VBCR October Vol 1, No 5 by Value-Based Cancer Care

Value-Based Care in Rheumatology

OCTOBER 2012 VOL 1 • NO 5

F R O M T H E P U B L I S H E R S O F A M E R I CA N H E A LT H & D R U G B E N E F I T S

www.ValueBasedRheumatology.com

First-Ever ACR Guidelines for the Management of Patients with Gout By Neil Canavan

High Emergency Department Utilization and Costs for Gout Detailed for First Time

Ted R. Mikuls, MD

Increasing incidence, expenditures By Rosemary Frei, MSc

he incidence of gout is on the rise, and with it the cost of care. Between 2006 and 2008, gout was associated with >280 million visits to the emergency department in the United States, with median costs increasing annually. In 2008, nearly 175,000 emergency department visits were made by patients with gout as their primary complaint, totaling $166

million, according to the first-ever analysis of gout-related utilization and cost of care in US emergency departments (Garg R, et al. Arthritis Care Res [Hoboken]. 2012 Sep 4 [Epub ahead of print]). These findings, the researchers note, confirm that gout, which is the most common inflammatory arthritis, Continued on page 16

Personalized Medicine

or the first time in its 78-year history, the American College of Rheumatology (ACR) has issued guidelines for the management of gout in October, which were published in 2 parts (Khanna D, et al. Arthritis Care Res. 2012;64:1431-1461). Continued on page 5

Patients with Fibromyalgia Improve Rapidly with Pregabalin First Japanese clinical trial for this condition By Charles Bankhead

atients with fibromyalgia had significant improvement in pain, sleep, and quality-of-life measures when treated with pregabalin

(Lyrica) versus placebo, according to the results of the first clinical trial of this condition in Japan (Ohta H, et al. Arthritis Res Ther. 2012;14:R217 [Epub Continued on page 10

Systemic Lupus Erythematosus: New Genetic Risk Factors for Thrombosis Identified Can inform clinical decision-making By Alice Goodman

hrombosis is more common in patients with systemic lupus erythematosus (SLE) than in the general population and is associated with increased mortality. Researchers have recently identified specific genetic risk factors for thrombosis in pa-

Continued on page 15

INSIDE GOUT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6 Gout management often inappropriate Lead in blood associated with gout FIBROMYALGIA . . . . . . . . . . . . . . . . .10 Motivation interviewing in patients provides mixed results FDA UPDATE . . . . . . . . . . . . . . . . . . . .14 Actemra indicated for RA Humira approved for ulcerative colitis Prolia indicated for men with OA PERSONALIZED MEDICINE in

Rheumatology

™

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tients with SLE, and results of their study suggest that these risk factors differ among ethnic groups (Kaiser R, et al. J Rheumatol. 2012;39:1603-1610). These findings may help predict which patients with SLE are at in-

ECONOMIC ISSUES IN RHEUMATOLOGY . . . . . . . . . . . . . . .17 Cost-effectiveness of biologics inﬂuenced by RA severity RHEUMATOLOGY UPDATE . . . .18 TNF inhibitors not linked to cancer OSTEOARTHRITIS . . . . . . . . . . . . . .20 Physicians’ bias in knee replacement

Rheumatology PRACTICE MANAGEMENT™

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Durst, RN; John Carlsen, MPH;e Lauren on, NMegan denKuchinski, Be conside eric MHA; t, Rei are mic b and o d . In J. AmJ. Harris, RN, mbL. urden withincause com red in RA utilizati f work p Daniel Neves, BA; Stephanie BSN; Glenna ursTraiger, emen RN, MSN, CNS-BC m l roduc addion a mana month plicatio t Inte e.co Vo tr re n e g a li e ll n tmen ment. 4,5 facto tivity, igence s of s of R Stakeholder Perspectivel 5by T. Kenney, Jr, RPh, MBA , NJames Bon t rs , d im D o is A is that H 2 l ease me co Marc w.A onset, may begin tion, diate sym nsidered ww h/Ap c p e to de b ril 20 term ut also to toms of linically arly and velop 12 p n disab CLINICAL ility. 1,6,7slow disea ain associa ecessary aggressiv e to m ted w Histo se prog ana it re ricall 012 Benefits of Novel Oral Anticoagulant Agents for Thromboprophylaxis www y, est ssion to p h inflamm ge ril 2 .AHD imate re /Ap after Total Hip or Knee Arthroplasty Bon s of w vent lon aarch line.c M g o rk dis om 2 l Richard J. 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offers an open forum for all healthcare participants to exchange ideas and present their data, innovations, and initiatives to facilitate patient-centered healthcare and benefit design models that meet the needs of all stakeholders—Distributors, Employers, Manufacturers, Patients, Payers, Providers, Purchasers, Regulators, and Researchers. Readers are invited to submit articles that aim at improving the quality of patient care and patient well-being while reducing or controlling costs, enhancing the health of communities and patient populations, as well as other topics relevant to benefit design with specific implications to policymakers, payers, and employers.

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Follow the Manuscript Instructions for Authors at www.AHDBonline.com Submit articles to editorial@engagehc.com. For more information, call 732-992-1892.

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

GOUT First-ever ACR guidelines for gout management Only 50% of physicians treat gout according to ACR guidelines Poorly managed gout major driver in increased healthcare utilization for veterans More….

ECONOMIC ISSUES IN RHEUMATOLOGY High emergency department utilization and cost for gout Cost-effectiveness of biologics affected by RA disease severity More….

RHEUMATOLOGY UPDATE FIBROMYALGIA

Editorial Assistant Jennifer Brandt jbrandt@the-lynx-group.com 732-992-1536

Motivation interviewing to encourage exercise provides mixed results More….

Director, Client Services Zach Ceretelle

PSORIATIC ARTHRITIS

Disease activity trajectory important in patients’ willingness to change RA medication No link between TNF inhibitors for RA and cancer More….

Apremilast shows promising results in 3 pivotal trials

OSTEOARTHRITIS

Senior Production Manager Lynn Hamilton Quality Control Director Barbara Marino Business Manager Blanche Marchitto Mission Statement Value-Based Care in Rheumatology provides a forum for payers, providers, and the entire rheumatology team to consider the cost-value issues particular to rheumatology treatments. This unique focus is achieved through news coverage from major rheumatology meetings and the rheumatic diseases literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care. Contact Information: For subscription information please contact: Telephone: 732-992-1880 Fax: 732-992-1881

FDA UPDATE Expanded indication for Actemra for RA Humira approved for ulcerative colitis Prolia indicated for men with osteoarthritis

PERSONALIZED MEDICINE in

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New genetic risk factors for thrombosis in patients with lupus Biomarker may lead to blood test to measure osteoarthritis severity

Effect of walking program on exercise adherence and physical activity Physician bias uncovered in knee replacement surgery recommendations Socioeconomic burden of OA-related hip and knee replacement reached “remarkable” levels More….

Rheumatology PRACTICE MANAGEMENT™ Accountable care organizations

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 Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2012 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Care in Rheumatology is a registered trademark of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America. The ideas and opinions expressed in Value-Based Care in Rheumatology do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Value-Based Care in Rheumatology should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication. 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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VBCR Advisory Editorial 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

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

Alan Menter, MD Director Baylor Psoriasis Research Center Dallas, TX

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

Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth Murray, UT

Ronald van Vollenhoven, MD, PhD Associate Professor Karlinska University Hospital Solna Stockholm, Sweden

Lynn Nishida, RPh Director, Clinical Services Catamaran Center of Excellence Northwest Region Portland, OR

F. Randy Vogenberg, RPh, PhD Principal Institute of Integrated Healthcare Sharon, MA

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

OCTOBER 2012

www.ValueBasedRheumatology.com

Value Propositions Immune Response BioPharma Applies for Orphan Designation for Its New Juvenile Rheumatoid Arthritis Vaccine Immune Response BioPharma, Inc, has submitted an application to the US Food and Drug Administration for an orphan designation for its new vaccine, Ravax, which targets the immune system of patients with juvenile rheumatoid arthritis (RA). “RAVAX is a first in class and best in class vaccine for rheumatoid arthritis, which works by down regulating aberrant T cells and treating the underlining causes of the RA disease. Orphan designation will allow for a more speedy development of RAVAX and will give us further flexibility in trial design and expand the RA vaccine use into the rare disease, JRA [juvenile RA], said David Buswell, Chief Operating Officer and Interim Chief Executive Officer of Immune Response BioPharma. The drug’s manufacturer believes that through vaccination with T-cell receptor peptides specific to the autoreactive T-cells, the patient’s immune system may be stimulated to downregulate and turn off the aberrant T-cells without involving normal cells. Ravax provides specific treatment without total immunosuppression, and, at the same time, uses typical pathways of self-regulating the immune system. The filing of the new application is seen as a step forward in the development of this unique vaccine for patients with juvenile RA, charting a new approach to therapy for this patient population. Immune Response BioPharma believes that the new vaccine may inhibit the T-cells that cause RA, which could prevent the development of or the deterioration of RA. The company has completed two phase 2 clinical trials with Ravax in patients with RA. A phase 2b trial with the vaccine involving 340 patients with RA showed a significant treatment response after the third injection using the American College of Rheumatology 20% response rate criteria (ACR20) in reducing swollen joint counts. Immune Response BioPharma, Inc, press release, October 23, 2012

Gout Can Be Cured If Properly Managed Gout is a common inflammatory arthritis with appropriate treatments and a well-understood disease mechanism, yet many patients are not receiving appropriate therapy; therefore, a disease that is curable is only seldom cured. The recent guidelines issued by the ACR for the management of this disease highlight the need for early treatment, including the treatment of acute gouty attacks within 24 hours, reducing serum urate levels to below 6 mg/dL, and prescribing appropriate pharmacotherapy with currently available medications that can control serum urate levels in these patients. In addition to the guidelines that are discussed in this issue of ValueBased Care in Rheumatology (page 1), another article also mentioned in this issue (page 6) highlights the current reality that only approximately 50% of physicians manage patients with gout according to the recent ACR recommendations, leaving much room for improvement to change the face of this disease by adhering to evidence-based practice guidelines. Discussing the question of why a curable disease is so seldom cured, Michael Doherty, MD, and colleagues note in a recent article that “Doctors often focus on managing acute attacks rather than viewing gout as a chronic progressive crystal deposition disease. Urate-lowering treatment is underprescribed and often underdosed. Appropriate education of patients and doctors…may help to overcome these barriers and improve management of this easily diagnosed and curable form of potentially severe arthritis.” Ann Rheum Dis. 2012;71:1765

VALUE-BASED CARE IN RHEUMATOLOGY

OCTOBER 2012

New Questionnaire Helps Rheumatologists and Patients Identify Foot and Ankle Problems in RA The majority of patients with RA have disabilities related to their foot or ankle; however, these problems are often being ignored by physicians and are not always properly managed. Now a new and simple questionnaire, which is available to the public free of charge, can help physicians and patients to detect foot and ankle problems in patients with RA. What makes this questionnaire different from many other general questionnaires is that it was specifically designed by rheumatologists in the United Kingdom to be directed toward patients with RA and not all patients with disabilities or pain. Most questionnaires that are designed to assess the foot in persons with musculoskeletal conditions do not involve the ankle in the assessment, even though the ankle is often affected in RA. The new questionnaire, called the Swindon Foot and Ankle Questionnaire, includes 10 quick questions, with accompanying illustrations of the foot, that can help patients to identify the exact location of their problem. This questionnaire can even be used by those patients who are not well-versed in medical terminology. The team that developed the questionnaire suggests that patients should be able to complete it in less than a minute. Waller R, et al. The Swindon Foot and Ankle Questionnaire. ISRN Rheumatology. 2012

Novel Approach to Autoimmune Diseases May Lead to New Therapies Researchers at Duke University Medical Center have found that reproducing a rare type of B-cell and infusing it back into the body may potentially be an effective way of treating autoimmune diseases, such as RA and multiple sclerosis. “Regulatory B-cells are a fairly new finding that we’re just beginning to understand,” said coauthor Thomas F. Tedder, PhD, Professor of Immunology, Duke University Medical Center. “B10 cells are important, because they make sure an immune response doesn’t get carried away, resulting in autoimmunity or pathology. This study shows for the first time that there is a highly controlled process that determines when and where these cells produce IL-10.” Dr Tedder and colleagues have been studying the reproduction of B10 cells in mice, showing that B10 cells only respond to specific antigens. Using this information, the researchers set out to see if B10 cells could be used as a cell-based therapy to regulate the immune response in patients with autoimmune diseases. “Autoimmune diseases are very complicated, so creating a single therapy that allows us to go after multiple disease targets without causing immunosuppression has proven difficult. Here we are hoping to take what Mother Nature has already created, improve on it by expanding the cells outside of the body, and then put them back in to let Mother Nature go back to work.” More research is needed to understand how to expand B10 cells and how they work in humans before B10-based therapies can be developed for patients with RA. Yoshizaki A, et al. Nature. 2012 Oct 14

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Gout

First-Ever ACR Guidelines for... The first part, titled “Systematic Nonpharmacologic and Pharmacologic Therapeutic Approaches to Hyperuricemia,” addresses several key considerations for treating patients with gout, including: ➤The need for lowering serum uric acid levels to <6 mg/dL ➤The appropriate dosing for firstand second-line treatment options, including guidance on the recently US Food and Drug Administration (FDA)-approved drugs febuxostat (Uloric) and pegloticase (Krystexxa) ➤Dietary recommendations ➤Recommendation that patients who are at high risk for severe allopurinol (Zyloprim) sensitivity undergo genetic testing for the HLA-B*5801 allele. “Acute gout attacks can be debilitating and [can] adversely affect patients’ quality of life,” said one of the lead authors of the guidelines, John D. Fitzgerald, MD, PhD, Acting Rheumatology Division Chief at the University of California, Los Angeles, in a September 28, 2012, press release on the guidelines (www.wiley.com/WileyCDA/Press Release/pressReleaseId-105332.html? print=true). “In order to improve patient care, the ACR funded this collaborative effort among US researchers to produce guidelines, outlining pharmacological therapies and nondrug treatments to manage gout,” Dr Fitzgerald said.

at a glance The new ACR guidelines for gout recommend: ➤ Target serum urate level to <6 mg/dL ➤ Initiate allopurinol 100 mg/day for early disease (<50 mg/day for patients with advanced kidney disease) ➤ Febuxostat (up to 80 mg/day) can be used to control hyperuricemia ➤ If these therapies fail, consider the use of probenecid, fonofibrate, losartan, or pegloticase ➤ Counsel patients about the importance of diet, urate control, risk for kidney and cardiovascular disease, and drug use that can affect urate levels (ie, diuretics)

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“To improve patient care, the ACR funded this collaborative effort among US researchers to produce guidelines, outlining pharmacological therapies and nondrug treatments to manage gout.” —John D. Fitzgerald, MD, PhD

Answering the Need Gout is the most common inflammatory arthritis representing a metabolic disorder that is characterized by inadequate elimination of uric acid from the blood; uric acid is a breakdown product of purines, which are essential components for making DNA and RNA. Elevated serum levels of uric acid (ie, hyperuricemia) lead to eventual precipitation and to deposition of urate crystals in the joints of the extremities, thereby causing severe inflammation and, often, debilitating pain. Gout affects an estimated 8.3 million adults in the United States, and its prevalence has been increasing in the past 20 years. Factors driving this increase include more incidences of comorbidities that promote hyperuricemia (eg, hypertension and type 2 diabetes), the use of diuretics for cardiovascular disease, and dietary trends. Although the number of patients with gout is rising, the authors of the new ACR guidelines state that, “Despite advanced understanding of the molecular bases of hyperuricemia and gouty inflammation and the extensive practice experience of many providers, substantial quality of care gaps exist in gout management.” The new guidelines were requested by the ACR and reflect the conclu-

Continued from cover

sions of recent clinical research in gout mechanisms and management, including recommendations regarding new pharmacologic agents for gout. To formulate the ACR recommendations, Dr Fitzgerald and colleagues reviewed medical literature published from the 1950s to the present. A task force panel of experts in the field, including 7 rheumatologists, 2 primary care physicians, 1 nephrologist, and 1 patient representative, then ranked and voted on the key findings. The recommendations reflect the role of a genetic component in gout in relation to testing for the HLAB*5801 allele before the initiation of therapy with the xanthine oxidase inhibitor allopurinol, acknowledging the potential role of personalized medicine in gout. Core Recommendations

1. Patient education on diet, lifestyle, and the management of comorbidities is a recommended core therapeutic measure in patients with gout Clinicians are urged to look for comorbid conditions that may be causing hyperuricemia (ie, renal disease); a checklist of these conditions is provided in the guidance. Accordingly, agents used to treat such comorbidities should be considered for their urate-elevating potential (ie, thiazides and loop diuretics). Those medicines deemed nonessential to the management of comorbid conditions should be reduced or eliminated. Regarding diet, the task force panel has provided a table of items grouped into the 3 recommendation categories of “avoid,” “limit,” and “encourage.” Examples include avoiding organ meats that have a high purine content, high fructose corn syrup, and, during a gout attack, any consumption of alcohol; limiting intake of most meats, sugar, salt, and alcohol; and encouraging a low-fat diet with vegetables.

2. Serum urate level should be lowered sufficiently to durably improve the signs and symptoms of gout, with the target of <6 mg/dL at minimum, and often <5 mg/dL The panel recommends a serum uric acid target of <6 mg/dL in all patients with gout, and a target of <5 mg/dL in patients who remain unable to achieve a durable reduction in gout episodes or symptoms, including tophi that are palpable or visible by physical examination. During the titration period after

OCTOBER 2012

treatment initiation, the panel recommends monitoring serum uric acid every 2 to 5 weeks. After target levels are achieved, serum uric acid levels should be assessed every 6 months.

3. Xanthine oxidase inhibitor (XOI) therapy with allopurinol or with febuxostat is recommended as the first-line pharmacologic urate-lowering therapy (ULT) approach In cases where XOIs are contraindicated as a result of concurrent medications or conditions or because of XOI intolerance, probenecid (Benemid) is recommended as an alternative firstline ULT. Regarding timing, ULT may be initiated during an acute gout attack, as long as effective antiinflammatory management has been instituted as well.

4. The starting dosage of allopurinol should be ≤100 mg daily and up to 80 mg daily in patients with moderate-to-severe chronic kidney disease (CKD), followed by gradual upward titration of the maintenance dose, which can exceed 300 mg daily, even in patients with CKD These recommendations are consistent with the previous guidelines from the FDA and the European League Against Rheumatism. The panel’s rationale for starting with this lower dose is to mitigate the potential for a severe allopurinol hypersensitivity reaction. Prescribing allopurinol in a dose of <300 mg daily is deemed valid by the task force panel in consideration of data showing that roughly 50% of all patients with gout fail to achieve target serum uric acid levels below that threshold. As the task force panel states, “Maintenance dosage of allopurinol can be raised above 300 mg per day, even in those with renal impairment, provided there is adequate patient education and regular monitoring for drug hypersensitivity and other adverse events.” The maximum FDA-approved dose of allopurinol is 800 mg/day. The maximum dose for febuxostat is 80 mg/day; however, the task force panel has found data to support a maximum dosing level of 120 mg/day. This dose level is approved in many countries outside of the United States in the setting of active disease refractory to appropriately dosed oral ULT.

5. Before the initiation of allopurinol, HLA-B*5801 screening should Continued on page 6

www.ValueBasedRheumatology.com

Gout

Only Half of Physicians Treat Gout According to New ACR Guideline Recommendations By Neil Canavan Cincinnati, OH—Results of a new study suggest that despite the availability of urate-lowering treatments (ULTs) and the newly published American College of Rheumatology (ACR) guidelines for the treatment of gout, which were initially introduced at last year’s ACR annual meeting, no more than 50% of physicians are currently following these recommendations. “The take-home message here is that adherence to the guidelines is not very good for any physician type,” lead investigator Robert J. Morlock, PhD, Head of Global Market Access and Health Economics Consultant, Ardea Biosciences, San Diego, CA, and Adjunct Faculty at Henry Ford Hospital, Detroit, MI, told Value-Based Care in Rheumatology. “Rheumatologists are slightly better than primary care providers, but neither group is treating enough of their patients to the guidelines.” The study was presented at the October 2012 meeting of the Academy of Managed Care Pharmacy. In their study, Dr Morlock and colleagues conducted a retrospective chart review of patients who were diagnosed with gout and were being seen by a rheumatologist or by a primary care physician (PCP). To be included in the study, patients had to be initiated with gout treatment with 1 of 2 xanthine oxidase inhibitors

(or ULTs)—allopurinol (Zyloprim; n = 621) or febuxostat (Uloric; n = 237)— and have had 1 year of follow-up.

“The take-home message here is that adherence to the guidelines is not very good for any physician type. Rheumatologists are slightly better than primary care providers, but neither group is treating enough of their patients to the guidelines.” —Robert J. Morlock, PhD

All treating physicians had to have at least 50 patients with a diagnosis of gout in their practice within the past year. There were 125 rheumatology practices (500 patients) and 124 PCPs (358 patients) included in the analysis. Chart reviews were performed on the last 5 patients treated within a given practice. The patient cohort was assessed for adherence to the ACR guidelines according to the following criteria: timely prophylaxis with a ULT, titration to a target serum uric acid level of <6 mg/dL, and the number of assess-

ments of serum uric acid in 12 months. Results of the analysis were striking. A key component of the guidelines—frequent monitoring of the patient—was routinely ignored. After an initial baseline measurement of serum uric acid, only 68% of rheumatologists, and 53% of PCPs performed a second assessment within the first 12 months after initiating treatment. “After 2 or more gout episodes in a year, the guidelines recommend treating with a ULT,” explained Dr Morlock. “That’s step 1. Step 2 asks that you then follow urate levels—but if [physicians] aren’t taking another laboratory value for a year or more, how can they say if the drug is optimally working or not?” Reflecting the lack of recommended follow-up, the majority of patients in this cohort did not achieve the suggested serum uric acid treatment goal of <6 mg/dL; only 50% of patients in rheumatology practices reached this target versus 36% of patients being treated by a PCP. The cut-off point is not arbitrary— the goal of long-term ULT is to reduce serum uric acid levels below the saturation point of monosodium urate so that new crystals do not form and so existing crystals are dissolved. Yet, lacking the data for serum uric acid levels, in this study 32% of rheumatol-

First-Ever ACR Guidelines Issued for... be considered in subpopulations where the allele is frequently elevated and where allele-positive subjects are at high risk for severe allopurinol sensitivity reactions (eg, Koreans with ≥stage 3 CKD and all patients of Han Chinese and Thai descent) The panel recommends that HLAB*5801 screening be performed with the rapid, widely available polymerase chain reaction–based approach. For inconclusive results, HLAB*5801 sequencing is advised. If a patient tests HLA-B*5801–positive, alternatives to allopurinol should be prescribed. The panel did not recommend universal HLA-B*5801 screening, citing data that indicate a prevalence of <2% of the allele for individuals outside of the highlighted risk groups.

“Our goal is that these guidelines, along with educating gout patients in effective treatment, will improve adherence, quality of care, and management of this painful and potentially chronically debilitating condition.”

The panel recommends the uricosuric agents probenecid, fenofibrate (TriCor; off-label use), or losartan (Cozaar; off-label use) as adjunctive therapy in a comprehensive ULT program in the refractory disease setting. Nine refractory disease case scenarios are described within the guidance.

—John D. Fitzgerald, MD, PhD

6. Combination oral ULT with 1 XOI agent and 1 uricosuric agent is appropriate when the serum urate target has not been met by appropriate dosing of an XOI

Supporting this recommendation, the task force panel cited data from 2 large clinical trials where 8-mg pegloticase every 2 weeks was effective in reducing serum uric acid to appropriate levels in 42% of patients. Of note, pegloticase as a first-line

OCTOBER 2012

“What I’d like to see managed care do is put metrics in place to measure or grade clinicians on following the guideline. If you have the laboratory assessments, you can adjust the treatment accordingly.” —Robert J. Morlock, PhD

Given the evidence that it takes several years for physicians to incorporate national guidelines into their daily practice, what can be done to improve guideline adherence sooner in face of the significant disease burden on patients? “What I’d like to see managed care do is put metrics in place to measure or grade clinicians on following the guideline,” Dr Morlock suggested. Lacking that, he advised physicians to simply do a bit more testing. “If you have the laboratory assessments, you can adjust the treatment accordingly.” ■

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7. Pegloticase is appropriate for patients with severe gout disease burden and refractoriness to, or intolerance of, appropriately dosed oral ULT options

VALUE-BASED CARE IN RHEUMATOLOGY

ogists and 57% of PCPs did not adjust their patients’ ULT dose to this treatment goal.

ULT was not recommended for any patient with gout. Safety and Quality of Care Commenting on the effort overall, Dr Fitzgerald stated in the press release, “The ACR gout guidelines are designed to emphasize safety, quality of therapy, and to reflect best practice based upon medical evidence available at this time. Our goal is that these guidelines, along with educating gout patients in effective treatment, will improve adherence, quality of care, and management of this painful and potentially chronically debilitating condition.” Part 2 of the guidelines, titled “Therapy and Antiinflammatory Prophylaxis of Acute Gouty Arthritis,” will be discussed in the December issue of this publication. ■

VOL. 1

NO. 5

ORENCIA® (abatacept) for injection for intravenous use injection, for subcutaneous use Brief Summary of Prescribing Information. For complete prescribing information, please consult official package insert. INDICATIONS AND USAGE Adult Rheumatoid Arthritis (RA) - ORENCIA® (abatacept) 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. ORENCIA may be used as monotherapy or concomitantly with diseasemodifying antirheumatic drugs (DMARDs) other than tumor necrosis factor (TNF) antagonists. Juvenile Idiopathic Arthritis - ORENCIA is indicated for reducing signs and symptoms in pediatric patients 6 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis. ORENCIA may be used as monotherapy or concomitantly with methotrexate (MTX). Important Limitations of Use - ORENCIA should not be administered concomitantly with TNF antagonists. ORENCIA is not recommended for use concomitantly with other biologic rheumatoid arthritis (RA) therapy, such as anakinra. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Concomitant Use with TNF Antagonists - In controlled clinical trials in patients with adult RA, patients receiving concomitant intravenous ORENCIA and TNF antagonist therapy experienced more infections (63%) and serious infections (4.4%) compared to patients treated with only TNF antagonists (43% and 0.8%, respectively) [see Adverse Reactions]. These trials failed to demonstrate an important enhancement of efficacy with concomitant administration of ORENCIA with TNF antagonist; therefore, concurrent therapy with ORENCIA and a TNF antagonist is not recommended. While transitioning from TNF antagonist therapy to ORENCIA therapy, patients should be monitored for signs of infection. Hypersensitivity - Of 2688 patients with adult RA treated with ORENCIA intravenously in clinical trials, there were two cases of anaphylaxis or anaphylactoid reactions. Other events potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred in less than 0.9% of ORENCIA-treated patients. Of the 190 patients with juvenile idiopathic arthritis treated with ORENCIA in clinical trials, there was one case of a hypersensitivity reaction (0.5%). Appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction [see Adverse Reactions]. Infections - Serious infections, including sepsis and pneumonia, have been reported in patients receiving ORENCIA. Some of these infections have been fatal. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy which in addition to their underlying disease, could further predispose them to infection. Physicians should exercise caution when considering the use of ORENCIA in patients with a history of recurrent infections, underlying conditions which may predispose them to infections, or chronic, latent, or localized infections. Patients who develop a new infection while undergoing treatment with ORENCIA should be monitored closely. Administration of ORENCIA should be discontinued if a patient develops a serious infection [see Adverse Reactions]. A higher rate of serious infections has been observed in adult RA patients treated with concurrent TNF antagonists and ORENCIA [see Warnings and Precautions]. Prior to initiating immunomodulatory therapies, including ORENCIA, patients should be screened for latent tuberculosis infection with a tuberculin skin test. ORENCIA has not been studied in patients with a positive tuberculosis screen, and the safety of ORENCIA in individuals with latent tuberculosis infection is unknown. Patients testing positive in tuberculosis screening should be treated by standard medical practice prior to therapy with ORENCIA. Antirheumatic therapies have been associated with hepatitis B reactivation. Therefore, screening for viral hepatitis should be performed in accordance with published guidelines before starting therapy with ORENCIA. In clinical studies with ORENCIA, patients who screened positive for hepatitis were excluded from study. Immunizations - Live vaccines should not be given concurrently with ORENCIA or within 3 months of its discontinuation. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving ORENCIA. The efficacy of vaccination in patients receiving ORENCIA is not

known. Based on its mechanism of action, ORENCIA (abatacept) may blunt the effectiveness of some immunizations. It is recommended that patients with juvenile idiopathic arthritis be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating ORENCIA therapy. Use in Patients with Chronic Obstructive Pulmonary Disease (COPD) - Adult COPD patients treated with ORENCIA developed adverse events more frequently than those treated with placebo, including COPD exacerbations, cough, rhonchi, and dyspnea. Use of ORENCIA in patients with RA and COPD should be undertaken with caution and such patients should be monitored for worsening of their respiratory status [see Adverse Reactions]. Immunosuppression - The possibility exists for drugs inhibiting T cell activation, including ORENCIA, to affect host defenses against infections and malignancies since T cells mediate cellular immune responses. The impact of treatment with ORENCIA on the development and course of malignancies is not fully understood [see Adverse Reactions]. In clinical trials in patients with adult RA, a higher rate of infections was seen in ORENCIA-treated patients compared to placebo [see Adverse Reactions]. ADVERSE REACTIONS Clinical Studies Experience in Adult RA Patients Treated with Intravenous ORENCIA - Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice. The data described herein reflect exposure to ORENCIA administered intravenously in patients with active RA in placebocontrolled studies (1955 patients with ORENCIA, 989 with placebo). The studies had either a double-blind, placebocontrolled period of 6 months (258 patients with ORENCIA, 133 with placebo) or 1 year (1697 patients with ORENCIA, 856 with placebo). A subset of these patients received concomitant biologic DMARD therapy, such as a TNF blocking agent (204 patients with ORENCIA, 134 with placebo). The majority of patients in RA clinical studies received one or more of the following concomitant medications with ORENCIA: MTX, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, TNF blocking agents, azathioprine, chloroquine, gold, hydroxychloroquine, leflunomide, sulfasalazine, and anakinra. The most serious adverse reactions were serious infections and malignancies. The most commonly reported adverse events (occurring in ≥10% of patients treated with ORENCIA) were headache, upper respiratory tract infection, nasopharyngitis, and nausea. The adverse events most frequently resulting in clinical intervention (interruption or discontinuation of ORENCIA) were due to infection. The most frequently reported infections resulting in dose interruption were upper respiratory tract infection (1.0%), bronchitis (0.7%), and herpes zoster (0.7%). The most frequent infections resulting in discontinuation were pneumonia (0.2%), localized infection (0.2%), and bronchitis (0.1%). Infections - In the placebo-controlled trials, infections were reported in 54% of ORENCIA-treated patients and 48% of placebo-treated patients. The most commonly reported infections (reported in 5-13% of patients) were upper respiratory tract infection, nasopharyngitis, sinusitis, urinary tract infection, influenza, and bronchitis. Other infections reported in fewer than 5% of patients at a higher frequency (>0.5%) with ORENCIA compared to placebo, were rhinitis, herpes simplex, and pneumonia [see Warnings and Precautions]. Serious infections were reported in 3.0% of patients treated with ORENCIA and 1.9% of patients treated with placebo. The most common (0.2-0.5%) serious infections reported with ORENCIA were pneumonia, cellulitis, urinary tract infection, bronchitis, diverticulitis, and acute pyelonephritis [see Warnings and Precautions]. Malignancies - In the placebo-controlled portions of the clinical trials (1955 patients treated with ORENCIA for a median of 12 months), the overall frequencies of malignancies were similar in the ORENCIA- and placebo-treated patients (1.3% and 1.1%, respectively). However, more cases of lung cancer were observed in ORENCIA-treated patients (4, 0.2%) than placebotreated patients (0). In the cumulative ORENCIA clinical trials (placebo-controlled and uncontrolled, open-label) a total of 8 cases of lung cancer (0.21 cases per 100 patient-years) and 4 lymphomas (0.10 cases per 100 patient-years) were observed in 2688 patients (3827 patient-years). The rate observed for lymphoma is approximately 3.5-fold higher than expected in an age- and gender-matched general population based on the National Cancer Institute’s Surveillance, Epidemiology, and End

Results Database. Patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma. Other malignancies included skin, breast, bile duct, bladder, cervical, endometrial, lymphoma, melanoma, myelodysplastic syndrome, ovarian, prostate, renal, thyroid, and uterine cancers [see Warnings and Precautions]. The potential role of ORENCIA (abatacept) in the development of malignancies in humans is unknown. Infusion-Related Reactions and Hypersensitivity Reactions Acute infusion-related events (adverse reactions occurring within 1 hour of the start of the infusion) in Studies III, IV, and V [see Clinical Studies (14.1) in Full Prescribing Information] were more common in the ORENCIA-treated patients than the placebo patients (9% for ORENCIA, 6% for placebo). The most frequently reported events (1-2%) were dizziness, headache, and hypertension. Acute infusion-related events that were reported in >0.1% and ≤1% of patients treated with ORENCIA included cardiopulmonary symptoms, such as hypotension, increased blood pressure, and dyspnea; other symptoms included nausea, flushing, urticaria, cough, hypersensitivity, pruritus, rash, and wheezing. Most of these reactions were mild (68%) to moderate (28%). Fewer than 1% of ORENCIA-treated patients discontinued due to an acute infusion-related event. In controlled trials, 6 ORENCIA-treated patients compared to 2 placebo-treated patients discontinued study treatment due to acute infusion-related events. Of 2688 patients treated with ORENCIA in clinical trials, there were two cases of anaphylaxis or anaphylactoid reactions. Other events potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred in less than 0.9% of ORENCIA-treated patients and generally occurred within 24 hours of ORENCIA infusion. Appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction [see Warnings and Precautions]. Adverse Reactions in Patients with COPD - In Study V [see Clinical Studies (14.1) in Full Prescribing Information], there were 37 patients with chronic obstructive pulmonary disease (COPD) who were treated with ORENCIA and 17 COPD patients who were treated with placebo. The COPD patients treated with ORENCIA developed adverse events more frequently than those treated with placebo (97% vs 88%, respectively). Respiratory disorders occurred more frequently in ORENCIA-treated patients compared to placebo-treated patients (43% vs 24%, respectively) including COPD exacerbation, cough, rhonchi, and dyspnea. A greater percentage of ORENCIA-treated patients developed a serious adverse event compared to placebo-treated patients (27% vs 6%), including COPD exacerbation (3 of 37 patients [8%]) and pneumonia (1 of 37 patients [3%]) [see Warnings and Precautions]. Other Adverse Reactions - Adverse events occurring in 3% or more of patients and at least 1% more frequently in ORENCIAtreated patients (n=1955) versus placebo (n=989) during placebo-controlled RA studies were: Headache (18%, 13%); Nasopharyngitis (12%, 9%); Dizziness (9%, 7%); Cough (8%, 7%); Back pain (7%, 6%); Hypertension (7%, 4%); Dyspepsia (6%, 4%); Urinary tract infection (6%, 5%); Rash (4%, 3%); Pain in extremity (3%, 2%), respectively. The ORENCIA group included 204 patients on concomitant biologic DMARDs (adalimumab, anakinra, etanercept, or infliximab). The placebo group included 134 patients on concomitant biologic DMARDs (adalimumab, anakinra, etanercept, or infliximab). Immunogenicity - Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in RA patients for up to 2 years following repeated treatment with ORENCIA. Thirty-four of 1993 (1.7%) patients developed binding antibodies to the entire abatacept molecule or to the CTLA-4 portion of abatacept. Because trough levels of abatacept can interfere with assay results, a subset analysis was performed. In this analysis it was observed that 9 of 154 (5.8%) patients that had discontinued treatment with ORENCIA for over 56 days developed antibodies. Samples with confirmed binding activity to CTLA-4 were assessed for the presence of neutralizing antibodies in a cellbased luciferase reporter assay. Six of 9 (67%) evaluable patients were shown to possess neutralizing antibodies. However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity. No correlation of antibody development to clinical response or adverse events was observed. The data reflect the percentage of patients whose test results were positive for antibodies to abatacept in specific assays. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons,

comparison of the incidence of antibodies to abatacept with the incidence of antibodies to other products may be misleading. Clinical Experience in MTX-Naive Patients - Study VI was an active-controlled clinical trial in MTX-naive patients [see Clinical Studies (14.1) in Full Prescribing Information]. The safety experience in these patients was consistent with Studies I-V. Clinical Experience in Adult RA Patients Treated with Subcutaneous ORENCIA (abatacept) - Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice. Study SC-I was a randomized, double-blind, double-dummy, non-inferiority study that compared the efficacy and safety of abatacept administered subcutaneously (SC) and intravenously (IV) in 1457 subjects with rheumatoid arthritis, receiving background MTX, and experiencing an inadequate response to MTX (MTX-IR) [see Clinical Studies (14.1) in Full Prescribing Information]. The safety experience and immunogenicity for ORENCIA administered subcutaneously was consistent with intravenous Studies I-VI. Due to the route of administration, injection site reactions and immunogenicity were evaluated in Study SC-I and two other smaller studies discussed in the sections below. Injection Site Reactions in Adult RA Patients Treated with Subcutaneous ORENCIA - Study SC-I compared the safety of abatacept including injection site reactions following subcutaneous or intravenous administration. The overall frequency of injection site reactions was 2.6% (19/736) and 2.5% (18/721) for the subcutaneous abatacept group and the intravenous abatacept group (subcutaneous placebo), respectively. All these injection site reactions (including hematoma, pruritus, and erythema) were mild (83%) to moderate (17%) in severity, and none necessitated drug discontinuation. Immunogenicity in Adult RA Patients Treated with Subcutaneous ORENCIA - Study SC-I compared the immunogenicity to abatacept following subcutaneous or intravenous administration. The overall immunogenicity frequency to abatacept was 1.1% (8/725) and 2.3% (16/710) for the subcutaneous and intravenous groups, respectively. The rate is consistent with previous experience, and there was no correlation of immunogenicity with effects on pharmacokinetics, safety, or efficacy. Immunogenicity and Safety of Subcutaneous ORENCIA Administration as Monotherapy without an Intravenous Loading Dose - Study SC-II was conducted to determine the effect of monotherapy use of ORENCIA on immunogenicity following subcutaneous administration without an intravenous load in 100 RA patients, who had not previously received abatacept or other CTLA4Ig, who received either subcutaneous ORENCIA plus MTX (n=51) or subcutaneous ORENCIA monotherapy (n=49). No patients in either group developed antiproduct antibodies after 4 months of treatment. The safety observed in this study was consistent with that observed in the other subcutaneous studies. Immunogenicity and Safety of Subcutaneous ORENCIA upon Withdrawal (Three Months) and Restart of Treatment - Study SC-III in the subcutaneous program was conducted to investigate the effect of withdrawal (three months) and restart of ORENCIA subcutaneous treatment on immunogenicity in RA patients treated concomitantly with MTX. One hundred sixtyseven patients were enrolled in the first 3-month treatment period and responders (n=120) were randomized to either subcutaneous ORENCIA or placebo for the second 3-month period (withdrawal period). Patients from this period then received open-label ORENCIA treatment in the final 3-month period of the study (period 3). At the end of the withdrawal period, 0/38 patients who continued to receive subcutaneous ORENCIA developed anti-product antibodies compared to 7/73 (9.6%) of patients who had subcutaneous ORENCIA withdrawn during this period. Half of the patients receiving subcutaneous placebo during the withdrawal period received a single intravenous infusion of ORENCIA at the start of period 3 and half received intravenous placebo. At the end of period 3, when all patients again received subcutaneous ORENCIA, the immunogenicity rates were 1/38 (2.6%) in the group receiving subcutaneous ORENCIA throughout, and 2/73 (2.7%) in the group that had received placebo during the withdrawal period. Upon reinitiating therapy, there were no injection reactions and no differences in response to therapy in patients who were withdrawn from subcutaneous therapy for up to 3 months relative to those who remained on subcutaneous therapy, whether therapy was reintroduced with or without an intravenous loading dose. The safety observed in this study was consistent with that observed in the other studies.

Clinical Studies Experience in Juvenile Idiopathic Arthritis In general, the adverse events in pediatric patients were similar in frequency and type to those seen in adult patients [see Warnings and Precautions, Adverse Reactions]. ORENCIA (abatacept) has been studied in 190 pediatric patients, 6 to 17 years of age, with polyarticular juvenile idiopathic arthritis. Overall frequency of adverse events in the 4-month, lead-in, open-label period of the study was 70%; infections occurred at a frequency of 36% [see Clinical Studies (14.2) in Full Prescribing Information]. The most common infections were upper respiratory tract infection and nasopharyngitis. The infections resolved without sequelae, and the types of infections were consistent with those commonly seen in outpatient pediatric populations. Other events that occurred at a prevalence of at least 5% were headache, nausea, diarrhea, cough, pyrexia, and abdominal pain. A total of 6 serious adverse events (acute lymphocytic leukemia, ovarian cyst, varicella infection, disease flare [2], and joint wear) were reported during the initial 4 months of treatment with ORENCIA. Of the 190 patients with juvenile idiopathic arthritis treated with ORENCIA in clinical trials, there was one case of a hypersensitivity reaction (0.5%). During Periods A, B, and C, acute infusion-related reactions occurred at a frequency of 4%, 2%, and 3%, respectively, and were consistent with the types of events reported in adults. Upon continued treatment in the open-label extension period, the types of adverse events were similar in frequency and type to those seen in adult patients, except for a single patient diagnosed with multiple sclerosis while on open-label treatment. Immunogenicity - Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in patients with juvenile idiopathic arthritis following repeated treatment with ORENCIA throughout the open-label period. For patients who were withdrawn from therapy for up to 6 months during the double-blind period, the rate of antibody formation to the CTLA-4 portion of the molecule was 41% (22/54), while for those who remained on therapy the rate was 13% (7/54). Twenty of these patients had samples that could be tested for antibodies with neutralizing activity; of these, 8 (40%) patients were shown to possess neutralizing antibodies. The presence of antibodies was generally transient and titers were low. The presence of antibodies was not associated with adverse events, changes in efficacy, or an effect on serum concentrations of abatacept. For patients who were withdrawn from ORENCIA during the double-blind period for up to 6 months, no serious acute infusion-related events were observed upon re-initiation of ORENCIA therapy. Postmarketing Experience - Adverse reactions have been reported during the postapproval use of ORENCIA. 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 ORENCIA. Based on the postmarketing experience in adult RA patients, the following adverse reaction has been identified during postapproval use with ORENCIA. â&#x20AC;˘ Vasculitis (including cutaneous vasculitis and leukocytoclastic vasculitis) DRUG INTERACTIONS TNF Antagonists - Concurrent administration of a TNF antagonist with ORENCIA has been associated with an increased risk of serious infections and no significant additional efficacy over use of the TNF antagonists alone. Concurrent therapy with ORENCIA and TNF antagonists is not recommended [see Warnings and Precautions]. Other Biologic RA Therapy - There is insufficient experience to assess the safety and efficacy of ORENCIA administered concurrently with other biologic RA therapy, such as anakinra, and therefore such use is not recommended. Blood Glucose Testing - Parenteral drug products containing maltose can interfere with the readings of blood glucose monitors that use test strips with glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ). The GDH-PQQ based glucose monitoring systems may react with the maltose present in ORENCIA for intravenous administration, resulting in falsely elevated blood glucose readings on the day of infusion. When receiving ORENCIA through intravenous administration, patients that require blood glucose monitoring should be advised to consider methods that do not react with maltose, such as those based on glucose dehydrogenase nicotine adenine dinucleotide (GDH-NAD), glucose oxidase, or glucose hexokinase test methods. ORENCIA for subcutaneous administration does not contain maltose; therefore, patients do not need to alter their glucose monitoring.

USE IN SPECIFIC POPULATIONS Pregnancy - Pregnancy Category C: There are no adequate and well-controlled studies of ORENCIA (abatacept) use in pregnant women. Abatacept has been shown to cross the placenta in animals, and in animal reproduction studies alterations in immune function occurred. ORENCIA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Abatacept was not teratogenic when administered to pregnant mice at doses up to 300 mg/kg and in pregnant rats and rabbits at doses up to 200 mg/kg daily representing approximately 29 times the exposure associated with the maximum recommended human dose (MRHD) of 10 mg/kg based on AUC (area under the time-concentration curve). Abatacept administered to female rats every three days during early gestation and throughout the lactation period, produced no adverse effects in offspring at doses up to 45 mg/kg, representing 3 times the exposure associated with the MRHD of 10 mg/kg based on AUC. However, at 200 mg/kg, 11 times the MRHD exposure, alterations in immune function were observed consisting of a 9-fold increase in T-cell dependent antibody response in female pups and thyroid inflammation in one female pup. It is not known whether these findings indicate a risk for development of autoimmune diseases in humans exposed in utero to abatacept. However, exposure to abatacept in the juvenile rat, which may be more representative of the fetal immune system state in the human, resulted in immune system abnormalities including inflammation of the thyroid and pancreas [see Nonclinical Toxicology (13.2) in Full Prescribing Information]. Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to ORENCIA, a pregnancy registry has been established. Healthcare professionals are encouraged to register patients and pregnant women are encouraged to enroll themselves by calling 1-877-311-8972. Nursing Mothers - It is not known whether ORENCIA is excreted into human milk or absorbed systemically after ingestion by a nursing infant. However, abatacept was excreted in rat milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ORENCIA, 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 - ORENCIA is indicated for reducing signs and symptoms in pediatric patients with moderately to severely active polyarticular juvenile idiopathic arthritis ages 6 years and older. ORENCIA may be used as monotherapy or concomitantly with MTX. Studies in juvenile rats exposed to ORENCIA prior to immune system maturity have shown immune system abnormalities including an increase in the incidence of infections leading to death as well as inflammation of the thyroid and pancreas [see Nonclinical Toxicology (13.2) in Full Prescribing Information]. Studies in adult mice and monkeys have not demonstrated similar findings. As the immune system of the rat is undeveloped in the first few weeks after birth, the relevance of these results to humans greater than 6 years of age (where the immune system is largely developed) is unknown. ORENCIA is not recommended for use in patients below the age of 6 years. The safety and effectiveness of ORENCIA in pediatric patients below 6 years of age have not been established. The safety and efficacy of ORENCIA in pediatric patients for uses other than juvenile idiopathic arthritis have not been established. Geriatric Use - A total of 323 patients 65 years of age and older, including 53 patients 75 years and older, received ORENCIA in clinical studies. No overall differences in safety or effectiveness were observed between these patients and younger patients, but these numbers are too low to rule out differences. The frequency of serious infection and malignancy among ORENCIA-treated patients over age 65 was higher than for those under age 65. 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 50 mg/kg have been administered intravenously without apparent toxic effect. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted.

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B5-B0001A2-09-11 Rev September 2011

Gout

Poorly Managed Gout a Driver for Increased Healthcare Utilization for Veterans Hospitalization rates rise with uncontrolled uric acid levels By Neil Canavan Cincinnati, OH—Patients with gout who have uncontrolled serum uric acid levels are much more likely to utilize healthcare resources, such as hospitalizations and outpatient services, compared with patients with gout whose serum uric acid levels are being effectively managed, according to data from a large study of veterans conducted by Eswar Krishnan, MD, MPhil, Assistant Professor of Medicine at the Stanford School of Medicine, Palo Alto, CA, and colleagues. The study was presented in a poster at the October 2012 meeting of the Academy of Managed Care Pharmacy. Several previous, smaller studies have suggested the relationship between uncontrolled gout and increased healthcare utilization; however, the impact of uncontrolled serum uric acid on “healthcare utilization among veterans with gout has not been well documented,” Dr

Krishnan and colleagues suggested. They undertook this investigation in response to the vast number of individuals in the Veterans Affairs system and the rising incidence of gout as the population ages. The data came from medical records from the Veterans Integrated Services Network between January 2002 and January 2011. The time course was divided into 6-month cycles. Mean serum uric acid levels were estimated for each 6-month cycle, with linear extrapolation used to estimate serum uric acid for any 6month period in which no measurement was taken. To qualify for the analysis, patients had to be aged >18 years, have had at least 2 diagnoses of gout, have a minimum of 2 serum uric acid measures within the eligibility period, have at least 1 year of follow-up, and have no comorbid inflammatory diseases. A total of 2553 veterans with gout

were included in the analysis. All participants were men (average age, 63.5 years), approximately 52% were white, and the mean body mass index was 31.1 kg/m2.

Patients with uncontrolled serum uric acid were at increased risk for all-cause and gout-related hospitalizations, as well as an elevated risk for all-cause and gout-related outpatient visits. Uncontrolled serum uric acid was defined as ≥7 mg/dL. The average duration of follow-up was approximately 6 years. The results showed that 50% of the 6-month cycles recorded values of

serum uric acid in the uncontrolled range (>7 mg/dL), whereas only 30% of patients had a serum uric acid level at or below the American College of Rheumatology–recommended threshold of 6 mg/dL. In addition, patients with uncontrolled serum uric acid were at increased risk for all-cause and goutrelated hospitalizations (hazard ratios [HRs], 1.25 and 1.49, respectively), as well as an elevated risk for all-cause and gout-related outpatient visits (HRs, 1.32 and 1.09, respectively) versus those with controlled gout. The numbers of gout-related and non–gout-related hospitalization and outpatient visits were also higher for veterans with uncontrolled gout (HRs, 1.47, 1.12, 1.23, and 1.00, respectively) versus those with controlled gout. Healthcare utilization was similarly increased, even when the cut-off point was reduced to a less stringent level of >6 mg/dL. ■

Lead in Blood Associated with Gout, New Analysis Shows By Rosemary Frei, MSc

hysicians should consider lead in the blood as a cause of gout in patients who do not appear to have other causes for their condition, according to researchers whose article on the topic was recently published (Krishnan E, et al. Ann Intern Med. 2012;157:233-241). The investigators found that people with a blood lead level between 2.6 and 26.8 mcg/dL had a 3.6-fold higher risk of gout than did those with a blood lead level of 0.18 to 1.2 mcg/dL. These individuals also had a nearly 2-fold higher likelihood of having hyperuricemia. The Centers for Disease Control and Prevention and the World Health Organization both consider a blood lead level of <25 mcg/dL to be nonelevated. This study challenges that threshold, and also points to the need for measurement of blood lead levels as a routine part of the search for secondary causes of gout. “In all cases of gout, clinicians

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at a glance ➤ Patients with gout who do not have other causes for this condition should be tested for lead in their blood ➤ People with blood lead levels between 2.6 and 26.8 mcg/dL have a 3.6-fold increased risk for gout and an almost double risk for hyperuricemia ➤ Current blood lead level thresholds should likely be lowered, because even 1.2 mcg/dL of lead in the blood is associated with increased incidence of gout ➤ Physicians should obtain lifetime lead exposure histories from patients, because lead accumulates in the bones and can affect patients long after exposure

should first try to identify an obvious cause—sometimes it is alcohol use, and sometimes it is a concomitant sickle-cell trait,” advised lead investigator Eswar Krishnan, MD, MPhil, Assistant Professor of Medicine at the Stanford School of Medicine, Palo Alto, CA, in an interview with ValueBased Care in Rheumatology. “If none is found, they should consider performing a blood lead level test.” The study included 6153 patients (aged ≥40 years) from the National Health and Nutrition Examination Survey (NHANES). In an accompanying editorial, Ashwini Sehgal, MD, Duncan Neuhauser Professor of Community Health Improvement and Professor of Epidemiology and Biostatistics, Bioethics, and Medicine at Case Western Reserve University, Cleveland, OH, noted that the study has significant merit because of its large national sample size. Dr Sehgal believes the current

OCTOBER 2012

thresholds for safe blood lead levels should be lowered, and healthcare providers “should obtain lifetime exposure histories from their patients

“In all cases of gout, clinicians should first try to identify an obvious cause— sometimes it is alcohol use, and sometimes it is a concomitant sickle-cell trait. If none is found, they should consider performing a blood lead level test.” —Eswar Krishnan, MD, MPhil

and consider checking blood levels, bearing in mind that lead accumulated in the bones long ago might still Continued on page 10

www.ValueBasedRheumatology.com

Fibromyalgia

Patients with Fibromyalgia Improve Rapidly... ahead of print]). Significant pain relief occurred within the first week of treatment with pregabalin and persisted over the 15-week duration of the trial. Significantly more patients reported being “very much improved” or “much improved” with pregabalin than with placebo (P = .078). Quality of sleep improved significantly in the pregabalin arm within the first week of treatment and remained significantly improved versus placebo through the end of the study. “In this, the first clinical trial in fibromyalgia patients in Japan, pregabalin demonstrated significant efficacy in pain reduction and also improved measures of sleep and functioning,” Hiroyoshi Ohta, MS, of Pfizer Japan in Tokyo, and colleagues concluded. “The drug was generally well tolerated, and adverse events [AEs] were consistent with prior trials and current product labeling. These data suggest that pregabalin may be an effective treatment option for the relief of pain and sleep problems in Japanese patients with fibromyalgia.” Approved in the United States for the treatment of fibromyalgia, pregabalin has not been evaluated exten-

sively in controlled trials of Asian patients, and there have not been any clinical trials of patients with fibromyalgia in Japan. For this study, investigators at 44 centers in Japan

“The drug was generally well tolerated, and adverse events were consistent with prior trials and current product labeling. These data suggest that pregabalin may be an effective treatment option for the relief of pain and sleep problems in Japanese patients with fibromyalgia.” —Hiroyoshi Ohta, MS

enrolled patients aged ≥18 years who met the 1990 American College of Rheumatology diagnostic criteria for fibromyalgia. A total of 498 patients (mean age, approximately 47 years) were ran-

Gout

Lead in Blood Associated with Gout... Continued from page 9 be able to cause harm.” Dr Krishnan and colleagues used a cross-sectional analysis of individuals from 2 cycles of NHANES, 2005-2006 and 2007-2008. People who were undergoing dialysis or who had a history of renal disease or an estimated glomerular filtration rate <10 mL/ min, because of the association between kidney disease, hyperuricemia, and gout. The 290 patients with gout in the NHANES sample were significantly older than the 5863 persons without gout (average age, 56.65 years vs 62.49 years, respectively). They also had greater renal impairment and were more likely to have comorbidities, such as obesity, hypertension, or diabetes. Mean blood lead level was 2.64 mcg/dL in the group with gout compared with 1.95 mcg/dL for those without gout. In addition, the

prevalence of gout and the mean concentration of serum urate increased linearly with higher blood lead levels, and people with hyperuricemia had a worse cardiovascular risk factor profile than those without the condition. Blood levels of cadmium and mercury were not correlated with gout. Furthermore, blood lead levels as low as approximately 1.2 mcg/dL were associated with increased gout prevalence, independent of other major risk factors. A multivariate logistic regression analysis, adjusting for confounding factors, showed that patients in the highest blood lead level quartile had greater risk for gout or hyperuricemia (range, 2.6-26.8 mcg/dL; odds ratio, 3.62 for gout, 1.84 for hyperuricemia) compared with those in the lowest blood lead level quartile (range, 0.181.20 mcg/dL). ■

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domized to placebo or to pregabalin at a starting dose of 150 mg daily, which was titrated over 3 weeks to a maintenance dose of 300 mg or 450 mg daily, and was continued for an additional 12 weeks. The mean duration of fibromyalgia was 62 months in the placebo group and 69.6 months among those receiving pregabalin. The primary end point was the mean pain score at the end of the study, as recorded daily by patients, who rated their pain over the previous 24 hours from 0 (no pain) to 10 (worst possible pain). The mean pain score was evaluated weekly during the trial. Secondary end points consisted of patient assessment of pain by visual analog scale (VAS; 0-100 mm), the Patient Global Impression of Change (PGIC), the Fibromyalgia Impact Questionnaire (FIQ), the 36-Item Short Form Health Survey (SF-36), the Hospital Anxiety and Depression Scale, self-rated sleep quality, and the Medical Outcomes Study (MOS) Sleep Scale. Encouraging Results The baseline pain score averaged between 6.4 and 6.5 in the 2 groups. When the trial ended, the pregabalin arm had a mean reduction of 1.48 from baseline compared with a reduction of 1.03 in the placebo group (P = .046). The proportions of patients with a ≥50% reduction in mean pain score at final assessment were 22.8% in the pregabalin group and 12.1% in the placebo group (P = .017). In addition, 40.4% of the patients treated with pregabalin had a ≥30% reduction in mean pain score compared with 30.6% of patients in the placebo group (P = .023). The VAS pain score averaged between 67 and 68 at baseline. At final assessment, the mean score was 47.42 with pregabalin, a reduction of 6.19 versus the placebo group (P = .013). PGIC results showed that 38.6% of the pregabalin group was “very much improved” or “much improved” at final assessment compared with 26.7% of the placebo group (P = .078). There was a significant improvement in FIQ total score, which was 3.33 lower in the pregabalin group versus in the placebo group (P = .014). The FIQ subscales of feeling good, pain, fatigue, and morning tiredness all showed significant differences in favor of the pregabalin arm. The physical functioning and vitali-

Continued from cover

at a glance ➤ The first Japanese study investigating the effect of pregabalin in patients with fibromyalgia showed significant improvements in pain, sleep, and quality of life ➤ The impact was quick, within the first week of treatment, and lasted throughout the trial ➤ Of the patients receiving pregabalin, 40.4% had a ≥30% reduction in mean pain score ➤ By the end of the study, 22.8% of those receiving pregabalin had a ≥50% reduction in mean pain score ➤ More adverse events were reported in the pregabalin arm than in the placebo group; the most common were somnolence, dizziness, nasopharyngitis, weight gain, and constipation

ty scales of the SF-36 were significantly improved with pregabalin (P = .006 and P = .052, respectively) versus with placebo. The mean change in quality-ofsleep score also showed significantly greater improvement with pregabalin at the last assessment (P <.001) and at every time point from week 1 through week 15 (P ≤.001). Multiple items on the MOS Sleep Scale improved significantly more with pregabalin, such as sleep disturbance (P <.001), sleep adequacy (P <.001), sleep quantity (P = .007), and awakening with shortness of breath or headache (P = .049). In addition, the composite MOS Sleep Scale score was significantly improved in the pregabalin group (P = .013). Adverse Events AEs and treatment-emergent AEs occurred more often in the pregabalin arm (90.0% and 82.4%, respectively) than in the placebo group (70.6% and 51.6%, respectively). The most common AEs in the pregabalin arm were somnolence, dizziness, nasopharyngitis, weight gain, and constipation. The authors reported that 9.6% of patients in the pregabalin arm withdrew because of AEs compared with 3.6% in the placebo arm. ■

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Psoriatic Arthritis

Apremilast Shows Promising Results in 3 Pivotal Trials of Patients with Psoriatic Arthritis By Alice Goodman

premilast, an investigational oral, small-molecule inhibitor of phosphodiesterase (PDE)-4 that modulates an intracellular network of proinflammatory and antiinflammatory mediators, is currently in phase 3 clinical trials (known as the PALACE trials) for the treatment of patients with psoriatic arthritis. PDE-4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells. PDE-4 inhibition elevates intracellular cAMP levels, which, in turn, downregulates the inflammatory response by modulating the expression of tumor necrosis factor (TNF)-alpha, interleukin-23, and other inflammatory cytokines. Elevation of cAMP also increased other anti-inflammatory cytokines.

The PALACE 2 and PALACE 3 trials met their primary end point, demonstrating a statistically significant improvement from baseline in the percentage of patients with psoriatic arthritis who were treated with apremilast and achieved at least a 20% improvement in American College of Rheumatology (ACR20) criteria. These 2 studies join PALACE 1, which also met the primary end point of ACR20 in the groups treated with apremilast, according to a September 6, 2012, press release from the manufacturer (http://ir.celgene.com/phoenix.zhtml ?c=111960&p=irol-newsArticle&ID= 1732178&highlight=). Together, the 3 PALACE studies comprise the most comprehensive psoriatic arthritis program to date intended for regulatory submission to

the US Food and Drug Administration (FDA). PALACE 1, 2, and 3 are each pivotal phase 3, multicenter, double-blind, placebo-controlled, parallel-group studies with 2 active treatment arms. Approximately 1500 patients with a wide spectrum of psoriatic arthritis were randomized in the combined PALACE trials in a 1:1:1 manner to receive apremilast 20 mg twice daily, 30 mg twice daily, or identically appearing placebo for 24 weeks, with an extension phase running through 52 weeks with all patients receiving apremilast. Patients included in the trials could have had previous treatment with oral disease-modifying antirheumatic drugs (DMARDs), biologic DMARDs, as well as previous failure with a TNF blocker therapy.

In each of the trials, apremilast was used alone or in combination with oral DMARDs. PALACE-3 includes a large subset of patients with significant skin involvement with psoriasis. In all 3 studies, significant improvement in ACR20 was maintained through week 24. In addition, consistent significant and clinically meaningful responses were observed in various measures of signs and symptoms of psoriatic arthritis and in physical function of patients receiving apremilast therapy through week 24. All 3 studies are currently ongoing, and the study extensions are blinded until all patients complete 52 weeks of treatment. A New Drug Application for apremilast is expected to be submitted to the FDA early next year. ■

Fibromyalgia

Motivation Interviewing of Patients with Fibromyalgia to Encourage Exercise Provides Mixed Results By Rosemary Frei, MSc

n intense program of telephone support does not have a significant effect on the motivation of patients with fibromyalgia to exercise or on their disease symptoms, according to the first randomized study to expressly address exercise in this patient population (Ang DC, et al. Clin J Pain. 2012 Oct 5 [Epub ahead of print]). Motivational interviewing, which was the modality tested in this study, involves trained professionals helping people resolve ambivalence about a behavior change—in this case, adherence to a regular exercise regimen. This approach was compared over 12 weeks with people in an education control group who had an equal number of fibromyalgia-relevant education sessions, all of which were conducted over the phone. Participants were assessed at baseline, immediately after the treatment sessions, and after 3 and 6 months. The investigators were surprised that the results did not show a higher percentage of patients in the motivational interview group who reported

an increase of at least 30 minutes per week in moderate-to-vigorous physical activity or a reduction in physical impairment resulting from fibromyalgia.

“I did not expect for the education control group to improve, but it did.” —Dennis C. Ang, MD, MS

“I did not expect for the education control group to improve, but it did— likely because education control subjects may have consciously or subconsciously increased their physical activity level, given that they were involved in an exercise trial,” said lead investigator Dennis C. Ang, MD, MS, Chief, Section on Rheumatology & Immunology, Wake Forest Baptist Medical Center, Winston-Salem, NC, in an interview with Value-Based Care in Rheumatology. Dr Ang conducted the study while

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he was at Indiana University-Purdue University, Indianapolis, IN. He and his colleagues randomized 107 people with fibromyalgia to 6 motivational interviewing sessions and another 109 people to 6 education sessions on fibromyalgia self-management. The motivational interview therapists who participated in the study had received roughly 24 hours of initial training in motivational interviews and approximate 60 hours of ongoing training before and during the study. The first 2 motivational interview sessions focused on increasing patient motivation to exercise, and the next 2 were devoted to strategies that strengthen commitment to exercise. The last 2 calls focused on followthrough strategies to prevent relapse to inactivity. For their part, participants in the education control group received educational health information on fibromyalgia, pain, fatigue, sleep, stress, and living well with fibromyalgia. There were no significant differences at any of the time points between the 2 groups in the primary

outcomes of increase in exercise and improvement in the scores on the Fibromyalgia Impact Questionnaire (FIQ)-Physical Impairment scale. However, more patients who had motivational interviewing than education control had meaningful improvements in FIQ scores (global symptom severity) at their 6-month follow-up (62.9% vs 49.5%; P = .06). Furthermore, those in the motivational interview group made greater gains on the 6-minute walk test compared with the education control group members. The motivational interview cohort also had a greater increase in the number of hours of physical activity immediately postintervention and a greater reduction in pain severity immediately postintervention and at their 3-month follow-up. Dr Ang said that his team intends to delve further into this approach. “We would like to know if motivational interviewing therapists’ degree of adherence to the principle of motivational interviewing was associated with increased physical activity.” ■

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PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

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,

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 duri during the double-blind, placebo-controlled portion of Studies RA-I, RA-II, RA-III and RA-IV w was 7% % for patients taking HUMIRA M and 4% % for placebo-treated patients. The m most common mm adverse reactions leading to discontinuation of HUMIRA M w were clinical flare reaction (0.7%), % rash (0.3%) % and pneumonia m (0.3%). % Infections In the controlled portions of the 32 global HUMIRA M clinical trials in adult patients w with RA, PsA, AS, CD D and Ps, the rate of serious infections w was 4.7 per 100 patient-years in 6694 HUMIRA-treated M patients versus a rate of 2.7 per 100 patient-years in 3749 control-treated patients. Serious infections observed included pneumonia, m septic arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis [see W Warnings and Precautions]. Tuberculosis and O Opportunistic Infections In 45 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD D and Ps that included 22,026 HUMIRA-treated M patients, the rate of reported active tuberculosis w was 0.22 per 100 patient-years and the

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

Placebo

(N=690) N=

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

FDA Update Expanded Indication for Actemra for Rheumatoid Arthritis The US Food and Drug Administration (FDA) has approved an expanded indication for tocilizumab (Actemra; Genentech), a humanized interleukin-6 receptor–inhibiting monoclonal antibody, for the treatment of adults with moderate-tosevere rheumatoid arthritis (RA) who have had an inadequate response to therapy with ≥1 disease-modifying antirheumatic drugs (DMARDs). Tocilizumab can be used as a singleagent therapy or in combination with methotrexate or with other DMARDs in this patient population. The expanded indication reinforces the safety and efficacy profile of this medication. This expanded indication is based on newly presented efficacy and safety data from the previous phase 3 clinical trials—OPTION, TOWARD, and LITHE; safety data from the postmarketing experience with tocilizumab since its initial FDA approval in 2010; as well as data from other clinical studies, including trials that evaluated this medication in a real-world setting. Tocilizumab is administered by injection. In the OPTION trial, 59% of patients who received tocilizumab and 48% of those receiving methotrexate achieved American College of Rheumatology 20% improvement cri-

teria (ACR20) at week 24 compared with 27% of patients receiving placebo plus methotrexate. Similarly, in LITHE, 56% of those receiving tocilizumab and 51% of those receiving a combination of tocilizumab plus methotrexate reached ACR20 at 24 weeks compared with 27% of the placebo plus methotrexate group. In addition, tocilizumab 4 mg/kg and 8 mg/kg slowed or inhibited the progression of structural damage in patients with RA compared with placebo plus methotrexate at week 52. Tocilizumab is already approved for the treatment of active systemic juvenile idiopathic arthritis in patients aged ≥2 years. (October 11, 2012)

Humira Approved for Ulcerative Colitis The FDA has approved a new indication for adalimumab (Humira; Abbott Laboratories) for the treatment of moderate-to-severe ulcerative colitis in adults, to control ulcerative colitis when immunosuppressant medicines, such as corticosteroids, azathioprine, and 6-mercaptopurine, have not worked. Adalimumab is an anti–tumor necrosis factor (TNF) that blocks proteins involved in abnormal inflammatory and immune responses. Ulcerative colitis is a chronic disease that causes inflammation and ulcers in the inner lining of the large intestine. “Each patient with ulcerative colitis

experiences the disease differently, and treatment must be adjusted to meet each individual’s needs,” said Donna Griebel, MD, Director of the Division of Gastroenterology and Inborn Errors Products in the FDA’s Center for Drug Evaluation and Research. This “approval provides an important new treatment option for patients who have had an inadequate response to conventional therapy.” Adalimumab is already approved for the treatment of RA, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, plaque psoriasis, and juvenile idiopathic arthritis. Adalimumab’s safety and effectiveness for ulcerative colitis were established in 2 clinical trials involving 908 patients who had never been treated with a TNF blocker, or who lost response to or were intolerant to TNF blockers. The approved dosing regimen for ulcerative colitis includes an initial dose of 160 mg, a second dose 2 weeks later of 80 mg, and a maintenance dose of 40 mg every other week thereafter. The drug should only be continued in patients who show evidence of clinical remission by 8 weeks of therapy. No new side effects were identified during clinical studies. Common side effects of adalimumab include infections, reactions at the injection site, headache, and rash. (September 28, 2012)

Prolia Receives New Indication for Men with Osteoporosis The FDA approved a new indication for the subcutaneous RANK ligand inhibitor denosumab (Prolia) for the treatment of bone mass loss in men with osteoporosis who are at high risk for fracture. Denosumab, 60 mg, is administered as a single injection by a healthcare provider every 6 months. The approval was based on 12month data from the pivotal phase 3 clinical trial ADAMO. The trial included 242 men (age, 30-85 years) with low bone mineral density (BMD) and who have had a major osteoporotic fracture. Treatment with denosumab resulted in significant increases in lumbar spine T-scores compared with placebo (5.7% vs 0.9%, respectively). In addition, increases in BMD were seen in all skeletal sites compared with placebo. The safety profile was similar to previous studies with denosumab in postmenopausal women. The most common adverse reactions reported (>5%) were back pain, arthralgia, and nasopharyngitis. Denosumab is already approved for the treatment of osteoporosis in postmenopausal women at high risk for fracture, and for patients who have failed or are intolerant of other therapies for osteoporosis. (September 20, 2012) ■

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Personalized Medicine in Rheumatology

creased risk for potentially fatal thrombotic events, allowing the provider to tailor treatments and prevention for the individual patient. In addition, the results further expand the understanding of a genetic basis for ethnic differences associated with thrombosis in patients with SLE. “In the future, genetic information may help predict which patients with SLE are at greatest risk for thrombotic events….Examining genetic risk factors for thrombosis in SLE may not only help to understand pathogenesis but also inform prediction of this SLE complication,” wrote Rachel Kaiser, MD, The Rosalind Russell Medical Research Center for Arthritis, University of California, San Francisco (UCSF), and coauthors. Increased Risk for Thrombosis Patients with SLE are at increased risk for thrombosis, and thrombosis generally occurs at younger ages, with more significant morbidity. Women aged 18 to 44 years who have SLE are hospitalized with myocardial infarction or stroke 9 times more often than the general population. The need for lifetime anticoagulation for the prevention of thrombosis has several drawbacks, including an increased risk for bleeding. Therefore, it is important to identify better predictors of thrombosis to enable prevention, the authors noted. Established risk factors—including the presence of antiphospholipid anti-

bodies, smoking, longer disease duration, older age at SLE diagnosis, and disease activity—do not completely explain excess thrombosis in patients with SLE. For example, only 10% of the 40% of patients with SLE who pro-

“In the future, genetic information may help predict which patients with SLE are at greatest risk for thrombotic events…. Examining genetic risk factors for thrombosis in SLE may not only help to understand pathogenesis but also inform prediction of this SLE complication.” —Rachel Kaiser, MD, et al

duce antiphospholipid antibodies have a thrombotic event, and 40% of those who have a thrombotic event are antiphospholipid antibody negative. Genetic Risk Factors Most known genetic risk factors for thrombosis in the general population are found mainly in whites, although there are striking ethnic differences in thrombosis in both the general population and in patients with SLE that have not been well studied. Blacks

have a 3- to 5-fold lower risk of deepvein thrombosis and pulmonary embolism compared with whites; however, blacks have a higher rate of venous thromboembolism. Understanding the genetics might explain some of the variations in thrombosis outcomes among patients with SLE of different ethnicities. The genetic variants fibrinogen gamma (FGG) rs2066865, methylenetetrahydrofolate reductase (MTHFR) rs1801133 and rs1801131, and factor V Leiden (FVL) rs6025 are associated with a risk for thrombosis among white patients with SLE, and FGG rs2066865 may be a risk factor for thrombosis in Hispanic patients with SLE. These and genetic risk factors for thrombosis may contribute to the difference in risk among patients with SLE beyond traditional explanations. The authors examined the single nucleotide polymorphisms that have been associated with thrombosis in the general population of whites or have been implicated in thrombosis and coagulation in 2 multiethnic cohorts of patients with SLE. The first was a multiethnic cohort of 1698 patients with SLE from UCSF. A replication cohort consisted of 1361 patients with SLE from the PROFILE cohort who were recruited from Northwestern University, Johns Hopkins University, the University of Alabama at Birmingham, the University of Texas Health Science Center at Houston, and the University of Puerto Rico.

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SLE: New Genetic Risk Factors for Thrombosis...

™

A rash on the leg of a 45-year-old woman, caused by systemic lupus erythematosus In the discovery cohort, 92% were women and 60% were white (the cohort also included 15% Hispanics, 13% Asian Americans, and 12% blacks). The mean age at SLE diagnosis was 33 years, and the mean disease duration was 9 years. Approximately 23% of patients had at least 1 thrombosis. Of all the patients, 35% were antiphospholipid antibody positive. In the replication cohort, characteristics were similar for age at disease onset and proportion of women, but there were fewer whites and Asian Americans and more blacks than in the discovery cohort. Only 12% of persons in the replication cohort experienced a thrombotic event. The authors attribute this difference in the percentage of thrombotic events between the cohorts in part to differences in recording thrombotic events. ■

See also Osteoarthritis

Biomarker May Lead to Blood Test to Measure Osteoarthritis Severity By Neil Canavan

eveloping new strategies for the prevention of osteoarthritis (OA) and its significant clinical burden is largely based on better understanding of the mechanism of OA disease and identification of potential biomarkers that may be involved in the progressive deterioration of the joints, including knee and hip. Researchers in Shanghai, China, have uncovered a new biomarker, the molecule fetuin-A, which their new study indicates is an excellent surrogate to gauge the severity of disease in patients with primary knee OA (Xiao J, et al. Serum fetuin-A levels are inversely associated with clinical severity in patients with primary knee

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osteoarthritis. Biomarkers. 2012 Oct 16 [Epub ahead of print]). If these observations are validated, the result would be the development of a simple blood test that would serve as a guide to therapy, including pharmacologic, joint-saving treatment decisions. As lead author, Jie Xiao, MD, Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, China, and colleagues, state in the article, “Risk assessment and the development of preventive or therapeutic interventions at the early stages of the disease could remarkably improve clinical outcomes and reduce healthcare costs.”

“The identification of novel biomarkers measurable in peripheral circulation and capable of predicting relevant outcomes in early OA is a critical issue for the development of preventive strategies and early-stage interventions.” —Jie Xiao, MD, et al

OA is a degenerative disorder of the synovial joints that is characterized by eventual cartilage destruction. The study investigators focused on

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knee OA in particular because it is the most prevalent form of the disease, as well as a major cause of physical disability and impaired quality of life in elderly patients. The rationale for investigating the diagnostic utility of fetuin-A in OA stems from observations made in the setting of rheumatoid arthritis (RA), which found that fetuin-A levels were significantly lower in patients with RA. On further investigation, fetuin-A, a glycoprotein that is synthesized and secreted from human liver cells, was discovered to be a mediator of chronic inflammatory disease. To assess the viability of fetuin-A as a diagnostic biomarker in patients with OA, the laboratory values for 215 patients with knee OA were measured Continued on page 16

www.ValueBasedRheumatology.com

Economic Issues in Rheumatology

High Emergency Department Utilization and Costs... is also very costly to the US healthcare system. Another, surprising, main finding of this study is that emergency department visit–related charges are significantly lower with gout as the primary diagnosis than with gout as a secondary diagnosis or not a diagnosis at all. “I was a little surprised by this finding, but not shocked,” lead investigator Ted R. Mikuls, MD, Professor of Internal Medicine at the University of Nebraska Medical Center and Omaha VA Medical Center, NE, told ValueBased Care in Rheumatology. “It’s very important to remember that gout often keeps ‘bad company,’ which includes other chronic health conditions, such as diabetes and heart disease. So, in cases where these latter

at a glance ➤ Gout is a common condition with a heavy economic toll on the US healthcare system ➤ In this first US analysis of gout-related emergency department utilization, gout was associated with 0.7% of all visits to the emergency department between 2006 and 2008 ➤ The median cost of goutrelated visits to the emergency department was $540 in 2006 and $667 in 2008, corresponding to $128 million and $166 million, respectively ➤ The median per-visit charges for gout as a secondary diagnosis were $960 in 2006 and $1187 in 2008—a 23.6% increase in 3 years

illnesses are the primary cause of [emergency department] visits, and gout is a secondary diagnosis, perhaps it’s not too surprising that costs would be even higher.”

“It’s very important to remember that gout often keeps ‘bad company,’ which includes other chronic health conditions, such as diabetes and heart disease.” —Ted R. Mikuls, MD

Utilization and Cost Rates These findings are based on an analysis of data from the Nationwide Emergency Department Sample (NEDS) between 2006 and 2008. NEDS tracks patient-related information and charges generated from emergency department visits for between 24 and 28 states in the United States. Between 2006 and 2008, gout was the primary or secondary diagnosis associated with >280 million visits to the emergency department, representing 0.7% of all emergency department

visits; it was the primary diagnosis for approximately 0.2% of those visits, annually. The median cost for a visit to the emergency department—with gout as the primary diagnosis—was $540 in 2006 and $667 in 2008, which corresponded to $128 million and $166 million in total emergency department– related charges, respectively. The median per-visit charges with gout as a secondary diagnosis were $960 and $1187 in 2006 and in 2008, respectively, representing a 23.6% increase within the span of 3 years. Gout-Related Characteristics The researchers examined individual patient characteristics, showing that after adjustment for an array of variables, men were 79% more likely than women to have a gout-related visit to the emergency department than a non–gout-related visit. Other patient characteristics associated with a propensity toward an emergency department visit for gout were age, an annual household income of <$38,000, and being treated in a hospital in the southern United States or in a nonmetropolitan area. Conversely, having Medicare as the payer was associated with a significantly lower propensity for a goutrelated emergency department visit than for those with private health insurance coverage. The researchers noted that factors such as having a median annual income of <$38,000 and being treated in rural or southern areas of the United States may be surrogates for poor healthcare access. They suggested another possibility that these dynamics are associated with other confounding factors that were not taken into account in the analysis, such as the prevalence of gout, race and eth-

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nicity, and differences in diet and alcohol intake. The Future “I think providers need to really think about novel ways of delivering gout care, because there are growing data to suggest that our current practices are failing a majority of gout sufferers,” said Dr Mikuls. The researchers suggest that gout-

“Providers need to really think about novel ways of delivering gout care, because there are growing data to suggest that our current practices are failing a majority of gout sufferers.” —Ted R. Mikuls, MD

related utilization of the emergency department is likely to increase “in the absence of effective interventions” that are focused on shifting gout care away from the emergency department and into the primary care setting. Furthermore, “the availability of highly novel but often more expensive diagnostic imaging modalities and urate-lowering therapies may add further to escalations in gout-related” overall cost of gout “in the near future.” Dr Mikuls and colleagues hope to continue to explore utilization trends related to gout and to investigate practice strategies to improve the quality of gout care and lower the significant cost and clinical burden it places on patients and on the US healthcare system. ■

Personalized Medicine

Biomarker May Lead to Blood Test... and then compared with the laboratory results from 76 healthy individuals. Serum fetuin-A levels were measured by an enzyme-linked immunosorbent assay. These results were then correlated with imaging analyses that were obtained from patients who underwent weight-bearing anteroposterior radiographs of the affected knee.

The severity of the disease symptoms was assessed with the Western Ontario and McMaster Universities Osteoarthritis Index. Results of this comparison demonstrated—for the first time—that serum fetuin-A levels independently and negatively correlated with greater clinical severity in patients with OA. When compared with radiographic

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data, the relative levels for this circulating serum biomarker also showed a significant decrease in advanced-stage disease compared with early-stage disease. As stated by the authors, these results indicate that fetuin-A may be protective against the development and progression of OA, and, on a mechanistic level, may reflect specific

biologic processes of OA. As to the clinical relevance, “The identification of novel biomarkers measurable in peripheral circulation and capable of predicting relevant outcomes in early OA is a critical issue for the development of preventive strategies and early-stage interventions,” Dr Xiao and colleagues wrote. ■

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Cost-Effectiveness for Biologics in RA Lower with Real-Life Data than with Randomized Trials Data By Rosemary Frei, MSc Phoenix, AZ—Cost-effectiveness values for biologics in patients with rheumatoid arthritis (RA) are half as high—indicating much lower value for money—when using real-life data rather than using results of randomized controlled trials (RCTs), a new meta-analysis that was presented at the 2012 annual meeting of the Society for Medical Decision Making has shown. Lead investigator Hawre J. Jalal, MD, MSc, from the School of Public Health at the University of Minnesota, Minneapolis, and colleagues from the National Data Bank for Rheumatic Diseases in Wichita, KS, and the University of Nebraska Medical Center in Omaha, conducted the meta-analysis to compare the use of RCT data in cost-effectiveness analyses versus patient outcomes in realworld settings. “Most cost-effectiveness analysis studies are based on medications’ efficacy in RCTs rather than on their reallife effectiveness. However, RCTs in RA have many documented limitations, including highly selective patient groups,” explained Dr Jalal.

“These have been studied extensively in the literature.” The team identified 9 RCT-based cost-effectiveness studies of biologics compared with nonbiologics in patients with RA that were published between 2000 and 2006. They then constructed 9 mathematical models using the sensitivity analysis results reported in the studies. This is the first time such an approach has been used in a metaanalysis. Sensitivity analyses are examinations of how the results are altered when study parameters are changed. They then calculated how the resulting incremental cost-effectiveness ratios (ICERs) for biologics and nonbiologics differ when data were used from RCTs or from real-life observational data from the large US National Data Bank for Rheumatic Diseases. The results showed that when effectiveness estimates are based on observational data rather than RCT efficacy estimates, the ICERs doubled. This translates into a halving of the costeffectiveness, because higher ICERs indicate lower cost-effectiveness (ie,

less value for the money spent). Nearly half (48%) of the total increase in ICER with observational data versus RCT data was a result of the initial disability improvement with the use of biologics, based on scores in the Health Assessment Questionnaire (HAQ) Disability Index.

“Most cost-effectiveness analysis studies are based on medications’ efficacy in RCTs rather than on their real-life effectiveness. However, RCTs in RA have many documented limitations, including highly selective patient groups.” —Hawre J. Jalal, MD, MSc

The initial disability improvement is significantly lower in real-life data than in RCTs. Other factors that significantly contributed to an increase in

the ICER for biologics with RCT data compared with observational data were the way the health-related quality of life associated with the HAQ was measured, HAQ progression among therapy nonresponders, and HAQ progression for nonbiologics. HAQ progression for biologics was the one factor that favored a lower ICER with RCT data. “What the latter finding means is that, following the short-term decrease in HAQ with biologics, HAQ values increase at a higher rate in RCTs than in real-life settings. This may be because RCTs are generally of short duration,” explained Dr Jalal. “This was the only input from our initial analysis that made biologics appear more costeffective based on efficacy data from RCTs than with effectiveness data from the observational database.” The bottom line is that biologics may be less cost-effective than initially thought, noted Dr Jalal. However, this analysis did not account for the indirect costs that may be affected by lower efficacy of nonbiologic therapies in RA, such as reduced productivity and absence from work. ■

Cost-Effectiveness of Biologics Affected by RA Disease Severity in a New Decision Model Using various patients’ willingness-to-pay thresholds Phoenix, AZ—A novel mathematical model can help to pinpoint when biologics become most cost-effective for various disease categories of patients with rheumatoid arthritis (RA). Researchers have found that with a willingness to pay of up to $100,000 per additional quality-adjusted lifeyear (QALY) gained from therapy, biologics could be cost-effective for mildly disabled elderly patients if their costs were cut by 60%. When the willingness-to-pay threshold is bumped up to $300,000 per QALY gained, biologics become costeffective for younger and more disabled patients. The researchers presented their findings at the 2012 annual meeting of the Society for Medical Decision Making. “We are finding that there may be a

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‘window of opportunity’ during which biologics are most cost-effective,” said lead investigator Hawre J. Jalal, MD, MSc, of the School of Public Health at the University of Minnesota, Minneapolis, when asked by ValueBased Care in Rheumatology about details of the study. He said, however, that the analysis of this research is at too early of a stage for him to be able to share all of the results. The model constructed by Dr Jalal and colleagues was a Markov decision processes model. Their goal was to identify the decision sequences of hypothetical RA patients that maximize the net health benefit. A spectrum of patient ages and quintile of levels of disability, as measured by Health Assessment QuestionnaireDisability Index (HAQ-DI) scores, were assessed.

The data for the study came from the National Data Bank for Rheumatic Diseases to define patients’ propensity to use biologic or nonbiologic therapies. The team also estimated direct and indirect costs— associated with productivity losses— from the literature, and calculated an average quality of life using the EuroQol 5D (EQ-5D) instrument for each HAQ-DI quartile. The researchers discounted both costs and benefits by 3% annually. Besides finding that biologics could be cost-effective either in mildly disabled elderly people with RA who have a willingness to pay of up to $100,000 per QALY, when the cost of biologics was reduced by 60%, or in younger and more disabled individuals with a willingness to pay of up to $300,000 per QALY, the researchers

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at a glance ➤ With a willingness to pay of up to $100,000 per additional QALY gained, biologics could be cost-effective for mildly disabled elderly patients with RA if their costs were cut by 60% ➤ When the willingness-to-pay threshold is $300,000 per QALY gained, biologics become cost-effective for younger and more disabled patients

also found that biologics are costeffective for patients who are diagnosed within the 2 previous years and who are more disabled.—RF ■

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Rheumatology Update

No Link between TNF Inhibitors for Rheumatoid Arthritis and Cancer, New Meta-Analysis Shows By Rosemary Frei, MSc

new, large meta-analysis indicates that at least 6 months of biologic therapy for rheumatoid arthritis (RA) does not increase the risk of cancer (Lopez-Olivo MA, et al. JAMA. 2012;308:898-908). The one exception found was a doubling of malignancy risk for patients with RA compared with controls after 52 weeks of treatment with tumor necrosis factor (TNF) inhibitors plus methotrexate. The absolute increased risk, however, was only 6 per 1000 patients and was not present at earlier or later time points, up to 156 weeks, or with any of the TNF inhibitors being used as monotherapy. Conflicting results from different types of studies, including observational studies, have been published, suggesting the potential for an association between the different biologic therapies used in RA and the poten-tial for malignancy. The US Food and Drug Administration (FDA) has recommended adding a warning to that effect to all TNF inhibitors. This large meta-analysis sought to resolve these conflicting reports, and it is the first systematic review investigating malignancy risk using evidence from randomized clinical trials (RCTs) only and in patients with RA only, based on data on all the available

biologic response modifiers. The team systematically reviewed 63 RCTs involving 29,423 patients with RA who were receiving biologic thera-

“The data available appear to suggest that there is no cumulative risk over time, but these data are also subject to bias. Clinical trials, however, are less subject to bias and, in the context of malignancies, are appropriate to evaluate rapid development of cancer.” —Maria A. Lopez-Olivo, MD, MSc, PhD, et al py for at least 24 weeks. Although the researchers have faith in their findings, they caution that a carcinogenic effect cannot be entirely excluded. They point out that the only significant increase in risk for malignancy that was found disappeared when a more conservative effect measure was used in the statistical analysis; there-

fore, this positive result was not consistent and could have just happened by chance. However, further monitoring from observational studies is needed to better understand the longer-term toxicity implications of these biologic agents. Maria A. Lopez-Olivo, MD, MSc, PhD, Instructor, Department of General Internal Medicine-Research, Division of Internal Medicine, at The University of Texas M.D. Anderson Cancer Center, Houston, and colleagues conducted the meta-analysis to take a close look at this area of controversy. They examined studies on all 9 biologic response modifiers that are approved by the FDA. Dr Lopez-Olivo and colleagues analyzed results from 71 publications on 63 different trials. All of the trials were multicenter, and 42 trials were multinational. The smallest number of patients in a trial was 20, and the largest was 1399. Follow-up ranged from 24 to 156 weeks, and dosing of the biologic response modifiers ranged from below the recommended doses to above them. Most of the patients (N = 15,989) were assigned to biologic response modifiers plus methotrexate and/or other disease-modifying antirheumatic drugs (DMARDs), 3615 to biologic response modifiers alone,

and 9819 to control groups. Only 4 of the trials were comparisons between biologic response modifiers. Pharmaceutical companies sponsored 56 of the trials, and the researchers of 3 others did not disclose the source of funding. The team expressed the results as both Peto odds ratios (ORs) and relative risks, and stated that “the Peto OR is preferred for uncommon events.” For all cancer types combined, the only significant increase in Peto OR, 2.1, was for a comparison of all TNF inhibitor plus DMARD combinations versus a DMARD alone at 52 weeks. The only significant decrease in Peto OR, 0.11, was for the non-TNF inhibitor anakinra plus methotrexate versus placebo plus methotrexate at 24 weeks. “The data available appear to suggest that there is no cumulative risk over time, but these data are also subject to bias. Clinical trials, however, are less subject to bias and, in the context of malignancies, are appropriate to evaluate rapid development of cancer,” Dr Lopez-Olivo and colleagues wrote. They caution that “clinicians should be aware that closer monitoring is recommended for patients who are receiving these types of drugs and who have had malignancies in the past.” ■

B-Cell Depletion Matches TNF Inhibition as Switching Option for Patients with RA Who Have Failed TNF Therapy By Charles Bankhead

or patients who have failed therapy with a tumor necrosis factor (TNF) inhibitor, switching to B-cell–depleting rituximab (Rituxan) may be a similar treatment option to switching to a different anti-TNF agent in terms of control of rheumatoid arthritis (RA), according to the results of a recent multicenter trial (Gomez-Reino JJ, et al. Ann Rheum Dis. 2012;71:1861-1864). Patients had similar disease activity scores at 6, 9, and 12 months whether they received another TNF inhibitor or the B-cell–depleting drug. Analysis of individual anti-TNF agents, however, showed that switching to rituximab led to significantly better disease control than did a change to a mono-

clonal TNF inhibitor, such as infliximab (Remicade) or adalimumab (Humira).

“In patients with RA who fail on treatment with a TNF antagonist, switching to rituximab is perhaps more efficacious than switching to an alternative TNF antagonist.” —Juan J. Gomez-Reino, MD, et al “Our results show that, in patients with RA who fail on treatment with a

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TNF antagonist, switching to rituximab is perhaps more efficacious than switching to an alternative TNF antagonist,” noted Juan J. GomezReino, MD, of Universidad de Santiago de Compostela in Barcelona, Spain, and colleagues in the article. Rituximab, in combination with methotrexate (Trexall), is indicated for the treatment of patients with moderate-to-severe RA who have had an inadequate response to one or more of the TNF antagonists. Observational studies have suggested that switching to rituximab might lead to control of RA that is similar to or better than what might be achieved by switching to a different TNF inhibitor after failure of ini-

tial anti-TNF therapy. Moreover, data are lacking on the efficacy of switching from one anti-TNF agent to another, as well as on the influence of anti-TNF sequencing on a subsequent change to rituximab, Dr GomezReino and colleagues pointed out in their introduction. To learn more about the options for switching after anti-TNF failure, investigators at 100 centers throughout Spain conducted a prospective observational clinical trial involving patients who had received inadequate disease control or who lost disease control during anti-TNF therapy. The trial included 1124 patients, 591 of whom received rituximab and 533 Continued on page 19

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Rheumatology Update

Disease Activity Trajectory Important Factor in Patients’ Willingness to Change Their RA Medication By Rosemary Frei, MSc Phoenix, AZ—New data indicate that clinicians and researchers should take into account the overall disease trajectory of patients with rheumatoid arthritis (RA), not only their disease activity at a given point, when recommending medication changes. The analysis presented at the 2012 annual meeting of the Society for Medical Decision Making showed a significant relationship between patients’ willingness to change their current treatment, illness trajectory, and disease activity. For example, people who overall have fluctuating or worsening RA are much more willing to change medications when they are experiencing a flare than when they are near remission, the findings indicate. “Studies using only contemporaneous assessments do not fully capture how disease activity influences willingness to change [medication],” said Liana Fraenkel, MD, MPH, Associate Professor of Medicine (Rheumatology), at Yale School of Medicine, New Haven, CT, and her colleagues. This is important, because “unwillingness of patients to change their current treatment can impede efforts to provide the best available care.” Dr Fraenkel and her colleagues recruited 156 volunteer patients with

RA for the study. They interviewed the patients at 4 regular intervals over a 6-month period. Of the total, 5 par-

“Studies using only contemporaneous assessments do not fully capture how disease activity influences willingness to change [medication]. Unwillingness of patients to change their current treatment can impede efforts to provide the best available care.” —Liana Fraenkel, MD, MPH

ticipants dropped out of the baseline interview, and thus the researchers excluded them from the analysis. All 4 interviews were completed by 94 patients; 28 patients completed 3 interviews, and 21 patients completed 2 interviews. In each interview, the patients’ disease activity was assessed using the Routine Assessment of Patient Index

Data (RAPID)4, a validated 40-point self-report measure (score of 5.67, near remission; 6.46, low disease activity; 6.82, moderate disease activity; 7.75, high disease activity). They also assessed the gap between the patients’ current and desired health state. In addition, an 11-point scale was used to gauge the patients’ willingness to change medications, which ranged from zero for “not willing” to 10 for “extremely willing.” Not surprisingly, the worse the patients’ disease activity was, the greater the discrepancy was between their current and desired health states. The researchers then put each subject’s disease trajectory into 1 of 4 categories, depending on the disease activity at each of the 4 time points (ie, stable, improving, declining, or fluctuating). The characteristics of patients in each of the 4 groups were similar, except there were significantly more females than males in the fluctuating and the improving groups, and significantly more males in the declining group. The results revealed that the patients’ willingness to change medication differed significantly, depending on their category of disease activity. This was the case despite the fact that there were only small differences

B-Cell Depletion Matches TNF Inhibition... who received an alternative TNF inhibitor. The primary outcome was change in the Disease Activity Score in 28 joints (DAS28). Follow-up assessments occurred at 6, 9, and 12 months, and investigators will continue follow-up for 3 years. Patients treated with rituximab had longer disease duration (>5 years, 79.3% vs 67.4%; P <.001), more extraarticular manifestations (36.7% vs 27.7%; P < .001), more incidences of a treatment history with >1 prior antiTNF agent (37.0% vs 11.4%; P <.001), and a higher DAS28 score at baseline (5.5 vs 5.0; P <.001). Overall, the treatment groups obtained similar disease control, as represented by DAS28 scores at 6, 9, and 12 months. Analysis of the data by

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mechanism of TNF inhibition revealed significant differences. Etanercept and rituximab had similar disease control at all assessments. In contrast, pooled results showed significant differences in DAS28 reductions that favored rituximab versus an adalimumab and infliximab combination at 6 months (–1.61 vs –1.04, respectively; P = .001) and at 12 months (–1.81 vs –1.55, respectively; P = .05). The absence of a significant difference between rituximab and the adalimumab and infliximab combination groups at 9 months “could reflect how [rituximab] is used in clinical practice (ie, retreatment when worsening),” the authors noted in the discussion of their findings. “In fact, this blunting of response to [rituximab] disappears at

12 months when the response is again better than in the TNF antagonist

“Our work further suggests that the improvement in DAS28 is larger in patients treated with [rituximab] than in those treated with monoclonal anti-TNF antibodies.” —Juan J. Gomez-Reino, MD, et al

group, perhaps due to the response to retreatment. A somewhat similar pic-

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in RAPID4 scores between the 4 disease activity categories.

Analysis of the interactions between disease trajectory category, disease activity at each time point, and willingness to change medication showed that disease activity alone, and disease trajectory together with disease activity, both significantly influenced willingness to change medication.

Continued from page 18 ture has been reported by others.” A greater proportion of patients treated achieved a good response by European League Against Rheumatism criteria at 6 months with rituximab than with the alternative TNF inhibitors (59% vs 45%; P = .025). Thereafter, the proportion of patients with good, moderate, or no response did not differ between the treatment groups. “Optimal treatment for patients with RA failing on TNF antagonists may include [rituximab],” Dr GomezReino and colleagues concluded. “Our work further suggests that the improvement in DAS28 is larger in patients treated with [rituximab] than in those treated with monoclonal antiTNF antibodies.” ■

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Osteoarthritis

Effect of a Walking Program on Exercise Adherence and Physical Disability in Patients with Osteoarthritis By Rosemary Frei, MSc

romoting physical activity in patients with osteoarthritis (OA) is important. Interventions that may motivate patients with OA to adhere to an exercise regimen to reduce the risk of physical disability related to this chronic disease can therefore be helpful for providers and for patients. New research has shown that it is possible to use an evidencebased aerobic walking program to help patients with OA minimize their symptoms (Brosseau L, et al. BMC Public Health. 2012;12:871). The investigators successfully implemented a supervised communitybased aerobic walking program (SCAWP) and combined it with education and counseling to boost adherence. In addition, they compared the outcomes from this combination with SCAWP alone or with self-directed walking. The combination approach did not result in increased exercise adherence over the year’s length of the study, but it did produce greater adherence over the short-term. “Our results indicated that if an older individual is adherent to a selfmanagement walking program for a long time, simple incentives, such as a pedometer, logbooks, and periodic 3-month assessment, seem to be successful in maintaining the good habits of regular walking in order to reduce knee pain, [increase] functional activities, and enhance quality of life,” Lucie Brosseau, PhD, Professor and

Research Chair of Rehabilitation Sciences at the University of Ottawa, Ontario, Canada, who led the project, told Value-Based Care in Rheumatology. The SCAWP Program The researchers randomized 69 participants with mild-to-moderate OA to SCAWP and a behavioral intervention, 79 to SCAWP alone, and 74 to a self-directed walking program. Members of all 3 groups also received an educational pamphlet describing the positive effects on OA of walking.

“If an older individual is adherent to a selfmanagement walking program for a long time, simple incentives...seem to be successful in maintaining the good habits of regular walking.” —Lucie Brosseau, PhD

The researchers were blinded to which group each participant was randomized to, and they followed participants for 12 months, as well as for an additional 6-month, unsupervised period. Participants took part in SCAWP via walking clubs in the Ottawa area. There were 3 weekly walking sessions

over a 12-month period, with each session beginning with a 10-minute warm-up followed by 45 minutes of aerobic walking and a 10-minute cooldown. The program was structured to first progressively increase exercise duration and heart-rate intensity, and then to maintain these. The behavioral intervention comprised one 2-hour group session weekly for 20 weeks. At the sessions, participants discussed short-term goal setting, and they received education on arthritis-related topics. Participants also had monthly face-to-face meetings for the first 6 months of the study. In the last 6 months, they received telephone counseling on both long-term goals and on strategies to stay with the walking program rather than drop out. Members of all 3 groups were provided with pedometers and logbooks to measure their daily walking time and any additional physical activity. They also received compensation for their participation in the study. Women (mean age, 63.4 years) comprised the majority of the study participants; their mean disease duration was 10.3 years. The dropout rate at 12 months was 40.6% in the combination group, 43.1% in the SCAWP-only group, and 49.3% in the self-directed group. Adherence Rates Adherence rates at 3 months were 80.2% for the combination cohort, 77% for the SCAWP-alone cohort, and 65.2%

for the self-directed walking cohort (P <.012 for combination vs self-directed). However at 6, 9, and 12 months, the rates were lower and similar in all 3 groups, producing an overall adherence of 60.4% in the combination group, 57.6% in the SCAWP-only group, and 55.1% in the self-directed group. The researchers also measured participants’ results on the Stanford Patient Education Research Center’s Arthritis Self-Efficacy Scale and found the only difference was significantly higher scores at 18 months in the selfdirected group’s “confidence about doing things.” An explanation for this result may be that participants in the self-directed group who did not drop out developed strategies to motivate them to walk alone during the 12-month phase and to continue during the 6-month followup phase, suggested Dr Brosseau. In contrast, participants in the other 2 groups were accustomed to being supervised by exercise therapists at the walking club during the 12-month study, and therefore they would have had to develop new behavioral strategies to motivate them to continue walking without supervision. “What is very interesting with this project is that individuals with mildto-moderate osteoarthritis of the knee ‘smile’ when they walk regularly following the progressive and effective prescribed program. When they stopped walking regularly, the pain came back,” remarked Dr Brosseau. ■

Physician Bias Uncovered in Recommendations for Knee Replacement Surgery Men more likely candidates than women Phoenix, AZ—Among the surprising findings of a survey presented at the 34th Annual Meeting of the Society for Medical Decision Making were that orthopedic surgeons are significantly more likely to recommend total knee arthroplasty (TKA) to men than to women, and that rheumatologists working in academic settings are much more likely to recommend such surgery than those working in nonacademic environments. The survey investigated what factors influence physicians’ recommen-

dations for or against TKA in younger patients with mild or moderate osteoarthritis (OA). The survey was given to 896 physicians—494 rheumatologists attending the 2011 American College of Rheumatology’s annual meeting and 406 orthopedic surgeons attending the 2012 American Academy of Orthopedic Surgeons annual meeting. “TKA rates are expected to vary, because the decision to undergo TKA is strongly influenced by patient preferences,” said lead investigator Liana

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“The decision to undergo TKA is strongly influenced by patient preferences. Nonetheless, our results demonstrate that rates of TKA are also influenced by physician bias.” —Liana Fraenkel, MD, MPH

Fraenkel, MD, MPH, Associate Professor of Medicine (Rheumatology), at Yale School of Medicine, New Haven,

CT. “Nonetheless, our results demonstrate that rates of TKA are also influenced by physician bias.” Dr Fraenkel called for the development of objective criteria for the appropriateness of TKA to reduce such bias. More than half (54%) of the surgeons performed more than 25 knee replacement surgeries annually. More than half (54%) of the rheumatologists see more than 20 patients monthly with knee OA. Each physician was presented with variants of a scenario of a 62-year-old person with knee OA who has moderate knee pain that limits strenuous Continued on page 21

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Osteoarthritis

The Socioeconomic Burden of Osteoarthritis-Related Hip and Knee Replacement Has Reached “Remarkable” Levels

steoarthritis (OA) is a major cause of impaired mobility, with significant impact especially on the joints, often leading to total hip or knee replacement, which reduces the patient’s quality of life in addition to having significant economic costs. The socioeconomic burden of total hip and knee replacement has soared to “remarkable” levels, according to Italian researchers (Piscitelli P, et al. Arthritis Care Res [Hoboken]. 2012;64:1320-1327). In this new study conducted in Italy between 2001 and 2005, the number of hip arthroplasties increased by 5.4% annually, and the number of knee arthroplasties increased by 13.4%. Among younger patients, lost work days exceeded 1 million in 2005. Hospital costs for these procedures surpassed €1 billion annually in Italy, and rehabilitation costs increased by more than 40%. “Our study confirms that the socioeconomic burden of total joint arthroplasties (TJAs), including revi-

at a glance ➤ OA has become the sixth leading cause of disability worldwide ➤ Hospital costs for these procedures surpassed €1 billion annually in Italy, and rehabilitation costs increased by more than 40% ➤ Between 2001 and 2005, the average per-patient cost was €16,835 for hip replacement and €15,358 for knee replacement

sion surgery, due to hip and knee osteoarthritis is growing and heavily affecting the working population,” Prisco Piscitelli, MD, of the University of Florence, and coauthors wrote in their article.

“The socioeconomic burden of total joint arthroplasties, including revision surgery, due to hip and knee osteoarthritis is growing and heavily affecting the working population.” —Prisco Piscitelli, MD, et al

“The socioeconomic burden of TJAs performed for symptomatic OA in Italy is remarkable and calls for the adoption of proper preventive measures,” they noted. An aging population and the growing obesity epidemic have helped drive increases in the prevalence and incidence of OA, which has become the sixth leading cause of disability worldwide, according to the World Health Organization. OA already accounts for more than 50% of hospital admissions related to rheumatology. The estimated medical costs for patients with OA are double those of patients without the condition. Increasing Incidence The investigators searched the Italian Ministry of Health database to identify hip and knee arthroplasties performed in Italy between 2001 and 2005 as a result of a diagnosis of OA.

Physician Bias Uncovered... activity despite medical management. Each physician was asked to rate his or her recommendation for knee replacement surgery on a 6-point scale ranging from very strongly recommended for TKA to very strongly recommended against TKA. Overall, 51% of the surgeons and rheumatologists recommended the procedure. The proportion recommending TKA ranged from 30% to 55% when the

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They excluded records related to hip arthroplasty in patients aged <25 years, because the reason for the surgery was unlikely to be OA. “The incidence of total hip replacement in Europe varies between 50 and 140 procedures per 100,000 inhabitants, with OA being the main cause for intervention,” noted Dr Piscitelli and colleagues. The results showed that the number of hip arthroplasties increased from 34,006 in 2001 to 41,816 in 2005, representing a change in incidence from 80.0 per 100,000 persons to 94.8 per 100,000 persons. Women accounted for more than 50% (almost 26,000) of the procedures. The number of knee arthroplasties rose from 26,751 in 2001 to 44,051 in 2005. The rate of the surgical procedure increased from 62.9 per 100,000 persons in 2001 to 99.9 per 100,000 persons in 2005. Women accounted for approximately 66% of the total number of procedures (N = 32,185). The largest proportion of total joint replacement was for people aged ≥65 years. However, the rate of growth in the number of procedures was highest for patients aged <65 years. The number of knee-prosthesis revisions increased from 1146 in 2001 to 2295 in 2005, representing an annualized growth rate of 17.4%. Productivity Loss and Costs OA-related healthcare costs are substantial, driven by arthroplasty procedures, nonsteroidal anti-inflammatory drugs (NSAIDs), agents to prevent NSAID-induced gastrointestinal side effects, and rehabilitation. Few studies have quantified the direct and indirect costs of TJA, particularly among members of the European Union.

By Charles Bankhead

Lateral x-ray of a right total knee replacement. Direct costs were estimated on the basis of a particular country’s diagnosis-related groups. For patients aged <65 years, the estimated indirect costs were associated with the loss of work productivity. The estimated number of work days lost as a result of TJA increased from 805,347 in 2001 to 1,017,937 in 2005. Hip arthroplasties accounted for a majority of the procedures (631,351), but the annualized growth rate was greater for knee procedures (12.0% vs 4.1%). Estimated total costs included hospital costs, rehabilitation, venous thromboembolism, and postoperative infection. The total cost increased from €972 million in 2001 to €1.381 billion in 2005. The estimated total cost for the 5-year period was almost €6 billion. Over the 5-year period, the average per-patient cost was €16,835 for hip replacement and €15,358 for knee replacement. ■

Continued from page 20

patient had mild radiographic OA and moderate pain, and from 39% to 71% when the patient had moderate radiographic OA and moderate pain. The survey results revealed that the average age of rheumatologists or surgeons who recommended TKA was significantly lower than those who did not recommend TKA. US surgeons were much more likely than their European counterparts to

recommend surgery (the majority of the physicians in both groups were practicing in the United States). As can be expected, both groups recommended the procedure more frequently for severe than for mild radiographic OA, but the difference was more pronounced among rheumatologists (60% vs 41%, P <.001) than surgeons (56% vs 47%, P = .05). Surgeons were much more likely to

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recommend TKA when the patient was male than female (59% vs 44%, P = .002), and rheumatologists had a higher propensity to recommend TKA for retired patients than for those who were still working (56% vs 42%, P = .002). The study was funded by the Arthritis Foundation and the National Institute of Health’s National Institute of Arthritis and Musculoskeletal and Skin Diseases.—RF ■

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Rheumatology Practice Management

™

Accountable Care Organizations: Riding the Wave of the Future By Jennifer Kirschenbaum, Esq, and Erica Youngerman, Esq

s healthcare reform changes the face of medical practice as we know it, certain initiatives are likely to play a prominent role in emerging practice structures. Among the programs predicted to take center stage are those offered by Medicare’s Shared Savings Program, in particular, accountable care organizations (ACOs).

Understanding the ACO Concept An ACO is defined by the Centers for Medicare & Medicaid Services (CMS) as “an organization of healthcare providers that agrees to be accountable for the quality, cost, and overall care of the Medicare beneficiaries who are enrolled in the traditional fee-for-service program who are assigned to it.” A stated goal of the ACO model is one that “promotes accountability for a patient population and coordinates items and services under parts A and B [of Medicare] and encourages investment in infrastructure and redesigned care processes for high quality and efficient service delivery” (42 USC § 1395jjj[a][1]). With the combined aims of reducing cost while increasing the quality of care, the model seems to be an efficient mechanism to navigate the changing healthcare landscape. The ACO model has existed for several years as a test program administered by CMS, and rapid growth of this model is anticipated. Of course, the concept of accountable care is not new, because the idea of coordinated care, increased quality, and decreased cost has been a shared goal of many different aspects of the healthcare industry for decades. If you are wondering what authority is out there to indicate this developing trend, look no further than healthcare reform itself. The Patient Protection and Affordable Care Act has identified ACOs as one of the waves of the future that will improve quality of care by encouraging physicians to collaborate with one another. At its core, an ACO is an entity formed to tabulate patient care data in a way that Medicare may then determine cost-savings, which the ACO would be eligible to share in. By way of a simplified example, if an ACO were able to evidence a lower rate of hospital admissions as a result of preventive care initiatives, the ACO

would allegedly be entitled to a portion of the shared savings. The beauty of the ACO model is that this structure does not require a practitioner to lose ownership or control over his/her practice. Instead, a practitioner may elect to participate with an ACO, sharing patient care data with the ACO, and to participate with shared savings. The ACO would be a separate entity, apart from your practice. ACOs may be physician owned, hospital and physician owned, owned by a hospital employing physicians, owned by a network of individual practices of physicians, or owned by others, as specified by the Secretary of Health and Human Services (42 USC § 1395jjj[b][1]).

For specialists, membership may be a “no-brainer,” because specialists may join as many ACOs as will have them. For specialists, membership may be a “no-brainer,” because specialists may join as many ACOs as will have them. Any such membership would likely be cemented by a contract defining the relationship. A barrier to the ACO model has been start-up cost. Because an ACO relies on, at its core, integration of data and patient care, all participants should be operable on collaborative electronic medical record (EMR) systems. Reading the previous statement may leave little to the imagination as to why large hospital systems and large practice groups are better suited to ACO formation than individual, smaller groups coming together and forming an ACO. The large hospital systems and large medical practices are presumably integrated and presumably better suited to absorbing the cost for hardware, software, training, and lag time, with the EMR integration required for the ACO model. Also, the start-up cost makes an ACO creation less desirable for specialists, such as oncologists, who arguably may have less to gain from this structure than primary care providers, the intended core of the model—each ACO is required to have primary care providers, accounting

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for more than 5000 Medicare beneficiaries at any given time. Although start-up costs may require a significant financial investment, there are financial advantages to the ACO model. The current payment structure, as practitioners are well aware, is untenable and is bankrupting Medicare. Medicare has had to find ways to incentivize physicians to keep costs down, and the ACO model is one of the answers to this dilemma. Under the Shared Savings Program, the model includes reimbursement for fee-for-service, plus a percentage of shared savings. The intended impact of this model is to provide for a model that enables reimbursement to shift from quantity to quality, with the ultimate aim of reducing costs to the healthcare system.

Choosing “Accountable” Care For betting individuals, a safe bet is that our current care delivery system is not sustainable, and changes will be coming. We are headed toward a modified system, where quality over quantity and preventive over reactive are valued. To ensure your practice keeps pace with anticipated changes in our healthcare delivery system, regardless of whether you intend to participate in an ACO or similar model, you may wish to consider the concepts set forth herein and better position your practice for accountability, including adopting EMRs and understanding new initiatives such as ACOs. ACO creation takes a village—ACO creation begins with doctors, lawyers, managers, billers, EMR companies, chief executive officers, accountants, and consultants, and requires significant start-up capital, as discussed above. For those interested in the ACO model, ACO participants must make a 3-year commitment to the program when they sign on; a structure must be implemented for receiving and distributing shared savings; processes must be in place to coordinate care, such as having remote patient monitoring; and the ACO must have at least 5000 beneficiaries who will all receive their primary care coverage through the ACO (42 USC § 1395jjj[b][2]). In order to receive financial incentives, quality-of-care measures must be in place, such as those for clinical processes and outcomes, and experience of care, and, in addition, there are numerous other requirements that must be in place in order to be eligible to participate in an ACO (42 USC § 1395jjj[b][2]).

It is also relevant to note that ACOs must be formed and operated in compliance with antitrust requirements. Those looking to participate in an ACO need to be wary of the fact that ACOs may be considered harmful to consumers by reducing competition. To assist ACOs, the Department of Justice and the Federal Trade Commission have created a procedure for voluntary expedited review. Before being admitted into the Shared Savings Program, newly formed ACOs may apply to both agencies for an antitrust analysis (www.justice. gov/atr/public/health_care/aco.html). It is advisable to consult with your healthcare counsel to ensure compliance with relevant antitrust laws and policies and to offer your ACO the best protection possible. Although the climb for an ACO creation is certainly uphill, it is not unhikable. And, with rolling admissions for ACO participants by CMS, the next application period being for a 2014 start date, the number of Notice of Intent to Apply letters is predicted to increase dramatically over the coming years. It is not being suggested that this system is going to be perfect and be the solution to all things wrong with our healthcare system as it stands today. In fact, a lot of information is still unavailable, and it appears that the Secretary of Health and Human Services is going to have a lot of authority over what payments are made. What is clear moving forward is that providers who fail to ready their practices now and leaders in the industry who do not get on board will fall to the back of the pack in the marathon that is healthcare today. ■ This article is for education and discussion purposes only and does not constitute legal advice.

Jennifer Kirschenbaum, Esq, manages Kirschenbaum & Kirschenbaum’s healthcare department, which specializes in representing healthcare practitioners in regulatory compliance, audit defense, licensure, and transactional matters. Erica Youngerman, Esq, is an associate in Kirschenbaum & Kirschenbaum’s healthcare practice. If you have a question for Jennifer or if you would like to discuss accountable care organizations, Jennifer may be reached at 516-747-6700 x302 or by e-mail at Jennifer@kirschenbaumesq. com. For more information about Kirschenbaum & Kirschenbaum’s healthcare practice, visit www.nyhealthcare attorneys.com.

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Healthy knee anatomy, degenerative arthritis of the knee and replacement surgery. Digital illustration.

X-ray Of A Knee Replacement In A 60 Year Old Man

An X-ray Of A Knee Replacement

Bionic Knee - lateral x-ray of a right total knee replacement. X-ray Of The Knee Of A 83 Year Old Woman Showing Degenerative Arthritis.

Systemic Lupus Erythematosus