressed in Value-Based Care in Rheumatology do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Value-Based Care in Rheumatology should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication. 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.

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OSTEOARTHRITIS

FIBROMYALGIA Impact on physical, cognitive, and emotional functioning

JUVENILE IDIOPATHIC ARTHRITIS Treatment gradually shifting toward biologics

VBCR Editorial Advisory Board Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield New York, NY 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 James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA Muhammad Asim Khan, MD Professor of Medicine Case Western Reserve University Cleveland, OH

Randall Krakauer, MD, FACP, FACR National Medical Director Medicare, Aetna Princeton, NJ 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

Kim A. Papp, MD, PhD Founder and President Probity Medical Research Waterloo, Ontario, Canada Edmund J. Pezalla, MD, MPH National Medical Director for Pharmacy Policy and Strategy Aetna Hartford, CT Ronald van Vollenhoven, MD, PhD Associate Professor Karlinska University Hospital Solna Stockholm, Sweden F. Randy Vogenberg, RPh, PhD Principal Institute of Integrated Healthcare Sharon, MA

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

December 2012

www.ValueBasedRheumatology.com

FDA Update Tofacitinib Approved for Rheumatoid Arthritis In November 2012, the US Food and Drug Administration (FDA) approved tofacitinib (Xeljanz; Pfizer) for adult patients with moderate-to-severe rheumatoid arthritis (RA) who do not adequately respond to or are intolerant of methotrexate. Tofacitinib is a Janus kinase inhibitor that is administered orally, at a dosage of 5 mg twice daily. The drug was approved under the FDA’s priority review process. Tofacitinib was evaluated in 7 clinical trials with adult patients with moderate-to-severe RA. In all of the trials, the patients receiving tofacitinib showed improved clinical re sponse and physical functioning compared with placebo. “Xeljanz provides a new treatment option for adults suffering from the debilitating disease of RA who have had a poor response to methotrexate,” said Badrul Chowdhury, MD, PhD, Director of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research. The most common adverse effects included upper respiratory tract infections, headache, diarrhea, and inflammation of the nasal passages as well as the upper part of the pharynx. In the clinical trials, tofacitinib was associated with an increased risk of serious infections, including opportunistic infections, as well as tuberculosis, some cancers, and lymphoma. Therefore, the medication carries a Boxed Warning related to these potential risks. In addition, treatment with tofacitinib is associated with increased cholesterol levels and liver enzymes, as well as decreased blood counts. The FDA approved tofacitinib with a Risk Evaluation and Mitigation Strategy program requiring safety information on the drug’s package insert label to advise patients and inform healthcare providers about the serious risks associated with the drug. Furthermore, the FDA is requiring the drug’s manufacturer to conduct a postmarketing study to evaluate the long-term effects in heart disease, cancer, and serious infections. This study will evaluate 2 doses of tofacitinib and will include a group of patients on another approved treatment to serve as a comparison. The manufacturer also will provide additional data on treatment with the 10-mg dose in patients with RA. (November 6, 2012) n

Value Propositions Facebook Offers a New Avenue for Rheumatologists to Connect with Patients

Patients are more social media savvy than ever, with many seeking out Facebook pages, Twitter posts, and YouTube videos as sources of medical information. Although such online communications between doctors and patients can be fraught with privacy and confidentiality issues, within properly established guidelines, social media can be a cost-effective outlet for information exchange, as rheumatologists and auxiliary staff at the Hospital for Special Surgery in New York City recently discovered. The 3 doctors, accompanied by a nurse practitioner and 2 social workers, participated in a live chat with approximately 250 patients with lupus who asked the panelists more than 65 questions. With the hospital’s social media expert acting as the moderator, the healthcare providers fielded questions according to their area of specialty, using laptops to type their responses back to the patients. The moderator used an iPad to continually refresh the chat’s page so that all questions were answered. Although the doctors were initially concerned about giving advice that could potentially conflict with treatment recommendations from the patients’ own doctors, they eventually found that the relatively anonymous atmosphere of the chat gave patients the freedom to ask questions specific to their condition. Ultimately, the doctors were able to help the patients understand that because lupus is a rheumatic disease, the condition needs to be managed by a rheumatologist. They found that the chat was a simple yet effective and efficient way to educate a large group of patients at once about lupus and the importance of having the disease managed by a rheumatologist. The Rheumatologist, December 2012

Mobile Device Users Can Now Access NIAMS Information on the Go

Acknowledging that many website users increasingly access online content on their mobile electronic device, the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) has implemented responsive design to deliver the content from the most-viewed pages on its website for easy accessibility, scrolling, and viewing on the smaller portable devices. Users can still access the entire NIAMS website from their portable device, but the content specific to diseases of the bones, joints, muscles, and skin is now available without the need to resize the text for the smaller screens. Web traffic on www.niams.nih.org coming from mobile devices increased 14% between June 2011 and September 2012, suggesting that patients with rheumatic diseases are seeking better and more efficient access to online content regarding their conditions. NIAMS press release, January 2, 2013

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DECEMber 2012

Oregon Receives Approval to Launch Health Exchange in 2013

Oregon’s Health Insurance Exchange, named Cover Oregon, received conditional approval from the Centers for Medicare & Medicaid Services to begin operating later this year. The exchange is designed to provide information about the quality, cost, and accessibility of the participating plans to small employers and individual insurance plan purchasers in a transparent way that makes each plan’s benefits package easy to compare so that consumers can make an informed decision. Based on the Affordable Care Act, health insurance exchanges are designed to offer uninsured or underinsured Americans subsidized health insurance coverage. The Executive Director of the exchange has reported that of 16 carriers who have expressed intention to participate in the exchange to date, 13 have filed to offer group insurance and 14 have filed to offer individual insurance, with most carriers intending to offer group and individual plans when the exchange begins operating in October 2013. Among the carriers who have filed notice to participate in Oregon’s exchange are Regence BlueCross BlueShield of Oregon, Kaiser Permanente, PacificSource Health Plans, and Providence Health Plans, all some of the state’s largest health insurance plans. Portland Business Journal, January 11, 2013

ISEI’s Position Statement on Exercise and Immune Function

The International Society of Exercise and Immunology (ISEI) issued a position statement last year on exercise and immune function. The ISEI differentiates between exercise and physical activity, noting that exercise is goal-oriented, such as to compete in sports or to improve the physical condition, and therefore has greater impact on the immune system than mere physical activity. The ISEI statement explains how exercise impacts cellular function and inflammation, which can directly affect patients with rheumatic diseases and autoimmune conditions, in negative and positive ways: ➤ Exercise can suppress the immune system, which increases susceptibility to infection ➤ During and immediately after exercise, the number of T-cells and B-cells decrease to levels below the preexercise period and return to normal levels within 24 hours; cell activity differs in athletic and sedentary people, with that activity being more sensitive the more athletic a person is ➤ Exercise can alter the measures of immunity by as much as 15% to 25% ➤ Exercise confers anti-inflammatory effects, including an increase in interleukin (IL)-1 and IL-10 levels. ISEI position statement, 2012

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Rheumatology Update

Year in Review: Clinical Perspectives... discussed a handful of articles with the most impact from each of 5 clinical areas: trials, observations, treatment studies (not clinical trials), translational medicine, and quirky reports. This article includes the first 3 categories; a separate article will cover translational medicine and quirky reports. Clinical Trials Tofacitinib (Xeljanz) 5 mg and 10 mg twice daily and adalimumab (Humira) 4 mg every 2 weeks were significantly better than placebo on the primary end point of an ACR 20% improvement criteria (ACR20) response at 6 months in a randomized study of 717 patients with rheumatoid arthritis (RA) on stable doses of methotrexate (Rheumatrex; van Vollenhoven RF, et al. N Engl J Med. 2012;367:508519). Six-month ACR20 responses occurred in 51.5% (5 mg) and 52.6% (10 mg) of the tofacitinib groups, 47.2% of the adalimumab group, and 28.3% of the placebo group. There also were improvements in the Health Assessment Questionnaire (HAQ) at 3 months and the 28-joint Disease Activity Score (DAS28) at 6 months in the treatment groups versus placebo. Tofacitinib had a tendency to increase levels of both low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. In a 6-month, double-blind, randomized controlled trial comparing methotrexate 15 mg weekly and placebo in patients with active psoriatic arthritis (PsA; Kingsley GH, et al. Rheumatology. 2012;51:1368-1377), there was no evidence that methotrexate improved synovitis clinically or serologically. Methotrexate did improve assessors’ and patients’ global assessment scores and had a positive effect on psoriasis skin scores. The findings “challenge us to ask the very important question: Should methotrexate continue to be used as an effective control of synovitis in patients with PsA?” Dr Isenberg said. In patients with moderate-to-severe RA who had an inadequate response to disease-modifying antirheumatic drugs, tocilizumab (Actemra) 8 mg/ kg every 4 weeks produced an ACR 50% improvement criteria response of 30.1% and an ACR20 response of 44% at 24 weeks, which were both significantly superior to placebo (Yazici Y, et al. Ann Rheum Dis. 2012;71:198-205). The rates of serious infection were 7.87 per 100 patientyears in the tocilizumab group versus 1.2 per 100 patient-years in the placebo group. A 2-year follow-up study comparVOL. 1

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ing 2 dosages of rituximab (Rituxan; either 500 mg intravenously × 2 plus methotrexate or 1 g × 2 plus methotrexate) versus placebo plus methotrexate in 755 patients found no radiologic progression of disease in 57% of the high-dose rituximab group versus 37% of the placebo group (Tak PP, et al. Ann Rheum Dis. 2012;71:351-357). The results with the lower rituximab dosage were less clear-cut. A pooled univariate and multivariate analysis showed superior systemic lupus erythematosus Responder Index rates at week 52 with belimumab (Benlysta; 1 mg/kg and 10 mg/kg) versus placebo in patients with low-complement, anti–double-stranded DNA positivity (van Vollenhoven RF, et al. Ann Rheum Dis. 2012;71:1343-1349). Belimumab was also beneficial in this group in regard to secondary end points (eg, severe flares, steroid use). “It seems like if we select appropriate patients, we will get much better responses with belimumab,” Dr Isenberg said. Clinical Observations In 2 North American cohorts of patients with Takayasu’s arteritis (TAK) or giant-cell arteritis (GCA), patients with TAK had more left carotid and mesenteric artery diseases, whereas those with GCA had more left and right auxiliary artery diseases (Grayson PC, et al. Ann Rheum Dis. 2012;71:1329-1334). Of the total patients, 56% were classified in a subgroup with little difference, which suggests that TAK and GCA may exist on a spectrum within the same disease. Of 813 patients with RA who were followed for a mean of 9.6 years, venous thromboembolic events were more than twice as common in patients with RA versus controls, whereas there were no significant increases in the rates of cerebrovascular and peripheral arterial events in patients with RA (Bacani AK, et al. Arthritis Rheum. 2012;64:53-61). Schreiber and colleagues assessed 386 patients with systemic sclerosis, comparing an easily applied formula to determine pulmonary function against data from right heart catheterization (Schreiber BE, et al. Arthritis Rheum. 2011;63:3531-3539). The formula, which incorporates mean pulmonary artery pressure, oxygen saturation, and diffusing capacity for carbon monoxide, can identify subgroups with low, average, or high prevalence of pulmonary hypertension, and thus should improve the selection of patients for right heart catheterization. In comparing 611 patients with

Continued from cover

PsA and 449 patients with psoriasis, the rates of hypertension, obesity, hyperlipidemia, type 2 diabetes, and admission to an intensive care unit were all significantly higher in the patients with inflammatory joint disease (Husted JA, et al. Arthritis Care Res [Hoboken]. 2011;63:1729-1735).

“The Kingsley study findings challenge us to ask the very important question: Should methotrexate continue to be used as an effective control of synovitis in patients with PsA?” —David A. Isenberg, MD, FRCP, FAMS

A comprehensive review of several databases found no overall increase in the risk of malignancy with long er exposure to tumor necrosis factor (TNF)-alpha blockers, with the sole exception of a small increase in skin cancer (Mariette X, et al. Ann Rheum Dis. 2011;70:1895-1904). Treatment Studies (Not Clinical Trials) Emery and colleagues studied 493 patients with an inadequate response to methotrexate and randomized them to 1 of 2 treatment strategies: a treatto-target strategy in which assessments were made 24 weeks after each course of rituximab, with retreatment if the patient was not in remission; or retreatment at the physician’s discretion at least 24 weeks after the first course and 16 weeks after later courses (Emery P, et al. Rheumatology [Oxford]. 2011;50:2223-2232). The treatto-target strategy was associated with significant improvement in the DAS28 and with lower HAQ Disability Index scores. It also resulted in significantly more patients achieving a major cliniDecember 2012

cal response and in a reduction in the incidence of RA flares. In a prospective study of 1991 pa tients receiving total knee replacement, the strongest determinants of achieving a favorable 6-month postoperative Oxford Knee Score were preoperative pain or function, the diagnosis of RA rather than osteoarthritis, deprivation (those in poorer areas did worse), and anxiety or depression (Judge A, et al. Rheumatology [Oxford]. 2012;51:1804-1813). Body mass index was not an important predictor. A retrospective case-control study of 54 cases of allopurinol (Zyloprim) hypersensitivity syndrome and 157 controls (ie, patients with gout and allopurinol hypersensitivity syndrome) found an increased risk of allopurinol hypersensitivity syndrome as the starting dosage of allopurinol increased (Stamp LK, et al. Arthritis Rheum. 2012;64:2529-2536). “The key point is that you need to start allopurinol rather cautiously if you want to avoid this syndrome,” Dr Isenberg said. “With normal kidney function, it is okay to start at 100 to 150 mg per day; with moderate chronic kidney disease, start with 50 mg per day; and for severe kidney disease, start with 50 mg per day on alternative days.” In a population-based study looking at risk factors for progressive multifocal leukoencephalopathy (PML) among >2 million patients with rheumatic diseases, 53 patients with PML were identified (Bharat A, et al. Arthritis Care Res [Hoboken]. 2012;64:612615). Most of the patients with PML were positive for HIV and/or cancer; 9 had received biologic drugs before a hospitalization for PML. The incidence of PML was very low (0.2 cases per 100,000 patients) among patients with rheumatic diseases in the absence of HIV and/or cancer. Soliman and colleagues looked at the British Society for Rheumatology’s biologic resister of 18,194 patients with RA in whom a first TNF-alpha blocking drug had failed (Soliman MM, et al. Arthritis Care Res [Hoboken]. 2012;64:1108-1115). Of these, 5338 patients switched from their first TNF-alpha blocker; 4158 of whom switched to a second TNF-alpha blocker and 1180 of whom switched to rituximab. Both the European League Against Rheumatism response and clinically important improvement in HAQ scores were superior in those patients who switched to rituximab rather than another TNF-alpha blocker. n

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Lupus

Latest Treatment Options for Lupus... be helpful in patients with nonrenal lupus and suboptimal response to initial therapy. “In my opinion, azathioprine [Imuran] appears to be helpful in about 50% of patients,” Dr Hahn said. Leflunomide (Arava) is another option; one study showed this drug achieved improvement in 30% of patients, and improvement was sustained while taking the drug. Other off-label options are mycophenolate mofetil (CellCept), belimumab (Benlysta), abatacept (Orencia), tumor necrosis factor inhibitors, and tocilizumab (Actemra) for lupus patients who have arthritis, but it is difficult to get reimbursement for these agents, she continued. Mycophenolate mofetil was as equally effective as intravenous cyclophosphamide (Cytoxan) for extrarenal manifestations of lupus in one study, but the benefits would have to outweigh the risks of this drug. Abatacept appears to be effective in some patients with polyarticular manifestations of lupus, Dr Hahn added. Belimumab is effective in treating patients with systemic lupus erythematosus (SLE), she stated. In a total of 1684 patients who were studied in phase 3 clinical trials of SLE, 51% responded to belimumab versus 38% for placebo at 1 year (P <.001). Belimumab reduced flares (including renal flares), reduced fatigue, and improved quality of life. Adverse events (AEs) of belimumab include infusion-related reactions in approximately 10% of patients, and this can be serious in approximately 1% of patients. Antihistamine and acetamin-

“Improvement can be induced in 75% of patients with currently available therapies, some of them off-label. New agents for lupus hold the promise of effective treatment for patients who are not doing well on their current therapy or have a lot of side effects.” —Bevra Hahn, MD ophen are advised before the first 2 infusions as prophylaxis, Dr Hahn said. In the large phase 3 clinical trials of belimumab, the rate of AEs was similar with belimumab and placebo— approximately 15%. Serious infections were reported in approximately 6% of patients in the belimumab cohort. Other relatively common side effects include headache, low-grade fever, increased arthralgia, nausea, and suicidal thinking. “Reconsider using belimumab in a patient with depression,” she stated.

Continued from cover

The recommended dose of belim umab is 10 mg/kg intravenously at days 0 and 2, at 4 weeks, and once monthly thereafter. Response is slow and can take up to 6 months. Patients with improved serum complement levels by 8 weeks are likely to respond. Stopping the use of belimumab should be considered after 6 months if there is no response. Patients who are antithyroglobulin antibody positive are candidates for belimumab, as are patients with active SLE despite standard therapy. Rituximab Rituximab (Rituxan) has achieved response rates of 70% to 80% in open-label trials, and responses are seen in patients who fail with other treatments, Dr Hahn said. However, 2 prospective randomized trials found no difference between rituximab and placebo in patients receiving background immunosuppressive therapy. “Post-hoc analysis showed significantly fewer flares in patients with nonrenal lupus who took rituximab. Some patients will have a good response to this drug,” Dr Hahn noted. CNS Lupus Neuropsychiatric criteria have been incorporated into the Systemic Lupus International Collaborative Clinics criteria for central nervous system (CNS) lupus, which refers to neurologic and psychiatric symptoms in lupus. Symptoms include seizures, psychosis, mononeuritis, myelitis, peripheral neuropathy, cranial neuropathy, and acute confusional state.

Biomarker Discovery in Lupus Has Much Room for Growth By Wayne Kuznar Washington, DC—Although biomarker progress is easily discernible in cardiology and oncology, researchers are only at the beginning of the long, winding road of biomarker discovery in lupus, said Mary K. Crow, MD, Physician-in-Chief, and Chair, Division of Rheumatology, and Director of the Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York City, at the 2012 meeting of the American College of Rheumatology. “We are really just beginning to apply and test candidate biomarkers on the appropriate testing populations,” said Dr Crow.

“There is a dynamic between biomarker development, candidate biomarker identification, and the elucidation of pathogenic mechanisms that makes this endeavor very valuable, at least in lupus.” —Mary K. Crow, MD

Challenges in Lupus Biomarkers One of the pertinent questions today regarding lupus biomarkers is whether one can predict the future development of systemic lupus erythematosus (SLE) in a healthy individual. “I think that is a dream. Perhaps the more pressing question is can we predict the future development of a lupus flare?” Dr Crow asked. Predicting the development of a lupus flare has significance in terms of patient management and drug development, she added. “There is a dynamic between biomarker development, candidate bio-

at a glance ➤ Off-label options for patients with lupus include mycophenolate mofetil, belimumab, abatacept, tumor necrosis factor inhibitors, and tocilizumab ➤ In phase 3 clinical trials, 51% of patients with lupus responded to belimumab versus 38% with placebo at 1 year ➤ The recommended dose of belimumab is 10 mg/kg IV at days 0 and 2, at 4 weeks, and once monthly thereafter “I believe worsening depression is a symptom of oncoming lupus flare,” Dr Hahn stated. The treatment of CNS lupus is an evolving area. First, determine whether the symptoms are caused by lupus, which will be the case in approximately 50% of patients, she said. Then determine whether the symptoms are vascular or nonvascular and inflammatory versus noninflammatory with laboratory tests and magnetic resonance imaging (MRI). The European League Against Rheumatism guidelines for CNS lupus include MRI analysis and treatment with steroids plus immunosuppressive therapy. Other causes of neuropsychiatric symptoms should be excluded. If stroke or transient ischemic attack occur, treat these and other cardiovascular conditions as you would patients without lupus, she said. n

See also Personalized Medicine marker identification, and the elucidation of pathogenic mechanisms that makes this endeavor very valuable, at least in lupus,” Dr Crow explained. “Lupus is a most complex disease. In trying to tackle the identification of candidate biomarkers, we have to keep the whole disease in mind.” Her presentation highlighted the significant practical challenges that limit the optimal management and outcomes in patients with SLE: • Recognizing the pathogenic basis of disease heterogeneity to enable the creation and the application of appropriately targeted therapies Continued on page 8

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Lupus

Biomarker Discovery in Lupus Has Much... • Recognizing the biomarkers of disease activity and the response to therapy that would allow for the monitoring of efficacy in clinical trials and for consistent patient management • Determining the future flare predictors that would enhance patient enrollment in clinical trials and permit the timely initiation of flare prevention treatment in practice. “In studying lupus, we are fortunate that the blood really does represent a window into the disease,” Dr Crow said. Phenotyping cells has proved to be beneficial, as has proteomic analysis, which has yet to be fully explored. Additional value can be extracted from gene expression analysis, microRNA, and genome methylation. Candidate biomarkers in SLE fall into several categories, including cell analysis, proteomics, genetic polymorphisms and mutations, epigenetic modifications, gene expression, and microRNA. Cell analysis candidate biomarkers include T follicular helper cells (ie, CXCR5, ICOS, PD-1), cell-bound complement activation products, and mitochondrial hyperpolarization. The proteomics category includes cytokines and the von Willebrand factor. Epigenetic modifications include differentially methylated loci. MicroRNA involves expression and circulating. Anti-dsDNA Research In one study involving a group of patients with lupus, researchers in Pittsburgh analyzed anti–double-stranded DNA (anti-dsDNA) levels. Although anti-dsDNA is specific,

according to Dr Crow it does not hold as much utility as researchers would like. In the study, an SLE diagnostic index was identified that

“It is important to remember that clinical judgment and assessment are at the core of diagnosing lupus. Biomarkers have much less to add than they do in terms of predicting disease flare and measuring or confirming disease activity,” —Mary K. Crow, MD was somewhat more helpful than anti-dsDNA in terms of identifying patients with lupus. “It is important to remember that clinical judgment and assessment are at the core of diagnosing lupus. Biomarkers have much less to add than they do in terms of predicting disease flare and measuring or confirming disease activity,” she said. Much of Dr Crow’s current research is focused on gene expression. “Gene expression analysis distinguishes patients with SLE from healthy controls, but shows apparent heterogeneity among patients,” she noted. “The goal of our research is to use longitudinal biologic data from patients with SLE analyzed in the context of clinical data to characterize disease heterogeneity, correlates of disease activity, and biologic precursors of a flare.”

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Dr Crow and her colleagues are now investigating the role of neutrophils in generating lupus flare. For future study, she plans to test the hypothesis that neutrophils are directly related to the development of anti-DNA autoantibodies and that both neutrophils and anti-DNA antibodies are primary mediators of lupus flare. “What was satisfying, based on our growing burden of data suggesting that neutrophils are important in lupus flares, was the fact that the top-ranked differentially expressed transcripts were virtually all related to neutrophil granulocyte signature,” she said. So what is a predictor of a future lupus flare? The use of a 4-gene score helps to predict a future flare, said Dr Crow. Patients with a low 4-gene score at nonflaring visits are less likely to develop flares than those who had a high 4-gene score, according to her study findings. In research designed to identify predictors of future flare, patients with SLE were subdivided into 2 groups based on the annual rate of mild-to-moderate and severe flares. There were 11 patients with >1 flare annually who were designated as high flaring; 11 patients with <1 flare annually were designated as low flaring. In a summary of biologic precursors of flare, a 4-gene score (ie, interferon-induced protein with tetratricopeptide repeats 3; killer cell lectin-like receptor subfamily B, member 1; cluster of differentiation 38; and matrix metalloproteinase-8)

was significantly higher at nonflaring visits in high-flaring versus low-flaring patients with SLE. Comparison of high-flaring and low-flaring patients with SLE at the time of nonflaring visits identifies the novel pathways and gene transcripts associated with subsequent flares. Overall, Dr Crow said that the identification of predictors of future flares and predictors of future development of disease will require more statistical tools and analysis. Promising candidates for further study include cell-bound complement activation products, cell phenotypes associated with disease activity, gene expression scores, plasma von Willebrand factors, and the novel transcripts identified in future-flaring patients with SLE. n

73,629 NHS-enrolled women (mean age, 43 years) completed the FFQ, and 45,544 women (mean age, 35 years) of the NHSII cohort completed the supplemental FFQ. Both questionnaires were designed to elicit information about foods and beverages that are common in adolescence (eg, milkshakes and other snack foods containing dairy products). Incident RA was confirmed in 652 women in the NHS cohort and in 148 women in the NHSII cohort. Incident SLE was confirmed in 122 women in the NHS cohort and in 54 women in the NHSII cohort. Using age- and caloric-adjusted and multivariate- adjusted analyses did not show any significant link between the vitamin

D intake during adolescence and the risk for adult-onset RA or SLE. In addition, no association was seen between sun exposure and/or sunscreen use during adolescence and adult-onset RA or SLE. Many studies have reported lower levels of vitamin D in patients with diagnosed SLE compared with controls, but other studies have found no association between adult dietary intake of vitamin D before the diagnosis of RA or SLE and the development of these conditions. This suggests that further studies are needed to explore the role of vitamin D in RA and SLE, and the impact of vitamin D intake throughout the life span and these conditions. n

at a glance ➤ Phenotyping cells has proved beneficial, as has proteomic analysis ➤ Additional value can be extracted from gene expression analysis, microRNA, and genome methylation ➤ Although anti-dsDNA is specific, it is not as useful as was expected ➤ The use of a 4-gene score helps to predict future flares ➤ A low score is associated with a reduced likelihood of developing flares

In The Literature Vitamin D Intake in Adolescence Not Linked to Lupus or Arthritis in Adulthood

Evidence is growing regarding the immunomodulatory effects of vitamin D, with potential involvement in autoimmune diseases. Early-life exposure to vitamin D has been associated with the development of autoimmune conditions, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), but no study has investigated the potential link between vitamin D intake during adolescence (a time of significant physiologic, immunologic, hormonal, and health-related lifestyle changes) and the risk for developing RA and SLE later in life. A new study

has recently investigated this specific association (Hiraki LT, et al. Arthritis Care Res. 2012;64:1829-1836). The study included women from 2 large, longitudinal cohort studies—the Nurses’ Health Study (NHS), which began in 1976, and the Nurses’ Health Study II (NHSII), which began in 1989. All women were asked to complete a questionnaire every 2 years to update their information regarding diet, drug therapies, anthropometrics, and diagnosed health conditions. The NHS questionnaire included a 116-item food frequency questionnaire (FFQ) and the NHSII cohort completed a 124-item supplemental FFQ. After excluding those reporting very low or very high caloric intake,

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Biomarker Panel an Objective Measure of Disease Activity, Treatment Response in Rheumatoid Arthritis By Wayne Kuznar Washington, DC—A panel of disease biomarkers can measure changes in disease activity in response to a range of therapies for rheumatoid arthritis (RA), researchers announced at the 2012 meeting of the American College of Rheumatology (ACR). Using a score derived from a panel of biomarkers known as Vectra DA, several studies confirmed changes in disease activity in response to the traditional disease-modifying therapy abatacept (Orencia) and interleukin (IL)-6 inhibition. The biomarker panel integrates 12 serum biomarkers associated with RA disease severity (Figure) into a single objective score, which may be used to inform treatment decisions. The 12 biomarkers in the panel include: • 1 adhesion molecule: vascular cell adhesion molecule-1 • 2 growth factors: epidermal growth factor and vascular endothelial growth factor-A • 2 cytokine receptors: IL-6 and tumor necrosis factor receptor type 1 • 2 matrix metalloproteinases: matrix metalloproteinase-1 (or collagenase-1) and matrix metalloproteinase-3 (or stromelysin-1) • 1 skeletal-related protein: chitinase 3– like protein • 2 hormones: leptin and resistin • 2 acute-phase proteins: serum amyloid A and C-reactive protein (CRP). The Data A team of Japanese investigators from the University of Occupational and Environmental Health, Kitakyu shu, Japan, conducted separate studies of the biomarker panel in patients with RA who received the IL-6 inhibitor tocilizumab (Actemra) or the Janus kinase inhibitor tofacitinib (Xeljanz). In one study, 52 patients with RA

received tocilizumab for at least 1 year; their biomarker disease activity score (DAS) was measured at baseline and again at week 52. A significant correlation was seen between the biomarker score and the score on the DAS 28-joint (DAS28)-erythrocyte sedimentation rate (ESR), DAS28-CRP, Clinical Disease Activity Index, and the Simplified Disease Activity Index (SDAI), as well as the health assessment questionnaire and the Modified Total Sharp Score (mTSS) that indicates structural damage.

“We have developed a molecular gold standard that is the equivalent of a carefully done examination, but now it is done in the blood where there is no subjectivity. We feel it has some advantages over standard measures of disease activity.” —David N. Chernoff, MD The biomarker score was able to differentiate between clinical remission and nonremission, as defined by other criteria, including the ACR/European League Against Rheumatism definition. The biomarker score reflected disease activity and tracked therapeutic effects; furthermore, remission, as defined by the biomarker score, was preferable to DAS28 for predicting good outcome in radiographic damage and in physical function. Using the biomarker score, 37 patients who received tofacitinib for 28 to 40 weeks in phase 2 or phase 3 clinical trials were evaluated. Clini-

Reprinted with permission.

cal remission defined by a biomarker score of ≤25 was seen in 40.5% of the patients, compared with 37.8% of patients based on the SDAI and 35.1% by the DAS28-ESR. The mean IL-6 levels decreased markedly at 1 year; 78% of the patients who achieved an IL-6 concentration ≤9 pg/mL had progression of mTSS by ≤0.5 compared with only 38% of the patients with IL-6 concentrations >9 pg/mL. A Molecular Gold Standard “We have developed a molecular gold standard that is the equivalent of a carefully done examination, but now it is done in the blood where there is no subjectivity,” said David N. Chernoff, MD, Senior Vice President of Medical Affairs, Crescendo Bioscience, the developer of Vectra DA. “We feel it has some advantages over standard measures of disease activity.” In a study conducted by researchers from Crescendo Bioscience, significant correlations were observed between the DAS28-CRP and the multibiomarker disease activity (MBDA) score

in 50 patients with RA who received abatacept plus methotrexate (Trexall) to placebo. Those randomized to abatacept plus methotrexate had significantly greater improvements in the MBDA score and the DAS28CRP versus those receiving placebo. The MBDA score also correlated with synovitis and osteitis scores. The panel of biomarkers also responded quickly to combination therapy using methotrexate and prednisone and correlated with the DAS28ESR in a 104-patient study. “Doctors have used low-dose prednisone in patients with RA for a very long time. It has very rapid effects, it makes people feel better, but no one really knows if it is appropriate to use steroids routinely in patients with RA,” Dr Chernoff said. “For the first time we are seeing why steroids have such a profound effect on disease activity and better x-ray outcomes. You can see it in the composite panel and the individual biomarkers. Molecular profiling is the new dawn of rheumatology.” n

Effects of the Microbiome on Rheumatoid Arthritis and Other Autoimmune Diseases By Phoebe Starr Washington, DC—Ongoing research using DNA sequencing is being used to examine how the microbiome in the oral cavity and in the gastrointestinal tract affects autoimmune diseases such as rheumatoid arthritis (RA), scientists explained at the 2012 meeting of the American College of Rheumatology.

“This is an old story with new technology. Scientists have known for about 400 years since the invention of the microscope that microbes exist. For centuries, however, scientists were unable to culture bacteria and did not have any idea of how many microbes are in the human body. Today, high-throughput DNA

sequencing bypasses the need for culturing,” said Jose U. Scher, MD, Director, Arthritis Clinic, New York University Hospital for Joint Diseases, New York City. Scientists are now able to classify the human microbiome and identify the genes associated with bacteria and other microorganisms, Dr Scher

explained. “DNA allows us to search for bacteria within the human body without the need for culturing. The idea is to better understand what trillions of microorganisms are doing in the human body and whether changes in their composition may affect physiology and pathology.” Basic research has shown that mice Continued on page 10

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Osteoarthritis

Osteoporosis Drug Has Positive Effects for Patients with Knee Osteoarthritis By Phoebe Starr Washington, DC—Strontium ranelate doses of 1 g daily and 2 g daily slowed the progression of knee osteoarthritis (OA) over a 3-year period in the double-blind placebo-controlled Strontium Ranelate in Knee Osteoarthritis Trial (SEKOIA), investigators reported at the 2012 meeting of the American College of Rheumatology. Fewer patients receiving the 1-g and 2-g doses of strontium ranelate developed radiologic progression over the threshold that predicts the need for knee surgery. The delay in radiographic progression in patients treated with strontium ranelate was accompanied by symptom improvement for patients treated with 2 g daily. “This study implies that this drug can reduce the number of patients with knee OA who require surgeries. Going forward, the 2-g daily dose would be the most appropriate for clinical practice, because it was associated with a 27% reduction in radiological joint space narrowing, a surrogate of cartilage loss, versus placebo. This translates into nearly a year for average radiological osteoarthritis pro gression saved over 3 years,” said lead author Jean-Yves Reginster, MD, President and Chairman, Department of Public Health Sciences, University of Liège, Belgium. “Fourteen patients are needed to treat with 2 g daily over 2 years to prevent 1 case of radiologic progression.”

Strontium ranelate is approved in more than 100 countries, but not in the United States, for the treatment of postmenopausal osteoporosis. Experts said that the drug manufacturer did not provide fracture data, which is part of the US Food and Drug Administration criteria for the approval for the treatment of osteoporosis. This drug is being investigated for the treatment of knee OA.

“The 2-g daily dose would be the most appropriate for clinical practice, because it was associated with a 27% reduction in radiological joint space narrowing, a surrogate of cartilage loss, versus placebo.” —Jean-Yves Reginster, MD Strontium is taken up by the bones and tooth enamel in the place of calcium. In clinical trials, the drug was found to aid bone growth; increase bone density; and lessen vertebral, peripheral, and hip fractures in women. The drug increases bone formation and reduces bone resorption, resulting in a rebalance of bone turnover in favor of bone formation. SEKOIA was conducted at 98 cen-

ters in 18 countries. The study enrolled 1683 patients aged ≥50 years with mild-to-moderate knee OA and randomized them to receive either 1 g or 2 g daily of strontium ranelate versus placebo. More than 66% of the participants were women (mean age, 63 years); the mean duration of knee OA was 7 years. At baseline, all of the participants had symptomatic disease and joint space width of between 2.5 mm and 5 mm in the medial compartment of the knee on radiographic imaging. For the primary end point of joint space narrowing, both doses of strontium ranelate were significantly superior to placebo. Joint space narrowing was –0.23 mm and –0.27 mm with the 1-g and 2-g doses of the drug, respectively, versus –0.37 mm with placebo. This represents differences of 0.14 mm compared with placebo for the 1-g dose (P <.001) and 0.1 mm for the 2-g dose (P = .018). A 0.5-mm decrease indicates a 5-fold greater need for knee surgery 5 to 10 years later, Dr Reginster explained. Although both doses were significantly superior to placebo for the primary end point of the study, only the 2-g dose achieved significant clinical benefits compared with placebo on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the WOMAC subscales for pain and knee functions. On the global WOMAC scale, strontium ranelate 2 mg achieved –52 versus –41 for placebo (P = .045); the difference

at a glance

➤ Strontium ranelate is being investigated for the treatment of knee OA ➤ Joint space narrowing was –0.23 mm and –0.27 mm with the 1-g and 2-g doses, respectively, versus –0.37 mm with placebo ➤ A 0.5-mm decrease indicates a 5-fold greater need for knee surgery 5 to 10 years later ➤ Only the 2-g dose achieved significant clinical benefits compared with placebo on the WOMAC scale was also significant for knee pain (P = .065) and physical function (P = .099). Adverse events (AEs) were comparable between strontium ranelate and placebo; 88% of the 1-g dose group, 88% of the 2-g dose group, and 87% of the placebo group reported an AE, and 17% of each group reported serious AEs. Dr Reginster and colleagues believe that strontium ranelate has several positive effects that may explain its benefits in patients with knee OA: The drug decreases the production of proteoglycans and type 2 collagen, and inhibits the production of cytokines that are associated with cartilage degradation. Strontium ranelate is contraindicated in patients with a history of deep-vein thrombosis. n

Personalized Medicine in Rheumatology

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Effects of the Microbiome on Rheumatoid Arthritis... predisposed to RA and other autoimmune diseases do not develop these diseases in a sterile environment with no exposure to microorganisms. Other studies have examined the role of microorganisms in directly activating cells in both the innate and the adaptive immune systems. Dr Scher and his colleagues are studying patients with new-onset RA to ascertain whether there is an association between subgingival and gut bacteria and the development of RA. At the same session, Susan Lynch, PhD, Associate Professor, Department of Medicine, and Director of the Colitis and Crohn’s Disease Microbiome Research Core, University of California, San Francisco, discussed the role of the microbiome in

gut immunity and in inflammatory bowel disease.

“This is an old story with new technology. Scientists have known for about 400 years since the invention of the microscope that microbes exist. Today, high-throughput DNA sequencing bypasses the need for culturing.” —Jose U. Scher, MD She explained that next-generation sequencing has led to the profiling of the 16S ribosomal RNA gene found in

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all bacteria and to identify which bacterium it came from. “If we sequence a pool of those genes amplified from a sample, we get an idea of which bacteria are present and how abundant they are, which essentially produces a microbial fingerprint for that sample,” Dr Lynch told listeners. Another technology that Dr Lynch and others are working with is a phylogenetic microarray that uses oligonucleotide probes on an array surface to target regions of the 16S ribosomal RNA gene that are specific to certain types of bacteria. She and other investigators are using this technology to help identify microorganisms that are present in a given sample, and the technology is particularly helpful in identifying species that discriminate between

health and disease states, she said. Dr Lynch is particularly interested in the influence of microbial exposures early in life on the development of the gastrointestinal microbiome that predisposes children to allergic diseases. Specific microorganisms can induce immune responses that are associated with autoimmune diseases, she continued. For example, segmented filamentous bacteria can induce the proliferation of Th17 cells, which are relatively recently identified T-helper cells that are associated with lupus, RA, and inflammatory bowel disease. “Clearly there is a relationship between the composition of the intestinal microbiome and autoimmune responses,” Dr Lynch stated. n VOL. 1

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DO NOT RE-SIZE Ad unit Project # must match this project # 64M-896403

HUMIRA® (adalimumab) WARNINGS: SERIOUS INFECTIONS AND MALIGNANCY SERIOUS INFECTIONS Patients treated with HUMIRA are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. HUMIRA should be discontinued if a patient develops a serious infection or sepsis. Reported infections include: • Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before HUMIRA use and during therapy. Treatment for latent TB should be initiated prior to HUMIRA use. • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness. • Bacterial, viral and other infections due to opportunistic pathogens, including Legionella and Listeria. The risks and benefits of treatment with HUMIRA should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with HUMIRA, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy. [See Warnings and Precautions and Adverse Reactions] MALIGNANCY Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which HUMIRA is a member. [See Warnings and Precautions] Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including HUMIRA. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases has occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants. INDICATIONS AND USAGE Rheumatoid Arthritis HUMIRA is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. HUMIRA can be used alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Juvenile Idiopathic Arthritis HUMIRA is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in pediatric patients 4 years of age and older. HUMIRA can be used alone or in combination with methotrexate. Psoriatic Arthritis HUMIRA is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis. HUMIRA can be used alone or in combination with non-biologic DMARDs. Ankylosing Spondylitis HUMIRA is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis. Crohn’s Disease HUMIRA is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy. HUMIRA is indicated for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab. Plaque Psoriasis HUMIRA is indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate. HUMIRA should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician [see Boxed Warnings and Warnings and Precautions]. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS (see also Boxed WARNINGS) Serious Infections Patients treated with HUMIRA are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease. The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections in patients with rheumatoid arthritis (RA); therefore, the concomitant use of HUMIRA and these biologic products is not recommended in the treatment of patients with RA [see Warnings and Precautions and Drug Interactions]. Treatment with HUMIRA should not be initiated in patients with an active infection, including localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. The risks and benefits of treatment should be considered prior to initiating therapy in patients: • with chronic or recurrent infection; • who have been exposed to tuberculosis; • with a history of an opportunistic infection; • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or • with underlying conditions that may predispose them to infection. Tuberculosis Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving HUMIRA, including patients who have previously received treatment for latent or active tuberculosis. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating HUMIRA and periodically during therapy. Treatment of latent tuberculosis infection prior to therapy with TNF blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Anti-tuberculosis therapy should also be considered prior to initiation of HUMIRA in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Tuberculosis should be strongly considered in patients who develop a new infection during HUMIRA treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis. Monitoring Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with HUMIRA, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with HUMIRA. HUMIRA should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with HUMIRA should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated. Invasive Fungal Infections For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy. Malignancies The risks and benefits of TNF-blocker treatment including HUMIRA should be considered prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF blocker in patients who develop a malignancy. Malignancies in Adults In the controlled portions of clinical trials of some TNF-blockers, including HUMIRA, more cases of malignancies have been observed among TNF-blocker-treated adult patients compared to control-treated adult patients. During the controlled portions of 32 global HUMIRA clinical trials in adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn’s disease (CD), and plaque psoriasis (Ps), malignancies, other than non-melanoma (basal cell and squamous cell) skin cancer,

03-A608 Humira PB-10.5x13(1.333).indd 1

PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION were observed at a rate (95% confidence interval) of 0.6 (0.38, 0.93) per 100 patient-years among 6694 HUMIRA-treated patients versus a rate of 0.5 (0.28, 1.05) per 100 patient-years among 3749 controltreated patients (median duration of treatment of 4 months for HUMIRA-treated patients and 4 months for control-treated patients). In 45 global controlled and uncontrolled clinical trials of HUMIRA in adult patients with RA, PsA, AS, CD and Ps, the most frequently observed malignancies, other than lymphoma and NMSC, were breast, colon, prostate, lung, and melanoma. The malignancies in HUMIRA-treated patients in the controlled and uncontrolled portions of the studies were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race). In controlled trials of other TNF blockers in adult patients at higher risk for malignancies (i.e., patients with COPD with a significant smoking history and cyclophosphamide-treated patients with Wegener’s granulomatosis), a greater portion of malignancies occurred in the TNF blocker group compared to the control group. Non-Melanoma Skin Cancer During the controlled portions of 32 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, and Ps, the rate (95% confidence interval) of NMSC was 0.7 (0.50, 1.11) per 100 patient-years among HUMIRA-treated patients and 0.2 (0.06, 0.56) per 100 patient-years among control-treated patients. All patients, and in particular patients with a medical history of prior prolonged immunosuppressant therapy or psoriasis patients with a history of PUVA treatment should be examined for the presence of NMSC prior to and during treatment with HUMIRA. Lymphoma and Leukemia In the controlled portions of clinical trials of all the TNF-blockers in adults, more cases of lymphoma have been observed among TNF blocker-treated patients compared to control-treated patients. In the controlled portions of 32 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, and Ps, 3 lymphomas occurred among 6694 HUMIRA-treated patients versus 1 among 3749 control-treated patients. In 45 global controlled and uncontrolled clinical trials of HUMIRA in adult patients with RA, PsA, AS, CD and Ps with a median duration of approximately 0.6 years, including 22,026 patients and over 32,000 patient-years of HUMIRA, the observed rate of lymphomas was approximately 0.11 per 100 patient-years. This is approximately 3-fold higher than expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race). Rates of lymphoma in clinical trials of HUMIRA cannot be compared to rates of lymphoma in clinical trials of other TNF blockers and may not predict the rates observed in a broader patient population. Patients with RA and other chronic inflammatory diseases, particularly those with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF blockers. Post-marketing cases of acute and chronic leukemia have been reported in association with TNF-blocker use in RA and other indications. Even in the absence of TNF-blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia. Malignancies in Pediatric Patients and Young Adults Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers (initiation of therapy ≤ 18 years of age), of which HUMIRA is a member. Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources including registries and spontaneous postmarketing reports. Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including HUMIRA. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases has occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants. Hypersensitivity Reactions In postmarketing experience, anaphylaxis and angioneurotic edema have been reported rarely following HUMIRA administration. If an anaphylactic or other serious allergic reaction occurs, administration of HUMIRA should be discontinued immediately and appropriate therapy instituted. In clinical trials of HUMIRA in adults, allergic reactions overall (e.g., allergic rash, anaphylactoid reaction, fixed drug reaction, non-specified drug reaction, urticaria) have been observed in approximately 1% of patients. Hepatitis B Virus Reactivation Use of TNF blockers, including HUMIRA, may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating TNF blocker therapy. Prescribers should exercise caution in prescribing TNF blockers for patients identified as carriers of HBV. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. In patients who develop HBV reactivation, HUMIRA should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Neurologic Reactions Use of TNF blocking agents, including HUMIRA, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis (MS) and optic neuritis, and peripheral demyelinating disease, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use of HUMIRA in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders. Hematological Reactions Rare reports of pancytopenia including aplastic anemia have been reported with TNF blocking agents. Adverse reactions of the hematologic system, including medically significant cytopenia (e.g., thrombocytopenia, leukopenia) have been infrequently reported with HUMIRA. The causal relationship of these reports to HUMIRA remains unclear. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on HUMIRA. Discontinuation of HUMIRA therapy should be considered in patients with confirmed significant hematologic abnormalities. Use with Anakinra Concurrent use of anakinra (an interleukin-1 antagonist) and another TNF-blocker, was associated with a greater proportion of serious infections and neutropenia and no added benefit compared with the TNF-blocker alone in patients with RA. Therefore, the combination of HUMIRA and anakinra is not recommended [see Drug Interactions]. Heart Failure Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. Cases of worsening CHF have also been observed with HUMIRA. Physicians should exercise caution when using HUMIRA in patients who have heart failure and monitor them carefully. Autoimmunity Treatment with HUMIRA may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with HUMIRA, treatment should be discontinued [see Adverse Reactions]. Immunizations In a placebo-controlled clinical trial of patients with rheumatoid arthritis, no difference was detected in anti-pneumococcal antibody response between HUMIRA and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with HUMIRA. Patients on HUMIRA may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving HUMIRA. It is recommended that juvenile idiopathic arthritis patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating HUMIRA therapy. Patients on HUMIRA may receive concurrent vaccinations, except for live vaccines. Use with Abatacept In controlled trials, the concurrent administration of TNF-blockers and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; the combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of abatacept with TNF-blockers including HUMIRA is not recommended [see Drug Interactions]. ADVERSE REACTIONS Clinical Studies Experience The most serious adverse reactions were: • Serious Infections [see Warnings and Precautions] • Malignancies [see Warnings and Precautions] The most common adverse reaction with HUMIRA was injection site reactions. In placebo-controlled trials, 20% of patients treated with HUMIRA developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 14% of patients receiving placebo. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation. The proportion of patients who discontinued treatment due to adverse reactions during the double-blind, placebo-controlled portion of Studies RA-I, RA-II, RA-III and RA-IV was 7% for patients taking HUMIRA and 4% for placebo-treated patients. The most common adverse reactions leading to discontinuation of HUMIRA were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%). Infections In the controlled portions of the 32 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD and Ps, the rate of serious infections was 4.7 per 100 patient-years in 6694 HUMIRA-treated patients versus a rate of 2.7 per 100 patient-years in 3749 control-treated patients. Serious infections observed included pneumonia, septic arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis [see Warnings and Precautions]. Tuberculosis and Opportunistic Infections In 45 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD and Ps that included 22,026 HUMIRA-treated patients, the rate of reported active tuberculosis was 0.22 per 100 patient-years and the

rate of positive PPD conversion was 0.07 per 100 patient-years. In a subgroup of 8940 U.S. and Canadian HUMIRA-treated patients, the rate of reported active TB was 0.07 per 100 patient-years and the rate of positive PPD conversion was 0.06 per 100 patient-years. These trials included reports of miliary, lymphatic, peritoneal, and pulmonary TB. Most of the TB cases occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease. In these global clinical trials, cases of serious opportunistic infections have been reported at an overall rate of 0.07 per 100 patient-years. Some cases of serious opportunistic infections and TB have been fatal [see Warnings and Precautions]. Autoantibodies In the rheumatoid arthritis controlled trials, 12% of patients treated with HUMIRA and 7% of placebo-treated patients that had negative baseline ANA titers developed positive titers at week 24. Two patients out of 3046 treated with HUMIRA developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms. The impact of long-term treatment with HUMIRA on the development of autoimmune diseases is unknown. Liver Enzyme Elevations There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of HUMIRA (40 mg SC every other week) in patients with RA, PsA, and AS with control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULN occurred in 3.5% of HUMIRA-treated patients and 1.5% of control-treated patients. Since many of these patients in these trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between HUMIRA and the liver enzyme elevations is not clear. In controlled Phase 3 trials of HUMIRA (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on Days 1 and 15, respectively, followed by 40 mg every other week) in patients with Crohn’s disease with control period duration ranging from 4 to 52 weeks, ALT elevations ≥ 3 x ULN occurred in 0.9% of HUMIRA-treated patients and 0.9% of control-treated patients. In controlled Phase 3 trials of HUMIRA (initial dose of 80 mg then 40 mg every other week) in patients with plaque psoriasis with control period duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of HUMIRA-treated patients and 1.8% of control-treated patients. Immunogenicity Patients in Studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab during the 6- to 12-month period. Approximately 5% (58 of 1062) of adult rheumatoid arthritis patients receiving HUMIRA developed low-titer antibodies to adalimumab at least once during treatment, which were neutralizing in vitro. Patients treated with concomitant methotrexate had a lower rate of antibody development than patients on HUMIRA monotherapy (1% versus 12%). No apparent correlation of antibody development to adverse reactions was observed. With monotherapy, patients receiving every other week dosing may develop antibodies more frequently than those receiving weekly dosing. In patients receiving the recommended dosage of 40 mg every other week as monotherapy, the ACR 20 response was lower among antibody-positive patients than among antibody-negative patients. The long-term immunogenicity of HUMIRA is unknown. In patients with juvenile idiopathic arthritis, adalimumab antibodies were identified in 16% of HUMIRA-treated patients. In patients receiving concomitant methotrexate, the incidence was 6% compared to 26% with HUMIRA monotherapy. In patients with ankylosing spondylitis, the rate of development of antibodies to adalimumab in HUMIRA-treated patients was comparable to patients with rheumatoid arthritis. In patients with psoriatic arthritis, the rate of antibody development in patients receiving HUMIRA monotherapy was comparable to patients with rheumatoid arthritis; however, in patients receiving concomitant methotrexate the rate was 7% compared to 1% in rheumatoid arthritis. In patients with Crohn’s disease, the rate of antibody development was 3%. In patients with plaque psoriasis, the rate of antibody development with HUMIRA monotherapy was 8%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 ug/ml. Among the patients whose serum adalimumab levels were < 2 ug/ml (approximately 40% of total patients studied), the immunogenicity rate was 20.7%. In plaque psoriasis patients who were on HUMIRA monotherapy and subsequently withdrawn from the treatment, the rate of antibodies to adalimumab after retreatment was similar to the rate observed prior to withdrawal. Other Adverse Reactions The data described below reflect exposure to HUMIRA in 2468 patients, including 2073 exposed for 6 months, 1497 exposed for greater than one year and 1380 in adequate and well-controlled studies (Studies RA-I, RA-II, RA-III, and RA-IV). HUMIRA was studied primarily in placebo-controlled trials and in long-term follow up studies for up to 36 months duration. The population had a mean age of 54 years, 77% were female, 91% were Caucasian and had moderately to severely active rheumatoid arthritis. Most patients received 40 mg HUMIRA every other week. Table 1 summarizes reactions reported at a rate of at least 5% in patients treated with HUMIRA 40 mg every other week compared to placebo and with an incidence higher than placebo. In Study RA-III, the types and frequencies of adverse reactions in the second year open-label extension were similar to those observed in the one-year double-blind portion. Table 1. Adverse Reactions Reported by ≥5% of Patients Treated with HUMIRA During Placebo-Controlled Period of Rheumatoid Arthritis Studies HUMIRA 40 mg subcutaneous Every Other Week (N=705) Adverse Reaction (Preferred Term) Respiratory Upper respiratory infection 17% Sinusitis 11% Flu syndrome 7% Gastrointestinal Nausea 9% Abdominal pain 7% Laboratory Tests* Laboratory test abnormal 8% Hypercholesterolemia 6% Hyperlipidemia 7% Hematuria 5% Alkaline phosphatase increased 5% Other Headache 12% Rash 12% Accidental injury 10% Injection site reaction ** 8% Back pain 6% Urinary tract infection 8% Hypertension 5% * Laboratory test abnormalities were reported as adverse reactions in European trials ** Does not include injection site erythema, itching, hemorrhage, pain or swelling

Placebo (N=690)

13% 9% 6% 8% 4% 7% 4% 5% 4% 3% 8% 6% 8% 1% 4% 5% 3%

Juvenile Idiopathic Arthritis Clinical Studies In general, the adverse reactions in the HUMIRA-treated pediatric patients in the juvenile idiopathic arthritis (JIA) trial were similar in frequency and type to those seen in adult patients [see Warnings and Precautions, Adverse Reactions]. Important findings and differences from adults are discussed in the following paragraphs. HUMIRA was studied in 171 pediatric patients, 4 to 17 years of age, with polyarticular JIA. Severe adverse reactions reported in the study included neutropenia, streptococcal pharyngitis, increased aminotransferases, herpes zoster, myositis, metrorrhagia, appendicitis. Serious infections were observed in 4% of patients within approximately 2 years of initiation of treatment with HUMIRA and included cases of herpes simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster. A total of 45% of children experienced an infection while receiving HUMIRA with or without concomitant MTX in the first 16 weeks of treatment. The types of infections reported in HUMIRA-treated patients were generally similar to those commonly seen in JIA patients who are not treated with TNF blockers. Upon initiation of treatment, the most common adverse reactions occurring in the pediatric population treated with HUMIRA were injection site pain and injection site reaction (19% and 16%, respectively). A less commonly reported adverse event in children receiving HUMIRA was granuloma annulare which did not lead to discontinuation of HUMIRA treatment. In the first 48 weeks of treatment, non-serious hypersensitivity reactions were seen in approximately 6% of children and included primarily localized allergic hypersensitivity reactions and allergic rash. Isolated mild to moderate elevations of liver aminotransferases (ALT more common than AST) were observed in children with JIA exposed to HUMIRA alone; liver enzyme test elevations were more frequent among those treated with the combination of HUMIRA and MTX than those treated with HUMIRA alone. In general, these elevations did not lead to discontinuation of HUMIRA treatment. In the JIA trial, 10% of patients treated with HUMIRA who had negative baseline anti-dsDNA antibodies developed positive titers after 48 weeks of treatment. No patient developed clinical signs of autoimmunity during the clinical trial. Approximately 15% of children treated with HUMIRA developed mild-to-moderate elevations of creatine phosphokinase (CPK). Elevations exceeding 5 times the upper limit of normal were observed in several patients. CPK levels decreased or returned to normal in all patients. Most patients were able to continue HUMIRA without interruption.

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Psoriatic Arthritis and Ankylosing Spondylitis Clinical Studies HUMIRA has been studied in 395 patients with psoriatic arthritis (PsA) in two placebo-controlled trials and in an open label study and in 393 patients with ankylosing spondylitis (AS) in two placebo-controlled studies. The safety profile for patients with PsA and AS treated with HUMIRA 40 mg every other week was similar to the safety profile seen in patients with RA, HUMIRA Studies RA-I through IV. Crohn’s Disease Clinical Studies HUMIRA has been studied in 1478 patients with Crohn’s disease in four placebo-controlled and two open-label extension studies. The safety profile for patients with Crohn’s disease treated with HUMIRA was similar to the safety profile seen in patients with RA. Plaque Psoriasis Clinical Studies HUMIRA has been studied in 1696 patients with plaque psoriasis in placebo-controlled and open-label extension studies. The safety profile for patients with plaque psoriasis treated with HUMIRA was similar to the safety profile seen in patients with RA with the following exceptions. In the placebo-controlled portions of the clinical trials in plaque psoriasis patients, HUMIRA-treated patients had a higher incidence of arthralgia when compared to controls (3% vs. 1%). Postmarketing Experience Adverse reactions have been reported during post-approval use of HUMIRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to HUMIRA exposure. Gastrointestinal disorders: Diverticulitis, large bowel perforations including perforations associated with diverticulitis and appendiceal perforations associated with appendicitis, pancreatitis Hepato-biliary disorders: Liver failure Immune system disorders: Sarcoidosis Nervous system disorders: Demyelinating disorders (e.g., optic neuritis, Guillain-Barré syndrome), cerebrovascular accident Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis, pulmonary embolism Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening psoriasis (all sub-types including pustular and palmoplantar), alopecia Vascular disorders: Systemic vasculitis, deep vein thrombosis DRUG INTERACTIONS Methotrexate Although methotrexate (MTX) reduces the apparent adalimumab clearance, the data do not suggest the need for dose adjustment of either HUMIRA or MTX. Biologic Products In clinical studies in patients with RA, an increased risk of serious infections has been seen with the combination of TNF blockers with anakinra or abatacept, with no added benefit; therefore, use of HUMIRA with abatacept or anakinra is not recommended in patients with RA [see Warnings and Precautions]. A higher rate of serious infections has also been observed in patients with RA treated with rituximab who received subsequent treatment

with a TNF blocker. There is insufficient information to provide recommendations regarding the concomitant use of HUMIRA and other biologic products for the treatment of RA, PsA, AS, Crohn’s Disease, and plaque psoriasis. Live Vaccines Live vaccines should not be given concurrently with HUMIRA [see Warnings and Precautions]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B - There are no adequate and well-controlled studies in pregnant women. Because animal reproduction and developmental studies are not always predictive of human response, HUMIRA should be used during pregnancy only if clearly needed. Pregnancy Registry: To monitor outcomes of pregnant women exposed to HUMIRA, a pregnancy registry has been established. Physicians are encouraged to register patients by calling 1-877-311-8972. Nursing Mothers It is not known whether adalimumab is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from HUMIRA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and efficacy of HUMIRA in pediatric patients for uses other than juvenile idiopathic arthritis (JIA) have not been established. Juvenile Idiopathic Arthritis In the JIA trial, HUMIRA was shown to reduce signs and symptoms of active polyarticular JIA in patients 4 to 17 years of age. HUMIRA has not been studied in children less than 4 years of age, and there are limited data on HUMIRA treatment in children with weight <15 kg. The safety of HUMIRA in pediatric patients in the JIA trial was generally similar to that observed in adults with certain exceptions [see Adverse Reactions]. Post-marketing cases of malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers including HUMIRA [see Warnings and Precautions]. Geriatric Use A total of 519 rheumatoid arthritis patients 65 years of age and older, including 107 patients 75 years of age and older, received HUMIRA in clinical studies RA-I through IV. No overall difference in effectiveness was observed between these subjects and younger subjects. The frequency of serious infection and malignancy among HUMIRA treated subjects over 65 years of age was higher than for those under 65 years of age. Because there is a higher incidence of infections and malignancies in the elderly population in general, caution should be used when treating the elderly. OVERDOSAGE Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies of HUMIRA have not been conducted to evaluate the carcinogenic potential or its effect on fertility. No clastogenic or mutagenic effects of HUMIRA were observed in the in vivo mouse micronucleus test or the Salmonella-Escherichia coli (Ames) assay, respectively. PATIENT COUNSELING INFORMATION Patients or their caregivers should be provided the HUMIRA “Medication Guide” and provided an opportunity to read it and ask questions prior to initiation of therapy. The healthcare provider should ask the patient questions to determine any risk factors for treatment. Patients developing signs and symptoms of infection should seek medical evaluation immediately. Patient Counseling Patients should be advised of the potential benefits and risks of HUMIRA. Physicians should instruct their patients to read the Medication Guide before starting HUMIRA therapy and to reread each time the prescription is renewed. • Infections Inform patients that HUMIRA may lower the ability of their immune system to fight infections. Instruct patients of the importance of contacting their doctor if they develop any symptoms of infection, including tuberculosis, invasive fungal infections, and reactivation of hepatitis B virus infections. • Malignancies Patients should be counseled about the risk of malignancies while receiving HUMIRA. • Allergic Reactions Patients should be advised to seek immediate medical attention if they experience any symptoms of severe allergic reactions. Advise latex-sensitive patients that the needle cap of the prefilled syringe contains latex. • Other Medical Conditions Advise patients to report any signs of new or worsening medical conditions such as congestive heart failure, neurological disease, autoimmune disorders, or cytopenias. Advise patients to report any symptoms suggestive of a cytopenia such as bruising, bleeding, or persistent fever. Ref: 03–A608-R28 Rev. May, 2012 64C-894702 MASTER 64M-896403

Rheumatology Practice Management

™

Advice for Streamlining Clinical Rheumatology Practice By Phoebe Starr Washington, DC—Creating an efficient rheumatology practice depends on acknowledging that your practice has inefficiencies, identifying the problems and challenges that lead to inefficiencies, and, finally, addressing them, according to business consultant Owen J. Dahl, MBA, Director, Owen Dahl Consulting, The Woodlands, TX, who spoke at the 2012 meeting of the American College of Rheumatology. “You can’t become efficient unless you have a culture that says you want to be efficient,” Mr Dahl said. Rheumatologists must lead the way for change in everyday practice, he told the audience. “Go back to your office and identify what you are going

at a glance ➤ Acknowledge that the practice has inefficiencies and identify the problems and challenges that lead to the inefficiencies ➤ Write a project charter to guide improvements in the business area of the practice ➤ View patient visits as a process from the time patients arrive at the clinic to the time they check out ➤ Eliminate any nonvalue steps in the process, and involve staff in implementing changes ➤ Identifying inefficiencies will help to streamline the patient visit process

to work on to change the culture. Talk to your key stakeholders, your fellow physicians, and staff. Tackle a simple issue first and then go on to the more

automotive industry. This principle rests on the idea that time may be wasted and that lags and delays in managing patient flow need to be

“You can’t become efficient unless you have a culture that says you want to be efficient. Go back to your office and identify what you are going to work on to change the culture. Talk to your key stakeholders, your fellow physicians, and staff. Tackle a simple issue first and then go on to the more challenging issues.” —Owen J. Dahl, MBA challenging issues,” Mr Dahl advised. Identifying team members, putting a charter together (more on that below), and evaluating the tools to use are key considerations. Change comes about by identifying the problem, developing a solution, implementing the solution, and following up on the progress of the implementation, he continued. A project charter is a written document that guides improvements in the business area of office practice. The charter identifies the task at hand and the team responsible for implementing change; it establishes the duties of each team member and sets a due date for implementation. Mr Dahl advocated “lean management,” a principle derived from the

addressed. Mr Dahl said that patient visits can be viewed as a process from the time a patient comes to clinic, moves through triage, and has to wait until he or she sees the provider; the process also includes postprovider time for prescription refills and scheduling new office visits, and it ends with check out. Identifying inefficiencies in this process will help to streamline the practice. It may be that patient wait time is a problem, or that check in or check out are causing delays. “Develop ways to make these steps more efficient, and eliminate unnecessary delays between these steps,” he advised. The goal of streamlining a rheumatology practice is to create more value

for the patient at each encounter and to accomplish this with less work. “We want to eliminate waste, eliminate variation, and eliminate the lag time between every step in the patient visit, because that creates lost value,” Mr Dahl stated. When identifying inefficiencies in one’s practice, question certain practices that appear to cause a lag or delay, and ask why the work is being done that way. “Never settle for the usual answer: ‘Because we have always done it that way,’” he advised. Lean management relies on expediting the work flow and eliminating any nonvalue steps in the process, reducing variations in the flow of patient visits, and involving the staff in implementing changes. Mr Dahl suggested using a series of questions, beginning with the word “why.” “Why have you always done something a certain way? Why must it be done that way? Why can’t it be done another way?” A patient satisfaction survey can be a helpful tool, he continued. This survey should have one key question that asks how likely the patient is to refer the practice to a friend or family member. He suggested using a scale from 1 to 10 for the answer, with 10 indicating “unlikely.” Then ask a second question about what experience led the patient to choose this ranking. Streamlining inefficiencies will achieve better patient satisfaction, eliminate duplications, make better use of available resources, and increase the quality of care, he said. n

03-A608 Humira PB-10.5x13(1.333).indd 2

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DECEMber 2012

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Health Economics Treat-to-Target Strategy for Rheumatoid Arthritis... Continued from cover monitoring and fine-tuning of therapy would be expected to increase the costs of the treatment of RA, the full economic implications of a treat-totarget strategy have not been quantified, according to Dr Bergman. More than 15,000 commercially insured adults with RA who had at least 1 prescription filled for a disease-modifying antirheumatic drug (DMARD) that was preceded by a rheumatologist encounter were identified from a research database and formed the study group. The patients were divided into those who were adherent, which was defined as having had a follow-up visit with a rheumatologist within 90 days after the initiation of a new DMARD, or nonadherent. Medical resource utilization during the following year was measured. Medical costs from a payer’s perspective were measured over the same time and adjusted to 2010 dollars. Overall, 71% of the patients were designated as adherent. At baseline, adherent patients had a mean of 4.2 rheumatologist visits compared with

a mean of 2.4 visits for nonadherent patients. Outpatient visits were also higher in the adherent versus nonadherent patients (12.8 vs 10.4, respectively). Outpatient costs were $4558 in the adherent group compared with $3630 in the nonadherent group.

“Adherent patients exhibited significantly fewer inpatient admissions and inpatient days, fewer emergency department visits, and less use of other medical services but significantly more outpatient visits than nonadherent patients.” —Martin J. Bergman, MD, FACR, FACP Nonbiologic DMARDs were instituted at the index date in 84.4% of the compliant group versus 87.6% of the nonadherent group; biologic

DMARDs were initiated in 15.5% and 12.4% of patients, respectively. “After adjusting for potential confounding, adherent patients exhibited significantly fewer inpatient admissions and inpatient days, fewer emergency department visits, and less use of other medical services but significantly more outpatient visits than nonadherent patients,” according to Dr Bergman. During follow-up, adherent pa tients had 14% fewer inpatient visits, 22% fewer inpatient days, 10% fewer emergency department visits, and 7% fewer other visits relative to nonadherent patients. Adherent patients had 5% more outpatient visits versus nonadherent patients. Inpatient costs were $933 lower in the adherent versus the nonadherent group ($3424 vs $4357, respectively), and outpatient costs were $1665 higher in the adherent group versus the nonadherent group ($13,453 vs $11,788, respectively). The benefits in terms of inpatient cost reduction overcame the increase

at a glance ➤ Treat-to-target principles include the frequent monitoring of RA disease activity and corresponding drug therapy adjustment at least every 3 months ➤ Adherent patients had 14% fewer inpatient visits, 22% fewer inpatient days, and 10% fewer emergency department visits ➤ Adherent patients had 5% more outpatient visits versus nonadherent patients ➤ Inpatient costs were $933 lower in the adherent group ➤ Outpatient costs were $1665 higher in the adherent group of outpatient costs, such that no significant difference in total medical service costs was observed between the 2 cohorts. The total medical service costs were $18,127 in adherent patients and $17,806 in nonadherent patients. n

Automated Cell Phone Monitoring Cuts Clinic Visits in Patients with Rheumatoid Arthritis By Phoebe Starrr Washington, DC—An automated cell phone system used to monitor pa tients with early rheumatoid arthri tis (RA) is a potential way to extend limited healthcare resources. During the first 6 months after diagnosis, the system was used to identify patients with early RA who needed timely attention and, at the same time, avoid unnecessary visits for patients who were doing well on their newly prescribed medications. Patient and provider satisfactions were high, according to a study presented by Tuulikki Sokka-Isler, MD, PhD, Head of Rheumatology, Jyväskylä Central Hospital, Finland, at the 2012 meeting of the American College of Rheumatology. More than 90% of the first 137 patients enrolled at 14 different clinics responded to a questionnaire saying that their experience was positive; 96% felt confident, safe, and taken care of, and 98% said they would recommend it to other people. “We have expanded this system now to hundreds of patients and it is working very well,” said Dr Sokka- Isler, who is coauthor of the study. “It is important to get patients with RA to remission as early as possible. We give them powerful medications VOL. 1

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and teach them compliance. They need to be monitored to improve outcomes. Some studies suggest monitoring them once a month for the best outcomes,” Dr Sokka-Isler told

“This technology could be useful in the United States, where there are currently shortages of rheumatologists. This automated cell phone system may be the wave of the future, with distant oversight between clinic visits. This is adjunctive, rather than replacing a visit to the doctor or nurse.” —Kelly O. Weselman, MD listeners at a press conference. “However, clinics may not have the resources for such frequent monitoring and patients may have difficulty traveling to the clinic over long distances, so we wanted to study a simpler way to monitor them,” she said. In Finland, it

can be especially difficult to travel in the winter, when daylight hours are very short and the roads are icy, Dr Sokka-Isler added. At Jyväskylä Central Hospital, patients with early RA are scheduled for a visit 3 months after the diagnosis, then another visit is scheduled 6 months later, and then patients come in for yearly check-ups. “Patients are vulnerable for the first 3 months of being prescribed medications. We educate patients at the time of diagnosis and register them for automated cell phone monitoring at the same time. The system is simple and easy to use,” she explained. Requirements are a cell phone and the ability to text. Three different questions are asked at spaced-out intervals, and the patient just has to push 1 button on the telephone. Two weeks after a diagnosis of RA, patients receive an automated phone call asking, “Are you taking your medications?” Two weeks later, another automated phone call asks, “Are you having any problems?” Two weeks after that, patients are asked by the system to assess their RA severity on a scale from 0 to 10. Each question requires only 1 key on the cell phone. December 2012

“If no problems are identified, the software continues to assess the patients automatically for the first 6 months. No nurse or doctor is needed,” Dr Sokka-Isler noted. However, if a problem is identified, an automatic alarm signal is sent to a nurse, who calls the patient within 2 working days. The nursing staff is also sent an automated e-mail message. Then she or he will evaluate whether the patient needs to come to the clinic. “We think this system will allow us to direct our resources in the clinic to the patients who really need them, and we think this may increase patient compliance. Long-term outcomes would improve if patients are under control in the first 6 months,” she stated. “This technology could be useful in the United States, where there are currently shortages of rheumatologists,” said Kelly O. Weselman, MD, a rheumatologist at Wellstar Rheumatology, Atlanta, GA. “This automated cell phone system may be the wave of the future, with distant oversight between clinic visits. This is adjunctive, rather than replacing a visit to the doctor or nurse,” she said. n

www.ValueBasedRheumatology.com

Arthritis Update Patients Who Fail Other Biologics Respond to Tofacitinib... Continued from cover “We observed a consistent improvement in signs and symptoms, physical function, and patient-reported outcomes with tofacitinib regardless of whether patients had an inadequate response to 1 or 2 prior TNF [tumor necrosis factor] inhibitors. No new safety signals emerged during the trial,” stated lead investigator Gerd Burmeister, MD, Professor, Charité Hospital Clinic for Rheumatology and Clinical Immunology, Berlin, Germany. Tofacitinib was recently approved by the US Food and Drug Administration for the treatment of moderateto-severe RA that is not responsive to methotrexate (Trexall). This new JAK inhibitor works by a different mechanism than other biologics used for the treatment of RA, and its oral formulation is perceived as an advantage. This pooled analysis included data for 614 patients whose disease had an inadequate response to TNF inhibitors and who were enrolled in 9 randomized phase 2 and phase 3 clinical trials of tofacitinib lasting ≥3 months. At month 3, tofacitinib 5-mg and 10-mg doses were superior to placebo for the treatment of the signs and symptoms of RA as measured by the

“We observed a consistent improvement in signs and symptoms, physical function, and patient-reported outcomes with tofacitinib regardless of whether patients had an inadequate response to 1 or 2 previous TNF inhibitors.” —Gerd Burmeister, MD ACR criteria for at least a 20%, 50%, or 70% improvement (ACR20/ACR50/ ACR70) from baseline. Improvement was observed regardless of whether

patients had failed treatment with 1, 2, or 3 previous TNF inhibitors. Both dosages were significantly superior to placebo based on the patient- reported outcomes for physical function (ie, Health Assessment Questionnaire Disability Index [HAQDI]), body pain (ie, the 36-Item ShortForm Health Survey [SF-36]), and fatigue (ie, Functional Assessment of Chronic Illness Therapy [FACIT]). In addition, the investigators looked at the long-term efficacy of tofacitinib based on 2 large phase 3 clinical trials and 3 long-term, open-label, 24-month extension studies. In this analysis, data were pooled for the 5-mg and the 10-mg doses of tofacitinib. ACR20/ACR50/ACR70 responses to tofacitinib that were observed at month 3 were maintained over 24 months. The rates of remission, as defined by DAS28 (Disease Activity Score in 28 joints), were also maintained for 24 months. Approximately 40% of the patients with RA that had failed on other biologic therapies had low disease activity over 24 months, Dr Burmeister said. Patient-reported outcomes measures (ie, HAQ-DI, SF-36, and FACIT) showed that responses favoring

at a glance ➤ Tofacitinib is an oral JAK inhibitor with a mechanism of action that is different from other biologics used for RA ➤ In clinical trials, tofacitinib has shown promising results in patients whose disease did not respond to other biologics ➤ Approximately 40% of patients whose RA failed treatment with other biologics had low disease activity for 24 months while using this JAK inhibitor tofacitinib remained consistent over 24 months. Despite these encouraging results, the investigators noted that more data are needed to determine the role of this drug in clinical practice. “Tofacitinib looks good in the initially promising trials. We need experience in routine clinical practice to define the role of this agent in moderate-to-severe RA,” stated Eric L. Matteson, MD, Chief of Rheumatology, Mayo Clinic, Rochester, MN, who was not involved in this study. n

IV Golimumab Delays Radiographic Progression in RA Washington, DC—Intravenous (IV) golimumab (Simponi) significantly delayed radiographic progression in patients with active moderate-to- severe rheumatoid arthritis (RA) for 1 year compared with placebo. All patients had active RA while receiving background treatment with methotrexate (Trexall). The benefits of IV golimumab that were seen at week 24 persisted through week 52. “These phase 3 data show that treatment with intravenous golimumab plus methotrexate induced and maintained improvements in the signs and symptoms of RA and inhibited the progression of structural damage. Such findings are encouraging for both rheumatologists and patients,” stated senior investigator Rene R. Westhovens, MD, PhD, Professor, Rheumatology Section, Catholic University of Leuven, Belgium, at the 2012 meeting of the American College of Rheumatology. Golimumab is a human monoclonal antibody that targets and neutralizes excess tumor necrosis factor (TNF)–alpha, which is associated with inflammation and damage to cartilage and bones.

Subcutaneous (SC) golimumab is approved by the US Food and Drug Administration for use in combination with methotrexate for the treatment of patients with moderate-to-severe RA and for the treatment of patients with active psoriatic arthritis (with or without methotrexate) and active ankylosing spondylitis.

“Treatment with intravenous golimumab plus methotrexate induced and maintained improvements in the signs and symptoms of RA and inhibited the progression of structural damage.” —Rene R. Westhovens, MD, PhD The IV formulation of golimumab is investigational and may have advantages over an SC injection formulation, especially for patients who have objections to or difficulty with self-injecting.

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This phase 3, international, multicenter, double-blind, placebo-controlled GO-FURTHER trial enrolled 592 adult patients with RA who had been receiving background methotrexate for at least 3 months and had active moderate-to-severe RA that was demonstrated by the presence of ≥6 tender and 6 swollen joints. The patients were randomized in a 2:1 ratio to a 30-minute IV infusion of golimumab 2 mg/kg or to placebo plus methotrexate at weeks 0 and 4, and then every 9 weeks. At week 16 and week 20, patients in the placebo group with <10% improvement in RA symptoms were allowed to cross over to IV golimu mab. By week 24, all of the patients randomized to placebo had crossed over to IV golimumab. At week 24, significant inhibition of the progression of structural damage was observed on x-ray in a greater percentage of patients randomized to IV golimumab compared with those receiving placebo; this inhibition persisted through week 52 in patients originally randomized to IV

golimumab, as well as in those who crossed over to IV golimumab during the trial. Radiographic progression was assessed by the change from baseline in the Sharp/van der Heijde (SvH) score, which measures joint destruction, joint erosion, and joint space narrowing; higher scores indicate greater structural damage. At week 24, the mean change from baseline SvH score was 0.03 with IV golimumab versus 1.09 with placebo (P <.001). At week 52, the mean change was 0.13 for the IV golimumab group versus 1.22 for placebo (P <.001). Between week 24 and week 52, no new safety concerns were reported. At 24 weeks, adverse events (AEs) occurred in 53% of the IV golimumab-treated patients and in 49% of the patients receiving placebo; serious AEs were documented in 4% and 2% of these patients, respectively. At week 52, when all patients were receiving IV golimumab, AEs were reported in 65% of the patients, and serious AEs were reported in 9% of the patients.—PS n VOL. 1

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Gout

Patients with Gout Considered Controlled with Urate-Lowering Therapy Often Continue to Flare See also Page 16 By Phoebe Starr

Washington, DC—Acute flares leading to hospitalizations and emergency department visits pose a significant health burden, yet approximately 75% of patients with gout who are considered “controlled” on urate-lowering therapy continued to have flares over a 1-year period, according to a study presented at the 2012 meeting of the American College of Rheumatology. Gout affects approximately 8.3 million patients in the United States, and its prevalence has doubled over the past decade. This new study suggests that current urate-lowering therapies are suboptimal in a majority of patients who are deemed controlled, and that additional therapies and practice patterns may be needed to reduce the medical and economic burden of gout flare in these patients. “Current urate-lowering therapy with allopurinol and febuxostat is widely used, yet can be limited by poor tolerability, compliance, and

variable efficacy. In multiple studies, these drugs have been shown to achieve the desired target serum urate level in less than half of patients. This

“In multiple studies, these drugs have been shown to achieve the desired target serum urate level in less than half of patients.” —Robert Morlock, PhD study shows that current treatment options for patients classified as controlled, yet continuing to flare, are not sufficient to adequately control future gout flares,” said coinvestigator Robert Morlock, PhD, Adjunct Faculty at Henry Ford Hospital, Detroit, MI. The study was a retrospective review that analyzed physician,

patient, and treatment characteristics in patients with gout who were considered “controlled” by their physician while receiving urate-lowering therapy despite having ≥2 flares annually. Control was defined as no desire to change the dose of the current urate-lowering therapy. A panel of rheumatologists (N = 125) and primary care physicians (N = 124) completed a structured case report for each of their last 5 consecutive patients with gout that included urate levels, flare counts, comorbidities, type and dose of urate-lowering therapy, duration of therapy, adherence, and other factors. Among 1245 patients with gout, 890 patients received treatment and 858 were receiving urate-lowering therapy—621 with allopurinol (Zyloprim) and 237 with febuxostat (Uloric). Among those receiving allopurinol, 83% were considered controlled and 17% uncontrolled; among those receiv-

ing febuxostat, 86% were considered controlled and 14% uncontrolled. Among allopurinol-treated patients who were considered controlled, 68% reported flares; 33% reported ≥1 flare and 35% reported ≥2 flares over a 1-year period. Among the febuxostat-treated group, 79% of the patients who were classified as controlled reported flares; 32% of the patients reported 1 flare, and 47% of the patients reported ≥2 flares over a 1-year period. Dosing characteristics were similar in the controlled and in the uncontrolled patients for both drugs. Patients with ≥2 flares were more likely to have tophi and comorbid conditions, including alcoholism, chronic kidney disease, congestive heart failure, and depression. After controlling for confounding risk factors, neither the type of physician nor the type of urate-lowering therapy predicted whether a patient was controlled and experienced ≥2 flares annually. n

Arthritis Update

Abatacept and Adalimumab Show Similar Efficacy and Safety in Rheumatoid Arthritis: Head-to-Head Comparison Washington, DC—Two different biologics were found to be similar for the treatment of patients with rheumatoid arthritis (RA) who were receiving background methotrexate (Trexall) in one of the first randomized trials to compare biologics head to head. After 1 year of treatment, abatacept (Orencia) and adalimumab (Humira) had similar efficacy and safety in the phase 3 AMPLE study that was reported as a late-breaking abstract at the 2012 meeting of the American College of Rheumatology (ACR). “Subcutaneous abatacept was comparable to adalimumab according to most efficacy measures, including radiographic progression. The safety of the 2 drugs was generally similar, with fewer discontinuations and injection-site reactions observed with abatacept,” stated lead author Michael Weinblatt, MD, Codirector of Clinical Rheumatology and Associate Director of the Center for Arthritis and Joint Diseases in the Division of Rheumatology, Immunology, and Allergy at Brigham and Women’s Hospital, Boston, MA. AMPLE is an ongoing, phase 3b, ran domized, investigator-blinded, 2-year VOL. 1

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study that randomized 646 biologicnaïve patients with RA in a 1:1 ratio to abatacept 125 mg weekly or to adalimumab 40 mg biweekly; 86.2% and 82%, respectively, of patients completed 12 months of therapy.

“This head-to-head study of 2 different classes of biologics shows that the 2 drugs are quite comparable in many ways.” —Eric M. Ruderman, MD Dr Weinberg reported that patients were not blinded to the treatment assigned, because it would have been too cumbersome to mask the treatments to try to make them look similar; therefore, the drugs were given by different routes and schedules, he said. Patients were included if they had active RA that showed an inadequate response to methotrexate. All patients were biologic-naïve. Demographic and disease characteristics were well balanced between the 2 treatment arms. The mean Disease Activ-

ity Score in 28 joints was 5.5, and the mean duration of RA was approximately 1.8 years. At 1 year, the primary end point of the ACR ≤20% criteria for improvement (ACR20) in the signs and symptoms of RA was achieved in 64.8% of the abatacept-treated patients versus 63.4% of the adalimumab-treated group. The 1.8% absolute difference between the 2 arms fulfilled the definition of noninferiority of the study design. Responses across all ACR measures were comparable, including ACR20, ACR50, and ACR70. The rate of patients achieving ACR50 was 46.2% with abatacept and 46% with adalimumab; the rate of patients achieving ACR70 was 29.2% and 26.2%, respectively. Nonradiographic disease progression rates were 85% for abatacept versus 89% for adalimumab. Both treatments had comparable safety, with similar rates of adverse events (AEs) and serious AEs. Serious AEs were reported in 20 abatacept-treated patients versus 11 patients in the adalimumab group. Furthermore, 7 patients in the abatacept group and 9 patients in the ada December 2012

limumab group had serious infections. Injection-site reactions occurred in 3.8% of the patients receiving abatacept versus 9.1% of those receiving adalimumab. “This study is important, because the challenge we have with all of these newer drugs is deciding which one is the right therapy for the right patient. This head-to-head study of 2 different classes of biologics shows that the 2 drugs are quite comparable in many ways,” commented Eric M. Ruderman, MD, Professor of Medicine-Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL. “The speed of response was quite similar, and the rate of radiographic progression was similar. It is a surprise that these drugs were more similar than different,” Dr Ruderman said. The important question is, which patients should get which drug. Dr Ruderman said, “The investigators plan to mine the data to identify subgroups that could have a preferential benefit from one or the other of these drugs. That is a question we need to answer,” he said.—PS n

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Gout

Gout Treatments Continue to Target Inflammation, Pain, with Many New Drugs in the Pipeline By Wayne Kuznar Washington, DC—The self-reported misery of many patients with gout is driving health professionals to stay at the forefront of administering effective treatments and expedient diagnoses to reduce pain and inflammation, one expert reported at the 2012 meeting of the American College of Rheumatology. Naomi Schlesinger, MD, Professor of Medicine, and Chief, Division of Rheumatology and Connective Tissue Research, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, said that patients with gout are, in their own words, “very miserable,” according to a 2010 Gout Attitudes Patient Survey. In the survey of 1000 patients with gout, respondents compared gout’s accompanying pain to severe burn (34%), breaking a bone (28%), or shattered glass piercing the skin (23%). Diagnostic Tools When diagnosing gout, topical ice can prove beneficial initially. “Application of topical ice,” she said, “should be part of the history taking and physical examination when one suspects acute gout or if the nature of the inflammatory arthritis is unclear.” However, “the gold standard of diagnosis is joint aspiration,” Dr Schlesinger added. The ideal is to identify monosodium urate crystals in the joint or in the tophus, she said. However, in practice, the clinician may lack experience in examining the synovial fluid, or the healthcare facility may lack the proper equipment. Advanced imaging may be a key to the future of diagnosing and treating gout appropriately, Dr Schlesinger said, citing the development of dual-energy computed tomography, which can highlight uric acid and calcium in specific colors. Pharmacologic Options Once diagnosed, the primary goal remains to control inflammation and pain. For acute attacks and chronic inflammation, the aim is to reduce the urate burden. “The goal is to initiate treatment as soon as possible and prescribe an adequate dose for a long enough period of time,” Dr Schlesinger said. Pharmacologic options to control pain and inflammation are nonsteroidal anti-inflammatory drugs

(NSAIDs), including the selective COX-2 inhibitors; oral colchicine; and corticosteroids. NSAIDs. The NSAIDs approved by the US Food and Drug Administration

Uricostatic drugs, such as the xanthine oxidase inhibitors—allopurinol (Zyloprim) and febuxostat (Uloric)— work to decrease uric acid synthesis. Uricolytic drugs—including peglo

“If you are thinking of using these medications in a patient with hypertension and you are using urate-lowering therapy for gout as well, that could be problematic, because they both compete for the [cytochrome] P450 enzymes in the liver. So you are actually reducing the work or the activity of the urate-lowering therapy.” —Naomi Schlesinger, MD

include indomethacin (Indocin), naproxen (Aleve), and sulindac (Clinoril). Colchicine. In the recent AGREE (Acute Gout Flare Receiving Colchicine Evaluation) trial, low-dose colchicine (1.2 mg, then 0.6 mg 1 hour later) was equally effective and better tolerated than high-dose colchicine. Pain reduction was ≥50% at 24 hours, but a gastrointestinal (GI) effect included diarrhea. Approximately 77% of the study participants had GI effects with high-dose colchicine; only 23% had effects with the low dose. Drugs in the pipeline. The 2 drugs in the pipeline currently in phase 3 clinical trials for the treatment of acute gout and prophylaxis that, according to Dr Schlesinger, “show promise” and are already approved for other indications include rilonacept (Arcalyst), an interleukin (IL)-1, and canakinumab (Ilaris), a human monoclonal antibody targeted at IL-1β. In phase 3 trials of canakinumab in patients with acute gout, patients received a subcutaneous injection of canakinumab 150 mg or triamcinolone 40 mg by intramuscular injection, which resulted in a significant decrease in pain at 72 hours, using the visual analog scale. Urate-Lowering Therapies Urate-lowering therapies continue to play a significant role in gout management, with several new drugs in the pipeline.

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ticase (Krystexxa) and Uricase-PEG 20, which is under development— catalyze conversion of uric acid into allantoin. Uricosuric drugs—including probe necid, benzobramone, losartan (Cozaar), and fenofibrate (Tricor)—inhibit the reabsorption of uric acid in the proximal tubule. Although losartan and fenofibrate are urate transporter 1 (URAT1) inhibitors, “to a minor degree they reduce serum urate by approximately 10%,” Dr Schlesinger said. “If you are thinking of using these medications in a patient with hypertension and you are using urate-lowering therapy for gout as well, that could be problematic, because they both compete for the [cytochrome] P450 enzymes in the liver. So you are actually reducing the work or the activity of the urate-lowering therapy.” The overall treatment goal for urate-lowering therapy is to lower serum urate to ≤6 mg/dL. Other treatment goals include no recurrence of or fewer acute attacks, fewer crystals in the joints, reduction in tophus size, and no recurrence of tophaceous deposits. “Plan to start urate-lowering therapy ‘low and go slow.’ Start at low doses and go slow with progressive increases of the dose,” Dr Schlesinger advised. Allopurinol is currently the urate- lowering therapy of choice. Febuxo

stat is also a leading urate-lowering therapy. Pegloticase, an intravenous formulation used in the “worst of the worst” cases of gout, may become a leading choice as induction therapy (lowering the uric acid pool). For pegloticase, although lowering serum urate to ≤6 mg/dL is a primary end point, secondary outcomes are also significant: complete resolution of ≥1 tophus within 25 weeks for 40% of patients. “We’ve never had a drug that worked so quickly to decrease and resolve tophi,” Dr Schlesinger pointed out. The drug also reduced tender joint count and improved patient- recorded outcomes. New urate-lowering therapies in phase 2 trials include oxypurinol (a xanthine oxidase inhibitor), MBX-102 (an URAT1 inhibitor), RDEA806 (an URAT1 inhibitor/uricosuric nonnucleoside reverse transcriptase inhibitor), and BCX4208 (a purine nucleoside phosphorylase inhibitor). Lesinurad (RDEA594, an URAT1 inhibitor devoid of antiviral effect) is in phase 3 clinical trials. The previously mentioned Uricase-PEG 20 (uricolytic agent, PEG-urate oxidase) is in phase 1 clinical trials. These therapies may become alternative treatments for patients who fail to reach their target serum urate level. According to Dr Schlesinger, the RDEA806 drug has been given to patients with AIDS, because it is an antiviral drug; many patients with AIDS have the metabolic syndrome. “They showed with this drug that it reduces the uric acid level,” she said. Patient Adherence to Therapy Treatment-induced attacks can often impact whether a patient ad- heres to the medications prescribed. “The problem is when we lower the uric acid pool, patients get attacked,” Dr Schlesinger said. One nonpharmacologic way to limit the possibility of attacks may lie in a bowl of cherries. Although there has been evidence since at least 1950 that eating one-half pound of cherries reduces gout attacks, recent randomized controlled trials show that cherry juice concentrate reduces acute gout versus the ingestion of pomegranate juice. Of approximately 92% of patients ingesting cherry juice daily for ≥4 months, a ≥50% decrease in acute attacks was seen, and 36% were free of attacks at 4 months. n VOL. 1

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Fibromyalgia

Impaired Brain Processing and Other Effects of Fibromyalgia By Phoebe Starr Washington, DC—The way patients with fibromyalgia experience pain may be a result of abnormal pain signal processing associated with reduced opioid receptor binding, according to a study presented during the 2012 meeting of the American College of Rheumatology. This study is the first to demonstrate the connection between µ-opioid receptor binding and the brain’s response to the pain of fibromyalgia, noted lead investigator Richard Harris, PhD, Assistant Professor, Department of Internal Medicine, University of Michigan, Ann Arbor. “In patients with fibromyalgia, the main inhibitory mechanisms are not working correctly, specifically the opioid receptors within the brain,” he told listeners. The study was based on the assessment of changes in blood oxygenation by functional magnetic resonance imaging in 18 female patients with fibromyalgia who were opioid-naïve. Patients received a painful stimulus to the thumb in varying intensity, and pain was measured by the short-form McGill Pain Questionnaire. Patients were treated with acupuncture and placebo acupuncture for pain reduction before and after exposure to the painful stimuli. The researchers also measured µ-opioid receptor binding before and after the painful stimuli. “When opioid receptor binding went down, the evoked brain pain response went up in key brain regions that are involved in pain processing, such as the insula and amygdala,” Dr Harris observed. He proposed 2 possible explanations—either that

the receptors were downregulated or that activating the receptors actually caused the pain. Dr Harris said that the results appeared to be paradoxical. “We found that patients with fibromyalgia either have too few micron receptors in their brains, or that when the micron receptors activate, they cause pain instead of lessening pain.” These findings may explain the lack of response to opioids in patients with fibromyalgia.

“When opioid receptor binding went down, the evoked brain pain response went up in key brain regions that are involved in pain processing.” —Richard Harris, PhD Sleep, Relationships, Cognition Several studies by another group of investigators led by Robert S. Katz, MD, Professor, Rush University, Chicago, IL, show that fibromyalgia has negative effects on physical, cognitive, and emotional functioning. In a small study of 16 patients with fibromyalgia (10 women, 6 men) and 3 controls, patients with fibromyalgia exhibited many more nocturnal awakenings and poor sleep efficiency. They also moved around at night quite a bit more than the controls. The research suggests that these sleep disturbances may prevent adequate rest of the patients’ tired and painful muscles. In the study, patients were given armband devices to monitor their

sleep at home on 4 consecutive nights. The researchers measured the duration of sleep, sleep efficiency, and the number of awakenings, and then compared these findings with patient self-reported sleep patterns on a visual analog scale. The ability to monitor patients’ sleep at home without the patient having to spend a night in a sleep laboratory is an inexpensive way to measure sleep quality, said the investigators. According to another study, fibromyalgia interferes with the ability to work. Pain, fatigue, and cognitive dysfunction were cited as the primary factors that limited the ability to work. Almost half (48.7%) of the 76 pa tients in this study (mostly women) were not working, 13.2% were working part time, and 38.2% were working full time. More than half (51.4%) of the patients who were not working cited fibromyalgia as the reason. The patients who were able to continue working credited several strategies, including being persistent, staying busy, maintaining a positive attitude, exercising, eating well, and getting enough sleep. The more disabled patients felt incapable of using these approaches. Patients with fibromyalgia reported more problems with language and spatial tasks than the controls without rheumatic diseases in a study based on assessment via questionnaires, suggesting that learning disabilities may be another part of a dysfunctional central nervous system in these patients. The study included 89 patients with fibromyalgia, 39 patients with rheumatoid arthritis (RA), 23 patients with sys-

temic lupus erythematosus (SLE), and 14 controls with no rheumatic disease. The fibromyalgia group had significantly worse reading and oral expressive language scores (P = .001) com-

“We found that patients with fibromyalgia either have too few micron receptors in their brains, or that when the micron receptors activate, they cause pain instead of lessening pain.” —Richard Harris, PhD pared with controls. They also scored worse in all 4 areas than the RA and SLE groups (range, P <.001-.007). Fibromyalgia takes a toll on relationships, according to an internet-based study of 763 female respondents with self-described fibromyalgia. The results were drawn from the part of a survey on the effect of fibromyalgia on relationships with family, friends, and coworkers. Spouses were perceived as the most supportive (59.1%) compared with other relationships; however, serious strains in all relationships were reported. Fibromyalgia had the most negative effects on relationships with coworkers, in-laws, and the subjects’ parents. The investigators suggested that better public education about the invisible but real symptoms of fibromyalgia may improve these relationships. n

IN THE LITERATURE Adalimumab Effective in Preventing Progression of Joint Damage in Early Arthritis

The treat-to-target guidelines recommend managing patients with early rheumatoid arthritis (RA) to achieve remission as a treatment goal. The success of biologic therapies in the management of patients with RA is gradually shifting the approach toward the inclusion of biologics in earlier phases of the disease. In line with this paradigm shift, a new study has set out to evaluate whether the combination of adalimumab (Humira) and methotrexate could help in the prevention or repression of early RA progression (Takeuchi T, et al. Ann VOL. 1

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Rheum Dis. 2013, January 11. Epub ahead of print). This randomized, double-blind, placebo-controlled, multicenter, 26- week-long study included 334 Japanese patients with early RA who had not been exposed to methotrexate or to a biologic agent. The goal of the study was to evaluate the safety and efficacy of using the combination of a biologic (adalimumab) plus metho trexate for the prevention of joint damage in patients with early RA (ie, ≤2 years). The primary end point was inhibition of radiographic progression (ie, change from baseline) as reflected in the Modified Total Sharp Score at 26 weeks.

A total of 334 patients were random ized to receive adalimumab 40 mg every other week and methotrexate 6 mg every week (N = 171), which was titrated to 8 mg every week in patients who did not achieve a ≥20% reduction in tender or swollen joint counts, or methotrexate alone (N = 163), using the same dosing schedule. The mean duration of RA was 0.3 years for all patients; 315 patients had high disease activity (>5.1), as measured by the 28-joint Disease Activity Score. Significantly more patients receving adalimumab plus methotrexate than those receiving methotrexate alone (62% vs 35.4%; P <.001) showed a significant decline in the radiographic December 2012

progression of RA (mean change, 1.5 vs 2.4; P <.001). The clinical response also favored the combination therapy, with significantly more patients in the adalimumab plus methotrexate group achieving American College of Rheumatology response criteria of 20%, 50%, 70%, and 90% improvement as early as the second week of therapy (12.9% vs 5.5%; P = .02). These improvements persisted to the end of the study in many patients. The combination therapy was well tolerated, with no new safety concerns. Overall, 7 patients in the combination group and 5 patients in the methotrexate-alone group withdrew from the study because of adverse events. n

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Juvenile Idiopathic Arthritis

Treatment of Systemic Juvenile Idiopathic Arthritis Is Changing Gradually Toward Biologics By Mark Knight Washington, DC—Medication use in patients with systemic juvenile idiopathic arthritis (JIA) is highly variable but is gradually shifting toward the increased use of biologic agents, according to presenters who participated at a symposium on the topic at the 2012 meeting of the American College of Rheumatology (ACR). Data from recent phase 3 clinical trials involving biologic agents may prompt further changes in treatment choices based on positive responses with these agents. A Gradual Shift Yukiko Kimura, MD, a pediatric rheumatologist at Hackensack University Medical Center, NJ, presented an overview of current practices in systemic JIA. Dr Kimura’s data show that the use of biologics, especially interleukin (IL)-1 and IL-6 inhibitors, has increased over time, accompanied by a decrease in the use of disease-modifying antirheumatic drugs. However, the use of methotrexate and glucocorticoids is still very common. The Childhood Arthritis & Rheumatology Research Alliance (CARRA), a consortium of pediatric rheumatologists in the United States and Canada, revealed that steroid-containing regimens were the most common choice of treatment in 2010, followed by methotrexate and an IL-1 inhibitor. The least popular choices in 2010 were an IL-6 inhibitor, a tumor necrosis factor (TNF) inhibitor, and a calcineurin inhibitor. As initial therapy, respondents were most likely to choose prednisone and intravenous pulse steroids. For patients with refractory JIA (defined as disease that does not respond to treatment after 3 months), an IL-1 inhibitor and an IL-6 inhibitor gained popularity. The prospective CARRA registry that has enrolled more than 8000 patients as of November 2012 shows that steroids are the most frequent choice of treatment for patients with systemic JIA, and they are chosen by >80% of the 418 pediatric rheumatologists in the registry. Methotrexate was chosen by >70% of the rheumatologists, a TNF inhibitor by approximately 60% of the rheumatologists, and an IL-1 inhibitor by approximately 50% of the rheumatologists. Methotrexate topped the list of current medications used, selected by approximately 50% of the rheumatologists. Corticosteroids and an IL-1 inhib-

itor were each selected by approximately 25% of the rheumatologists, and a TNF inhibitor by approximately 20% of the rheumatologists.

“Anakinra may be more effective for systemic symptoms than for polyarthritis, [and] it likely can reduce the need for corticosteroids. Perhaps the earlier that anakinra is started, the better the response is going to be.” —Ronald M. Laxer, MD, FRCP

IL-1 and IL-6 Inhibitors

Anakinra Recent data with IL-1– and IL-6– inhibiting agents were discussed by Ronald M. Laxer, MD, FRCP, Professor of Pediatrics and Medicine at the University of Toronto and a staff rheumatologist at The Hospital for Sick Children, Toronto, Ontario, Canada. Anakinra (Kineret) is a recombinant molecule that links into the IL-1 receptor site to prevent signal transduction. Early response to anakinra is good, but that response is lost over time, Dr Laxer said. “Anakinra may be more effective for systemic symptoms than for polyarthritis, [and] it likely can reduce the need for corticosteroids,” he noted. “Perhaps the earlier that anakinra is started, the better the response is going to be.” Canakinumab and Tocilizumab Canakinumab (Ilaris), a humanized monoclonal antibody, binds IL-1 beta in the circulation to prevent it from binding with the receptor. Tocilizumab (Actemra) is a humanized monoclo-

value-based CARE in Rheumatology

DECEMber 2012

nal antibody against the IL-6 receptor. Each drug has been studied in shortterm randomized clinical trials, and both demonstrate rapid response with good relative safety in the short-term. Results show good responses, as measured by ACR50 or ACR30 improvement criteria. With tocilizumab, “there is an early mild response, with about a 30% ACR50 response at 2 weeks, and it continues to climb over the 12-week period,” Dr Laxer said. A JIA-adapted ACR30 response combined with the absence of a fever at week 12 occurred in 85.3% of the tocilizumab recipients compared with 24.3% of the placebo recipients. The JIA-adapted ACR 50%, 70%, and 90% improvement criteria (ACR50/70/90) responses were also significantly greater in the tociliz umab group. In a 4-week randomized study, the response to canakinumab as a single subcutaneous dose was superior to placebo for the primary and secondary end points at day 15: an adapted ACR Pediatric 30 criteria response (aACRPed30), 83.7% versus 9.8%; an aACRPed50, 67.4% versus 4.9%; and an aACRPed100, 32.6% versus 0%, respectively (all P <.001). “Given the response at day 15, there might be an earlier response to canakinumab,” Dr Laxer suggested. Overall, there was a 63% relative risk reduction in the flare rate with canakinumab versus placebo. A 2-year, open-label, follow-up study showed continuing increases in the aACRPed30/50/70/90 responses to tocilizumab over time. At 2 years, the aACRPed90 approached 80%, and 60% of the patients in the tocilizumab group were able to stop taking steroids. Four serious adverse events (AEs) occurred in 3 patients randomized to tocilizumab (ie, varicella, septic arthritis, and urticarial/angioedema), and 2 serious AEs occurred in patients randomized to canakinumab (ie, varicella and macrophage activation syndrome). Timothy Buekelman, MD, a pediatric rheumatologist at the University of Alabama, Birmingham, called for the use of biologics at the time of diagnosis in patients with systemic JIA, adding that steroid-sparing therapy should be a treatment goal because of the side effects associated with systemic glucocorticoids. Methotrexate is often used as a steroid-sparing therapy; however, patients with JIA can rarely reduce their dosage of prednisone when using methotrexate.

The ACR guidelines for the treatment of systemic JIA say that methotrexate is “inappropriate for initial management of patients with active fever and active arthritis,” Dr Buekelman noted. Very early use of biologics in pa tients with systemic JIA is supported by data from clinical trials, he said. The ACR70 response at 3 months in the blinded phase of a clinical trial of toci lizumab for the treatment of patients with systemic JIA was 71% and, in an open-label extension of this study, the ACR70 response improved to 87% at 12 months. A similar excellent ACR70 response of 63% was achieved with canakinumab at 8 months (during glucocorticoid taper) for the treatment of patients with systemic JIA. “This is a highly effective target for this condition,” Dr Buekelman said. Targeting IL-1 also appears to be successful for treating synovitis in patients with systemic JIA, according to Dr Buekelman. Anakinra has been shown to improve the number of active joints versus placebo at 1 month, and, in a clinical trial of canakinu mab, the median number of active joints decreased from 10 to 1 during the first 2 months of open-label use in 177 patients. Adalimumab for Pediatric Patients with JIA Children and adolescents with JIA often experience growth impairment. In another phase 3 clinical trial presented at the meeting, researchers explored the impact of adalimumab (Humira) therapy on pediatric patients with JIA in terms of growth parameters. This randomized, double-blind, parallel-group study included 171 pa tients aged 4 to 17 years. Overall, 144 patients met the ACRPed30 response criteria at week 16, and 133 entered the double-blind phase. All patients who received ≥1 dose of adalimumab, with or without methotrexate, were included in the final analysis. At baseline, 55 patients were in the ≤33 percentile group for weight and 77 patients were in the >33 percentile group. Response rates for ACRPed30/50/70/90 improved over time in both groups. Long-term (32 week) treatment with adalimumab, with or without metho trexate, was associated with mainte nance of growth in patients with impaired growth at baseline; it also improved JIA symptoms in all patients, regardless of baseline growth status. n VOL. 1

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