VBCR May Vol 1, No 2 by Value-Based Cancer Care

Value-Based Care in Rheumatology

MAY 2012 VOL 1 • NO 2

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

Trends in RA Management: A Survey of Health Plans and Rheumatologists

leading large-molecule therapies in the treatment of rheumatoid arthritis (RA). Based on the results of the 2012 Rheumatology Reimbursement Report, health plans and rheumatologists agree that the pricing of promising investigational oral agents for RA now in the pipeline will very likely drive the placement of these drugs in the sequencing of therapeutic choices. In other words, small-molecule drug manufacturers should not consider their market entrants to be in a class of their own. Instead, the new oral therapies (when and if approved) will be compared with currently prescribed biologic therapies before Continued on page 9

Early Aggressive Therapy Effective in Polyarticular Juvenile Idiopathic Arthritis By Phoebe Starr Chicago, IL—Similar to adults, early aggressive treatment with a biologic therapy in children with polyarticular juvenile idiopathic arthritis (JIA) is beneficial in achieving remission, as demonstrated in the double-blind, randomized Trial of Early Aggressive

By Sy Schlager, MD, PhD

By Rhonda Greenapple, MSPH President, Reimbursement Intelligence, Madison, NJ

ew oral therapies, such as Janus kinase (JAK) inhibitors and spleen tyrosine kinase inhibitors, will be challenged to break the grip on the market held by the

Is Personalized Medicine Possible in Lupus?

Therapy in Juvenile Idiopathic Arthritis (TREAT in JIA), which is one of the few studies to focus on children with JIA. Early aggressive treatment improved the signs and symptoms of polyarticular JIA, as well as the per-

elimumab (Benlysta) has recently been approved in the United States for the treatment of systemic lupus erythematosus (SLE), with a specific indication for use in adult patients with active, autoantibody-positive disease who are currently receiving standard therapies. However, the optimal use of this agent in SLE has not been well defined. In a recent study (van Vollenhoven RF, et al. Ann Rheum Dis. 2012 Apr 5) pooled data from 2 randomized, placebo-controlled clinical trials of 1684 patients with SLE (all antinuclear antibody– or anti-dsDNA–positive) were used to evaluate the factors that predict response to belimumab

therapy. All patients were treated with standard therapies, including steroids, hydroxychloroquine, and/or immunosuppressive agents, in conjunction with belimumab or placebo. The primary outcome was improvement in the SLE Responder Index (SRI), a composite measure of disease activity developed for use in clinical trials of belimumab. In univariate analysis and analysis of patients grouped according to disease activity, predictors of an improved SRI at week 52 in response to belimumab included high disease activity at baseline defined by Safety Of Estrogens In Lupus Erythematosus Continued on page 16

New Payment Models Will Emphasize Value and Shared Savings/Risks From fee-for-service to performance-based reimbursement By Wayne Kuznar Chicago, IL—The US healthcare and payment delivery model is in transition toward shifting from a volumebased fee-for-service (FFS) model to a performance-based model, with clinicians assuming more risk. Better stewardship of the dollar will be critically important through this transition, with reimbursement mov-

ing ultimately to a global payment, according to Warren H. Skea, PhD, FAHA, Director, PricewaterhouseCoopers’ Health Industries Advisory Practice, at the 2011 meeting of the American College of Rheumatology. “The new reimbursement model will be population-based,” Dr Skea said. Continued on page 18

Continued on page 20

INSIDE VALUE PROPOSITIONS

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NIH awards $10.5 million for the study of molecular genes

MANAGEMENT™

RA MANAGEMENT . . . . . . . . . . . . . . . .

A methotrexate-first strategy can be successful

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Understanding Office of Inspector General and how to prepare your practice JUVENILE IDIOPATHIC ARTHRITIS . . . . . . . . . . . . . . . . . . . . . .

Factors for improved response identified

Mycophenolate superior to azathioprine for lupus maintenance PERSONALIZED MEDICINE in

FIBROMYALGIA

LUPUS

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Rheumatology

Rheumatology PRACTICE

™

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Potential new molecular biomarkers

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New insights into this complex syndrome

The Rheumatology Featuring

Insights Service Subscribe today to the essential roadmap to navigating reimbursement in one of today’s most challenging and competitive markets Updated a minimum of six times per year Based on ongoing parallel surveys of 100 rheumatologists and 50 managed care decision makers Delivers concise and insightful commentary focused on implications for current and emerging immunology brands

Subscribers receive: 1. The 2012 Rheumatology Reimbursement Report 2. Quarterly updates on key topics including biosimilars, manufacturer and sales force reimbursement effectiveness, and rheumatology practice and specialty pharmacy trends – topics tailored to meet subscribers’ key interests and strategic issues 3. Updates throughout the year driven by market and competitive events Premium subscribers also have access to customized, fast-turnaround research with members of the Reimbursement Intelligence Network, our panel of leading managed care decision makers

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In This Issue

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

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889 Associate Editor Lara J. Lorton lara@engagehc.com 732-992-1892 Editorial Assistant Jennifer Brandt jennifer@generaladminllc.com 732-992-1536 Sales Assistant Zach Ceretelle 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: 732-992-1538 Fax: 732-992-1881

RA MANAGEMENT

JUVENILE IDIOPATHIC ARTHRITIS

Are you prepared for the 2012 changes in RA management? A methotrexate-first strategy can be successful Half-dose etanercept as effective as full-dose in moderately active RA More….

Factors for improved response identified More….

Value-Based Care in Rheumatology, ISSN applied, is published 6 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. 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, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. 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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NO. 2

TNF inhibitors associated with increased risk of nonmelanoma skin cancer More….

GOUT FIBROMYALGIA

Rilonacept investigated for the prevention of acute gout flares

New insights into this complex syndrome

LUPUS Mycophenolate superior to azathioprine for lupus maintenance

CORRECTIONS

PERSONALIZED MEDICINE in

Rheumatology

™

Potential molecular biomarkers to assess treatment response in RA More….

Rheumatology PRACTICE MANAGEMENT™ Understanding Office of Inspector General and how to prepare your practice More….

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

DRUG THERAPY

In the April 2012 issue of Value-Based Care in Rheumatology, the article titled “Rheumatology Roundup Corrals Most Salient Studies Presented at 2011 ACR/ARH” provided several citations from John J. Cush, MD, and Arthur F. Kavanaugh, MD, from their oral presentations at the meeting. Dr Cush and Dr Kavanaugh did not review nor approve of this report before publication. We apologize for any potential misrepresentation contained in this report, and for using their photos without their permission. In the April 2012 issue, Dr Max Hamburger was incorrectly cited as being affiliated with the International Rheumatology Network. We apologize for the error.

VBCR Advisory Editorial Board Editor-in-Chief Sy Schlager, MD, PhD President & Chief Medical Officer Therapeutic Window, LLC Southlake, TX

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

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

Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield New York, NY

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

Gary L. Johnson, MD, MS, MBA Regional Medical Director Humana, Inc. Madison, WI

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

Atheer A. Kaddis, PharmD Vice President, Managed Markets Diplomat Specialty Pharmacy Swartz Creek, MI

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

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

James T. Kenney, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA

Lynn Nishida, RPh Director, Clinical Pharmacy Services RegenceRX Portland, OR

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

MAY 2012

www.ValueBasedRheumatology.com

Value Propositions Six Practical Ways to Monitor RA Disease Activity Tight control of rheumatoid arthritis (RA) disease activity is emerging as the new standard of care, and the Rheumatoid Arthritis Disease Activity Measures Working Group (RADAM-WG) of the American College of Rheumatology (ACR) now recommends 6 disease activity measures for use in routine clinical practice. The recommendations were coauthored by Jaclyn Anderson, DO, MS, Medical Director at Abbott Laboratories, Abbott Park, IL. After a systematic review of the literature and application of exclusion criteria and ratings by community rheumatologists, the RADAM-WG recommends the Clinical Disease Activity Index, the Disease Activity Score with 28-joint counts (with either the erythrocyte sedimentation rate or C-reactive protein), the Patient Activity Scale (PAS), PAS-II, Routine Assessment of Patient Index Data with 3 measures, and the Simplified Disease Activity Index. These 6 instruments were recommended because they: • Are accurate reflections of disease activity • Are sensitive to change • Discriminate well between low, moderate, and high disease activity states • Have remission criteria • Are feasible to perform in clinical practice settings, with each measure requiring <5 minutes to perform. By applying these tools systematically in clinical practice, physicians will be able to treat to target and effectively implement the ACR recommendations for the treatment of RA, thereby reducing costs and optimizing patient care. Anderson J, et al. Arthritis Care Res. 2012;64:640-647.

rating scale, or verbal rating scale • Acetaminophen as the first step in treatment of persistent pain • Avoidance of systemic glucocorticoids for routine pain management, unless there is also inflammation • Tricyclic antidepressants and neuromodulators for adjuvant use only, and no use of muscle relaxants or benzodiazepines for pain relief • Weak opioids can be used for short-term treatment of pain; long-term use should be monitored, and strong opioid use should be avoided unless in exceptional cases • Adding a drug with a different mode of action if acetaminophen or nonsteroidal anti-inflammatory drug (NSAID) monotherapy is inadequate, but not combining ≥2 NSAIDs • Using the lowest effective NSAID dose • Attention to existing guidelines for the safety of specific drugs during preconception, pregnancy, and lactation • Methotrexate (Trexall) can be safely combined with standard doses of acetaminophen and/or NSAIDs (excluding anti-inflammatory doses of aspirin, ≥650 mg daily) • Acetaminophen as first choice for pain relief in patients with gastrointestinal comorbidities, but only cautious use of nonselective NSAIDs in combination with proton-pump inhibitors (PPIs) or cyclooxygenase (COX)-2 selective inhibitors with PPIs • Acetaminophen as first choice for pain relief in patients with preexisting hypertension, or cardiovascular or renal disease, and only cautious use of NSAIDs, including COX-2 selective inhibitors. Whittle SL, et al. Rheumatology (Oxford). 2012 March 24.

RA Treatment Lags Behind ACR Recommendations NIH Awards $10.5 Million to New Technologies for the Study of Molecular Genes

The National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH), has awarded $10.5 million to 10 researchers to develop technologies that will assist research on millions of genomic elements that play a role in determining what genes are expressed, and at what levels in different cells. This has particular implications for cancer therapies. These multiyear grants are part of the Encyclopedia of DNA Elements (ENCODE) project, which promotes research on the role that the human genome plays in health and disease. “The ENCODE project is providing a Rosetta Stone to understand how the sequence of the human genome forms the words that tell our bodies how to work at the molecular level,” said Eric D. Green, MD, PhD, Director of the NHGRI. “Researchers are beginning to use the ENCODE catalogs to understand how variation in the DNA sequence might influence diseases such as cancer and autoimmune disorders,” said Mike Pazin, PhD, Program Director for ENCODE in NHGRI’s Division of Extramural Research. NIH News, April 25, 2012.

New Recommendations for Pain Associated with Inflammatory Arthritis

Inflammatory arthritis is characterized by pain, stiffness, loss of function, and impaired quality of life. For patients with inflammatory arthritis, pain management is an important aspect of their care. The 3e Initiative (Evidence, Expertise, Exchange) is focused on evidence-based care in rheumatology by providing practical recommendations to enhance the value of pain management in patients with inflammatory arthritis. The 3e Initiative report cites 11 evidence-based recommendations for drug therapy to manage pain in patients with inflammatory arthritis, as well as a new treatment algorithm for clinical use. The recommendations include: • Routine measurement of pain using the visual analog scale, numerical

VALUE-BASED CARE IN RHEUMATOLOGY

MAY 2012

Because RA is a chronic, disabling disease that if not properly treated can result in increased direct and indirect costs to the healthcare system, failure to adhere to evidence-based guidelines may negatively impact the value proposition in providing care to these patients. Leslie R. Harrold, MD, MPH, Associate Professor, Department of Medicine, University of Massachusetts Medical School, and colleagues report in a recent article that treatment for RA in the United States did not change at all after publication of guidelines from the ACR in December 2008. According to the Consortium of Rheumatology Researchers of North America registry, more than 50% of patients with RA who have moderate-to-severe disease still do not receive care consistent with the ACR guidelines, mostly because they are undertreated. For example, after 1 visit, only 24% to 37% of biologic-naïve patients receiving methotrexate (Rheumatrex) monotherapy who had moderate or high disease activity and a poor prognosis received care consistent with the ACR recommendations; after 2 visits, 34% to 56% of patients received care consistent with the ACR recommendations. The percentages were not significantly different for those patients receiving multiple nonbiologic disease-modifying antirheumatic drugs. Potential reasons for these results include the following: • The inability of rheumatologists to prospectively use objective measures of disease activity, calculated with one of several disease assessment instruments that are applicable to office-based practices (eg, Clinical Disease Activity Index, Routine Assessment of Patient Index Data, global arthritis score), and thus are unable to properly capture disease activity status • “Clinical inertia,” which is defined as the failure to accelerate treatment for patients with uncontrolled, chronic diseases • A lack of clinician awareness of the ACR treatment guidelines, although they were published in a prominent rheumatology journal, are available on the ACR website, and were highlighted in a plenary session at the ACR annual meeting immediately after publication of the guidelines • Lack of understanding regarding the benefits and risks of biologic therapies • Patient and provider preferences. Harrold LR, et al. Arthritis Rheum. 2012;64:630-638.

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RA Management

Changes in the Management of Rheumatoid Arthritis: Are You Prepared for 2012? By Sy Schlager, MD, PhD Chicago, IL—The development of biomarkers as tools for the measurement of disease activity to predict disease progression and response to certain therapies and the investigation of new classes of agents for the treatment of rheumatoid arthritis (RA) are 2 major advances in the management of patients with RA. Among the novel biomarkers used to assess patients with RA is a group of antibodies to modified citrullinecontaining autoantigens, which are variations of the anticyclic citrullinated peptides that are routinely used today. These new markers include a mutated citrullinated vimentin (MCV), a modified form of MCV (modMCV), a salinized form of MCV, and antimodified vimentin. Personalized Medicine A study by Ljung and colleagues that was presented at the 2011 American College of Rheumatology (ACR) meeting demonstrated that positive anti-MCV or anti-modMCV antibodies predicted a poor response to tumor necrosis factor (TNF) antagonists in patients with RA. These data may presage the dawn

at a glance ➤ Advances in RA, including the development of biomarkers to measure disease activity and new drug classes, are signaling a move toward value-based, personalized care in RA ➤ Vectra DA is a useful tool in gauging patient risk for radiographic progression and functional disability ➤ Unique classes of small organic molecules are being developed for RA, including JAK inhibitors, SyK inhibitors, and phosphodiesterase and other kinase inhibitors ➤ Tofacitinib, an oral JAK inhibitor, significantly reduced the signs and symptoms of RA, radiographic progression of structural damage, and disease activity in patients with an inadequate response to MTX or TNF inhibitors

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of an era of personalized medicine in rheumatology, where selection of therapeutic agents for individual patients is based on the presence of certain biomarkers. This is especially important in providing value-based care, because of the high cost associated with the biologic agents used to treat patients with RA.

Rheumatology is now entering a new phase of development of unique classes of small organic molecules for the treatment of RA, including JAK inhibitors, SyK inhibitors, as well as phosphodiesterase (eg, PDE-4) and other kinase inhibitors (eg, BTK, PI3K, and TKI). Vectra DA As presented in an abstract by Allaart and colleagues at the 2011 ACR meeting, the recent launch of Vectra DA, a multibiomarker disease activity (MBDA) algorithm that combines 12 serum biomarkers of inflammatory activity, is an advance in following disease progression over time in patients with RA. This MBDA measures levels of cytokines and cytokine receptors, adhesion molecules, growth factors, matrix metalloproteinases, skeletalrelated proteins, hormones, and acutephase proteins—which have all been shown to reflect the diverse biology driving RA—and combines the results of the testing into a single score. When this MBDA was applied to patients who had been enrolled in the Behandel Strategieën (BeSt) study, it was found to be best correlated with changes in Sharp scores, suggesting that these biomarkers may be a useful tool in gauging a patient’s risk for radiographic progression and functional disability over time. Moreover, the efficacy of therapy can be objectively assessed over time using the MBDA instead of repeated radiographic studies. Small Oral Molecules Rheumatology is now entering a new phase of development of unique

classes of small organic molecules for the treatment of RA, including Janus kinase (JAK) inhibitors, spleen tyrosine kinase (SyK) inhibitors, as well as phosphodiesterase (eg, PDE-4) and other kinase inhibitors (eg, BTK, PI3K, and TKI). Among the oral JAK inhibitors, tofacitinib has been the most extensively studied. Tofacitinib and fostamatinib In a series of phase 3 clinical studies, tofacitinib 10 mg was shown to significantly reduce the signs and symptoms of RA (ACR 20 response rates), reduce radiographic progression of structural damage as measured by mean change from baseline in modified Total Sharp Scores, improve physical function (Health Assessment Questionnaire Disability Index), and reduce disease activity (Disease Activity Score in Rheumatoid Arthritis <2.6) in patients with an inadequate response to methotrexate (MTX) or TNF inhibitors. Onset of activity was observed within 2 weeks of therapy with tofacitinib and efficacy persisted through followup periods ranging from 3 to 6 months. Adverse events An important issue with both tofacitinib and fostamatinib, a SyK inhibitor, is their safety profiles. Adverse events (AEs) associated with tofacitinib include serious infections, neutropenia, significant increases in low-density lipoprotein cholesterol, and increases in serum creatinine levels. AEs associated with fostamatinib included

hypertension requiring antihypertensive medication, diarrhea, infections, and elevations in liver enzymes. How would these new oral com-

All of these developments are significantly altering and complicating the management of patients with RA, and they signal a move toward value-based, personalized care.

pounds fit into a management algorithm in patients with RA? Most rheumatologists start a patient who is newly diagnosed with RA on MTX and then move to a TNF antagonist if MTX alone is ineffective. Failure or intolerance on this regimen could prompt switching to a second TNF antagonist, switching to a biologic with a different mechanism of action (eg, abatacept, rituximab), or switching to one of the oral JAK or SyK inhibitors. This final decision may well depend on an individual patient’s preference for oral therapy rather than an injectable or infusible therapy, and the cost of these new agents, which has yet to be determined. All of these developments are significantly altering and complicating the management of patients with RA, and they signal a move toward valuebased, personalized care. ■

FDA Panel Recommends Approval of Tofacitinib The US Food and Drug Administration (FDA) Arthritis Advisory Committee voted 8 to 2 to recommend approval of Pfizer’s tofacitinib for the treatment of moderately to severely active rheumatoid arthritis (RA). If approved by the FDA, tofacitinib would be the first oral agent available for patients with RA, and would be dosed as 5 mg or 10 mg twice daily. The 2 major concerns expressed by the panel with respect to tofacitinib were: • Whether it is effective in halting

MAY 2012

radiographically detected progression of joint damage • Regarding the drug’s safety profile, which includes treatment duration– and dose-dependent increases in the rates of malignancy and serious infections, and significant increases in serum lipid and cholesterol levels. For these reasons, the panel seemed to prefer approval of the 5mg dose, because it appears to be as effective as the 10-mg dose and it may be associated with fewer adverse events. (May 9, 2012) ■

www.ValueBasedRheumatology.com

RA Management

A Methotrexate-First Strategy Can Be Successful in Rheumatoid Arthritis By Wayne Kuznar Chicago, IL—More than 25% of patients with rheumatoid arthritis (RA) who are started on methotrexate (Trexall, Rheumatrex) alone achieve clinical remission at week 24, and the remission is durable out to 2 years, said James R. O’Dell, MD, Professor of Internal Medicine, Division of Rheumatology, University of Nebraska Medical Center, Omaha, at the 2011 meeting of the American College of Rheumatology. In the Treatment of Early Aggressive RA (TEAR) trial, 755 patients were randomized to 1 of 4 treatment arms. One arm received methotrexate and etanercept (Enbrel) from the outset, and a second arm was assigned to methotrexate, sulfasalazine (Azulfidine), and hydroxychloroquine (Plaquenil; triple therapy) from the outset. In the other 2 arms, patients were initiated on methotrexate alone and stepped up to either etanercept or triple therapy at week 24 if they could not achieve a Disease Activity Score in 28 joints (DAS28) of ≤3.2 on methotrexate monotherapy. To be included, patients had to have active, poor-prognosis RA, which is defined as rheumatoid factor–positive disease or anticyclic citrullinated peptide–positive disease, or the presence

There was an immediate advantage to using all drugs together when measuring DAS28 remission at 24 weeks, “but if you measure outcome between 1 and 2 years, there is no advantage clinically, and you should make the decision to step up to these other therapies based on clinical outcome.” —James R. O’Dell, MD of at least 2 erosions. Disease duration had to be <3 years and only limited

prior exposure to disease-modifying antirheumatic drug therapy was allowed. Oral prednisone was permitted at ≤10 mg/day. The mean disease duration was 3.6 months, and patients’ mean DAS28 at baseline was 5.8. Patients in the methotrexate monotherapy arm had dose escalation (from a starting dose of 10 mg) to 15 mg and to 20 mg at weeks 6 and 12, respectively, if they had a single tender or swollen joint at either time point. In the primary analysis, at 24 weeks, patients assigned to combination treatment had clinically superior responses on DAS28, but the difference was lost by 36 weeks after nonresponders stepped up to double or triple therapy. Radiographic outcomes between the 4 treatment arms from treatment initiation to week 102 were nearly identical. “There was no radiographic penalty for waiting to make the decision clinically [to step up after initial methotrexate therapy],” said Dr O’Dell. In the group assigned to methotrexate monotherapy, 72% had a DAS28 >3.2 and stepped up to either etanercept or sulfasalazine/hydroxychloroquine, whereas 28% had low disease activity (DAS28 ≤3.2) and remained

on methotrexate monotherapy. Patients who stepped up had significantly more tender and swollen joints and a higher mean DAS28 score than those who did not require step-up therapy. Of patients receiving methotrexate alone, 28% achieved DAS28 remission at week 24, and these responders maintained a durable response to 2 years. Of patients receiving methotrexate alone, 57% achieved a meaningful clinical response, which was defined as a DAS28 improvement of at least 1.2 points by week 24. There was an immediate advantage to using all drugs together when measuring the outcome (DAS28 remission) at 24 weeks, “but if you measure outcome between 1 and 2 years, there is no advantage clinically to doing that, and you should make the decision to step up to these other therapies based on clinical outcome,” he said. “The methotrexate responders do not progress radiographically at 2 years,” he said. Mean radiographic progression in radiographic Sharp scores over 2 years was 0.15 in those staying on methotrexate alone compared with 1.22 in those who received step-up therapy and 1.01 in those assigned to immediate double or triple therapy. ■

After Biologics Are Introduced, Hip and Knee Replacement Procedures Decline for Primary Diagnosis of Rheumatoid Arthritis Chicago, IL—The number of total hip replacement (THR) and total knee replacement (TKR) surgeries has declined among patients with a primary diagnosis of rheumatoid arthritis (RA) since the introduction of biologic agents. “This consistent and significant finding suggests that the availability of biologic agents, as well as other changes in the therapeutic approach to RA, may confer long-term benefits to both RA patients and healthcare systems,” concluded Neeta Tandon of Janssen Scientific Affairs, LLC, Horsham, PA, on a retrospective analysis of a large database of hospital inpatient stays, presented at the 2011 meeting of the American College of Rheumatology.

The researchers analyzed patient hospital discharge data between 1993 and 2008 using the Nationwide Inpatient Sample (NIS) of the Healthcare Cost and Utilization Project. The NIS contains discharge data from more than 1000 US hospitals from 1988 to 2009, allowing analysis of trends over time. To capture the trends for THR and TKR, data were compared between patients with RA before and after the introduction of infliximab (Remicade) in 1999, adalimumab (Humira) in 2002, and etanercept (Enbrel) in 1998, and to patients without a diagnosis of RA. A coding algorithm was used to identify the 1.7 million patients having THR or TKR procedures, 58,036 of

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MAY 2012

“The availability of biologic agents, as well as other changes in the therapeutic approach to RA, may confer long-term benefits to both RA patients and healthcare systems.” —Neeta Tandon whom had a diagnosis of RA. The number of annual THR surgeries more than doubled between 1993

and 2008—from 25,987 to 56,478— whereas, the number of annual TKR procedures more than tripled—from 38,136 to 125,881—during this period. The number of THR and TKR surgeries increased for patients with RA as a secondary diagnosis and for patients with no indication of RA. During the same time, the number of THR and TKR procedures for patients with a primary diagnosis of RA was decreasing. Patients with RA as a primary or a secondary diagnosis had a significant 28% decrease (P <.01) in the likelihood of RA being the primary reason for undergoing THR or a TKR procedure after the time that biologic agents were introduced.—WK ■

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In The Literature ACR Revises Advice on DMARDs, Biologics, and Switching Therapies An American College of Rheumatology (ACR) working group has reported the 2012 ACR updates to the 2008 ACR recommendations on the use of disease-modifying antirheumatic drugs (DMARDs) and biologic agents in patients with rheumatoid arthritis (RA; Singh JA, et al. Arthritis Care Res. 2012;64:625-639). In an accompanying editorial (Daikh DI, et al. Arthritis Care Res. 2012;64: 648-651), David I. Daikh, MD, PhD, and E. William St. Clair, MD, write, “A rigorous, standardized approach that includes a comprehensive, critical review of the literature is essential. This update of ACR RA treatment recommendations uses such an approach, reflecting the importance and value that is placed on quality and validity in the development of all ACR guidelines and recommendations. The authors are also to be congratulated on their efforts to make these recommendations relevant for many patients with RA and to address frequent decision points that will be applicable in most clinical settings.” The working group developed 4 major changes from the 2008 ACR recommendations: • The recommendations cover 3 additional biologics (certolizumab [Cimzia], tocilizumab [Actemra], and golimumab [Simponi]) in addition to adalimumab (Humira), etanercept (Enbrel), infliximab (Remicade), abatacept (Orencia), and rituximab (Rituxan) • For the first time, the recommendations address the question of switching between drugs (both conventional DMARDs and biologics) • New recommendations regarding the use of 2 new vaccines (one for herpes zoster to prevent shingles and one for human papillomavirus to prevent cervical cancer), as well as vaccines for pneumococcal disease, influenza, and hepatitis, for patients with RA • A novel treatment target of no disease activity or remission in both patients with early RA and those with established RA.

Glucocorticoids May Increase Suicide Risk Systemic glucocorticoid use may increase the risk for suicidal behavior and neuropsychiatric disorders such as depression, mania, delirium, and panic disorder, according to a large study from the United Kingdom that included data from 1990 through 2008 (Fardet L, et al. Am J Psychiatry. 2012;

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169:491-497). The study included data from almost 372,700 adult patients in a primary care setting. Compared with equivalent patients who were not receiving corticosteroids, the hazard ratio (HR) for corticosteroidexposed patients for suicide or suicide attempt was 6.89 (95% confidence interval [CI], 4.52-10.50); for delirium, 5.14

(95% CI, 4.54-5.82); for mania, 4.35 (95% CI, 3.67-5.16); for depression, 1.83 (95% CI, 1.72-1.94); and for panic disorder, 1.45 (95% CI, 1.15-1.85). Patients with a history of neuropsychiatric disorders and those treated with higher dosages of oral glucocorticoids had an increased risk of neuropsychiatric outcomes. Although older

male patients had an increased risk for delirium and mania, younger patients had an increased risk of suicide for suicide attempt. Early monitoring can be facilitated by the education of patients and their families about these adverse events and through increasing physicians’ awareness about their occurrence. ■

CALL FOR PAPERS r RA pies fo Thera iologic s in B d n e Tr

BUSIN ESS

Trends Rheum in Biologic T THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT Value Arthriti herapies for Survey atoidDESIGN CTIVE ll about PERSPE o s: It’s A s: Result R f ti E ri P D h L a rt O A yers STAKEH matoid ™

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IE TS/ PAYERS, al ith A ct T ov l . w pe as ns rs pr PA ed to achi from the th d rs r ap ne 20 em regard ne 11, Re erging n of pe of 100 and analyze ing co ate win is porting e is alig imbu trends functio an individual d quan verage obtained that therapy. rh practic are the ultim providers re matoid arthrit in reim titative rsement Inte is also a to represen eumatologist r of prers % bursem llig and qu s paid fo in healthcare ed valuable membe le, with 84% quests for rheu of at least 81 ysician ent alitative ence, a healt tions, an t more than 80 and 50 healt ider to a ph of patients Value hcare re data via h plan is artic ast 61% of re ing approvals ore intensive d the su million th be cons eatment or p se ay ou pa pa e le co m gr arch co rveys w yers (m rallel-s Resul vered liv report s of at need m it in a more the sam What oing tr to a similar tru % ts m te ed er rg to pa ra : 55 ct ho es e ica Pa de w le ur ny de . nd The su s l e yers re un ab t signed determ ive rveys in and pharmac online survey , ogics (a ests), patient can rece po to patient that treatmen nsidered valu y for that indi ol in rte fo bi in EDITORIAL d usin rce a re g cove cluded y direct s e co pa RA ag requ at thritis g tier rage st sponse ap en scribing necessarily be ust not only to manage th of such t for their ar manner. mean th r for each proximately ors) who m t and pr ts remains th rategies for placement, pr s bers s thisBeginning d A New en 150 qu questio RA biol oviders may no a payer, who who also ha e key dr ior auth or mem ior- treatm d coordinate TORS: Doe apies or othe esn. og (6 in the t by orizatio in an nts and/ pr EC ther way th 8% and 54% iver for the ch ics. Among buy-MBA extent treatment bu n, and ete MD, of patie nditions and stem timely ICAL DIR forcing stepDavidcoB.mNash, pl pr ei ps , oi sp ov r re co ce ’s ou pl onses id spectiv gr co sy MED vidual op en t been t yet; indicate ans would ely) repo of a biologic ers, experienc ntracting in medical multiple althcare drugs m in ould st egretfully, no has not ye ulard unce at pric needs of lly compelling within the he t be aligned yers sh rtainty anage biolog rted that they agent. A maj e with older irreg e pa a pa strategies? R abou ua ics ority of e us edicine eBUSINESS , Surv tment di with eq imizing valu and payers m s and costs of pa ased m se trea one day soon to ey responses rity to biologic t how therap over the next d not anticip such pt ate a ch yers change ence-b continue to s s show th eutic po s 2 to 4 id er ap w et ev rh ou m ities. O at physicians various benefit ange the to at we sit Trendsl in for Rheumatoid Arthritis: Resultsldfrom a ye para Therapies es. Pe th useBiologic e le by ed, and rds ther shows th prescribing an approval of an affect the curreioning of new ars. Payers’ ase stat ngfu of means they view th er, smal al reco reSurvey Payers and Providers the artic Drug achiev r certain dise t of meani at paye d reimbu in ic nt re di re nt ed ca re he ay m an im tio l-m w rs an d fu fo en ™ ectronic burs is n fo rsem & olec t. the w idence ization el Rhonda Greenapple, s ities the advancem with n Health eatmen ing ev MSPHl,Conclus ture treatmen d providers ar ent landscap r early treatm ement landsc ule g ent of ts for RA promot ere. 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Friedman, ains FRCSC s an a bs of a major viduals who st 10 years. 3 Be dence of og must be tantial health life, loss of whole. 1,4 In ad d caA. are of cause R only pr useKaddis, of disabi Stakeholder Perspective by Atheer PharmD work pr dicare w cons Ms Gre lity, the orking age A oduc Becaus idered in RA utilization an enapple ec d are fact tivity, onomic LLC, M is within e complicatio managemen 4,5 or burden s adison, President, Reim th m at NJ.tinued treatmen onths of di ns of RA may t. bursemen se t Intellig Con immed t is considered ase onset, ea begin to deve ence, ia rly lop clinical tion, bu te symptoms ly nece and aggressiv Vol 5, 91 of t No 2 term di also to slow di pain associat ssary to man e nefits l l gMBe arch sa se ru bi /A 1,6, D lit pril 20 y. 7 Hist ase progress ed with infla age ealth & 12 H m io or m an n ically, es ato eric timates prevent long m l Am of work nline.co www.A disabiliHDBo HDBo www.A nline.

MARCH/APRIL 2012 fits, thereby op et bene manag

s and Pro viders from a

Rheu ies for Therap Biologic

com

Vol 5,

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12 /April 20 March

Americ an H

ealth &

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fits

American Health & Drug Benefits 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. Areas of High Interest Include: Adherence Concerns • Benefit Design • Case Studies • Comorbidities and Cost Issues • Comparative Effectiveness Research • Cost Analyses • Decision-Making Tools • Ethics in Medicine •

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MAY 2012

www.ValueBasedRheumatology.com

RA Management

Half-Dose Etanercept as Effective as Full-Dose Etanercept in Patients with Moderately Active Rheumatoid Arthritis By Phoebe Starr Chicago, IL—After achieving low disease activity (LDA) while receiving full-dose induction etanercept (Enbrel) therapy at 36 weeks, patients with moderately active rheumatoid arthritis (RA) can be maintained on half-dose etanercept instead of fulldose etanercept for a further 52 weeks, according to the Study Comparing Etanercept in Combination with Methotrexate in Subjects with Rheumatoid Arthritis (PRESERVE), which was presented as a late-breaking poster at the 2011 meeting of the American College of Rheumatology (ACR). “This is the first randomized trial for adults with moderately active RA, despite methotrexate treatment evaluating both induction of DAS28 (Disease Activity Score 28) LDA and clinical, functional, and radiographic outcomes with etanercept full-dose continuation, reduction, or elimination on a background of methotrexate,” said lead author, Josef Smolen, MD, Chairman of the Department of Rheumatology, Medical University of Vienna, Austria. Both etanercept regi-

mens were significantly superior after a 9-month induction of LDA compared with a step down to placebo. Dr Smolen said that more research is needed on the longer-term implica-

“Although the findings are off label, doctors can reassure patients with moderately active RA that half doses of etanercept will work as well as full doses once they have achieved LDA.” —Eric M. Ruderman, MD tions of these observations at 52 weeks, and it is not clear if this observation with etanercept can be generalized to other biologic therapies. Commenting on the cost implications of this study, Eric M. Ruderman, MD, Professor of Rheumatology Medicine at Northwestern University

Feinberg School of Medicine in Chicago, IL, said that “although the findings are off label, doctors can reassure patients with moderately active RA that half doses of etanercept will work as well as full doses once patients have achieved LDA.” “This is one of the first studies to look at this, and it has huge cost implications. A course of full-dose etanercept costs about $26,000 per year,” stated Dr Ruderman. The study enrolled 604 patients with moderately active RA who achieved LDA as shown by DAS28 or remission on full-dose etanercept (50 mg) plus methotrexate at 36 weeks and then entered into a double-blind phase. Patients were randomized to 3 different arms for 52 weeks of treatment: etanercept 50 mg once weekly plus methotrexate (n = 202), etanercept 25 mg once weekly plus methotrexate (n = 202), or placebo plus methotrexate (n = 200) for 52 weeks. Of the 497 patients who completed the study, both etanercept groups were superior to the placebo/metho-

trexate group. LDA was maintained in 82.6% of the higher-dose etanercept group and 79.1% in the half-dose etanercept group versus 42.6% of the placebo group (P <.0001 vs either etanercept group). A significantly greater percentage of patients had a DAS28 score of <2.6 at week 88 in both etanercept dosing groups (66.7% for the higher dose and 60.2% for halfdose etanercept) versus placebo/ methotrexate (29.4%; P <.0001 vs either etanercept group). Both etanercept regimens were superior to placebo plus methotrexate on other measures of disease activity and health, including the simplified disease activity index; ACR criteria for at least a 20%, 50%, or 70% improvement (ACR 20/50/70); and a Health Assessment Questionnaire score of ≤0.5. Safety was comparable between the 3 treatment arms. Serious adverse events were reported in 35 patients (5.8%), including 2 deaths (0.3%) in the higher-dose etanercept group as a result of pulmonary embolism and septicemia. ■

Screening for JC Polyomavirus Not Yet Useful in Rheumatic Patients Treated with Rituximab By Wayne Kuznar Chicago, IL—Routine screening for replicating JC polyomavirus (JCPyV) or serum antibodies does not seem to be warranted in rheumatic patients treated with rituximab (Rituxan). JCPyV is a DNA virus that causes progressive multifocal leukoencephalopathy (PML), which is a demyelinating disease of the brain. Rituximab treatment has been identified as a risk factor for the development of PML caused by JCPyV infection, and this risk has been quantified at approximately 1 of 30,000. (Natalizumab treatment is also a risk factor with the risk quantified at 1.5 of 1000.) Reactivation of persistent JCPyV infection is thought to be responsible for the development of PML. In a study conducted by Jens Verheyen, MD, National Reference Center for Papilloma and Polyoma Viruses, Institute of Virology, University of Cologne, Germany, and colleagues, patterns of JCPyV infections were scrutinized in 65 patients with rheumatic diseases, all of whom were treated with at least 1 cycle of rituximab. No

patient showed any neurologic symptoms during the course of the study.

“Interestingly, the amount of antibodies detected was significantly higher in patients shedding JCPyV in the urine.” —Jens Verheyen, MD Blood samples were analyzed for JCPyV in all patients, and antibodies for JCPyV were analyzed in the urine in a subset. Samples were taken before and after at least 1 cycle of rituximab in 21 patients (baseline group); in 44 patients, all samples were collected during ongoing treatment (rituximab treatment group). In the baseline group, JCPyV DNA was detected in 33% of samples. In the rituximab treatment group, 43% of urine samples were positive at the beginning, and only 1 switch from negative to positive occurred during the observation period. These percentages are similar to those in healthy

VALUE-BASED CARE IN RHEUMATOLOGY

MAY 2012

individuals tested for the prevalence of JCPyV in the urine in previous studies when adjusted for the older age of patients in this current analysis, noted Dr Verheyen. Therefore, “rituximab treatment did not seem to influence the shedding of JCPyV in the urine of patients with rheumatic disease,” Dr Verheyen said. Using a JCPyV assay, JCPyV antibodies in the blood were detected in 79.6% of 54 patients tested. “Interestingly, the amount of antibodies detected was significantly higher in patients shedding JCPyV in the urine,” he said. By comparison, using the same assay, the prevalence of JCPyV antibodies in healthy individuals aged 50 to 70 years is 43% to 68%, respectively, based on reports in the literature, which suggest that treatment with rituximab did not significantly influence the detection rates of JCPyV antibodies in patients with rheumatic diseases. “Even though we analyzed multiple blood samples, we were only able to detect JCPyV DNA in the blood samples of 2 [of 65] patients [3%]; in

1 patient, we were able to analyze another blood sample, and this was negative 1 month later,” Dr Verheyen pointed out. In patients treated with natalizumab, the rate of JCPyV in the blood has ranged from 0.3% to 63%, and the rate of transient viremia has been 2% to 7%. At the moment, high- and low-risk groups cannot be sufficiently distinguished through the use of screening for JCPyV in patients treated with rituximab, concluded Dr Verheyen. ■ Editor’s Note: In January 2012, the Food and Drug Administration (FDA) approved the first test for assessing the risk of multifocal leukoencephalopathy in patients treated with natalizumab. The Stratify JCV Antibody ELISA test screens for the presence of antibodies to JCPyV. According to the FDA, a total of 201 cases of PML have been reported among approximately 96,582 patients treated with natalizumab through January 4, 2012.

VOL. 1

NO. 2

RA Management

Trends in RA Management... assuming a prominent—or even comparable—position in relation to the injectable agents that now dominate the market, such as adalimumab (Humira), infliximab (Remicade), and etanercept (Enbrel). The Rheumatology Report provides key answers to these questions. After the American College of Rheumatology (ACR) conference in Chicago, IL, in November 2011, Reimbursement Intelligence surveyed 50 pharmacy and medical directors representing leading national and regional health plans, as well as 100 rheumatologists involved in patient care. The survey results reveal key trends in payer and provider approaches to RA management. Rheumatoid Arthritis Driving Specialty Drug Costs Increasing attention to the management of RA by health plans and providers is well warranted in the current environment, considering that RA is currently the top therapeutic category in terms of its contribution to specialty drug trends. According to the Medco 2011 Drug Trend Report, RA therapies (and other immune disorder medications) in 2011 contributed 29.4% to specialty drugs, ahead of multiple sclerosis (MS; 24.2%) and cancer (20.3%).1 RA agents also led all clinical categories in terms of contribution to the total health plan specialty pharmacy costs at 27.2%, again followed by MS and cancer drugs (20.8% and 17.2%, respectively).1

This should not be surprising, given that approximately 1.3 million people in the United States suffer from RA, which is nearly 1% of the US adult population.2 The impact of RA on patients is significant, according to a 2011 report from the American Autoimmune Related Diseases Association3: • The estimated average earnings of patients with RA can be reduced by as much as $4500 annually • The number of jobs that patients with RA can perform drops dramatically—from 11.5 million to 2.6 million • Approximately 50% of patients with RA become unable to work within 10 years of disease onset • The direct medical cost of RA in the United States approaches $5 billion annually, with nearly 70% of this cost attributable to hospitalizations and home-care nursing. Payer Strategies in Rheumatoid Arthritis In recent years, payers have implemented numerous strategies to manage the outcomes and costs of RA. The most important aspect impacting formulary and coverage decisions had been a health plan’s “ability to reduce disease progression and severity,” a measure cited by 72% of plans, according to the 2011 EMD Serono Specialty Digest.4 Other prominent RA management strategies include4: • Following health plan guidelines (70%) • Reducing adverse reactions (62%)

Impact of Premium Price When Positioning Small-Molecule Compounds Figure 1 vs Current Biologics in RA Treatment Strategies

Q: Assuming small-molecule drugs are at a 15% to 20% premium price to current biologics, how will they change your plan’s treatment strategy? Rheumatologists Payers 30

28% 26%

23% 20%

19%

18%

15 12% 10 7%

6% 4%

5 0 They will be used after MTX, but before TNF inhibitors

They will be used after initial TNF inhibitor failure

They will be used after switching to a new class after TNF inhibitor failure

They will be used after self-injected biologics but before infusion biologics

They will be used as last line after all current biologics have failed

MTX indicates methotrexate; RA, rheumatoid arthritis; TNF, tumor necrosis factor.

VOL. 1

NO. 2

Not sure at this time

Continued from cover

• Decreasing hospitalizations and other healthcare costs (57%) • Increasing adherence and persistency (54%). But what of the future of the management of RA, especially with respect to therapeutic decisionmaking? What factors do payers and rheumatologists think will drive decision-making and allow them to achieve their clinical and cost objectives in the years ahead?

Biologics for RA treatment are not currently a tightly controlled category, nor will they be in the near future. Patients and providers will still have treatment choices, but as the market becomes more crowded, pricing pressures and contracting may lead to tighter controls. Price Will Drive Orals in Therapy Formulary Placement by Payers Many of the headlines coming out of the 2011 ACR conference touted the presentation of clinical studies discussing the potential benefits of 2 oral agents for RA currently in the pipeline—a possible game changer in a sector long dominated by injectable (and expensive) tumor necrosis factor (TNF) inhibitors. The 2 oral drugs—tofacitinib, a JAK inhibitor, and apremilast, a phosphodiesterase-4 inhibitor—are considered to be small-molecule agents. Data presented at the 2011 ACR meeting suggest that both agents offer promise for patients with RA.5 The development of other oral medications may suggest that patients will be more likely to take their RA medications in a tablet form than selfinjecting or traveling to a hospital or a clinic for infusion, but that may not happen right away. Survey results suggest that the adoption of oral drugs will be driven largely by price. Payer responses suggest that if the new drugs are priced at parity with the leading injectable products, there is no clear positioning outlook for the small-molecule agents. If the oral agents are priced higher, at a 15% to 20% premium to biologics (Figure 1), payers and rheumatologists suggested that the new drugs will be positioned after TNF inhibitors. Payer responses also indicate that,

MAY 2012

at price parity to currently available biologics, there is no clear therapeutic preference for the small-molecule drugs; if the latter are priced at a 15% to 20% discount, they will likely be positioned ahead of TNF inhibitors. Cost-Offsetting Helps Enhance Adherence Although further research is necessary to fully understand medication adherence in patients with RA,6 survey responses from rheumatologists suggest that cost is a motivating factor among patients. Cost-offsetting for patients is the factor most valued by rheumatologists, because they believe it improves patient adherence. Specifically, with regard to copayment assistance programs (utilized by manufacturers to help reduce consumer costs for TNF inhibitors), 78% of rheumatologists in the survey noted that copayments improve patient adherence with therapy (Figure 2, page 10). Status Quo in Payers’ Approach to RA Management Apparently, regardless to potential new oral therapies, health plans see little or no reason to change the ways in which they manage their patients with RA. By a significant margin, 68% of payers said that they were not forecasting any changes in RA management methods during the next 2 to 4 years, and only 32% of plans suggested that changes may be implemented (Figure 3, page 10). When asked to identify the types of changes that they may use, no consistency was apparent among responses. The following is a sample of responses provided: • “As new therapies come to market, and some go the route of biosimilar, we will make changes.” • “We will have preferred biological agents in this [RA] area.” • “We plan to have a preferred specialty tier.” • “We will select agents based on cost-effectiveness, and contract with industry for a price advantage for a favorable spot on formulary.” • “With the advent of CER [comparative effectiveness research] data and the use of e-prescribing, it will give us diagnosis and better efficacy data to better clinically manage these patients.” In addition, 2 payers indicated that they would implement step-therapy regimens in their RA management programs. Continued on page 10

www.ValueBasedRheumatology.com

Gout

Rilonacept in the Prevention of Acute Gout Flares FDA panel votes against approval of a supplemental BLA application By Sy Schlager, MD, PhD

out flares occurring during the early months of urate-lowering therapy are thought to result from the release of urate crystals from deposits softened by the treatment. These crystals trigger the release of interleukin (IL)-1, thus leading to a cascade of inflammation and flares of acute joint pain. Traditionally, the vast majority of gout flares have been managed with nonsteroidal anti-inflammatory drugs (NSAIDs), colchicines, or steroids. A recent phase 2 study showed that gout attacks occurring during the first few months of urate-lowering therapy can be nearly eliminated by adding the IL-1 inhibitor rilonacept (Arcalyst) at the initiation of allopurinol (Zyloprim; Schumacher HR, et al. Arthritis Rheum. 2012;64:876-884). In this double-blind study, 83 adult patients with hyperuricemia and gout were randomized to receive rilonacept (loading dose of

320 mg followed by 160 mg weekly) or placebo administered subcutaneously and were started on allopurinol (300 mg daily, titrated to a serum urate level of <6 mg/dL).

A recent phase 2 study showed that gout attacks occurring during the first few months of uratelowering therapy can be nearly eliminated by adding the rilonacept at the initiation of allopurinol. The mean number of gout flares per patient through week 12 was significantly lower in the rilonacept group than in the placebo group (6 flares vs 33 flares, respectively; P = .001), and the proportion of patients experienc-

ing a gouty flare during the 12 weeks was also significantly lower in the rilonacept group than in the placebo group (14.6% vs 45.2%, respectively; P = .003). At week 16, no rebound in the flare rate was observed for 6 weeks after discontinuation of rilonacept or placebo. Adverse events (AEs) were similar in the rilonacept and placebo groups, with the most common reported AEs being infections and musculoskeletal disorders. A higher percentage of patients receiving rilonacept than placebo controls completed the 12-week evaluation period (98% vs 79%, respectively; P = .015). Although the findings of this study indicate that rilonacept can reduce the frequency of gouty flares during the initial period of treatment with uratelowering therapy, inhibiting IL-1 is probably not the only factor involved in the flares; rilonacept prevented most, but not all, flares. In the real-

world setting, rilonacept is likely to be used when conventional therapy (ie, NSAIDs, colchicines, steroids) has failed or is not well tolerated. Despite these recent findings, the US FDA Arthritis Advisory Committee voted on May 8, 2012, against the approval of a supplemental Biologic License Application (BLA) for rilonacept to prevent gout flares. The supplemental BLA asked for approval of the use of rilonacept as an 80-mg subcutaneous injection once weekly for 16 weeks after a 160-mg loading dose for the prevention of gout flares during initiation of uric acid– lowering therapy in patients with gout. The main objections to the application centered around the supporting clinical data, which the majority of panel members said had failed to adequately demonstrate the safety of the drug and its improved efficacy over current standard therapy. ■

Trends in RA Management... Continued from page 9 Conclusions A general observation from these survey findings is that biologics for RA treatment are not currently a tightly controlled category, nor will they be in the near future. Patients and providers will still have treatment choices, but as the market becomes more crowded, pricing pressures and contracting may lead to tighter con-

trols. In addition, payers will have a broader ability to review the RA category and build comparative effectiveness models. For drug manufacturers wishing to capture market share, responses to questions related to therapy management preferences suggest that it is easier to capture market share with a second-line biologic than with a first-

line agent, and that newer secondand third-generation biologic therapies (including non-TNFs) are not yet differentiated from older biologic compounds or even from one another. Also, it is apparent that an indication for use in early RA will not increase market opportunity for manufacturers. A final word of caution for mar-

Impact of Copay Programs on Adherence to RA Figure 2 Therapy, as Reported by Rheumatologists

Likelihood of Payer Changes in RA Management Figure 3 Methods in the Next 2 to 4 Years

Q: Are copay programs improving patient adherence to therapy?

Q: Do you plan to change the management of RA therapies in the next 2 to 4 years?

No 22%

Yes 32% No 68%

Yes 78%

RA indicates rheumatoid arthritis.

VALUE-BASED CARE IN RHEUMATOLOGY

MAY 2012

keters of the oral, small-molecule compounds that are likely to enter the market soon is that, for now, payers and providers do not perceive a “natural” positioning for these emerging therapies in the management of patients with RA. In other words, these drugs will need to prove their clinical value and cost-effectiveness before they are widely adopted by payers and providers. ■

References 1. Medco Health Solutions, Inc. 2011 Drug Trend Report. 2011. www.drugtrendreport.com/2011-report. Accessed January 24, 2012. 2. Arthritis Foundation. Who Gets Rheumatoid Arthritis? 2012. www.arthritis.org/who-gets-rheumatoid-arthritis. php. Accessed January 24, 2012. 3. American Autoimmune Related Diseases Association, National Coalition of Autoimmune Patient Groups. The Cost Burden of Autoimmune Disease: The Latest Front in the War on Healthcare Spending. 2011. www.aarda.org/pdf/cbad.pdf. Accessed January 25, 2012. 4. EMD Serono. EMD Serono Specialty Digest, 7th Edition. Managed care strategies for specialty pharmaceuticals. 2011. http://specialtydigest.emdserono.com/ User/DigestLibrary.aspx. Accessed April 27, 2012. 5. Mednet. Non-TNF inhibitor biologics: expanding opportunities for rheumatoid arthritis control. Press release. November 5, 2011. http://mednet.adverdea. com/en/report/nontnf-inhibitor-biologics-expandingopportuniti.html. Accessed April 27, 2012. 6. Salt E, Frazier S. Adherence to disease modifying anti-rheumatic drugs in rheumatoid arthritis patients: a narrative review of the literature. Orthop Nurs. 2010; 29:260-275.

VOL. 1

NO. 2

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MANY THREATS: Rheumatoid Arthritis. Psoriatic Arthritis. Ankylosing Spondylitis.

Indications1 Moderate to severe rheumatoid arthritis: HUMIRA is indicated, alone or in combination with methotrexate or other non-biologic DMARDs, 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. Psoriatic arthritis: HUMIRA is indicated, alone or in combination with non-biologic DMARDs, for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis. Ankylosing spondylitis: HUMIRA is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis.

Please see Brief Summary of full Prescribing Information on last pages of this advertisement.

ONE

40 mg every other week. Some patients with RA not receiving methotrexate may benefit from increasing the frequency to 40 mg every week.

Safety Considerations1 Serious Infections: Patients treated with HUMIRA are at increased risk for developing serious infections that may lead to hospitalization or death. These infections include active tuberculosis (TB), reactivation of latent TB, invasive fungal infections, and bacterial, viral, and other infections due to opportunistic pathogens. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Malignancies: Lymphoma, including a rare type of T-cell lymphoma, and other malignancies, some fatal, have been reported in patients treated with TNF blockers, including HUMIRA. Other Serious Adverse Reactions: Patients treated with HUMIRA also may be at risk for other serious adverse reactions, including anaphylaxis, hepatitis B virus reactivation, demyelinating disease, cytopenias, pancytopenia, heart failure, and a lupus-like syndrome. Reference: 1. HUMIRA Injection [package insert]. North Chicago, IL: Abbott Laboratories.

Please see Important Safety Information, including BOXED WARNING on Serious Infections and Malignancy, on the following page.

Important Safety Information1 SERIOUS INFECTIONS Patients treated with HUMIRA are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. HUMIRA should be discontinued if a patient develops a serious infection or sepsis. Reported infections include: s !CTIVE TUBERCULOSIS 4" INCLUDING REACTIVATION OF LATENT 4" 0ATIENTS WITH 4" HAVE FREQUENTLY PRESENTED WITH DISSEMINATED OR EXTRAPULMONARY DISEASE 0ATIENTS SHOULD BE TESTED FOR LATENT 4" BEFORE (5-)2! USE AND DURING THERAPY 4REATMENT FOR LATENT 4" SHOULD BE INITIATED PRIOR TO (5-)2! USE s )NVASIVE FUNGAL INFECTIONS INCLUDING HISTOPLASMOSIS COCCIDIOIDOMYCOSIS CANDIDIASIS ASPERGILLOSIS BLASTOMYCOSIS AND PNEUMOCYSTOSIS 0ATIENTS WITH HISTOPLASMOSIS OR OTHER INVASIVE FUNGAL INFECTIONS MAY PRESENT WITH DISSEMINATED RATHER THAN LOCALIZED DISEASE !NTIGEN 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. s "ACTERIAL VIRAL AND OTHER INFECTIONS DUE TO OPPORTUNISTIC PATHOGENS INCLUDING ,EGIONELLA AND ,ISTERIA 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 (5-)2! INCLUDING THE POSSIBLE DEVELOPMENT OF 4" IN PATIENTS WHO TESTED NEGATIVE FOR LATENT 4" INFECTION PRIOR TO INITIATING THERAPY s $O NOT START (5-)2! IN PATIENTS WITH AN ACTIVE INFECTION INCLUDING LOCALIZED INFECTIONS s 0ATIENTS OLDER THAN YEARS PATIENTS WITH CO MORBID CONDITIONS AND OR PATIENTS TAKING CONCOMITANT IMMUNOSUPPRESSANTS MAY BE AT GREATER RISK OF INFECTION s %XERCISE CAUTION IN PATIENTS WITH CHRONIC OR RECURRENT INFECTION OR WITH UNDERLYING CONDITIONS WHICH MAY PREDISPOSE THEM TO INFECTION PATIENTS WHO HAVE BEEN EXPOSED TO 4" PATIENTS WITH A HISTORY OF OPPORTUNISTIC INFECTION OR PATIENTS WHO HAVE RESIDED OR TRAVELED IN REGIONS WHERE 4" OR MYCOSES ARE ENDEMIC s 0ATIENTS WHO DEVELOP A NEW INFECTION SHOULD UNDERGO A PROMPT AND COMPLETE DIAGNOSTIC WORKUP AND APPROPRIATE ANTIMICROBIAL THERAPY SHOULD BE INITIATED s $RUG INTERACTIONS WITH BIOLOGIC PRODUCTS #ONCURRENT USE OF ANAKINRA OR ABATACEPT WITH (5-)2! IS NOT RECOMMENDED AS THE COMBINATION OF ANAKINRA OR ABATACEPT WITH 4.& BLOCKERS HAS BEEN ASSOCIATED WITH AN INCREASED RISK OF SERIOUS INFECTIONS 4HIS RISK HAS ALSO BEEN OBSERVED WITH RHEUMATOID ARTHRITIS PATIENTS TREATED WITH RITUXIMAB WHO RECEIVED SUBSEQUENT TREATMENT WITH A 4.& BLOCKER -!,)'.!.#9 ,YMPHOMA AND OTHER MALIGNANCIES SOME FATAL HAVE BEEN REPORTED IN CHILDREN AND ADOLESCENT PATIENTS TREATED WITH 4.& BLOCKERS OF WHICH (5-)2! IS A MEMBER 0OSTMARKETING CASES OF HEPATOSPLENIC 4 CELL LYMPHOMA (34#, A RARE TYPE OF 4 CELL LYMPHOMA HAVE BEEN REPORTED IN PATIENTS TREATED WITH 4.& 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 MERCAPTOPURINE CONCOMITANTLY WITH A 4.& BLOCKER AT OR PRIOR TO DIAGNOSIS )T IS UNCERTAIN WHETHER THE OCCURRENCE OF (34#, IS RELATED TO USE OF A 4.& BLOCKER OR A 4.& blocker in combination with these other immunosuppressants. s 4HE RISKS AND BENElTS OF (5-)2! TREATMENT SHOULD BE CONSIDERED PRIOR TO INITIATING OR CONTINUING THERAPY IN A PATIENT WITH KNOWN MALIGNANCY s -ORE CASES OF MALIGNANCIES WERE OBSERVED AMONG (5-)2! TREATED PATIENTS COMPARED TO CONTROL PATIENTS IN CLINICAL TRIALS s .ON MELANOMA SKIN CANCER .-3# HAS BEEN REPORTED DURING CLINICAL TRIALS FOR (5-)2! TREATED PATIENTS !LL PATIENTS PARTICULARLY THOSE WITH HISTORY OF PROLONGED IMMUNOSUPPRESSANT OR 056! THERAPY SHOULD BE EXAMINED FOR THE PRESENCE OF .-3# PRIOR TO AND DURING TREATMENT WITH (5-)2! s )N (5-)2! CLINICAL TRIALS THERE WAS AN APPROXIMATE FOLD HIGHER RATE OF LYMPHOMA THAN EXPECTED IN THE GENERAL 5 3 POPULATION 0ATIENTS WITH CHRONIC INmAMMATORY DISEASES PARTICULARLY WITH HIGHLY ACTIVE DISEASE AND OR CHRONIC EXPOSURE TO IMMUNOSUPPRESSANT THERAPIES MAY BE AT HIGHER RISK OF LYMPHOMA THAN THE GENERAL POPULATION EVEN IN THE ABSENCE OF 4.& BLOCKERS s 0OSTMARKETING CASES OF ACUTE AND CHRONIC LEUKEMIA WERE REPORTED WITH 4.& BLOCKER USE s !PPROXIMATELY HALF OF THE POSTMARKETING CASES OF MALIGNANCIES IN CHILDREN ADOLESCENTS AND YOUNG ADULTS RECEIVING 4.& BLOCKERS WERE LYMPHOMAS OTHER CASES INCLUDED RARE MALIGNANCIES ASSOCIATED WITH IMMUNOSUPPRESSION AND MALIGNANCIES NOT USUALLY OBSERVED IN CHILDREN AND ADOLESCENTS (90%23%.3)4)6)49 s !NAPHYLAXIS AND ANGIONEUROTIC EDEMA HAVE BEEN REPORTED RARELY FOLLOWING (5-)2! ADMINISTRATION s )F A SERIOUS ALLERGIC REACTION OCCURS STOP (5-)2! AND INSTITUTE APPROPRIATE THERAPY (%0!4)4)3 " 6)253 2%!#4)6!4)/. s 5SE OF 4.& BLOCKERS INCLUDING (5-)2! MAY INCREASE THE RISK OF REACTIVATION OF HEPATITIS " VIRUS ("6 IN PATIENTS WHO ARE CHRONIC CARRIERS 3OME CASES HAVE BEEN FATAL s 0ATIENTS AT RISK FOR ("6 INFECTION SHOULD BE EVALUATED FOR PRIOR EVIDENCE OF ("6 INFECTION BEFORE INITIATING 4.& BLOCKER THERAPY s %XERCISE CAUTION IN PATIENTS WHO ARE CARRIERS OF ("6 AND MONITOR THEM DURING AND AFTER TREATMENT WITH (5-)2! s $ISCONTINUE (5-)2! AND BEGIN ANTIVIRAL THERAPY IN PATIENTS WHO DEVELOP ("6 REACTIVATION s %XERCISE CAUTION WHEN CONSIDERING RESUMPTION OF (5-)2! THERAPY AFTER APPROPRIATE TREATMENT FOR ("6 .%52/,/')# 2%!#4)/.3 s 4.& BLOCKERS INCLUDING (5-)2! HAVE BEEN ASSOCIATED IN RARE CASES WITH NEW ONSET OR EXACERBATION OF CENTRAL NERVOUS SYSTEM AND PERIPHERAL DEMYELINATING DISEASES INCLUDING MULTIPLE SCLEROSIS OPTIC NEURITIS AND 'UILLAIN "ARRÏ SYNDROME s %XERCISE CAUTION WHEN CONSIDERING (5-)2! FOR PATIENTS WITH THESE DISORDERS (%-!4/,/')# 2%!#4)/.3 s 2ARE REPORTS OF PANCYTOPENIA INCLUDING APLASTIC ANEMIA HAVE BEEN REPORTED WITH 4.& BLOCKERS -EDICALLY SIGNIlCANT CYTOPENIA E G THROMBOCYTOPENIA LEUKOPENIA HAS BEEN INFREQUENTLY REPORTED WITH (5-)2! s #ONSIDER STOPPING (5-)2! IN PATIENTS WITH SIGNIlCANT HEMATOLOGIC ABNORMALITIES #/.'%34)6% (%!24 &!),52% s 7ORSENING OR NEW ONSET CONGESTIVE HEART FAILURE #(& MAY OCCUR s %XERCISE CAUTION IN PATIENTS WITH #(& AND MONITOR THEM CAREFULLY !54/)--5.)49 s 4REATMENT WITH (5-)2! MAY RESULT IN THE FORMATION OF AUTOANTIBODIES AND RARELY IN DEVELOPMENT OF A LUPUS LIKE SYNDROME s $ISCONTINUE TREATMENT IF SYMPTOMS OF A LUPUS LIKE SYNDROME DEVELOP IMMUNIZATIONS s 0ATIENTS ON (5-)2! SHOULD NOT RECEIVE LIVE VACCINES s )T 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 (5-)2! THERAPY !$6%23% 2%!#4)/.3 s 4HE MOST COMMON ADVERSE REACTIONS IN (5-)2! CLINICAL TRIALS INCIDENCE WERE INFECTIONS E G UPPER RESPIRATORY SINUSITIS INJECTION SITE REACTIONS HEADACHE AND RASH Reference: 1. HUMIRA Injection [package insert]. North Chicago, IL: Abbott Laboratories.

0LEASE SEE "RIEF 3UMMARY OF FULL 0RESCRIBING )NFORMATION on the following pages of this advertisement. ©2011 Abbott Laboratories Abbott Park, IL 60064 64C-759105 ©2012 64C-xxxxxx March January 2011 2012 Printed Printed in U.S.A. in U.S.A.

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

PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION versus a rate of 0.5 (0.28, 1.05) per 100 patient-years among 3749 control-treated 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 Ū 18 years of age), of which HUMIRA is a member. Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources including registries and spontaneous postmarketing reports. Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including HUMIRA. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases has occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants. Hypersensitivity Reactions In postmarketing experience, anaphylaxis and angioneurotic edema have been reported rarely following HUMIRA administration. If an anaphylactic or other serious allergic reaction occurs, administration of HUMIRA should be discontinued immediately and appropriate therapy instituted. In clinical trials of HUMIRA in adults, allergic reactions overall (e.g., allergic rash, anaphylactoid reaction, fixed drug reaction, non-specified drug reaction, urticaria) have been observed in approximately 1% of patients. Hepatitis B Virus Reactivation Use of TNF blockers, including HUMIRA, may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating TNF blocker therapy. Prescribers should exercise caution in prescribing TNF blockers for patients identified as carriers of HBV. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. In patients who develop HBV reactivation, HUMIRA should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Neurologic Reactions Use of TNF blocking agents, including HUMIRA, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis (MS) and optic neuritis, and peripheral demyelinating disease, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use of HUMIRA in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders. Hematological Reactions Rare reports of pancytopenia including aplastic anemia have been reported with TNF blocking agents. Adverse reactions of the hematologic system, including medically significant cytopenia (e.g., thrombocytopenia, leukopenia) have been infrequently reported with HUMIRA. The causal relationship of these reports to HUMIRA remains unclear. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on HUMIRA. Discontinuation of HUMIRA therapy should be considered in patients with confirmed significant hematologic abnormalities. Use with Anakinra Concurrent use of anakinra (an interleukin-1 antagonist) and another TNF-blocker, was associated with a greater proportion of serious infections and neutropenia and no added benefit compared with the TNF-blocker alone in patients with RA. Therefore, the combination of HUMIRA and anakinra is not recommended [see Drug Interactions]. Heart Failure Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. Cases of worsening CHF have also been observed with HUMIRA. Physicians should exercise caution when using HUMIRA in patients who have heart failure and monitor them carefully. Autoimmunity Treatment with HUMIRA may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with HUMIRA, treatment should be discontinued [see Adverse Reactions]. Immunizations In a placebo-controlled clinical trial of patients with rheumatoid arthritis, no difference was detected in anti-pneumococcal antibody response between HUMIRA and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with HUMIRA. Patients on HUMIRA may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving HUMIRA. It is recommended that juvenile idiopathic arthritis patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating HUMIRA therapy. Patients on HUMIRA may receive concurrent vaccinations, except for live vaccines. Use with Abatacept In controlled trials, the concurrent administration of TNF-blockers and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; the combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of abatacept with TNF-blockers including HUMIRA is not recommended [see Drug Interactions]. ADVERSE REACTIONS Clinical Studies Experience The most serious adverse reactions were: • Serious Infections [see Warnings and Precautions] • Malignancies [see Warnings and Precautions] The most common adverse reaction with HUMIRA was injection site reactions. In placebo-controlled trials, 20% of patients treated with HUMIRA developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 14% of patients receiving placebo. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation. The proportion of patients who discontinued treatment due to adverse reactions during the double-blind, placebo-controlled portion of Studies RA-I, RA-II, RA-III and RA-IV was 7% for patients taking HUMIRA and 4% for placebo-treated patients. The most common adverse reactions leading to discontinuation of HUMIRA were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%). Infections In the controlled portions of the 32 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD and Ps, the rate of serious infections was 4.7 per 100 patient-years in 6694 HUMIRA-treated patients versus a rate of 2.7 per 100 patient-years in 3749 control-treated patients. Serious infections observed included pneumonia, septic arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis [see Warnings and Precautions]. Tuberculosis and Opportunistic Infections In 45 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD and Ps that included 22,026 HUMIRA-treated patients, the rate of reported active tuberculosis was 0.22 per 100 patient-years and the rate of positive PPD conversion was 0.07 per 100 patient-years. In a subgroup of 8940 U.S. and Canadian HUMIRAtreated patients, the rate of reported active TB was 0.07 per 100 patient-years and the rate of positive PPD

conversion was 0.06 per 100 patient-years. These trials included reports of miliary, lymphatic, peritoneal, and pulmonary TB. Most of the TB cases occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease. In these global clinical trials, cases of serious opportunistic infections have been reported at an overall rate of 0.07 per 100 patient-years. Some cases of serious opportunistic infections and TB have been fatal[see Warnings and Precautions]. Autoantibodies In the rheumatoid arthritis controlled trials, 12% of patients treated with HUMIRA and 7% of placebo-treated patients that had negative baseline ANA titers developed positive titers at week 24. Two patients out of 3046 treated with HUMIRA developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms. The impact of long-term treatment with HUMIRA on the development of autoimmune diseases is unknown. Liver Enzyme Elevations There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of HUMIRA (40 mg SC every other week) in patients with RA, PsA, and AS with control period duration ranging from 4 to 104 weeks, ALT elevations ū 3 x ULN occurred in 3.5% of HUMIRA-treated patients and 1.5% of control-treated patients. Since many of these patients in these trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between HUMIRA and the liver enzyme elevations is not clear. In controlled Phase 3 trials of HUMIRA (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on Days 1 and 15, respectively, followed by 40 mg every other week) in patients with Crohn’s disease with control period duration ranging from 4 to 52 weeks, ALT elevations ū 3 x ULN occurred in 0.9% of HUMIRA-treated patients and 0.9% of control-treated patients. In controlled Phase 3 trials of HUMIRA (initial dose of 80 mg then 40 mg every other week) in patients with plaque psoriasis with control period duration ranging from 12 to 24 weeks, ALT elevations ū 3 x ULN occurred in 1.8% of HUMIRA-treated patients and 1.8% of control-treated patients. Immunogenicity Patients in Studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab during the 6- to 12-month period. Approximately 5% (58 of 1062) of adult rheumatoid arthritis patients receiving HUMIRA developed low-titer antibodies to adalimumab at least once during treatment, which were neutralizing in vitro. Patients treated with concomitant methotrexate had a lower rate of antibody development than patients on HUMIRA monotherapy (1% versus 12%). No apparent correlation of antibody development to adverse reactions was observed. With monotherapy, patients receiving every other week dosing may develop antibodies more frequently than those receiving weekly dosing. In patients receiving the recommended dosage of 40 mg every other week as monotherapy, the ACR 20 response was lower among antibody-positive patients than among antibody-negative patients. The long-term immunogenicity of HUMIRA is unknown. In patients with juvenile idiopathic arthritis, adalimumab antibodies were identified in 16% of HUMIRA-treated patients. In patients receiving concomitant methotrexate, the incidence was 6% compared to 26% with HUMIRA monotherapy. In patients with ankylosing spondylitis, the rate of development of antibodies to adalimumab in HUMIRAtreated patients was comparable to patients with rheumatoid arthritis. In patients with psoriatic arthritis, the rate of antibody development in patients receiving HUMIRA monotherapy was comparable to patients with rheumatoid arthritis; however, in patients receiving concomitant methotrexate the rate was 7% compared to 1% in rheumatoid arthritis. In patients with Crohn’s disease, the rate of antibody development was 3%. In patients with plaque psoriasis, the rate of antibody development with HUMIRA monotherapy was 8%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 ug/ml. Among the patients whose serum adalimumab levels were < 2 ug/ml (approximately 40% of total patients studied), the immunogenicity rate was 20.7%. In plaque psoriasis patients who were on HUMIRA monotherapy and subsequently withdrawn from the treatment, the rate of antibodies to adalimumab after retreatment was similar to the rate observed prior to withdrawal. Other Adverse Reactions The data described below reflect exposure to HUMIRA in 2468 patients, including 2073 exposed for 6 months, 1497 exposed for greater than one year and 1380 in adequate and well-controlled studies (Studies RA-I, RA-II, RA-III, and RA-IV). HUMIRA was studied primarily in placebo-controlled trials and in long-term follow up studies for up to 36 months duration. The population had a mean age of 54 years, 77% were female, 91% were Caucasian and had moderately to severely active rheumatoid arthritis. Most patients received 40 mg HUMIRA every other week. Table 1 summarizes reactions reported at a rate of at least 5% in patients treated with HUMIRA 40 mg every other week compared to placebo and with an incidence higher than placebo. In Study RA-III, the types and frequencies of adverse reactions in the second year open-label extension were similar to those observed in the one-year double-blind portion. Table 1. Adverse Reactions Reported by Ű5% of Patients Treated with HUMIRA During Placebo-Controlled Period of Rheumatoid Arthritis Studies b HUMIRA 40 mg subcutaneous Every Other Week b (N=705) Adverse Reaction (Preferred Term) b b bbRespiratory 17% bbbbbUpper respiratory infection bbbbbSinusitis 11% 7% bbbbbFlu syndrome Gastrointestinal b bbbbbNausea 9% 7% bbbbbAbdominal pain Laboratory Tests* b bbbbbLaboratory test abnormal 8% bbbbbHypercholesterolemia 6% bbbbbHyperlipidemia 7% bbbbbHematuria 5% bbbbbAlkaline phosphatase increased 5% Other b bbbbbHeadache 12% bbbbbRash 12% bbbbbAccidental injury 10% bbbbbInjection site reaction ** 8% bbbbbBack pain 6% bbbbbUrinary tract infection 8% bbbbbHypertension 5% * bLaboratory test abnormalities were reported as adverse reactions in European trials ** Does not include injection site erythema, itching, hemorrhage, pain or swelling

Placebo (N=690) b b 13% 9% 6% b 8% 4% b 7% 4% 5% 4% 3% b 8% 6% 8% 1% 4% 5% 3%

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

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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 Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening psoriasis (all sub-types including pustular and palmoplantar) Vascular disorders: Systemic vasculitis 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. Revised: December, 2011 Ref: 03-A569-R27 Abbott Laboratories North Chicago, IL 60064, U.S.A. 64C-757903 MASTER

64C-759105

LUPUS

Is Personalized Medicine... Continued from cover National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) scores ≥10, low complement levels, elevated antidsDNA levels, and steroid use. In addition to improvements in the SRI, belimumab was associated with a reduced risk of SLE flares, improved measures of health-related quality of life (HRQOL), and reduced use of steroids. Thus, belimumab, especially at 10 mg/kg, had greater therapeutic benefit than standard therapy in patients with higher disease activity at baseline. The approval of belimumab by the US Food and Drug Administration generated much excitement among the rheumatology community, although the excitement has been tempered by lack of specific guidance from initial studies about the optimal clinical scenarios in which to use belimumab. Now, there are data to provide guidance on when to use the drug in patients with SLE by suggesting that it may be most effective in improving disease activity when used to treat active SLE defined by high SELENA-SLEDAI

scores, low complement levels, high dsDNA, and corticosteroid use.

There are data to provide guidance on when to use the drug in patients with SLE by suggesting that it may be most effective in improving disease activity. Of note, the SRI as an outcome in SLE is somewhat controversial, because it was developed specifically for use in belimumab studies; as a result of its composite nature, it is not readily calculated in routine clinical settings. Despite this limitation, the improvements in flares, HR-QOL, and steroid use show that belimumab is leading to more readily identifiable improvements in SLE. Going forward, however, further studies will be needed to understand the role of this agent in specific manifestations of SLE, such as renal and neuropsychiatric disease, and in impacting the overall mortality rate. ■

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Mycophenolate Is Superior to Azathioprine for Lupus Maintenance Therapy For patients with lupus nephritis who have responded to induction therapy, mycophenolate mofetil (CellCept) is superior to azathioprine (Azasan) in maintaining a renal response to treatment and in preventing relapse, according to a recent study (Dooley MA, et al. N Engl J Med. 2011;365: 1886-1895). In a 36-month, randomized, double-blind, phase 3 study, a total of 227 patients were randomly assigned to maintenance treatment with mycophenolate mofetil (N = 116) or azathioprine (N = 111). With respect to primary end point, time to treatment failure (hazard ratio [HR], 0.44; 95% confidence interval, 0.25-0.77; P = .003), and to time to renal flare and time to rescue therapy (HR, <1.00; P <.05), mycophenolate mofetil was superior to azathioprine. Adverse events, which for the most part were minor infections and gastrointestinal disorders, occurred in

>95% of patients in both cohorts (P = .68). Serious adverse events were found in 33.3% of patients receiving azathioprine and in 23.5% of those patients receiving mycophenolate mofetil (P = .11).

For patients with lupus nephritis who have responded to induction therapy, mycophenolate mofetil is superior to azathioprine in maintaining a renal response to treatment and in preventing relapse. The withdrawal rate as a result of adverse events was higher with azathioprine than with mycophenolate mofetil (39.6% vs 25.2%, respectively; P = .02). ■

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Potential Molecular Biomarkers of Treatment Response in Rheumatoid Arthritis By Sy Schlager, MD, PhD

he effective use of biologic disease-modifying antirheumatic drugs (DMARDs) has dramatically improved the treatment of rheumatoid arthritis (RA) over recent years. However, for at least 33% of patients with RA, tumor necrosis factor (TNF) inhibitor therapy produces an inadequate clinical response. Indeed, responses to biologic agents vary across different patient populations, especially with respect to differences in duration and reversibility of disease. Many studies have shown that although TNF antagonists improve clinical signs and symptoms of RA in patients in whom conventional DMARDs had produced inadequate responses, the American College of Rheumatology (ACR) 20 response criteria (ACR20) for TNF inhibitors generally range from 20% to 40% response rates. Similarly, in those with an inadequate response to TNF inhibitors, the newer biologic agents can achieve ACR20 response rates at 24 weeks, ranging from 17% with golimumab (Simponi) to 40% with tocilizumab (Actemra). Moreover, only rituximab (Rituxan) has shown significant inhibition of progression of joint destruc-

at a glance â&#x17E;¤ The use of biologic DMARDs has dramatically improved the treatment of patients with RA â&#x17E;¤ Individualized plans are needed so each patient can receive optimal treatment, while avoiding unnecessary exposure to toxic side effects and the costs of ineffective agents â&#x17E;¤ Genetic markers may predict a patientâ&#x20AC;&#x2122;s response to RA treatment â&#x17E;¤ Identifying the most suitable predictive biomarkers has the potential to reduce healthcare costs and improve outcomes â&#x17E;¤ Several lines of evidence support the diagnostic and prognostic use of autoantibodies in the pathogenesis of RA, but current data are inconclusive regarding their use

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tion in this highly refractory population. These differences in response rates among the same class of biologic agents, and the fact that not all patients with RA respond to biologics, indicate the heterogeneity of patients and the disease. Thus, an individualized approach to the management of RA is needed so that each patient can receive optimal treatment, while avoiding unnecessary exposure to potentially toxic side effects and the costs of a biologic agent that may not be effective for that patient. A recently published review (Emery P, et al. Ann Rheum Dis. 2011;70:20632070) examined the current evidence for markers with prognostic capabilities in RA and assessed their potential in predicting individual treatment responses to biologic agents and informing clinical practice. The markers that were examined included patient clinical characteristics, genetic markers, and protein molecular biomarkers. Several studies from patient registries have shown that high levels of disability at baseline and being a smoker are predictive of a poor response to TNF antagonists. Moreover, lower baseline Disease Activity Score in 28 joints, Health Assessment Questionnaire scores, and concurrent use of conventional DMARDs appear to be associated with improved TNF inhibitor responses. Age, sex, disease duration, and the previous number of DMARDs used were not predictive of TNF inhibitor response. It is unclear whether any of the baseline characteristics are useful as potential markers of response or simply represent prognostic indicators. The recognition that variation in response to treatment may be linked to genetic traits has led to the study of genetic markers as predictors of response to treatment. Such analyses provide a way of using genetics in a fully translational approach, from both a screening and therapeutic response perspective to informing clinical practice. Specifically, polymorphisms in genes encoding for TNFÎą, the major histocompatibility region, the p38 network, STAT4, PTPN22, PAD14, CTLA4, Traf1/C5, and FCđ?&#x203A;žRIIIA have all been the focus of a number of studies. In this regard, there is evidence of an association between single nucleotide polymorphisms at position 308 of the TNF promoter gene (TNF-308 geno-

type) and responsiveness to etanercept, infliximab, and adalimumab. The predictive and prognostic use of these data have yet to be clarified. Furthermore, there is evidence in patients with early RA that the presence of 2 HLA-DRB1 alleles encoding the shared epitope (SE) is associated with response to etanercept, and that an increased number of HLA-DRB1 SE copies is correlated with an improved clinical response to adalimumab.

An individualized approach to the management of RA is needed so that each patient can receive optimal treatment, while avoiding unnecessary exposure to potentially toxic side effects and the costs of a biologic agent that may not be effective for that patient. Although the SE motif is not considered a robust genetic marker for predicting response to TNF antagonists, it may be useful as a prognostic marker for RA. Other gene polymorphisms have also been studied for their value in predicting response to TNF antagonist therapy, but further properly powered studies are required to define the potential of the promising genetic markers. In addition, new methods to uncover genetic biomarkers need to be developed and studied. Preliminary proteomic studies to uncover protein molecular biomarkers that are predictive of response to TNF antagonists have shown that a combination of 24 biomarkers comprising autoantibodies and cytokines was associated with patients having a good response to etanercept, whereas 6 plasma biomarkers enabled the detection of patient responses to infliximab with high sensitivity and specificity. Similarly, apolipoprotein A-1 was predictive of a good response to infliximab, whereas the presence of platelet factor 4 was associated with no response. Other studies have shown that cytokine profiling, biomarkers involved in cartilage turnover and bone resorption, and levels of RANKL and the RANKL to osteoprotegerin ratio

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can be used to identify responders to TNF antagonists. In addition, clinical studies with golimumab have shown that multiple biomarkers associated with the TNF cellular signaling pathway may be predictive of response to therapy with this agent, including CRP, IL-6, MMP-3, ENRAGE, Îą 2 microglobulin, insulin, von Willebrand factor, leptin, apo CIII, and bone alkaline phosphatase levels. Similar studies with rituximab have shown that patients with a type 1 interferon low signature have significantly greater responses to this agent than those with a high signature. Autoantibodies play a key role in the pathogenesis of RA, and several lines of evidence support the diagnostic and prognostic use of these molecules. Unfortunately, the current data are inconclusive regarding the use of autoantibodies in predicting response to TNF inhibitors, abatacept (Orencia), rituximab, or tocilizumab. There has also been work to correlate the presence or depletion of B-cell subsets as a predictor of reduced response or early relapse, particularly after treatment with rituximab. Thus far, the data require further validation before they can be recommended for use in clinical practice. Although there is an increasing need for an individualized treatment strategy for patients with RA, which is guided by strong predictors of response to therapy, we are not quite there yet. Additional well-designed studies are required to confirm the predictive potential of the most promising genetic markers. Furthermore, to date, no robust protein biomarkers have been confirmed as predicting response to TNF inhibitors. Although rheumatoid factor and anticytoplasmic antibodies have yielded the most consistent data to suggest that seropositivity for these markers has the potential to predict response to rituximab in patients with RA, further research is needed to validate these data, to suggest the optimum order of treatment for seronegative patients, and to determine if similar strategies can be achieved with other biologic agents. Given the desire to achieve individualized treatment for patients with RA, research in this area is ongoing to identify the most suitable predictive biomarkers, which has the potential to reduce healthcare costs and to improve outcomes. â&#x2013;

www.ValueBasedRheumatology.com

Rheumatology Practice Management

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New Payment Models Will Emphasize... Physicians in private practice are experiencing financial pressures that make private practices increasingly difficult to sustain; as reimbursement is reduced, Medicare and Medicaid grow, health records go electronic, and other operating costs increase. Many physicians cannot compete with the rich recruitment packages being offered by hospitals. The end result is that new physicians are increasingly seeking hospital employment. FFS is still the dominant model for reimbursement for hospitals and physicians. This mode will continue for the next year or 2, said Dr Skea, but payment reform is reaching a stage of bundled payment for episodes of care and payment for higher value, in which providers can share in savings from better care coordination and disease management. “Care will no longer be acute care– centric; it is all about transitioning the patient, with the primary care physician as the quarterback,” as with a medical home, he stated. “It is about value, and that word is going to keep coming up over and over again. Value is the combination of quality and cost,” Dr Skea said. “There is bipartisan support for this concept.” The trend is toward downsizing. Significant consolidation in healthcare will occur, Dr Skea predicted, “whether its apposition of practices into mega-practices or large multispecialty practices, but also in the hospital industry as well. We will continue to see the downward spiral in the number of hospitals.” “What we will see are hospitals and physicians aligning in preparation for the future model of payment.

The two will be taking risk together,” Dr Skea added. Accountable Care Organizations On the horizon are the fully accountable care organizations (ACOs), under which systems of care assume responsibility for patients across providers and settings over time.

“Care will no longer be acute care–centric; it is all about transitioning the patient, with the primary care physician as the quarterback.” —Warren H. Skea, PhD, FAHA

“In the new model under an ACO, your hospital is not your revenue center, it is your cost center. That fundamental change scares a lot of hospital administrators and many people in the healthcare industry,” Dr Skea said. Ultimately, an ACO breaks down the silos that currently exist within the healthcare industry, and puts it under one umbrella, he said. This umbrella is designed to facilitate the transition of care and the communication of information to make care more seamless, thereby avoiding failures or disruptions that often occur with the handoff of patients between providers. Health information technology will be the backbone of the ACO model. Some of the low-hanging fruit is avoidance of emergency department visits for conditions that do not require emergent care, he said, because the

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responsibility for the entire episode of care will lie with the ACO. For Medicare ACOs, 2 different models of payment exist. The Pioneer model is more advanced, and is designed for healthcare organizations that already have experience in coordinating care for patients across care settings. The Medicare Shared Savings Program (MSSP) is a different entry point for ACOs, and is better suited for groups just getting started with care coordination. Shared-savings models work by sharing the savings derived from spending below benchmarks. Depending on the model, 50% to 70% of the savings can be assumed by the ACO. “The caveat is that you are not eligible for these shared savings if you do not meet the quality parameters first,” Dr Skea pointed out. “Under MSSP, you have to hit 70% of the parameters.” A separate tax identification number is required for an ACO to contract with Medicare. An ACO may consist of a hospital, a primary care group, a specialty group, and other providers such as home healthcare. Providers outside the ACO, such as mental health facilities, home health services, and rehabilitation services, may also be contractually obliged to an ACO with some shared risk. “The entities involved will be allowed to be somewhat fluid and dynamic in the sense that it is done at a grassroots level,” commented Dr Skea. After receiving 1300 public comments on the proposed ACO regulations, the Centers for Medicare & Medicaid Services responded with significant changes to make the program more attractive for prospective

at a glance ➤ The US healthcare payment system is shifting from a volume-based FFS model to a performance-based model, with clinicians assuming more risk ➤ “Value” is the combination of quality and cost, and there is bipartisan support for the concept in Washington, DC ➤ An ACO places healthcare under one umbrella, facilitating the transition of care and communication of information more seamless ➤ With some shared-savings models, 50% to 70% of the savings can be assumed by the ACO, but to be eligible the organization must meet quality parameters first ➤ The Centers for Medicare & Medicaid Services eliminated shared losses for the first 2 years for MSSP, with up to 50% sharing of savings

participants. The proposed rule established shared savings and losses, but the final rule eliminated shared losses for the first 2 years for an MSSP (with up to 50% sharing of savings). Under the Pioneer model, however, the ACO does take on risk, but also a higher level of shared savings. The number of reportable quality metrics has decreased from 65 under the proposed rule to 33 under the final rule. ■

Understanding Office of Inspector General Initiatives and How to Prepare Your Practice By Jennifer Kirschenbaum, Esq, and Erica Youngerman, Esq

nexpected and unwanted oversight is becoming a more frequent element of practice, making it imperative that you understand current investigation and audit initiatives, and how to prepare and protect your practice.

Understanding the Office of Inspector General The US Department of Health and Human Services (HHS) Office of Inspector General (OIG), which is

tasked with protecting the integrity of the HHS programs and operations by “detecting and preventing fraud, waste, and abuse; identifying opportunities to improve program economy, efficiency, and effectiveness; and holding accountable those who do not meet program requirements or who violate Federal laws,”1 has taken a leading role in such investigations and audits. OIG accomplishes its mandate by deploying its staff of approximately 1800 professionals throughout the

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United States to conduct audits, evaluations, and investigations, as well as coordinating and overseeing third parties conducting audit activities on OIG’s behalf.1 OIG investigates a wide variety of conduct,2 and may seek civil monetary penalties against any person who, for example: (i) presents or causes to be presented claims to a Federal health program that the person knows or should have known is for an item or service that was not provided as claimed or is false or fraudu-

lent3; (ii) violates the antikickback statute by knowingly or willfully paying or receiving remuneration for referrals of federal healthcare program beneficiaries4; or (iii) presents or causes to be presented a claim that person knows or should know is for a service which may not be made under the physician self-referral or Stark law.5 In the past several months, OIG has reported on the following activity: 1. On or around January 17, 2012, Continued on page 19

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Rheumatology Practice Management

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Understanding Office of Inspector General... Buchanan County Health Center in Iowa agreed to pay $406,030 for allegedly employing an individual that it knew or should have known was excluded from participating in federal healthcare programs, potentially violating the Civil Monetary Penalties Law.6 2. On or around November 30, 2011, as a result of a self-disclosure, Evergreen Health Center, PC, in Lebanon, MO, agreed to pay $83,012.58 for allegedly submitting claims for services not provided, potentially violating the Civil Monetary Penalties Law.6 3. On or around October 4, 2011, as a result of a self-disclosure, County of Monterey d/b/a Natividad Medical Center of California agreed to pay $174,508.46 for allegedly entering into a professional medical services agreement with a physician group for certain call coverage and clinic services where the compensation terms offered incentives for the physician group to refer private practice patients to the center, potentially violating the Civil Monetary Penalties Law.7 Available statistics show that as a result of OIG’s efforts during fiscal year (FY) 2010, OIG reported recovering: (i) $3.8 billion in investigation receivables that were court ordered or agreed to be paid through civil settlements; and (ii) $1.1 billion in audit receivables as a result of OIG audit disallowance recommendations.1 Because of the many fruits of OIG’s labor, OIG has increased its efforts since FY 2010 to increase recoveries by incorporating more sophisticated reviews and expanding the scope of its investigations. OIG Initiatives For many practices devoting their resources and attention to patient care, minimal time is spent reviewing operations and policies in a way that protects the practice against an OIG investigation or other audit initiative, which puts such practices at a severe disadvantage that is somewhat easily preventable. Certainly, some practices that are targeted by OIG or other authorities or payers are in the category of committing egregious wrong doing, whereas others have simply not taken the time to ensure that they are operating under the proper structure. Staying abreast of the changes to the numerous documentation requirements while also taking care of your patient population is not an easy task.

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There are, however, certain steps you may take to place yourself in a better position to limit exposure. Understanding the OIG Work Plan for Fiscal Year 2012 is one such step. OIG’s initiatives are not a secret; in fact, each October, OIG publishes its initiatives for the coming year. Reviewing the Work Plan and understanding where areas of exposure may exist in your practice is a somewhat simple first step to limiting exposure. Two examples of oncology-related initiatives are as follows: 1. Payments for off-label anticancer pharmaceuticals and biologicals: OIG states that it will focus a review on “Medicare payments for drugs and biologicals used on an off-label basis…in anticancer chemotherapeutic regimens to determine whether patients with particular indications were prescribed anticancer drugs approved by FDA for such indications before resorting to anticancer drugs not approved for those indications.”8 2. Medicare outpatient payments for drugs: OIG will review Medicare outpatient payments to providers for certain drugs and the administration of those drugs (eg, chemotherapy) to determine whether Medicare overpaid providers because of incorrect coding or overbilling of units.8 OIG explains that prior reviews have identified certain drugs, particularly chemotherapy drugs, as vulnerable to incorrect coding. OIG provides additional insight into the 2 aforementioned initiatives by stating that in calendar year 2007, Medicare payments for anticancer drugs totaled approximately $2.7 billion, which, as is readily apparent by OIG’s Work Plan, is more money than OIG believes was proper for reimbursement. Practices billing for anticancer drugs will be targeted this year, as specified in OIG’s Work Plan, and how those practices will be selected will likely be a result of data mining. The initiated investigations will focus on whether those targeted practices and providers accurately and completely billed for services provided, and also whether such providers have reported units of service as the number of times that a service or procedure was performed.8 For those practices targeted for prescribing offlabel drugs, OIG specified it will be looking to determine whether there were improvements in the patients’ medical condition before the use of off-label drugs.

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The OIG Work Plan states that “if the beneficiaries’ medical conditions improved before the use of off-label drugs, [OIG] will determine how much Medicare could have saved had the previously administered anticancer drugs continued to be used,”8 and presumably seek to recoup such amounts from the practice. OIG states as its authority to recoup such monies that “Medicare covers FDA-approved drugs used for off-label indications in anticancer chemotherapeutic regimens when such uses are supported in authoritative compendia identified by the Secretary of HHS.”8 Ramifications of Exposure When appropriate, OIG has the authority to impose civil monetary penalties assessments and administrative sanctions, as well as collaborating with the Department of Justice and other government executive branch agencies capable of bringing charges.1 OIG is authorized to seek different amounts of civil monetary penalties and assessments based on the type of violation at issue.1 For example, in a case of false or fraudulent claims, the OIG may seek a penalty of up to $10,000 for each item or service improperly claimed, and an assessment of up to 3 times the amount improperly claimed.9 In a kickback case, OIG may seek a penalty of up to $50,000 for each improper act and damages of up to 3 times the amount of remuneration at issue (regardless of whether some of the remuneration was for a lawful purpose).10 Protecting Your Practice Protecting your practice from an OIG investigation begins with preventive compliance. This entails ensuring that your practice is properly structured to comply with numerous rules and regulations, including the selfreferral laws. To place your practice in the best position possible, you should seek the advice of competent healthcare counsel to either structure your practice when it is created or to review your existing structure for compliance. In addition to proper structuring, your practice should adopt policies and procedures to govern how your practice operates, including the adoption of a compliance plan that details acceptable billing practices. Also, as part of your practice’s compliance, I strongly recommend working with an external coding and billing expert, brought in specifically to examine your practice and diagnose any areas of exposure. Although

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you may have a dynamic team in place handling the billing operations for your practice, having a review of your documentation and coding by an expert specializing in your practice area who has reviewed documentation and coding of many other practices and is familiar with billing requirements for your specialty will not only likely place you in a more protected position, but also potentially highlight areas where you may increase your accounts receivable. The bottom line with investigations such as OIG’s initiatives is that with electronic records and billing, oversight has dramatically changed and it is now much easier to target practices potentially overutilizing, upcoding, or abusing the reimbursement system. Those practices continuing with “business as usual,” and ignoring the warning signs that it is time to adapt and modify as the oversight has, will likely have a much greater chance of being targeted.l ■ References 1. US Department of Health & Human Services, Office of Inspector General Work Plan: Fiscal Year 2012. Introductory message from the Office of Inspector General. http://oig.hhs.gov/reports-andpublications/archives/workplan/2012/WP00Intro.pdf. Accessed March 6, 2012. 2. 42 CFR § 1003.102. 3. 42 U.S.C. § 1320a-7a(a)(1)(A) and (B). 4. 42 U.S.C. § 1320a-7b(b); 42 U.S.C. § 1320a-7a(a)(7). 5. 42 U.S.C. § 1395nn(g)(3). 6. US Department of Health & Human Services, Office of Inspector General. False and fraudulent claims. http://oig.hhs.gov/fraud/enforcement/cmp/false_ claims.asp. Accessed March 6, 2012. 7. US Department of Health & Human Services, Office of Inspector General. Kickback and physician selfreferral. http://oig.hhs.gov/fraud/enforcement/cmp/ kickback.asp. Accessed March 6, 2012. 8. US Department of Health & Human Services, Office of Inspector General Work Plan: Fiscal Year 2012 Part I: Medicare Part A and Part B. http://oig.hhs. gov/reports-and-publications/archives/workplan/ 2012/WP01-Mcare_A+B.pdf. Accessed March 6, 2012. 9. 42 CFR § 1003.103. 10. 42 U.S.C. § 1320a-7a.

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 ways to protect your practice, she can be reached at 516-747-6700 x302 or by email at Jennifer@kirschenbaumesq.com. For more information about Kirschenbaum & Kirschenbaum’s healthcare practice, visit www.nyhealthcareattorneys.com.

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Juvenile Idiopathic Arthritis

Early Aggressive Therapy Effective in... centage of patients with inactive disease and clinical remission. The study was presented at the 2011 Annual Meeting of the American College of Rheumatology (ACR). Approximately 300,000 children in the United States are currently diagnosed with JIA. Polyarticular JIA, the most severe form of JIA, carries the burden of severe associated morbidity. “This is the first randomized, double-blind clinical trial using inactive disease and remission as the main outcomes. This study sets a new standard for treatment, response, and outcomes for children with polyarticular JIA. Achieving 70% improvement by 4 months and inactive disease by 6 months are achievable goals. One of the most remarkable findings was the importance of early treatment. There does appear to be a window of opportunity for JIA as there is for rheumatoid arthritis,” stated lead author Carol Wallace, MD, Professor of Pediatric Rheumatology at Children’s Hospital and Regional Medical Center, and the University of Washington School of Medicine, Seattle. TREAT was a multicenter, prospective, double-blind, placebo-controlled trial conducted in 15 centers; 85 chil-

dren with polyarticular JIA were randomized to methotrexate (Trexall, Rheumatrex), etanercept (Enbrel),

“This study sets a new standard for treatment, response, and outcomes for children with polyarticular JIA.” —Carol Wallace, MD plus prednisolone (MEP arm, giving a biologic upfront) or methotrexate, etanercept placebo, and prednisolone placebo (MTX arm) for up to 12 months. At enrollment, median age was 11.1 years and median disease duration was 4.1 months. At 4 months, patients who achieved at least a 70% response as assessed by the ACR pediatric 70 were continued on their blinded treatment; those who did not reach this end point were given open-label MEP. At 6 months, patients who reached the primary end point of clinically inactive disease

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were continued on their treatment. Patients who did not achieve clinically inactive disease at 6 months received unblinded etanercept and prednisone in addition to methotrexate until 12 months. At 4 months, ACR pediatric 70 was achieved in 30 of the 42 patients (71%) in the MEP arm versus 19 of the 43 patients (44%) in the MTX arm. At 6 months, clinically inactive disease was achieved in 17 of the 42 patients (40%) in the MEP arm versus 10 of the 43 patients (23%) randomized to MTX. According to Dr Wallace, the definition of clinically inactive disease used in this study had stringent criteria that included no affected joints, no symptoms, no eye involvement, normal sedimentation rate, and physician’s global assessment of no active arthritis. “Nearly one third of patients overall achieved clinical inactive disease by 6 months of therapy, which is remarkable,” she stated. The strongest predictor of achieving clinically inactive disease at 6 months was disease duration. The odds of achieving clinically inactive disease increased by 30% for each month earlier that treatment was initiated after

the onset of symptoms (P = .011). Patients in both arms of the study showed significant improvement at 6 months on physicians’ global assessments of disease activity, parents’ global assessments of well-being, number of joints with arthritis, and number of joints with limited motion. At 12 months, clinical remission (defined as 6 months of inactive disease on medication at 12 months) was achieved in 21% of those in the MEP arm versus 7% of those randomized to the MTX arm. The frequency of grade 3 or higher adverse events was similar in both arms of the study. In a separate interview, Stacy Ardoin, MD, Assistant Professor, Division of Rheumatology and Immunology, at Ohio State University Medical Center in Columbus, said that not all children with JIA should have early aggressive treatment, but that the study is reassuring regarding safety and disease control with this approach. “We need more data on optimal therapy for JIA. It is not clear [yet] whether it is best to initiate treatment with less-intensive therapy and then add biologics, or to start with our strongest therapies,” she said. ■

Factors Identified for Improved Response to Treatment for Juvenile Idiopathic Arthritis By Phoebe Starr Chicago, IL—An excellent response to etanercept (Enbrel) in patients with juvenile idiopathic arthritis (JIA) was significantly associated with younger age and less disability at disease onset, as well as less use of antirheumatic drugs before initiating etanercept. A poor response was significantly associated with onset of systemic JIA and with female sex. The results from an observational study by Marieke H. Otten, MD, MSc, of the Department of Pediatrics/ Pediatric Rheumatology, Erasmus Medical Center Sophia Children’s Hospital, Rotterdam, the Netherlands, and colleagues will be useful for selecting patients with JIA who are likely to respond to etanercept and for avoiding use of this expensive drug in patients unlikely to benefit from receiving it. The use of disease-modifying antirheumatic drugs (DMARDs) earlier in the course of disease has improved outcomes in patients with JIA. “A treatment goal of reaching inactive disease

now seems realistic. However, inactive disease is still not achieved in a substantial number of patients, and current approaches need to be optimized even more,” said Dr Otten, lead author of the study. The study was published online (Otten MH, et al. JAMA. 2011; 306: 2340-2347) to coincide with its presentation at the 2011 American College of Rheumatology meeting. Although etanercept has been approved in Europe and the United States for approximately a decade, no studies have explored predictors of response in children. The study was based on the Arthritis and Biologicals in Children Register that includes all patients with JIA in the Netherlands who are currently or were previously receiving treatment with biologic agents since 1999, when biologics were first introduced. The study population included 262 patients with JIA who were previously biologically naïve when they initiated treatment with

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etanercept. Of the participants, 71% were female, the median age at JIA onset was 6.9 years, and the median age at the start of etanercept was 12.4 years; 46 (18%) patients had systemiconset JIA, and the median age at initiation of etanercept was 12.4 years.

“A treatment goal of reaching inactive disease now seems realistic.” —Marieke H. Otten, MD, MSc Responses evaluated at 15 months were categorized as excellent, intermediate, and poor. An excellent response (defined as inactive disease or discontinuation as a result of disease remission) was observed in 85 patients (32%). An intermediate response (defined as >50% improvement from baseline but no evidence of inactive disease) was seen in 92 patients (46%). A poor response (defined as <50% improve-

ment from baseline or discontinuation because of ineffectiveness or intolerance) was seen in 85 patients (32%). During the first 15 months of the study, 1 or more adverse events (AEs) were reported in 119 patients, including infectious, noninfectious, and serious AEs. AEs were reported in 37 patients with an excellent response, 36 patients with an intermediate response, and 46 patients with a poor response. A secondary analysis was performed in 262 patients with a median follow-up of 35.6 months after initiation of etanercept. Over a period of 4 to 7 years, 37% to 49% of patients achieved inactive disease. Only 39 patients (15%) tried to discontinue etanercept (of which 15 relapsed and needed to restart etanercept). There were no head-to-head comparisons with other DMARDs, so it is not known whether patients with a suboptimal response could have had a better response to another agent, Dr Otten stated. ■

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Drug Therapy

TNF Inhibitors Associated with Increased Risk of Nonmelanoma Skin Cancer but Not Lymphoma By Rosemary Frei, MSc

meta-analysis of studies of malignancies associated with tumor necrosis factor (TNF) inhibitors indicates the drugs are associated with a 45% increased risk for developing a nonmelanoma skin cancer but not with a significantly increased risk for lymphoma (Mariette X, et al. Ann Rheum Dis. 2011;70:18951904). The combined studies comprise more than 40,000 patients and almost 150,000 patient-years of exposure to TNF inhibitors. “This analysis brings together the latest information on malignancy associated with rheumatoid arthritis [RA] among people taking TNF inhibitors,” commented Edward Keystone, MD, FRCP, a senior consultant in rheumatology at Mount Sinai Hospital, and Professor of Medicine, University of Toronto, Ontario. “And it shows that while nonmelanoma skin cancer is increased, solid malignancies are not. These agents have become the mainstay of treatment in people who fail methotrexate, and their benefits outweigh the risks, but clinicians should be aware of the fact that nonmelanoma skin cancer can occur.” The European team that undertook the meta-analysis analyzed 21 papers and 8 abstracts published or presented since 1998 that included data on malignancies among people with RA receiving TNF inhibitors. The investigators determined that the relative risk for malignancy was not increased in

patients receiving TNF inhibitors compared with controls treated with disease-modifying antirheumatic drugs (DMARDs), even among those taking TNF inhibitors for a long duration. By analyzing the data of 3 rheumatology-related databases, the investigators found that the relative risk of

risk of nonmelanoma skin cancer,” stated lead investigator Xavier Mariette, MD, and colleagues. They note that their results contrast with those from 2 meta-analyses that show an odds ratio of 3.3 for developing malignancies among patients with RA being treated with infliximab,

“These agents have become the mainstay of treatment in people who fail methotrexate, and their benefits outweigh the risks, but clinicians should be aware of the fact that nonmelanoma skin cancer can occur.” —Edward Keystone, MD, FRCP

melanoma was not significantly elevated with TNF inhibitor therapy (1.79; 95% confidence interval [CI], 0.92-2.67). The relative risk of lymphoma also was not significantly elevated in people with RA receiving TNF inhibitors compared with those receiving classic DMARDs (1.11; 95% CI, 0.70-1.51). However, the standardized incidence ratio for lymphoma in people taking TNF inhibitors was significantly elevated, at 2.55 (95% CI, 1.93-3.17), compared with people without RA in the general population. “This meta-analysis provides clear evidence that treatment with TNF [inhibitors] results in a 45% increased

adalimumab, or etanercept (Bongartz T, et al. JAMA. 2006;295:2275-2285; Bongartz T, et al. Ann Rheum Dis. 2009; 68:1177-1183). However, the investigators state that possible differences in exposure to the interventions and comparators were not taken into account, and that the increased risk occurred only among people taking higher doses of TNF inhibitors. These findings follow another recent meta-analysis that showed a 2-fold increased risk for nonmelanoma skin cancer but not for other cancers with the use of TNF inhibitors in patients with RA (Askling J, et al. Pharmacoepidemiol Drug Saf. 2011;20:119-130).

at a glance ➤ TNF inhibitors are associated with a 45% increased risk for nonmelanoma skin cancer but not for lymphoma ➤ The relative risks of melanoma and lymphoma were not significantly elevated with TNF inhibitors compared with DMARDs, even in those taking TNF inhibitors for a long duration ➤ Another recent meta-analysis showed a 2-fold increased risk for nonmelanoma skin cancer but not for other cancers with the use of TNF inhibitors in patients with RA ➤ Additional studies are needed to solidify the evidence base, especially for individual malignancies “This systematic review and metaanalysis provides reassurance to physicians and patients that the treatment of RA patients with TNF inhibitors does not increase the risk of malignancy, particularly lymphoma,” the authors concluded. “However, it does appear to increase the risk of skin cancer, including melanoma.” They encourage researchers to publish additional studies to add to the solidity of the evidence base, particularly for individual malignancies. ■

TNF Inhibitors Are Not Linked to Serious Infection Risk By Wayne Kuznar Chicago, IL—Patients who initiate treatment with tumor necrosis factor (TNF) inhibitors for autoimmune diseases are not as likely to develop serious infections as those who start treatment with nonbiologic drugs, according to a study presented at the 2011 American College of Rheumatology meeting. In a retrospective cohort study comparing TNF inhibitors with nonbiologic therapies, Carlos G. Grijalva, MD, MPH, Assistant Professor of Preventive Medicine, Division of Pharmacoepidemiology, Vanderbilt University, Nashville, TN, and colleagues found the rate of serious infections to be approximately 8 per 100 personyears with each type of treatment. Most previous safety studies of

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TNF inhibitors had small sample sizes, short follow-up periods, and grouped TNF inhibitors in a single category. The investigators used a multi-institution collaboration of 4 large databases (Kaiser Permanente Northern California, New Jersey and Pennsylvania Pharmaceutical Assistance programs, Tennessee Medicaid, and national Medicare/Medicaid), together known as the Safety Assessment of Biologic Therapies (SABER), to assemble cohorts of patients with rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriatic arthritis, and matched controls for each group. The databases were examined for the incidence of hospitalization for

serious infections. The sample included 10,484 comparator pairs with RA, 2323 pairs with IBD, and 3215 pairs with psoriasis and spondyloarthropathies. A propensity score matching analysis was used to control for potential confounders. Follow-up lasted for a maximum of 1 year. A total of 1172 infections that required hospitalization occurred between 1998 and 2007, with 53% being pneumonia or skin and softtissue infections. Among patients with RA who started treatment with a TNF inhibitor, the rate of serious infection requiring hospitalizations was 8.16 per 100 personyears, which was not significantly different from the rate of 7.78 per 100

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person-years among patients with RA who started therapy with a regimen of a nonbiologic disease-modifying antirheumatic drug. Differences in the rates of hospitalization for serious infections emerged between the TNF inhibitors. Among the patients with RA, the rate of serious infection with infliximab (Remicade) was 26% higher than for etanercept (Enbrel) and 23% higher than for adalimumab (Humira), commented Dr Grijalva. Among patients with RA, baseline use of corticosteroids was associated with a dose-dependent increase in risk for infections, ranging from a 32% increase in risk with baseline dosages Continued on page 22

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Fibromyalgia

Fibromyalgia: New Insights into a Complex Syndrome By Sy Schlager, MD, PhD

lthough completely misunderstood and often maligned, fibromyalgia (FM) is a functional somatic syndrome estimated to affect 2% to 4% of the population, with a female to male incidence ratio of approximately 4:1. Onset is typically between the ages of 20 and 60 years, with a mean age of 49 years. The puzzling symptoms of FM may include any number of signs and symptoms— chronic (>3 months) and widespread or localized pain and allodynia, hyperesthesia, fatigue, sleep disturbance, joint stiffness, difficulty swallowing, functional bowel abnormalities (especially irritable bowel syndrome), numbness, tingling, cognitive dysfunction, depression, anxiety, and comorbid rheumatologic conditions. Affected patients report increased difficulty with activities of daily living, including walking and climbing stairs. FM has a profound impact on the affected patient’s quality of life. It can interfere with the ability to work, thereby resulting in loss of productivity, and it can result in emotional problems. FM is a controversial diagnosis that lacks scientific consensus. The diagnostic criteria for FM were first released in 1990 and are currently being updated by the American College of Rheumatology (ACR); they include evaluation of the major clinical symptoms and a focus on chronic widespread pain with at least 11 of 18 predefined tender points throughout the musculoskeletal system. However, recent studies emphasize the degree and number of somatic symptoms rather than tender points as indicators. The ACR preliminary diagnostic criteria use the Widespread Pain Index and the Symptom Severity

Scale, which both have a score range of 0 to 12; scores of >6 on either scale are considered diagnostic of FM. There is significant debate regarding the value of clinical and radiologic workup of these patients, especially because FM is primarily a diagnosis of exclusion. If

FM is a functional somatic syndrome estimated to affect 2% to 4% of the population, with a femaleto-male incidence ratio of approximately 4:1. FM is suspected, autonomic dysfunction questionnaires and the Fibromyalgia Impact Questionnaire may aid in diagnosing it and monitoring patients’ responses to therapy. Recent research on scientific and clinical hypotheses for the pathophysiology and etiology of FM include: • Genetic predisposition • External triggers, such as psychological stress trauma or infection • Disruption of normal dopaminerelated neurotransmission • Abnormal serotonin metabolism • Deficient growth hormone secretion • Psychological factors, such as major depression • Autonomic dysfunction • Aberrant immune response to intestinal bacteria. Optimal, value-based approaches to FM therapies are also the subject of intense debate. For example, there is the question of the appropriate healthcare provider to manage patients with FM—is it the rheumatologist, neurologist, psychiatrist, or primary care physician?

Currently the US Food and Drug Administration (FDA)-approved pharmacologic approaches to managing FM include pregabalin (Lyrica), duloxetine (Cymbalta), and milnacipran (Savella). The comparative safety and efficacy of these 3 agents have been studied in 17 randomized controlled trials involving a total of 7739 patients with FM. All 3 drugs were found to be superior to placebo for fatigue, with milnacipran and pregabalin being superior to duloxetine. Improvements in sleep disturbance were found only with milnacipran, and only pregabalin was found to be superior to placebo in treating depressed mood. In terms of pain management, all 3 agents were associated with an approximate 30% reduction in pain, with no significant differences among them. This suggests that drug choice should primarily be symptom-based. Other therapies, including aerobic exercise, hydrotherapy, and multicomponent therapy, should be offered as adjunctive therapy.

There is significant debate regarding the value of clinical and radiologic workup of these patients, especially because FM is primarily a diagnosis of exclusion. There are also anecdotal data on non–FDA-approved medications, including tricyclic antidepressants, tramadol (Ultram), opioids, and combination therapies (eg, trazodone [Desyrel] plus pregabalin), each of which is

at a glance ➤ FM is a functional somatic syndrome estimated to affect 2% to 4% of the population, with a female-to-male incidence ratio of approximately 4:1 ➤ FM is generally misunderstood and is primarily a diagnosis of exclusion ➤ With numerous and varying symptoms, FM greatly affects quality of life and activities of daily living ➤ The approaches to the treatment of FM include pharmacologic and nonpharmacologic options, with drug choice largely based on symptoms

associated with specific cautions regarding their use (eg, some opioids may worsen symptoms of FM). Nonpharmacologic approaches to treatment have also been studied, including cognitive behavioral therapy (eg, mindfulness-based stress reduction) and complementary and alternative medicine therapies, including meditative movement therapy, massage therapy, acupuncture, and traditional Chinese medicine. There is ongoing active research regarding FM to further our understanding of the disease, including use of functional magnetic resonance imaging, investigation of opioid receptors in the brain, and somatic analyses. Further study will be required before these efforts impact clinical practice. ■

TNF Inhibitors... Continued from page 21 <5 mg daily to nearly triple the risk with dosages >10 mg daily. “The findings were consistent across diseases,” said Dr Grijalva. Among patients with psoriasis or spondyloarthropathy, the risk of infections was higher for patients receiving glucocorticoid doses of 5 to 10 mg daily (hazard ratio [HR] 2.01; 95% confidence interval [CI], 1.083.73) and >10 mg daily (HR 2.77; 95% CI, 1.44-5.32) compared with no glucocorticoid use. The data provide reassurance for patients and providers that TNF

Differences in the rates of hospitalization for serious infections emerged between the TNF inhibitors. Among the patients with RA, the rate of serious infection with infliximab was 26% higher than for etanercept and 23% higher than for adalimumab. —Carlos G. Grijalva, MD, MPH inhibitors did not increase the risk of serious infections when compared

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with other nonbiologic treatments, Dr Grijalva said.

In an editorial that accompanied the publication of the study (Grijalva CD, et al. JAMA. 2011;306:2331-2339), Will Dixon, PhD, of the University of Manchester, England, and David T. Felson, MD, MPH, of Boston University School of Medicine, wrote, “These intriguing findings need replication in other studies. Nevertheless, the report by Dr Grijalva et al raises important questions about the comparative safety of immunosuppressant and biologic therapy and may prompt a reevaluation of antiTNF safety.” ■

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