vbcr may vol 1, no 2

www.ValueBasedRheumatology.com

MAY 2012 VOL 1• NO 2Value-Based

Care inRheumatologyFROM THE PUBLISHERS OF AMERICAN HEALTH & DRUG BENEFITS®

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Trends in RA Management: A Survey of Health Plans andRheumatologists By Rhonda Greenapple, MSPHPresident, Reimbursement Intelligence, Madison, NJ

Is Personalized MedicinePossible in Lupus?By Sy Schlager, MD, PhD

© Engage Healthcare Communications, LLC

Belimumab (Benlysta) has recent-ly been approved in the UnitedStates for the treatment of sys-

temic lupus erythematosus (SLE),with a specific indication for use inadult patients with active, autoanti-body-positive disease who are cur-rently receiving standard therapies.However, the optimal use of this agentin SLE has not been well defined.

In a recent study (van VollenhovenRF, et al. Ann Rheum Dis. 2012 Apr 5)pooled data from 2 randomized,placebo-controlled clinical trials of1684 patients with SLE (all antinu-clear antibody– or anti-dsDNA–posi-tive) were used to evaluate the factorsthat predict response to belimumab

therapy. All patients were treated withstandard therapies, including steroids,hydroxychloroquine, and/or immuno -suppressive agents, in conjunctionwith belimumab or placebo. The pri-mary outcome was improvement inthe SLE Responder Index (SRI), acomposite measure of disease activi-ty developed for use in clinical trialsof belimumab.

In univariate analysis and analysisof patients grouped according to dis-ease activity, predictors of an im -proved SRI at week 52 in response tobelimu mab included high diseaseactivity at baseline defined by SafetyOf Estrogens In Lupus Erythematosus

New oral therapies, such asJanus kinase (JAK) inhibitorsand spleen tyrosine kinase

inhibitors, will be challenged to breakthe grip on the market held by the

leading large-molecule therapies inthe treatment of rheumatoid arthritis(RA). Based on the results of the 2012Rheumatology Reimbursement Report,health plans and rheumatologistsagree that the pricing of promisinginvestigational oral agents for RAnow in the pipeline will very likelydrive the placement of these drugs inthe sequencing of therapeutic choices.

In other words, small-moleculedrug manufacturers should not con-sider their market entrants to be in aclass of their own. Instead, the neworal therapies (when and if approved)will be compared with currently pre-scribed biologic therapies before

Early Aggressive TherapyEffective in PolyarticularJuvenile Idiopathic ArthritisBy Phoebe Starr

Chicago, IL—Similar to adults, earlyaggressive treatment with a biologictherapy in children with polyarticularjuvenile idiopathic arthritis (JIA) isbeneficial in achieving remission, asdemonstrated in the double-blind,randomized Trial of Early Aggressive

Therapy in Juvenile Idiopathic Arthri -tis (TREAT in JIA), which is one ofthe few studies to focus on childrenwith JIA. Early aggressive treatmentimproved the signs and symptoms ofpolyarticular JIA, as well as the per-

VALUE PROPOSITIONS . . . . . . . . . . .4NIH awards $10.5 million for the study of molecular genes

RA MANAGEMENT . . . . . . . . . . . . . . . .5A methotrexate-first strategy can be successful

LUPUS . . . . . . . . . . . . . . . . . . . . . . . . . . .16Mycophenolate superior to azathioprine for lupus maintenance

PERSONALIZED MEDICINE inRheumatology™ . . . 17

Potential new molecular biomarkers

Rheumatology PRACTICEMANAGEMENT™ . . . . . . . . . . . . . . . .18Understanding Office of InspectorGeneral and how to prepare yourpractice

JUVENILE IDIOPATHIC ARTHRITIS . . . . . . . . . . . . . . . . . . . . . .20Factors for improved response identified

FIBROMYALGIA . . . . . . . . . . . . . . . . .22New insights into this complex syndrome

I N S I D E

Continued on page 16

Continued on page 9


New Payment Models WillEmphasize Value and SharedSavings/RisksFrom fee-for-service to performance-based reimbursementBy Wayne Kuznar

Chicago, IL—The US healthcare andpayment delivery model is in transi-tion toward shifting from a volume-based fee-for-service (FFS) model to aperformance-based model, with clini-cians assuming more risk.

Better stewardship of the dollar willbe critically important through thistransition, with reimbursement mov-

ing ultimately to a global payment,according to Warren H. Skea, PhD,FAHA, Director, Pricewaterhouse -Coopers’ Health Industries AdvisoryPractice, at the 2011 meeting of theAmerican College of Rheumatology.

“The new reimbursement model willbe population-based,” Dr Skea said.


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3VOL. 1 I NO. 2 MAY 2012 I www.ValueBasedRheumatology.com

In This Issue

PublisherNicholas [email protected]

Associate PublisherMaurice [email protected]

Editorial DirectorDalia [email protected]

Associate EditorLara J. [email protected]

Editorial AssistantJennifer [email protected]

Sales AssistantZach Ceretelle

Senior Production ManagerLynn Hamilton

Quality Control Director Barbara Marino

Business ManagerBlanche Marchitto

Mission StatementValue-Based Care in Rheumatology provides a forum forpayers, providers, and the entire rheumatology teamto consider the cost-value issues particular to rheuma-tology treatments. This unique focus is achievedthrough news coverage from major rheumatologymeetings and the rheumatic diseases literature, sup-plemented with commentaries and perspectives fromthose involved in evaluating therapies, treatingpatients, and paying for care.

Contact Information:For subscription information please contact: Telephone: 732-992-1538 Fax: 732-992-1881

Permission requests to reprint all or part of any articlepublished in this magazine should be addressed to [email protected].

Address all editorial queries to: [email protected]: 732-992-1536 Fax: 732-992-1881

Value-Based Care in Rheumatology, ISSN applied, ispublished 6 times a year by Engage Healthcare Com -munications, LLC, 241 Forsgate Drive, Suite 205A,Monroe Township, NJ 08831. Copyright © 2012 byEngage Healthcare Communications, LLC. Allrights reserved. Value-Based Care in Rheumatology isa registered trademark of Engage Health careCommuni cations, LLC. No part of this publicationmay be reproduced or transmitted in any form or byany means now or hereafter known, electronic ormechanical, including photocopy, recording, or anyinformational storage and retrieval system, withoutwritten permission from the publisher. Printed inthe United States of America.

The ideas and opinions expressed in Value-BasedCare in Rheumatology do not necessarily reflect thoseof the editorial board, the editors, or the publisher.Publication of an advertisement or other productmentioned in Value-Based Care in Rheumatologyshould not be construed as an endorsement of theproduct or the manufacturer’s claims. Readers areencouraged to contact the manufacturers about anyfeatures or limitations of products mentioned.Neither the editors nor the publisher assume anyresponsibility for any injury and/or damage to per-sons or property arising out of or related to any useof the material mentioned in this publication.Postmaster: Correspondence regarding subscriptionsor change of address should be directed to CIRCULA-TION DIRECTOR, Value-Based Care in Rheumatology,241 Forsgate Drive, Suite 205A, Monroe Township,NJ 08831. Fax: 732-992-1881. Yearly subscriptionrates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3years: $199.00 USD.

VBCR Advisory Editorial Board

RA MANAGEMENTAre you prepared for the 2012 changes in RAmanagement?A methotrexate-first strategy can be successful Half-dose etanercept as effective as full-dose inmoderately active RAMore….

GOUTRilonacept investigated for the prevention ofacute gout flares

LUPUSMycophenolate superior to azathioprine forlupus maintenance

PERSONALIZED MEDICINE inRheumatology™

Potential molecular biomarkers to assess treatment response in RA

More….

Rheumatology PRACTICEMANAGEMENT™

Understanding Office of Inspector General andhow to prepare your practiceMore….

JUVENILE IDIOPATHIC ARTHRITISFactors for improved response identifiedMore….

DRUG THERAPYTNF inhibitors associated with increased riskof nonmelanoma skin cancerMore….

FIBROMYALGIANew insights into this complex syndrome

Value-Based CareinRheumatology

FROM THE PUBLISHERS OF AMERICAN HEALTH & DRUG BENEFITS®

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Muhammad Asim Khan, MDProfessor of MedicineCase Western Reserve UniversityCleveland, OH

Randall Krakauer, MD, FACP,FACRNational Medical DirectorMedicare, AetnaPrinceton, NJ

Alan Menter, MDDirectorBaylor Psoriasis Research CenterDallas, TX

Matthew Mitchell, PharmD, MBA Manager, Pharmacy ServicesSelectHealthMurray, UT

Lynn Nishida, RPhDirector, Clinical Pharmacy ServicesRegenceRXPortland, OR

Gary M. Owens, MDPresidentGary Owens AssociatesPhiladelphia, PA

Kim A. Papp, MD, PhDFounder and PresidentProbity Medical ResearchWaterloo, Ontario, Canada

Edmund J. Pezalla, MD, MPHNational Medical Director forPharmacy Policy and StrategyAetnaHartford, CT

Ronald van Vollenhoven, MD, PhDAssociate ProfessorKarlinska University Hospital SolnaStockholm, Sweden

F. Randy Vogenberg, RPh, PhDPrincipalInstitute of Integrated HealthcareSharon, MA

Editor-in-ChiefSy Schlager, MD, PhDPresident & Chief Medical OfficerTherapeutic Window, LLC Southlake, TX

Scott Breidbart, MD Chief Medical OfficerEmpire BlueCross BlueShieldNew York, NY

Gary L. Johnson, MD, MS, MBARegional Medical DirectorHumana, Inc.Madison, WI

Atheer A. Kaddis, PharmDVice President, Managed MarketsDiplomat Specialty PharmacySwartz Creek, MI

James T. Kenney, RPh, MBA Pharmacy Operations ManagerHarvard Pilgrim Health CareWellesley, MA

CORRECTIONSIn the April 2012 issue of Value-Based Care in

Rheumatology, the article titled “RheumatologyRoundup Corrals Most Salient Studies Presented at2011 ACR/ARH” provided several citations fromJohn J. Cush, MD, and Arthur F. Kavanaugh, MD,from their oral presentations at the meeting. DrCush and Dr Kavanaugh did not review nor approveof this report before publication. We apologize forany potential misrepresentation contained in thisreport, and for using their photos without theirpermission.

In the April 2012 issue, Dr Max Hamburger wasincorrectly cited as being affiliated with theInternational Rheumatology Network. We apologizefor the error.

4 VALUE-BASED CARE IN RHEUMATOLOGY I MAY 2012 VOL. 1 I NO. 2

Six Practical Ways to Monitor RA Disease ActivityTight control of rheumatoid arthritis (RA) disease activity is emerging

as the new standard of care, and the Rheumatoid Arthritis DiseaseActivity Measures Working Group (RADAM-WG) of the AmericanCollege of Rheuma tology (ACR) now recommends 6 disease activity

measures for use in routine clinical practice. The rec-ommendations were coauthored by Jaclyn Anderson,DO, MS, Medical Director at Abbott Labora tories,Abbott Park, IL.

After a systematic review of the literature and appli-cation of exclusion criteria and ratings by communityrheumatologists, the RADAM-WG recommends theClinical Disease Activity Index, the Disease Activity

Score with 28-joint counts (with either the erythrocyte sedimentation rateor C-reactive protein), the Patient Activity Scale (PAS), PAS-II, RoutineAssessment of Patient Index Data with 3 measures, and the SimplifiedDisease Activity Index. These 6 instruments were recommended becausethey:• 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 recommendationsfor the treatment of RA, thereby reducing costs and optimizing patient care.

Anderson J, et al. Arthritis Care Res. 2012;64:640-647.

NIH Awards $10.5 Million to New Technologiesfor the Study of Molecular Genes

The National Human Genome Research Institute (NHGRI), part of theNational Institutes of Health (NIH), has awarded $10.5 million to 10researchers to develop technologies that will assist research on millions ofgenomic elements that play a role in determining what genes areexpressed, and at what levels in different cells. This has particular impli-cations for cancer therapies.

These multiyear grants are part of the Encyclopedia of DNA Elements(ENCODE) project, which promotes research on the role that the humangenome plays in health and disease.

“The ENCODE project is providing a Rosetta Stone to understand howthe sequence of the human genome forms the words that tell our bodieshow 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 understandhow variation in the DNA sequence might influence diseases such as can-cer and autoimmune disorders,” said Mike Pazin, PhD, Program Directorfor ENCODE in NHGRI’s Division of Extramural Research.

NIH News, April 25, 2012.

New Recommendations for Pain Associatedwith Inflammatory Arthritis

Inflammatory arthritis is characterized by pain, stiffness, loss of function,and impaired quality of life. For patients with inflammatory arthritis, painmanagement is an important aspect of their care. The 3e Initiative(Evidence, Expertise, Exchange) is focused on evidence-based care inrheumatology by providing practical recommendations to enhance thevalue of pain management in patients with inflammatory arthritis.

The 3e Initiative report cites 11 evidence-based recommendations for drugtherapy to manage pain in patients with inflammatory arthritis, as well as anew treatment algorithm for clinical use. The recommendations include:• Routine measurement of pain using the visual analog scale, numerical

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 avoidedunless in exceptional cases

• Adding a drug with a different mode of action if acetaminophen or non-steroidal 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 ofaspirin, ≥650 mg daily)

• Acetaminophen as first choice for pain relief in patients with gastroin-testinal comorbidities, but only cautious use of nonselective NSAIDs incombination with proton-pump inhibitors (PPIs) or cyclooxygenase(COX)-2 selective inhibitors with PPIs

• Acetaminophen as first choice for pain relief in patients with preexistinghypertension, or cardiovascular or renal disease, and only cautious useof NSAIDs, including COX-2 selective inhibitors. Whittle SL, et al. Rheumatology (Oxford). 2012 March 24.

RA Treatment Lags Behind ACR RecommendationsBecause RA is a chronic, disabling disease that if not properly treated can

result in increased direct and indirect costs to the healthcare system, failureto adhere to evidence-based guidelines may negatively impact the value

proposition in providing care to these patients.Leslie R. Harrold, MD, MPH, Associate Professor,

Depart ment of Medicine, University of MassachusettsMedical School, and colleagues report in a recent articlethat treatment for RA in the United States did not changeat all after publication of guidelines from the ACR inDecember 2008.

According to the Consortium of Rheumatology Re -searchers of North America registry, more than 50% of patients with RAwho have moderate-to-severe disease still do not receive care consistentwith the ACR guidelines, mostly because they are undertreated. Forexample, after 1 visit, only 24% to 37% of biologic-naïve patients receiv-ing methotrexate (Rheumatrex) mono therapy who had moderate or highdisease activity and a poor prognosis received care consistent with theACR recommendations; after 2 visits, 34% to 56% of patients receivedcare consistent with the ACR recommendations.

The percentages were not significantly different for those patients receiv-ing multiple nonbiologic disease-modifying antirheumatic drugs. Potentialreasons for these results include the following:• The inability of rheumatologists to prospectively use objective meas-

ures of disease activity, calculated with one of several disease assess-ment instruments that are applicable to office-based practices (eg,Clinical Disease Activity Index, Routine Assessment of Patient IndexData, global arthritis score), and thus are unable to properly capturedisease activity status

• “Clinical inertia,” which is defined as the failure to accelerate treatmentfor patients with uncontrolled, chronic diseases

• A lack of clinician awareness of the ACR treatment guidelines, althoughthey were published in a prominent rheumatology journal, are availableon the ACR website, and were highlighted in a plenary session at theACR 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.

Value Propositions


Chicago, IL—The development ofbiomarkers as tools for the measure-ment of disease activity to predictdisease progression and response tocertain therapies and the investiga-tion of new classes of agents for thetreatment of rheumatoid arthritis(RA) are 2 major advances in themanagement of patients with RA.

Among the novel biomarkers usedto assess patients with RA is a groupof antibodies to modified citrulline-containing auto antigens, which arevariations of the anticyclic citrullinat-ed peptides that are routinely usedtoday. These new markers include amutated citrullinated vimentin (MCV),a modified form of MCV (modMCV),a salinized form of MCV, and anti-modified vimentin.

Personalized MedicineA study by Ljung and colleagues

that was presented at the 2011American College of Rheumatology(ACR) meeting demonstrated thatpositive anti-MCV or anti-modMCVantibodies predicted a poor responseto tumor necrosis factor (TNF) antag-onists in patients with RA.

These data may presage the dawn

of an era of personalized medicine inrheumatology, where selection oftherapeutic agents for individualpatients is based on the presence ofcertain biomarkers. This is especiallyimportant in providing value-basedcare, because of the high cost associ-ated with the biologic agents used totreat patients with RA.

Vectra DAAs presented in an abstract by

Allaart and colleagues at the 2011 ACRmeeting, the recent launch of VectraDA, a multibiomarker disease activity(MBDA) algorithm that combines 12serum biomarkers of inflammatoryactivity, is an advance in followingdisease progression over time in pa -tients with RA.

This MBDA measures levels ofcytokines and cytokine receptors,adhesion molecules, growth factors,matrix metalloproteinases, skeletal-related proteins, hormones, and acute-phase proteins—which have all beenshown to reflect the diverse biologydriving RA—and combines the resultsof the testing into a single score. Whenthis MBDA was applied to patientswho had been enrolled in theBehandel Strategieën (BeSt) study, itwas found to be best correlated withchanges in Sharp scores, suggestingthat these biomarkers may be a usefultool in gauging a patient’s risk forradiographic progression and func-tional disability over time. Moreover,the efficacy of therapy can be objec-tively assessed over time using theMBDA instead of repeated radio -graphic studies.

Small Oral MoleculesRheumatology is now entering a

new phase of development of unique

classes of small organic molecules forthe treatment of RA, including Januskinase (JAK) inhibitors, spleen tyro-sine kinase (SyK) inhibitors, as well asphosphodiesterase (eg, PDE-4) andother kinase inhibitors (eg, BTK, PI3K,and TKI). Among the oral JAK in -hibitors, tofacitinib has been the mostextensively studied.

Tofacitinib and fostamatinibIn a series of phase 3 clinical studies,

tofacitinib 10 mg was shown to signif-icantly reduce the signs and symp-toms of RA (ACR 20 response rates),reduce radiographic progression ofstructural damage as measured bymean change from baseline in modi-fied Total Sharp Scores, improve phys-ical function (Health AssessmentQuestionnaire Disability Index), andreduce disease activity (DiseaseActivity Score in Rheumatoid Arthritis<2.6) in patients with an inadequateresponse to methotrexate (MTX) orTNF inhibitors.

Onset of activity was observed with-in 2 weeks of therapy with tofacitiniband efficacy persisted through follow-up periods ranging from 3 to 6 months.

Adverse eventsAn important issue with both tofaci-

tinib and fostamatinib, a SyK inhibitor,is their safety profiles. Adverse events(AEs) associated with tofacitinib in -clude serious infections, neutropenia,significant increases in low-densitylipoprotein cholesterol, and increasesin serum creatinine levels. AEs associ-ated with fostamatinib included

hypertension requiring antihyperten-sive medication, diarrhea, infections,and elevations in liver enzymes.

How would these new oral com-

pounds fit into a management algo-rithm in patients with RA? Mostrheumatologists start a patient who isnewly diagnosed with RA on MTXand then move to a TNF antagonist ifMTX alone is ineffective.

Failure or intolerance on this regi-men could prompt switching to a sec-ond TNF antagonist, switching to abiologic with a different mechanism ofaction (eg, abatacept, rituximab), orswitching to one of the oral JAK orSyK inhibitors. This final decision maywell depend on an individual patient’spreference for oral therapy rather thanan injectable or infusible therapy, andthe cost of these new agents, which hasyet to be determined.

All of these developments are sig-nificantly altering and complicatingthe management of patients with RA,and they signal a move toward value-based, personalized care. �

Changes in the Management of Rheumatoid Arthritis:Are You Prepared for 2012?By Sy Schlager, MD, PhD

RA Management

� 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

at a glance

Rheumatology is nowentering a new phase ofdevelopment of uniqueclasses of small organicmolecules for the treatmentof RA, including JAKinhibitors, SyK inhibitors, aswell as phosphodiesterase (eg, PDE-4) and other kinase inhibitors (eg, BTK,PI3K, and TKI).

The US Food and Drug Admin -istration (FDA) Arthritis AdvisoryCommittee voted 8 to 2 to recom-mend approval of Pfizer’s tofaci-tinib for the treatment of moderatelyto severely active rheumatoid arthri-tis (RA). If approved by the FDA,tofacitinib would be the first oralagent available for patients with RA,and would be dosed as 5 mg or 10mg twice daily.

The 2 major concerns expressedby the panel with respect to tofaci-tinib were:• Whether it is effective in halting

radiographically detected progres-sion of joint damage• Regarding the drug’s safety pro-file, which includes treatment dura-tion– and dose-dependent increasesin the rates of malignancy and seri-ous infections, and significantincreases in serum lipid and choles-terol levels.

For these reasons, the panelseemed to prefer approval of the 5-mg dose, because it appears to be aseffective as the 10-mg dose and itmay be associated with feweradverse events. (May 9, 2012) �

FDA Panel Recommends Approval of Tofacitinib

All of these developmentsare significantly altering andcomplicating themanagement of patientswith RA, and they signal amove toward value-based,personalized care.


RA Management

Chicago, IL—The number of total hipreplacement (THR) and total kneereplacement (TKR) surgeries hasdeclined among patients with a pri-mary diagnosis of rheumatoid arth -ritis (RA) since the introduction ofbiologic agents.

“This consistent and significant find-ing suggests that the availability of bio-logic agents, as well as other changes inthe therapeutic approach to RA, mayconfer long-term benefits to both RApatients and healthcare systems,” con-cluded Neeta Tandon of JanssenScientific Affairs, LLC, Hor sham, PA,on a retrospective analysis of a largedatabase of hospital inpatient stays,presented at the 2011 meeting of theAmerican College of Rheumatology.

The researchers analyzed patienthospital discharge data between 1993and 2008 using the NationwideInpatient Sample (NIS) of the Health -care Cost and Utilization Project. TheNIS contains discharge data frommore than 1000 US hospitals from1988 to 2009, allowing analysis oftrends over time.

To capture the trends for THR andTKR, data were compared betweenpatients with RA before and after theintroduction of infliximab (Remicade)in 1999, adalimumab (Humira) in 2002,and etanercept (Enbrel) in 1998, and topatients without a diagnosis of RA.

A coding algorithm was used toidentify the 1.7 million patients hav-ing THR or TKR procedures, 58,036 of

whom had a diagnosis of RA.The number of annual THR surger-

ies more than doubled between 1993

and 2008—from 25,987 to 56,478—whereas, the number of annual TKRprocedures more than tripled—from38,136 to 125,881—during this period.

The number of THR and TKR sur-geries increased for patients with RAas a secondary diagnosis and forpatients with no indication of RA.During the same time, the number ofTHR and TKR procedures forpatients with a primary diagnosis ofRA was decreasing.

Patients with RA as a primary or asecondary diagnosis had a significant28% decrease (P <.01) in the likeli-hood of RA being the primary reasonfor undergoing THR or a TKR proce-dure after the time that biologicagents were introduced.—WK �

After Biologics Are Introduced, Hip and Knee ReplacementProcedures Decline for Primary Diagnosis of Rheumatoid Arthritis

“The availabilityof biologicagents, as wellas otherchanges in the

therapeutic approach to RA,may confer long-termbenefits to both RA patientsand healthcare systems.” —Neeta Tandon

Chicago, IL—More than 25% ofpatients with rheumatoid arthritis(RA) who are started on methotrexate(Trexall, Rheumatrex) alone achieveclinical remission at week 24, and theremission is durable out to 2 years,said James R. O’Dell, MD, Professorof Internal Medicine, Divi sion ofRheuma tology, University of NebraskaMedical Center, Omaha, at the 2011meeting of the American College ofRheumatology.

In the Treatment of Early Ag gressiveRA (TEAR) trial, 755 patients wererandomized to 1 of 4 treatment arms.One arm received methotrexate andetaner cept (Enbrel) from the outset, anda second arm was assigned to metho -trexate, sulfasalazine (Azulfidine),and hydroxy chloroquine (Plaquenil;triple therapy) from the outset. In theother 2 arms, patients were initiatedon methotrexate alone and steppedup to either etanercept or triple ther-apy at week 24 if they could notachieve a Disease Activity Score in 28joints (DAS28) of ≤3.2 on methotrex-ate monotherapy.

To be included, patients had to haveactive, poor-prognosis RA, which isdefined as rheumatoid factor–positivedisease or anticyclic citrullinated pep-tide–positive disease, or the presence

of at least 2 erosions. Disease durationhad to be <3 years and only limited

prior exposure to disease-modify -ing antirheumatic drug therapy wasallowed. Oral prednisone was permit-ted at ≤10 mg/day.

The mean disease duration was 3.6months, and patients’ mean DAS28at baseline was 5.8. Patients in themethotrexate monotherapy arm haddose escalation (from a starting dose of10 mg) to 15 mg and to 20 mg at weeks6 and 12, respectively, if they had asingle tender or swollen joint at eithertime point.

In the primary analysis, at 24weeks, patients assigned to combina-tion treatment had clinically superiorresponses on DAS28, but the differ-ence was lost by 36 weeks after non -responders stepped up to double ortriple therapy.

Radiographic outcomes between the4 treatment arms from treatment initia-tion to week 102 were nearly identical.“There was no radiographic penalty forwaiting to make the decision clinically[to step up after initial methotrexatetherapy],” said Dr O’Dell.

In the group assigned to methotrex-ate monotherapy, 72% had a DAS28>3.2 and stepped up to either etaner-cept or sulfasalazine/hydroxychloro-quine, whereas 28% had low diseaseactivity (DAS28 ≤3.2) and remained

on methotrexate monotherapy.Patients who stepped up had sig-

nificantly more tender and swollenjoints and a higher mean DAS28score than those who did not requirestep-up therapy.

Of patients receiving methotrexatealone, 28% achieved DAS28 remissionat week 24, and these respondersmaintained a durable response to 2years. Of patients receiving methotrex-ate alone, 57% achieved a meaningfulclinical response, which was definedas a DAS28 improvement of at least1.2 points by week 24.

There was an immediate advantageto using all drugs together when meas-uring the outcome (DAS28 remission)at 24 weeks, “but if you measure out-come between 1 and 2 years, there is noadvantage clinically to doing that, andyou should make the decision to stepup to these other therapies based onclinical outcome,” he said.

“The methotrexate responders donot progress radiographically at 2years,” he said. Mean radiographic pro -gression in radiographic Sharp scoresover 2 years was 0.15 in those stayingon methotrexate alone compared with1.22 in those who received step-uptherapy and 1.01 in those assigned toimmediate double or triple therapy. �

A Methotrexate-First Strategy Can Be Successful in Rheumatoid ArthritisBy Wayne Kuznar

There was an immediateadvantage to using all drugstogether when measuringDAS28 remission at 24weeks, “but if you measureoutcome between 1 and 2years, there is no advantageclinically, and you shouldmake the decision to step upto these other therapiesbased on clinical outcome.”

—James R. O’Dell, MD


ACR Revises Advice onDMARDs, Biologics, andSwitching Therapies

An American College of Rheu -matology (ACR) working group hasreported the 2012 ACR updates to the2008 ACR recommendations on theuse of disease-modifying anti rheu -matic drugs (DMARDs) and biologicagents in patients with rheumatoidarthritis (RA; Singh JA, et al. ArthritisCare Res. 2012;64:625-639).

In an accompanying editorial (DaikhDI, et al. Arthritis Care Res. 2012;64:648-651), David I. Daikh, MD, PhD,and E. William St. Clair, MD, write,“A rigorous, standardized approachthat includes a comprehensive, criticalreview of the literature is essential.This update of ACR RA treatmentrecommendations uses such anapproach, reflecting the importanceand value that is placed on qualityand validity in the development of allACR guidelines and recommenda-tions. The authors are also to be con-gratulated on their efforts to makethese recommendations relevant formany patients with RA and to addressfrequent decision points that will beapplicable in most clinical settings.”

The working group developed 4major changes from the 2008 ACRrecommendations:• The recommendations cover 3

additional biologics (certolizumab[Cimzia], tocilizumab [Actemra],and golimumab [Simponi]) inaddition to adalimumab (Humira),etanercept (Enbrel), infliximab(Remicade), abatacept (Orencia),and rituximab (Rituxan)

• For the first time, the recommen -dations address the question ofswitching between drugs (both con-ventional DMARDs and biologics)

• New recommendations regardingthe use of 2 new vaccines (one forherpes zoster to prevent shinglesand one for human papillomavirusto prevent cervical cancer), as wellas vaccines for pneumococcal dis-ease, influenza, and hepatitis, forpatients with RA

• A novel treatment target of no dis-ease activity or remission in bothpatients with early RA and thosewith established RA.

Glucocorticoids MayIncrease Suicide Risk

Systemic glucocorticoid use mayincrease the risk for suicidal behaviorand neuropsychiatric disorders suchas depression, mania, delirium, andpanic disorder, according to a largestudy from the United Kingdom thatincluded data from 1990 through 2008(Fardet L, et al. Am J Psychiatry. 2012;

169:491-497). The study included datafrom almost 372,700 adult patients ina primary care setting.

Compared with equivalent patientswho were not receiving cortico steroids,the hazard ratio (HR) for corticosteroid-exposed patients for suicide or suicideattempt was 6.89 (95% confidence inter-val [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 neuropsy-chiatric disorders and those treatedwith higher dosages of oral glucocor-ticoids had an increased risk of neu-ropsychiatric outcomes. Although older

male patients had an increased riskfor delirium and mania, youngerpatients had an increased risk of sui-cide for suicide attempt.

Early monitoring can be facilitatedby the education of patients and theirfamilies about these adverse eventsand through increasing physicians’awareness about their occurrence. �

In The Literature

CALL FOR PAPERS

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Trends in Biologic Therapies for RA

91

www.AHDBon

line.com l Ameri

can Health & D

rug Benefits l

Vol 5, No 2 l Ma

rch/April 2012

Biologic Therapies for Rheumatoid Arthritis: It’s All about Value

Value has been de

fined as the relat

ionship between

benefits and cos

ts. Using mathe

matical concepts

,

value has been d

escribed as “valu

e = benefits/cost”

or

the units of ben

efit derived from

a given number

of

units of costs. A

pplying this defi

nition, if we wis

h to

maximize the val

ue of a therapy, th

ere are only 2 wa

ys

to achieve it:

either by increa

sing the benefit

s

obtained from th

e therapy, or by

decreasing the co

st

paid for that the

rapy.

Value in healthca

re is also a functio

n of perspective.

What may be co

nsidered valuabl

e to an individu

al

patient undergoi

ng treatment or

to a physician p

re-

scribing that trea

tment to a simila

r group of patien

ts

may not necessar

ily be considered

valuable to the sa

me

extent by a payer

, who must not on

ly pay for that in

di-

vidual’s treatmen

t but who also h

as to manage th

e

needs of multipl

e groups of patie

nts and/or memb

ers

with equally com

pelling medical co

nditions and prio

r-

ities. Optimizing

value within the

healthcare syste

m

means that physic

ians and payers m

ust be aligned in

the way they vie

w the various ben

efits and costs of

a

given treatment.

Achieving such op

timization is whe

re the article by

Ms Greenapple in

this issue of American Health & Drug

Benefits fits in. In h

er article, Ms Gr

eenapple shows

that providers and

payers, at least wh

en it comes to the

use of biologics fo

r the treatment of

rheumatoid arthr

i-

tis, have much m

ore in common th

an not when look

-

ing at value with

in this drug class

. The findings fro

m

this survey have

several importa

nt implications

to

providers, payers

, and patients/pla

n members.

PROVIDERS: Providers can

practice more

autonomously in

addressing the ne

eds of the patien

t

with rheumatoid

arthritis. They c

an do this by foll

ow-

ing evidence-bas

ed guidelines as

they initiate tre

at-

ment with diseas

e-modifying antir

heumatic drugs,

and

only progress to

more costly biol

ogic therapies w

hen

they need to imp

rove treatment be

nefits, thereby op

ti-

mizing the value

of treatment. S

uch staged mana

ge-

ment is aligned w

ith payer coverag

e policies.

PAYERS: For payers, this

issue is a matter o

f expec-

tation. Knowing t

hat providers pra

ctice using the sam

e

specialty guidelin

es that payers foll

ow will allow pay

ers

to expect that th

eir contracted pr

oviders will “do th

e

right thing” whe

n it comes to pr

omoting evidenc

e-

based medicine

when treating pa

tients with rheu

ma-

toid arthritis.

PATIENTS/PLAN MEMBERS: When provide

r

practice is aligne

d with plan polic

y, patients or pla

n

members are the

ultimate winners

. As is described

in

this article, with

84% of provider

s reporting appro

val

rates of at least 61

% of requests for

rheumatoid arthr

itis

biologics (and 55

% reporting appro

vals of at least 81

%

of such requests)

, patients who n

eed more intens

ive

treatment for the

ir arthritis can re

ceive it in a mo

re

timely and coordi

nated manner.

MEDICAL DIRECTORS: Does this mean

that

payers should sto

p enforcing step

therapies or oth

er

such strategies? R

egretfully, not ye

t; complete buy-

in

to evidence-ba

sed medicine

has not yet be

en

achieved, and we

continue to see

treatment irregula

r-

ities for certain d

isease states. Per

haps one day soo

n,

with the advance

ment of meaning

ful use parameter

s

by providers, alo

ng with electron

ic medical record

s

and decision su

pport systems p

romoting eviden

ce-

based medicine, w

e will be able to g

et there. After al

l,

reaching such a

goal for rheumat

oid arthritis, or

any

other significan

t condition, w

ould not only

be

admirable, but m

ore important, it

would provide gre

at

value in healthc

are.

Albert Tzeel, MD, MHSA, FACPE

National Medica

l Director, Human

aOne

Milwaukee, WI

STAKEHOLDER PERSPECTIVE

Continued

BUSINESS

83

www.AHDBonline.com l American Health & Drug Benefits l

Vol 5, No 2 l March/April 2012

R heumatoid arthritis (RA) is a chronic systemic

autoimmune disorder and the most common form

of inflammatory arthritis.1 RA affects 1% of the

population, most often adults aged 40 to 70 years.2

Recent epidemiologic data indicate that the incidence of

RA in women has risen in the past 10 years.3 Because RA

affects many individuals who are of working age and

remains a major cause of disability, the economic burden

of RA adds a significant cost not only to patients and

their families, but also to society as a whole.1,4 In addi-

tion, reduced quality of life, loss of work productivity,

and substantial healthcare utilization are factors that

must be considered in RA management.4,5

Because complications of RA may begin to develop

within months of disease onset, early and aggressive

treatment is considered clinically necessary to manage

immediate symptoms of pain associated with inflamma-

tion, but also to slow disease progression to prevent long-

term disability.1,6,7 Historically, estimates of work disabili-

Ms Greenapple is President, Reimbursement Intelligence,

LLC, Madison, NJ.

Trends in Biologic Therapies forRheumatoid Arthritis: Results from a

Survey of Payers and Providers

Rhonda Greenapple, MSPHBackground: Advances in therapies for rheumatoid arthritis (RA), particularly biologics,

have transformed the treatment paradigm for RA. However, the associated costs of these

therapies result in a significant economic burden on the healthcare system. As a chronic

disease requiring lifelong treatment, most health plans now position RA drugs as a high-

priority therapeutic category.Objective: To identify provider and payer practices and perceptions regarding coverage

of RA biologics in the current marketplace, as well as emerging trends in reimbursement

practices.Method: In November 2011, Reimbursement Intelligence, a healthcare research company,

collected and analyzed quantitative and qualitative data via parallel-structure online surveys

of 100 rheumatologists and 50 health plan payers (medical and pharmacy directors) who

represent more than 80 million covered lives. The surveys included approximately 150 ques-

tions, and the surveys were designed to force a response for each question.

Results: Payers reported using tier placement, prior authorization, and contracting in

determining coverage strategies for RA biologics. Among providers, experience with older

RA agents remains the key driver for the choice of a biologic agent. A majority of payers

and providers (68% and 54%, respectively) reported that they did not anticipate a change

in the way their plans would manage biologics over the next 2 to 4 years. Payers’ re -

sponses indicated uncertainty about how therapeutic positioning of newer, small-molecule

drugs at price parity to biologics would affect the current reimbursement landscape.

Survey responses show that approval of an indication for early treatment of RA is not likely

to change the prescribing and reimbursement landscape for RA biologics. This survey fur-

ther shows that payers and providers are generally aligned in terms of perceptions of cur-

rent and future treatments for RA. Conclusion: Advances in RA therapies allow patients increasing options for effective dis-

ease management. However, the high cost of biologic therapies and the need for lifelong

treatment raise economic concerns. Payer satisfaction with current therapies and uncer-

tainty about added value of new therapies will create challenges for new medications

coming to market. Am Health Drug Benefits.2012;5(2):83-92www.AHDBonline.com

Disclosures are at end of text

Stakeholder Perspective,page 91

EDITORIAL

A New BeginningDavid B. Nash, MD, MBA

BUSINESS

Trends in Biologic Therapies for Rheumatoid Arthritis: Results from a Survey of Payers and ProvidersRhonda Greenapple, MSPH

Stakeholder Perspective by Albert Tzeel, MD, MHSA, FACPE

Impact of the Removal of the Monthly Liver Function Test Requirement for AmbrisentanLouise A. Durst, RN; John Carlsen, MHA; Megan Kuchinski, MPH; Lauren Harner, JD; Daniel Neves, BA; Stephanie J. Harris, RN, BSN; Glenna L. Traiger, RN, MSN, CNS-BC

Stakeholder Perspective by James T. Kenney, Jr, RPh, MBA

CLINICAL

Benefits of Novel Oral Anticoagulant Agents for Thromboprophylaxis after Total Hip or Knee ArthroplastyRichard J. Friedman, MD, FRCSC

Stakeholder Perspective by Atheer A. Kaddis, PharmD

™

©2012 Engage Healthcare Communications, LLCwww.AHDBonline.com

MARCH/APRIL 2012 VOLUME 5, NUMBER 2

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS


Screening for JC Polyomavirus Not Yet Useful in RheumaticPatients Treated with RituximabBy Wayne Kuznar

Chicago, IL—Routine screening forreplicating JC polyomavirus (JCPyV)or serum antibodies does not seem tobe warranted in rheumatic patientstreated with rituximab (Rituxan).

JCPyV is a DNA virus that causesprogressive multifocal leukoencep h -alopathy (PML), which is a demyeli-nating disease of the brain. Rituximabtreatment has been identified as a riskfactor for the development of PMLcaused by JCPyV infection, and thisrisk has been quantified at approxi-mately 1 of 30,000. (Natalizumabtreatment is also a risk factor with therisk quantified at 1.5 of 1000.)Reactiva tion of persistent JCPyVinfection is thought to be responsiblefor the development of PML.

In a study conducted by Jens Ver -heyen, MD, National Reference Centerfor Papilloma and Polyoma Viruses,Institute of Virology, Uni versity ofCologne, Germany, and colleagues,patterns of JCPyV infections were scru-tinized in 65 patients with rheumaticdiseases, all of whom were treatedwith at least 1 cycle of rituximab. No

patient showed any neurologic symp-toms during the course of the study.

Blood samples were analyzed forJCPyV in all patients, and antibodiesfor JCPyV were analyzed in the urinein a subset. Samples were taken beforeand after at least 1 cycle of rituximabin 21 patients (baseline group); in 44patients, all samples were collectedduring ongoing treatment (rituximabtreatment group).

In the baseline group, JCPyV DNAwas detected in 33% of samples. In therituximab treatment group, 43% ofurine samples were positive at thebeginning, and only 1 switch fromnegative to positive occurred duringthe observation period. These percent-ages are similar to those in healthy

individuals tested for the prevalenceof JCPyV in the urine in previousstudies when adjusted for the olderage of patients in this current analysis,noted Dr Verheyen.

Therefore, “rituximab treatment didnot seem to influence the shedding ofJCPyV in the urine of patients withrheumatic disease,” Dr Verheyen said.

Using a JCPyV assay, JCPyV anti-bodies in the blood were detected in79.6% of 54 patients tested. “Inter -estingly, the amount of antibodiesdetected was significantly higher inpatients shedding JCPyV in the urine,”he said. By comparison, using the sameassay, the prevalence of JCPyV anti-bodies in healthy individuals aged 50to 70 years is 43% to 68%, respectively,based on reports in the literature,which suggest that treatment with rit-uximab did not significantly influencethe detection rates of JCPyV antibodiesin patients with rheumatic diseases.

“Even though we analyzed multi-ple blood samples, we were only ableto detect JCPyV DNA in the bloodsamples of 2 [of 65] patients [3%]; in

1 patient, we were able to analyzeanother blood sample, and this wasnegative 1 month later,” Dr Verheyenpointed out. In patients treated withnatalizumab, the rate of JCPyV in theblood has ranged from 0.3% to 63%,and the rate of transient viremia hasbeen 2% to 7%.

At the moment, high- and low-riskgroups cannot be sufficiently distin-guished through the use of screeningfor JCPyV in patients treated with ri -tuximab, concluded Dr Verheyen. �

“Interestingly, the amountof antibodies detected wassignificantly higher inpatients shedding JCPyV inthe urine.” —Jens Verheyen, MD

Editor’s Note: In January 2012,the Food and Drug Administration(FDA) approved the first test forassessing the risk of multifocalleukoencephalopathy in patientstreated with natalizumab. TheStratify JCV Antibody ELISA testscreens for the presence of antibod-ies to JCPyV. According to theFDA, a total of 201 cases of PMLhave been reported amongapproximately 96,582 patientstreated with natalizumab throughJanuary 4, 2012.

RA Management

Chicago, IL—After achieving lowdisease activity (LDA) while receiv-ing full-dose induction etanercept(Enbrel) therapy at 36 weeks, patientswith moderately active rheumatoidarthritis (RA) can be maintained onhalf-dose etanercept instead of full-dose etanercept for a further 52weeks, according to the Study Com -paring Etanercept in Combination withMetho trexate in Subjects with Rheuma -toid Arthritis (PRESERVE), which waspresented as a late-breaking poster atthe 2011 meeting of the AmericanCollege of Rheumatology (ACR).

“This is the first randomized trialfor adults with moderately active RA,despite methotrexate treatment evalu-ating both induction of DAS28(Disease Activity Score 28) LDA andclinical, functional, and radiographicoutcomes with etanercept full-dosecontinuation, reduction, or elimina-tion on a background of methotrex-ate,” said lead author, Josef Smolen,MD, Chairman of the Department ofRheumatology, Medical University ofVienna, Austria. Both etanercept regi-

mens were significantly superior aftera 9-month induction of LDA com-pared with a step down to placebo. DrSmolen said that more research isneeded on the longer-term implica-

tions of these observations at 52weeks, and it is not clear if this obser-vation with etanercept can be general-ized to other biologic therapies.

Commenting on the cost implica-tions of this study, Eric M. Ruderman,MD, Professor of RheumatologyMedicine at Northwestern University

Feinberg School of Medicine inChicago, IL, said that “although thefindings are off label, doctors can reas-sure patients with moderately activeRA that half doses of etanercept willwork as well as full doses oncepatients have achieved LDA.”

“This is one of the first studies tolook at this, and it has huge cost impli-cations. A course of full-dose etaner-cept costs about $26,000 per year,”stated Dr Ruderman.

The study enrolled 604 patients withmoderately active RA who achievedLDA as shown by DAS28 or remissionon full-dose etanercept (50 mg) plusmethotrexate at 36 weeks and thenentered into a double-blind phase.Patients were randomized to 3 differ-ent arms for 52 weeks of treatment:etanercept 50 mg once weekly plusmethotrexate (n = 202), etanercept 25mg once weekly plus methotrexate(n = 202), or placebo plus methotrex-ate (n = 200) for 52 weeks.

Of the 497 patients who completedthe study, both etanercept groupswere superior to the placebo/metho -

trexate group. LDA was maintained in82.6% of the higher-dose etanerceptgroup and 79.1% in the half-dose etan-ercept group versus 42.6% of theplacebo group (P <.0001 vs eitheretanercept group). A significantlygreater percentage of patients had aDAS28 score of <2.6 at week 88 inboth etanercept dosing groups (66.7%for the higher dose and 60.2% for half-dose etanercept) versus placebo/methotrexate (29.4%; P <.0001 vseither etanercept group).

Both etanercept regimens were supe-rior to placebo plus methotrexate onother measures of disease activity andhealth, including the simplified diseaseactivity index; ACR criteria for at least a20%, 50%, or 70% improvement (ACR20/50/70); and a Health AssessmentQuestionnaire score of ≤0.5.

Safety was comparable between the3 treatment arms. Serious adverseevents were reported in 35 patients(5.8%), including 2 deaths (0.3%) inthe higher-dose etanercept group as aresult of pulmonary embolism andsepticemia. �

Half-Dose Etanercept as Effective as Full-Dose Etanerceptin Patients with Moderately Active Rheumatoid Arthritis By Phoebe Starr

“Although the findings areoff label, doctors canreassure patients withmoderately active RA thathalf doses of etanercept will work as well as fulldoses once they haveachieved LDA.”

—Eric M. Ruderman, MD


Trends in RA Management... Continued from cover

RA Management

assuming a prominent—or even com-parable—position in relation to theinjectable agents that now dominatethe market, such as adalimumab(Humira), infliximab (Remicade), andetanercept (Enbrel).

The Rheumatology Report provideskey answers to these questions. Afterthe American College of Rheu ma tology(ACR) conference in Chicago, IL, inNovember 2011, Reimburse ment Intel-ligence surveyed 50 pharmacy andmedical directors representing leadingnational and regional health plans, aswell as 100 rheumatologists involved inpatient care. The survey results revealkey trends in payer and providerapproaches to RA management.

Rheumatoid Arthritis DrivingSpecialty Drug Costs

Increasing attention to the manage-ment of RA by health plans andproviders is well warranted in the cur-rent environment, considering thatRA is currently the top therapeuticcategory in terms of its contribution tospecialty drug trends.

According to the Medco 2011 DrugTrend Report, RA therapies (and otherimmune disorder medications) in 2011contributed 29.4% to specialty drugs,ahead of multiple sclerosis (MS; 24.2%)and cancer (20.3%).1

RA agents also led all clinical cate-gories in terms of contribution to thetotal health plan specialty pharmacycosts at 27.2%, again followed by MSand cancer drugs (20.8% and 17.2%,respectively).1

This should not be surprising, giventhat approximately 1.3 million peoplein the United States suffer from RA,which is nearly 1% of the US adultpopulation.2 The impact of RA onpatients is significant, according to a2011 report from the American Auto -immune Related Dis eases Association3:• The estimated average earnings of

patients with RA can be reduced byas much as $4500 annually

• The number of jobs that patientswith RA can perform drops dra-matically—from 11.5 million to2.6 million

• Approximately 50% of patientswith RA become unable to workwithin 10 years of disease onset

• The direct medical cost of RA in theUnited States approaches $5 billionannually, with nearly 70% of thiscost attributable to hospitalizationsand home-care nursing.

Payer Strategies in Rheumatoid Arthritis

In recent years, payers have imple-mented numerous strategies to man-age the outcomes and costs of RA. Themost important aspect impacting for-mulary and coverage decisions hadbeen a health plan’s “ability to reducedisease progression and severity,” ameasure cited by 72% of plans,according to the 2011 EMD SeronoSpecialty Digest.4 Other prominent RAmanagement strategies include4:• Following health plan guidelines

(70%)• Reducing adverse reactions (62%)

• Decreasing hospitalizations andother healthcare costs (57%)

• Increasing adherence and persis-tency (54%).But what of the future of the

management of RA, especially withrespect to therapeutic decision-making? What factors do payers andrheumatologists think will drivedecision-making and allow them toachieve their clinical and cost objec-tives in the years ahead?

Price Will Drive Orals in TherapyFormulary Placement by Payers

Many of the headlines coming outof the 2011 ACR conference touted thepresentation of clinical studies dis-cussing the potential benefits of 2 oralagents for RA currently in the pipe -line—a possible game changer in asector long dominated by injectable(and expensive) tumor necrosis factor(TNF) inhibitors.

The 2 oral drugs—tofacitinib, a JAKinhibitor, and apremilast, a phospho-diesterase-4 inhibitor—are consideredto be small-molecule agents. Data pre-sented at the 2011 ACR meeting sug-gest that both agents offer promise forpatients with RA.5

The development of other oralmedications may suggest that patientswill be more likely to take their RAmedications in a tablet form than self-injecting or traveling to a hospital or aclinic for infusion, but that may nothappen right away.

Survey results suggest that theadoption of oral drugs will be drivenlargely by price. Payer responses sug-gest that if the new drugs are priced atparity with the leading injectableproducts, there is no clear positioningoutlook for the small-molecule agents.

If the oral agents are priced higher,at a 15% to 20% premium to biologics(Figure 1), payers and rheumatologistssuggested that the new drugs will bepositioned after TNF inhibitors.

Payer responses also indicate that,

at price parity to currently availablebiologics, there is no clear therapeuticpreference for the small-moleculedrugs; if the latter are priced at a 15%to 20% discount, they will likely bepositioned ahead of TNF inhibitors.

Cost-Offsetting Helps Enhance Adherence

Although further research is neces-sary to fully understand medicationadherence in patients with RA,6 sur-vey responses from rheumatologistssuggest that cost is a motivating factoramong patients.

Cost-offsetting for patients is thefactor most valued by rheumatolo-gists, because they believe it improvespatient adherence.

Specifically, with regard to copay-ment assistance programs (utilized bymanufacturers to help reduce consumercosts for TNF inhibitors), 78% of rheu -matologists in the survey noted thatcopayments improve patient adher-ence with therapy (Figure 2, page 10).

Status Quo in Payers’ Approach to RA Management

Apparently, regardless to potentialnew oral therapies, health plans seelittle or no reason to change the waysin which they manage their patientswith RA. By a significant margin, 68%of payers said that they were not fore-casting any changes in RA manage-ment methods during the next 2 to 4years, and only 32% of plans suggest-ed that changes may be implemented(Figure 3, page 10).

When asked to identify the types ofchanges that they may use, no consis-tency was apparent among responses.The following is a sample of responsesprovided:• “As new therapies come to market,

and some go the route of biosimilar,we will make changes.”

• “We will have preferred biologicalagents in this [RA] area.”

• “We plan to have a preferred spe-cialty tier.”

• “We will select agents based oncost-effectiveness, and contract withindustry for a price advantage for afavorable spot on formulary.”

• “With the advent of CER [compara-tive effectiveness research] dataand the use of e-prescribing, it willgive us diagnosis and better effica-cy data to better clinically managethese patients.”In addition, 2 payers indicated that

they would implement step-therapyregimens in their RA managementprograms.

RheumatologistsPayers

Figure 1 Impact of Premium Price When Positioning Small-Molecule Compoundsvs 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?

30

25

20

15

10

5

0

19%

6%

28%

20% 19%18%

4%

18%

23%

26%

7%

12%

They will beused afterMTX, but

before TNFinhibitors

They will beused after initial TNF

inhibitor failure

They will beused after

self-injected biologics but

before infusionbiologics

They will beused as last

line after all current

biologics havefailed

Not sure at this time

They will beused after

switching to anew class after

TNF inhibitor failure

MTX indicates methotrexate; RA, rheumatoid arthritis; TNF, tumor necrosis factor.Continued on page 10

Biologics for RA treatmentare not currently a tightlycontrolled category, nor willthey be in the near future.Patients and providers willstill have treatment choices,but as the market becomesmore crowded, pricingpressures and contractingmay lead to tighter controls.


ConclusionsA general observation from these

survey findings is that biologics forRA treatment are not currently a tight-ly controlled category, nor will theybe in the near future. Patients andproviders will still have treatmentchoices, but as the market becomesmore crowded, pricing pressures andcontracting may lead to tighter con-

trols. In addition, payers will have abroader ability to review the RA cate-gory and build comparative effective-ness models.

For drug manufacturers wishingto capture market share, responses toquestions related to therapy manage-ment preferences suggest that it iseasier to capture market share with asecond-line biologic than with a first-

line agent, and that newer second-and third-generation biologic thera-pies (including non-TNFs) are notyet differentiated from older biolog-ic compounds or even from oneanother. Also, it is apparent that anindi cation for use in early RA willnot increase market opportunity formanufacturers.

A final word of caution for mar-

keters of the oral, small-moleculecompounds that are likely to enter themarket soon is that, for now, payersand providers do not perceive a “nat-ural” positioning for these emergingtherapies in the management ofpatients with RA. In other words,these drugs will need to prove theirclinical value and cost-effectivenessbefore they are widely adopted bypayers and providers. �

References1. Medco Health Solutions, Inc. 2011 Drug Trend Report.2011. www.drugtrendreport.com/2011-report. AccessedJanuary 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 Associa -tion, National Coalition of Autoimmune PatientGroups. The Cost Burden of Autoimmune Disease:The Latest Front in the War on Healthcare Spending.2011. www.aarda.org/pdf/cbad.pdf. Accessed January25, 2012.4. EMD Serono. EMD Serono Specialty Digest, 7thEdition. Managed care strategies for specialty pharma-ceuticals. 2011. http://specialtydigest.emdserono.com/User/DigestLibrary.aspx. Accessed April 27, 2012.5. Mednet. Non-TNF inhibitor biologics: expandingopportunities for rheumatoid arthritis control. Pressrelease. November 5, 2011. http://mednet.adverdea.com/en/report/nontnf-inhibitor-biologics-expanding-opportuniti.html. Accessed April 27, 2012.6. Salt E, Frazier S. Adherence to disease modifyinganti-rheumatic drugs in rheumatoid arthritis patients:a narrative review of the literature. Orthop Nurs. 2010;29:260-275.

Trends in RA Management... Continued from page 9

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

Q: Are copay programs improving patient adherenceto therapy?

No 22%

Yes 78%

RA indicates rheumatoid arthritis.

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

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

No 68%

Yes 32%

RA indicates rheumatoid arthritis.

Gout flares occurring during theearly months of urate-lower-ing therapy are thought to

result from the release of urate crys-tals from deposits softened by thetreatment. These crystals trigger there lease of interleukin (IL)-1, thus lead-ing to a cascade of inflammation andflares of acute joint pain. Traditionally,the vast majority of gout flares havebeen managed with nonsteroidalanti-inflammatory drugs (NSAIDs),colchicines, or steroids.

A recent phase 2 study showed thatgout attacks occurring during the firstfew months of urate-lowering therapycan be nearly eliminated by adding theIL-1 inhibitor rilonacept (Arcalyst) atthe initiation of allopurinol (Zyloprim;Schumacher HR, et al. Arthritis Rheum.2012;64:876-884). In this double-blindstudy, 83 adult patients with hyper-uricemia and gout were randomizedto receive rilonacept (loading dose of

320 mg followed by 160 mg weekly) orplacebo administered subcutaneouslyand were started on allopurinol (300mg daily, titrated to a serum uratelevel of <6 mg/dL).

The mean number of gout flares perpatient through week 12 was signifi-cantly lower in the rilonacept groupthan in the placebo group (6 flares vs33 flares, respectively; P = .001), andthe proportion of patients experienc-

ing a gouty flare during the 12 weekswas also significantly lower in therilonacept group than in the placebogroup (14.6% vs 45.2%, respectively;P = .003). At week 16, no rebound inthe flare rate was observed for 6 weeksafter discontinuation of rilonacept orplacebo. Adverse events (AEs) weresimilar in the rilonacept and placebogroups, with the most common report-ed AEs being infections and muscu-loskeletal disorders. A higher percent-age of patients receiving rilonaceptthan placebo controls completed the12-week evaluation period (98% vs79%, respectively; P = .015).

Although the findings of this studyindicate that rilonacept can reduce thefrequency of gouty flares during theinitial period of treatment with urate-lowering therapy, inhibiting IL-1 isprobably not the only factor involvedin the flares; rilonacept preventedmost, but not all, flares. In the real-

world setting, rilonacept is likely to beused when conventional therapy (ie,NSAIDs, colchicines, steroids) hasfailed or is not well tolerated.

Despite these recent findings, theUS FDA Arthritis Advisory Commit -tee voted on May 8, 2012, against theap prov al of a supplemental BiologicLicense Appli cation (BLA) for rilona-cept to prevent gout flares.

The supplemental BLA asked forapproval of the use of rilonacept as an80-mg subcutaneous injection onceweekly for 16 weeks after a 160-mgloading dose for the prevention of goutflares during initiation of uric acid–lowering therapy in patients with gout.

The main objections to the applica-tion centered around the supportingclinical data, which the majority ofpanel members said had failed toadequately demonstrate the safety ofthe drug and its improved efficacyover current standard therapy. �

Rilonacept in the Prevention of Acute Gout FlaresFDA panel votes against approval of a supplemental BLA applicationBy Sy Schlager, MD, PhD

Gout

A recent phase 2 studyshowed that gout attacksoccurring during the firstfew months of urate-lowering therapy can benearly eliminated by addingthe rilonacept at theinitiation of allopurinol.

Help manage

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.

Pleasethis

Please see Brief Summarythis advertisement.

Summary of full Prescribing advertisement.

Prescribing Information

Information on last pages

pages of

Reference: 1. HUMIRA Injection [package insert]. North Chicago, IL: Abbott Laboratories.

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.

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

0

Pleaseon

Please see Importanton Serious Infections

Important Safety Information, Infections and Malignancy,

Information, including Malignancy, on the following

BOXED WARNING following page.

WARNING

Important Safety Information1

SERIOUS INFECTIONSPatients 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:

patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.

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

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

blocker in combination with these other immunosuppressants.

IMMUNIZATIONS

on the following pages of this advertisement.

©2011 Abbott Laboratories Abbott Park, IL 60064 64C-xxxxxx March 2011 Printed in U.S.A.

Reference: 1. HUMIRA Injection [package insert]. North Chicago, IL: Abbott Laboratories.

on the following pages of this advertisement.

©2012 Abbott Laboratories Abbott Park, IL 60064 64C-759105 January 2012 Printed in U.S.A.

C

64C-xxxxxx March 2011 Printed in U.S.A.

64C-759105 January 2012 Printed in U.S.A.

4 1

HUMIRA® (adalimumab) PROFESSIONAL BRIEF SUMMARYCONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

WARNINGS: SERIOUS INFECTIONS AND MALIGNANCYSERIOUS INFECTIONSPatients 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 benefi ts 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]MALIGNANCYLymphoma 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 infl iximab. 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 conco mitant 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 benefi ts 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.TuberculosisCases 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 confi rmed, 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.MonitoringPatients 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 InfectionsFor 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 benefi ts 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 AdultsIn 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% confi dence interval) of 0.6 (0.38, 0.93) per 100 patient-years among 6694 HUMIRA-treated patients

versus a rate of 0.5 (0.28, 1.05) per 100 patient-years among 3749 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 signifi cant 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 CancerDuring the controlled portions of 32 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, and Ps, the rate (95% confi dence 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 LeukemiaIn 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 infl ammatory 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 AdultsMalignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers (initiation of therapy 18 years of age), of which HUMIRA is a member. Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources including registries and spontaneous postmarketing reports. Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including HUMIRA. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases has occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants. Hypersensitivity Reactions In postmarketing experience, anaphylaxis and angioneurotic edema have been reported rarely following HUMIRA administration. If an anaphylactic or other serious allergic reaction occurs, administration of HUMIRA should be discontinued immediately and appropriate therapy instituted. In clinical trials of HUMIRA in adults, allergic reactions overall (e.g., allergic rash, anaphylactoid reaction, fi xed drug reaction, non-specifi ed 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 identifi ed as carriers of HBV. Adequate data are not available on the safety or effi cacy 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 signifi cant 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 confi rmed signifi cant 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 benefi t compared with the TNF-blocker alone in patients with RA. Therefore, the combination of HUMIRA and anakinra is not recommended [see Drug Interactions].Heart FailureCases 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. AutoimmunityTreatment 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].ImmunizationsIn 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 infl uenza 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 benefi t 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 proportio n 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 fl are reaction (0.7%), rash (0.3%) and pneumonia (0.3%). InfectionsIn 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 InfectionsIn 45 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD and Ps that included 22,026 HUMIRA-treated patients, the rate of reported active tuberculosis was 0.22 per 100 patient-years and the rate of positive PPD conversion was 0.07 per 100 patient-years. In a subgroup of 8940 U.S. and Canadian HUMIRA-treated patients, the rate of reported active TB was 0.07 per 100 patient-years and the rate of positive PPD

conversion was 0.06 per 100 patient-years. These trials included reports of miliary, lymphatic, peritoneal, and pulmonary TB. Most of the TB cases occurred within the fi rst eight months after initiation of therapy and may refl ect 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 Precaut ions].Autoantibodie sIn 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 a cute liver failure in pat ients receiving TNF-blockers. In controlled Phase 3 trials of HUMIRA (40 mg SC every other week) in patients with RA, PsA, and AS with control period duration ranging from 4 to 104 weeks, ALT elevations 3 x ULN occurred in 3.5% of HUMIRA-treated patients and 1.5% of control-treated patients. Since many of these patients in these trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between HUMIRA and the liver enzyme elevations is not clear. In controlled Phase 3 trials of HUMIRA (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on Days 1 and 15, respectively, followed by 40 mg every other week) in patients with Crohn’s disease with control period duration ranging from 4 to 52 weeks, ALT elevations

3 x ULN occurred in 0.9% of HUMIRA-treated patients and 0.9% of control-treated patients. In controlled Phase 3 trials of HUMIRA (initial dose of 80 mg then 40 mg every other week) in patients with plaque psoriasis with control period duration ranging from 12 to 24 weeks, ALT elevations 3 x ULN occurred in 1.8% of HUMIRA-treated patients and 1.8% of control-treated patients. ImmunogenicityPatients 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 identifi ed in 16% of HUMIRA-treated patients. In patients receiving concomitant methotrexate, the incidence was 6% compared to 26% with HUMIRA monotherapy. In patients with ankylosing spondylitis, the rate of development of antibodies to adalimumab in HUMIRA-treated patients was comparable to patients with rheumatoid arthritis. In patients with psoriatic arthritis, the rate of antibody development in patients receiving HUMIRA monotherapy was comparable to patients with rheumatoid arthritis; however, in patients receiving concomitant methotrexate the rate was 7% compared to 1% in rheumatoid arthritis. In patients with Crohn’s disease, the rate of antibody development was 3%. In patients with plaque psoriasis, the rate of antibody development with HUMIRA monotherapy was 8%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 ug/ml. Among the patients whose serum adalimumab levels were < 2 ug/ml (approximately 40% of total patients studied), the immunogenicity rate was 20.7%. In plaque psoriasis patients who were on HUMIRA monotherapy and subsequently withdrawn from the treatment, the rate of antibodies to adalimumab after retreatment was similar to the rate observed prior to withdrawal. Other Adverse ReactionsThe data described below refl ect exposure to HUMIRA in 2468 patients, i ncluding 2073 exposed fo r 6 months, 1497 exposed for greater than one year and 1380 in adequate and well-controlled studies (Studies RA-I, RA-II, RA-III, and RA-IV). HUMIRA was studied primarily in placebo-controlled trials and in long-term follow up studies for up to 36 months duration. The population had a mean age of 54 years, 77% were female, 91% were Caucasian and had moderately to severely active rheumatoid arthritis. Most patients received 40 mg HUMIRA every other week. Table 1 summarizes reactions reported at a rate of at least 5% in patients treated with HUMIRA 40 mg every other week compared to placebo and with an incidence higher than placebo. In Study RA-III, the types and frequencies of adverse reactions in the second year open-label extension were similar to those observed in the one-year double-blind portion.

Table 1. Adverse Reactions Reported by 5% of Patients Treated with HUMIRA During Placebo-Controlled Period of Rheumatoid Arthritis Studies

HUMIRA40 mg subcutaneous

Every Other Week

Placebo

(N=705) (N=690)

Adverse Reaction (Preferred Term)Respiratory

Upper respiratory infection 17% 13%Sinusitis 11% 9%Flu syndrome 7% 6%

GastrointestinalNausea 9% 8%Abdominal pain 7% 4%

Laboratory Tests*Laboratory test abnormal 8% 7%Hypercholesterolemia 6% 4%Hyperlipidemia 7% 5%Hematuria 5% 4%Alkaline phosphatase increased 5% 3%

OtherHeadache 12% 8%Rash 12% 6%Accidental injury 10% 8%Injection site reaction ** 8% 1%Back pain 6% 4%Urinary tract infection 8% 5%Hypertension 5% 3%

* Laboratory test abnormalities were reported as adverse reactions in European trials** Does not include injection site erythema, itching, hemorrhage, pain or swelling

Juvenile Idiopathic Arthritis Clinical StudiesIn general, the adverse reactions in the HUMIRA-treat ed pediatric patients in the juvenile idiopathi c arthritis (JIA) trial were similar in frequency and type to those seen in adult patients [see Warnings and Precautions, Adverse Reactions]. Important fi ndings 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 a dverse 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 concomita nt MTX in the fi rst 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 fi rst 48 weeks of treatment, non-serious hypersensitivity reactions were seen in approximatel y 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 obse rved 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 antibodie s 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 StudiesHUMIRA has been studied in 395 patie nts with psoriatic arthritis (PsA) in two placebo-controlled tri als and in an open label study and in 393 patients with ankylosing spondylitis (AS) in two placebo-controlled studies. The safety profi le for patients with PsA and AS treated with HUMIRA 40 mg every other week was similar to the safety profi le seen in patients with RA, HUMIRA Studies RA-I through IV.

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LUPUS

National Assessment-Systemic LupusErythematosus Disease Activity Index(SELENA-SLEDAI) scores ≥10, lowcomplement levels, elevated anti-dsDNA levels, and steroid use. In addi-tion to improvements in the SRI, beli-mumab was associated with a re ducedrisk of SLE flares, im proved measuresof health-related quality of life (HR-QOL), and reduced use of steroids.Thus, belimumab, especially at 10mg/kg, had greater therapeutic benefitthan standard therapy in patients withhigher disease activity at baseline.

The approval of belimumab bythe US Food and Drug Admin -istration generated much excitementamong the rheumatology communi-ty, although the excitement has beentempered by lack of specific guid-ance from initial studies about theoptimal clinical scenarios in whichto use belimumab. Now, there aredata to provide guidance on whento use the drug in patients with SLEby suggesting that it may be mosteffective in improving disease activ-ity when used to treat active SLEdefined by high SELENA-SLEDAI

scores, low complement levels, highdsDNA, and corticosteroid use.

Of note, the SRI as an outcome inSLE is somewhat controversial,because it was developed specificallyfor use in belimumab studies; as aresult of its composite nature, it is notreadily calculated in routine clinicalsettings. Despite this limitation, theimprovements in flares, HR-QOL,and steroid use show that belimu -mab is leading to more readily iden-tifiable improvements in SLE. Goingforward, however, further studieswill be needed to understand the roleof this agent in specific manifesta-tions of SLE, such as renal and neu-ropsychiatric disease, and in impact-ing the overall mortality rate. �

Is Personalized Medicine...Continued from cover

For patients with lupus nephritiswho have responded to induction ther-apy, mycophenolate mofetil (CellCept)is superior to azathioprine (Azasan)in maintaining a renal response totreatment and in preventing relapse,according to a recent study (DooleyMA, et al. N Engl J Med. 2011;365:1886-1895).

In a 36-month, randomized, dou-ble-blind, phase 3 study, a total of227 patients were randomly assignedto maintenance treatment withmycophenolate mofetil (N = 116) orazathioprine (N = 111). With respectto primary end point, time to treat-ment failure (hazard ratio [HR], 0.44;95% confidence interval, 0.25-0.77;P = .003), and to time to renal flareand time to rescue therapy (HR, <1.00;P <.05), mycophenolate mofetil wassuperior to azathioprine.

Adverse events, which for the mostpart were minor infections and gas-trointestinal disorders, occurred in

>95% of patients in both cohorts (P =.68). Serious adverse events werefound in 33.3% of patients receivingazathioprine and in 23.5% of thosepatients receiving mycophenolatemofetil (P = .11).

The withdrawal rate as a result ofadverse events was higher with aza-thioprine than with mycophenolatemofetil (39.6% vs 25.2%, respectively;P = .02). �

Mycophenolate Is Superior to Azathioprine for LupusMaintenance Therapy

There are data to provideguidance on when to usethe drug in patients withSLE by suggesting that itmay be most effective inimproving disease activity.

For patients with lupusnephritis who haveresponded to inductiontherapy, mycophenolatemofetil is superior toazathioprine in maintaininga renal response totreatment and in preventingrelapse.

Crohn’s Disease Clinical StudiesHUMIRA has been studied in 1478 patients with Crohn’s disease in fo ur placebo-controlled and two ope n-label extension studies. The safety profi le for patients with Crohn’s disease treated with HUMIRA was similar to the safety profi le seen in patients with RA. Plaque Psoriasis Clinical StudiesHUMIRA has been studied in 1696 patients with plaque psoriasis in placebo-controlled and open-label extension studies. The safety profi le for patients with plaque psoriasis treated with HUMIRA was similar to the safety profi le 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. B ecause 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 associat ed with diverticulitis and appendiceal perforations associated with appendicitis, pancreatitis Respiratory disorders: Interstitial lung disease, including pulmonary fi brosis Skin reactions: Stev ens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsenin g psoriasis (all sub-types including pustular and palmoplantar) Vascular disorders: Systemic vasculitis

DRUG INTERACTIONS Methotrexate Although methotrexate (MTX) reduces the apparent adalimumab clearan ce, the data do not suggest the n eed 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 benefi t; 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 insuffi cient 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 Precauti ons].

USE IN SP ECIFIC POPULATIONS Pregnancy Pregnancy Category B - There are no adequate and well-contro lled studies in pregnant wome n. 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 ha s 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 systemical ly after ingestio n. 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 effi cacy of HUMIRA in pediatric patients for uses other than juvenile idio pathic arthriti s (JIA) have not been established. Juvenile Idiopathic ArthritisIn the JIA trial, HUMIRA was shown to reduce signs and symptoms of act ive polyarticular JIA in patie nts 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 i n adults with certain exceptions [see Adverse Reactions]. Post-marketing cases of malignancies, some fatal, have been reported among children, adolescents, an d 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 ye ars 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 evide nce 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 be en 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 benefi ts and risks of HUMIRA. Physic ians 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 fi ght infecti ons. 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.

• MalignanciesPatients should be counseled about the risk of malignancies while receiving HUMIRA.

• Allergic ReactionsPatients 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 prefi lled syringe contains latex.

• Other Medical ConditionsAdvise 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, 2011Ref: 03-A569-R27Abbott LaboratoriesNorth Chicago, IL 60064, U.S.A.

64C-757903 MASTER

64C-759105

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The effective use of biologic dis-ease-modifying antirheumaticdrugs (DMARDs) has dramati-

cally improved the treatment ofrheumatoid arthritis (RA) over recentyears. However, for at least 33% ofpatients with RA, tumor necrosis fac-tor (TNF) inhibitor therapy producesan inadequate clinical response.Indeed, responses to biologic agentsvary across different patient popula-tions, especially with respect to dif-ferences in duration and reversibilityof disease.

Many studies have shown thatalthough TNF antagonists improveclinical signs and symptoms of RAin patients in whom conventionalDMARDs had produced inadequateresponses, the American College ofRheumatology (ACR) 20 response cri-teria (ACR20) for TNF inhibitors gen-erally range from 20% to 40% responserates. Similarly, in those with an inad-equate response to TNF inhibitors, thenewer biologic agents can achieveACR20 response rates at 24 weeks,ranging from 17% with golimumab(Simponi) to 40% with tocilizumab(Actemra). Moreover, only rituximab(Rituxan) has shown significant inhi-bition of progression of joint destruc-

tion in this highly refractory popula-tion. These differences in responserates among the same class of biologicagents, and the fact that not allpatients with RA respond to biologics,indicate the heterogeneity of patientsand the disease.

Thus, an individualized approachto the management of RA is neededso that each patient can receive opti-mal treatment, while avoiding unnec-essary exposure to potentially toxicside effects and the costs of a biologicagent that may not be effective forthat patient.

A recently published review (EmeryP, et al. Ann Rheum Dis. 2011;70:2063-2070) examined the current evidencefor markers with prognostic capabili-ties in RA and assessed their potentialin predicting individual treatmentresponses to biologic agents and in -forming clinical practice. The mark-ers that were examined includedpatient clinical characteristics, geneticmarkers, and protein molecular bio-markers. Several studies from patientregistries have shown that high levelsof disability at baseline and being asmoker are predictive of a poorresponse to TNF antagonists. More -over, lower baseline Disease ActivityScore in 28 joints, Health AssessmentQuestion naire scores, and concurrentuse of conventional DMARDs appearto be associated with improved TNFinhibitor responses. Age, sex, diseaseduration, and the previous number ofDMARDs used were not predictive ofTNF inhibitor response. It is unclearwhether any of the baseline character-istics are useful as potential markers ofresponse or simply represent prognos-tic indicators.

The recognition that variation inresponse to treatment may be linkedto genetic traits has led to the study ofgenetic markers as predictors ofresponse to treatment. Such analysesprovide a way of using genetics in afully translational approach, from botha screening and therapeutic responseperspective to informing clinical prac-tice. Specifically, polymorphisms ingenes encoding for TNFα, the majorhistocompatibility region, the p38 net-work, STAT4, PTPN22, PAD14, CTLA-4, Traf1/C5, and FC𝛾RIIIA have all beenthe focus of a number of studies. Inthis regard, there is evidence of anassociation between single nucleotidepolymorphisms at position 308 of theTNF promoter gene (TNF-308 geno-

type) and responsiveness to etaner-cept, infliximab, and adalimumab. Thepredictive and prognostic use of thesedata have yet to be clarified. Further -more, there is evidence in patientswith early RA that the presence of2 HLA-DRB1 alleles encoding theshared epitope (SE) is associated withresponse to etanercept, and that anincreased number of HLA-DRB1 SEcopies is correlated with an improvedclinical response to adalimumab.

Although the SE motif is not consid-ered a robust genetic marker for pre-dicting response to TNF antagonists, itmay be useful as a prognostic markerfor RA. Other gene polymorphismshave also been studied for their valuein predicting response to TNF antago-nist therapy, but further properly pow-ered studies are required to define thepotential of the promising geneticmarkers. In addition, new methods touncover genetic biomarkers need to bedeveloped and studied.

Preliminary proteomic studies touncover protein molecular biomark-ers that are predictive of response toTNF antagonists have shown that acombination of 24 biomarkers com-prising autoantibodies and cytokineswas associated with patients having agood response to etanercept, whereas6 plasma biomarkers enabled thedetection of patient responses toinfliximab with high sensitivity andspecificity. Similarly, apolipoproteinA-1 was predictive of a good responseto infliximab, whereas the presence ofplatelet factor 4 was associated withno response.

Other studies have shown thatcytokine profiling, biomarkers in -volved in cartilage turnover and boneresorption, and levels of RANKL andthe RANKL to osteoprotegerin ratio

can be used to identify responders toTNF antagonists. In addition, clinicalstudies with golimumab have shownthat multiple biomarkers associatedwith the TNF cellular signaling path-way may be predictive of response totherapy with this agent, includingCRP, IL-6, MMP-3, ENRAGE, �α 2micro globulin, insulin, von Wille -brand factor, leptin, apo CIII, andbone alkaline phosphatase levels.Similar studies with rituximab haveshown that patients with a type 1interferon low signature have signifi-cantly greater responses to this agentthan those with a high signature.

Autoantibodies play a key role inthe pathogenesis of RA, and severallines of evidence support the diagnos-tic and prognostic use of these mole-cules. Unfortunately, the current dataare inconclusive regarding the use ofautoantibodies in predicting responseto TNF inhibitors, abatacept (Orencia),rituximab, or tocilizumab. There hasalso been work to correlate the pres-ence or depletion of B-cell subsets as apredictor of reduced response or earlyrelapse, particularly after treatmentwith rituximab. Thus far, the datarequire further validation before theycan be recommended for use in clini-cal practice.

Although there is an increasingneed for an individualized treatmentstrategy for patients with RA, whichis guided by strong predictors ofresponse to therapy, we are not quitethere yet. Additional well-designedstudies are required to confirm thepredictive potential of the most prom-ising genetic markers. Further more, todate, no robust protein biomarkershave been confirmed as predictingresponse to TNF inhibitors. Althoughrheumatoid factor and anticytoplas-mic antibodies have yielded the mostconsistent data to suggest thatseropositivity for these markers hasthe potential to predict response to ri -tuximab in patients with RA, furtherresearch is needed to validate thesedata, to suggest the optimum order oftreatment for seronegative patients,and to determine if similar strategiescan be achieved with other biologicagents. Given the desire to achieveindividualized treatment for patientswith RA, research in this area is ongo-ing to identify the most suitable predic-tive biomarkers, which has the poten-tial to reduce healthcare costs and toimprove outcomes. �

Potential Molecular Biomarkers of TreatmentResponse in Rheumatoid ArthritisBy Sy Schlager, MD, PhD

An individualized approachto the management of RA isneeded so that each patientcan receive optimaltreatment, while avoidingunnecessary exposure topotentially toxic side effectsand the costs of a biologicagent that may not beeffective for that patient.

at a glance� The use of biologic DMARDs

has dramatically improved the

treatment of patients with RA

� 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

� Genetic markers may predict

a patient’s response to RA

treatment

� Identifying the most suitable

predictive biomarkers has the

potential to reduce healthcare

costs and improve outcomes

� 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

Personalized Medicine in Rheumatology™


Unexpected and unwantedoversight is becoming a morefrequent element of practice,

making it imperative that you under-stand current investigation and auditinitiatives, and how to prepare andprotect your practice.

Understanding the Office ofInspector General

The US Department of Health andHuman Services (HHS) Office ofInspector General (OIG), which is

tasked with protecting the in tegrity ofthe HHS programs and operations by“detecting and preventing fraud,waste, and abuse; identifying opportu-nities to improve program economy,efficiency, and effectiveness; and hold-ing accountable those who do not meetprogram requirements or who violateFederal laws,”1 has taken a leading rolein such investigations and audits.

OIG accomplishes its mandate bydeploying its staff of approximately1800 professionals throughout the

United States to conduct audits, eval-uations, and investigations, as well ascoordinating and overseeing thirdparties conducting audit activities onOIG’s behalf.1 OIG investigates a widevariety of conduct,2 and may seek civilmonetary penalties against any per-son who, for example: (i) presents orcauses to be presented claims to aFederal health program that the per-son knows or should have known isfor an item or service that was not pro-vided as claimed or is false or fraudu-

lent3; (ii) violates the antikickbackstatute by knowingly or willfully pay-ing or receiving remuneration forreferrals of federal healthcare pro-gram beneficiaries4; or (iii) presents orcauses to be presented a claim thatperson knows or should know is for aservice which may not be made underthe physician self-referral or Stark law.5

In the past several months, OIG hasreported on the following activity:1. On or around January 17, 2012,

Understanding Office of Inspector General Initiativesand How to Prepare Your PracticeBy Jennifer Kirschenbaum, Esq, and Erica Youngerman, Esq


Physicians in private practice areexperiencing financial pressures thatmake private practices increasinglydifficult to sustain; as reimbursementis reduced, Medicare and Medicaidgrow, health records go electronic, andother operating costs increase. Manyphysicians cannot compete with therich recruitment packages being of -fered by hospitals. The end result isthat new physicians are increasinglyseeking hospital employment.

FFS is still the dominant model forreimbursement for hospitals andphysicians. This mode will continuefor the next year or 2, said Dr Skea,but payment reform is reaching astage of bundled payment for epi -sodes of care and payment for highervalue, in which providers can share insavings from better care coordinationand disease management.

“Care will no longer be acute care–centric; it is all about transitioning thepatient, with the primary care physi-cian as the quarterback,” as with amedical home, he stated.

“It is about value, and that word isgoing to keep coming up over andover again. Value is the combination ofquality and cost,” Dr Skea said. “Thereis bipartisan support for this concept.”

The trend is toward downsizing.Significant consolidation in health -care will occur, Dr Skea predicted,“whether its apposition of practicesinto mega-practices or large multispe-cialty practices, but also in the hospi-tal industry as well. We will continueto see the downward spiral in thenumber of hospitals.”

“What we will see are hospitalsand physicians aligning in prepara-tion for the future model of payment.

The two will be taking risk together,”Dr Skea added.

Accountable Care OrganizationsOn the horizon are the fully account -

able care organizations (ACOs), underwhich systems of care assume respon-sibility for patients across providersand settings over time.

“In the new model under an ACO,your hospital is not your revenue cen-ter, it is your cost center. That funda-mental change scares a lot of hospitaladministrators and many people inthe healthcare industry,” Dr Skea said.

Ultimately, an ACO breaks downthe silos that currently exist within thehealthcare industry, and puts it underone umbrella, he said. This umbrella isdesigned to facilitate the transition ofcare and the communication of infor-mation to make care more seamless,thereby avoiding failures or disrup-tions that often occur with the hand-off of patients between providers.Health information technology will bethe backbone of the ACO model.

Some of the low-hanging fruit isavoidance of emergency departmentvisits for conditions that do not requireemergent care, he said, because the

responsibility for the entire episode ofcare will lie with the ACO.

For Medicare ACOs, 2 differentmodels of payment exist. The Pioneermodel is more advanced, and isdesigned for healthcare organizationsthat already have experience in coor-dinating care for patients across caresettings. The Medicare Shared SavingsProgram (MSSP) is a different entrypoint for ACOs, and is better suitedfor groups just getting started withcare coordination.

Shared-savings models work bysharing the savings derived fromspending below benchmarks. Depend -ing on the model, 50% to 70% of thesavings can be assumed by the ACO.“The caveat is that you are not eligiblefor these shared savings if you do notmeet the quality parameters first,” DrSkea pointed out. “Under MSSP, youhave to hit 70% of the parameters.”

A separate tax identification num-ber is required for an ACO to contractwith Medicare. An ACO may consistof a hospital, a primary care group, aspecialty group, and other providerssuch as home healthcare. Providersoutside the ACO, such as mentalhealth facilities, home health services,and rehabilitation services, may alsobe contractually obliged to an ACOwith some shared risk. “The entitiesinvolved will be allowed to be some-what fluid and dynamic in the sensethat it is done at a grassroots level,”commented Dr Skea.

After receiving 1300 public com-ments on the proposed ACO regula-tions, the Centers for Medicare &Medicaid Services responded withsignificant changes to make the pro-gram more attractive for prospective

participants. The proposed rule estab-lished shared savings and losses, butthe final rule eliminated shared lossesfor the first 2 years for an MSSP (withup to 50% sharing of savings). Underthe Pioneer model, however, the ACOdoes take on risk, but also a higherlevel of shared savings. The numberof reportable quality metrics has de -creased from 65 under the proposedrule to 33 under the final rule. �

“Care will no longer beacute care–centric; it is allabout transitioning thepatient, with the primarycare physician as thequarterback.”

—Warren H. Skea, PhD, FAHA

New Payment Models Will Emphasize... Continued from cover

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

Rheumatology Practice Management™


Rheumatology Practice Management™

Buchanan County Health Center inIowa agreed to pay $406,030 forallegedly employing an individualthat it knew or should have knownwas excluded from participating infederal healthcare programs, poten-tially violating the Civil MonetaryPenalties Law.6

2. On or around November 30, 2011,as a result of a self-disclosure, Ever - green Health Center, PC, in Lebanon,MO, agreed to pay $83,012.58 forallegedly submitting claims forservices not provided, potentiallyviolating the Civil Monetary Penal -ties Law.6

3. On or around October 4, 2011, as aresult of a self-disclosure, County ofMonterey d/b/a Nativi dad MedicalCenter of California agreed to pay$174,508.46 for allegedly enteringinto a professional medical servicesagreement with a physician groupfor certain call coverage and clinicservices where the compensationterms offered incentives for thephysician group to refer privatepractice patients to the center,potentially violating the Civil Mon -etary Penalties Law.7

Available statistics show that as aresult of OIG’s efforts during fiscalyear (FY) 2010, OIG reported recover-ing: (i) $3.8 billion in investigationreceivables that were court ordered oragreed to be paid through civil settle-ments; and (ii) $1.1 billion in auditreceivables as a result of OIG auditdisallowance recommendations.1 Be -cause of the many fruits of OIG’slabor, OIG has increased its effortssince FY 2010 to increase recoveriesby incorporating more sophisticatedreviews and expanding the scope ofits investigations.

OIG InitiativesFor many practices devoting their

resources and attention to patientcare, minimal time is spent reviewingoperations and policies in a way thatprotects the practice against an OIGinvestigation or other audit initiative,which puts such practices at a severedisadvantage that is somewhat easilypreventable. Certainly, some prac-tices that are targeted by OIG orother authorities or payers are in thecategory of committing egregiouswrong doing, whereas others havesimply not taken the time to ensurethat they are operating under theproper structure. Staying abreast ofthe changes to the numerous docu-mentation requirements while alsotaking care of your patient popula-tion is not an easy task.

There are, however, certain stepsyou may take to place yourself in abetter position to limit exposure.Under standing the OIG Work Plan forFiscal Year 2012 is one such step. OIG’sinitiatives are not a secret; in fact, eachOctober, OIG publishes its initiativesfor the coming year. Reviewing theWork Plan and understanding whereareas of exposure may exist in yourpractice is a somewhat simple firststep to limiting exposure. Two exam-ples of oncology-related initiatives areas follows:1. Payments for off-label anticancer

pharmaceuticals and biologicals:OIG states that it will focus areview on “Medicare payments fordrugs and biologicals used on anoff-label basis…in anticancer chemo -therapeutic regimens to determinewhether patients with particularindications were prescribed anti-cancer drugs approved by FDA forsuch indications before resorting toanticancer drugs not approved forthose indications.”8

2. Medicare outpatient payments fordrugs: OIG will review Medicareoutpatient payments to providersfor certain drugs and the administra-tion of those drugs (eg, chemo -therapy) to determine whetherMedicare overpaid providers be -cause of incorrect coding or over-billing of units.8 OIG explains thatprior reviews have identified cer-tain drugs, particularly chemother-apy drugs, as vulnerable to incor-rect coding.OIG provides additional insight

into the 2 aforementioned initiativesby stating that in calendar year 2007,Medicare payments for anticancerdrugs totaled approximately $2.7 bil-lion, which, as is readily apparent byOIG’s Work Plan, is more money thanOIG believes was proper for reim-bursement. Practices billing for anti-cancer drugs will be targeted this year,as specified in OIG’s Work Plan, andhow those practices will be selectedwill likely be a result of data mining.

The initiated investigations willfocus on whether those targeted prac-tices and providers accurately andcompletely billed for services provid-ed, and also whether such providershave reported units of service as thenumber of times that a service or pro-cedure was performed.8 For thosepractices targeted for prescribing off-label drugs, OIG specified it will belooking to determine whether therewere improvements in the patients’medical condition before the use ofoff-label drugs.

The OIG Work Plan states that “ifthe beneficiaries’ medical conditionsimproved before the use of off-labeldrugs, [OIG] will determine howmuch Medicare could have saved hadthe previously administered anti-cancer drugs continued to be used,”8

and presumably seek to recoup suchamounts from the practice. OIG statesas its authority to recoup such moniesthat “Medicare covers FDA-approveddrugs used for off-label indicationsin anticancer chemotherapeutic regi-mens when such uses are supportedin authoritative compendia identifiedby the Secretary of HHS.”8

Ramifications of ExposureWhen appropriate, OIG has the

authority to impose civil monetarypenalties assessments and administra-tive sanctions, as well as collaboratingwith the Department of Justice andother government executive branchagencies capable of bringing charges.1

OIG is authorized to seek differentamounts of civil monetary penaltiesand assessments based on the type ofviolation at issue.1 For example, in acase of false or fraudulent claims, theOIG may seek a penalty of up to$10,000 for each item or serviceimproperly claimed, and an assess-ment of up to 3 times the amountimproperly claimed.9 In a kickbackcase, OIG may seek a penalty of up to$50,000 for each improper act anddamages of up to 3 times the amountof remuneration at issue (regardless ofwhether some of the remunerationwas for a lawful purpose).10

Protecting Your PracticeProtecting your practice from an

OIG investigation begins with preven-tive compliance. This entails ensuringthat your practice is properly struc-tured to comply with numerous rulesand regulations, including the self-referral laws. To place your practice inthe best position possible, you shouldseek the advice of competent health-care counsel to either structure yourpractice when it is created or to reviewyour existing structure for compli-ance. In addition to proper structur-ing, your practice should adopt poli-cies and procedures to govern howyour practice operates, including theadoption of a compliance plan thatdetails acceptable billing practices.

Also, as part of your practice’scompliance, I strongly recommendworking with an external coding andbilling expert, brought in specificallyto examine your practice and diag-nose any areas of exposure. Although

you may have a dynamic team inplace handling the billing operationsfor your practice, having a review ofyour documentation and coding byan expert specializing in your practicearea who has reviewed documenta-tion and coding of many other prac-tices and is familiar with billingrequirements for your specialty willnot only likely place you in a moreprotected position, but also potential-ly highlight areas where you mayincrease your accounts receivable.

The bottom line with investigationssuch as OIG’s initiatives is that withelectronic records and billing, over-sight has dramatically changed and itis now much easier to target practicespotentially overutilizing, upcoding, orabusing the reimbursement system.Those practices continuing with“business as usual,” and ignoring thewarning signs that it is time to adaptand modify as the oversight has, willlikely have a much greater chance ofbeing targeted.l �

References1. US Department of Health & Human Services,Office of Inspector General Work Plan: Fiscal Year2012. Introductory message from the Office ofInspector General. http://oig.hhs.gov/reports-and-publications/archives/workplan/2012/WP00-Intro.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, Officeof 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, Officeof Inspector General. Kickback and physician self-referral. http://oig.hhs.gov/fraud/enforcement/cmp/kickback.asp. Accessed March 6, 2012.8. US Department of Health & Human Services, Officeof Inspector General Work Plan: Fiscal Year 2012 PartI: 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 dis-cussion purposes only and does notconstitute legal advice.

Jennifer Kirschenbaum, Esq, managesKirschenbaum & Kirschenbaum’s health -care department, which specializes inrepresenting healthcare practitioners inregulatory compliance, audit defense,licensure, and transactional matters.Erica Youngerman, Esq, is an associate inKirschenbaum & Kirschenbaum’s health-care practice. If you have a question forJennifer or if you would like to discussways to protect your practice, she can bereached at 516-747-6700 x302 or by e-mail at [email protected] more information about Kirschenbaum& Kirschenbaum’s healthcare practice,visit www.nyhealthcareattorneys.com.

Understanding Office of Inspector General... Continued from page 18


centage of patients with inactive dis-ease and clinical remission. The studywas presented at the 2011 AnnualMeeting of the American College ofRheumatology (ACR).

Approximately 300,000 children inthe United States are currently diag-nosed with JIA. Polyarticular JIA, themost severe form of JIA, carries theburden of severe associated morbidity.

“This is the first randomized, dou-ble-blind clinical trial using inactivedisease and remission as the mainoutcomes. This study sets a new stan-dard for treatment, response, and out-comes for children with polyarticularJIA. Achieving 70% improvement by 4months and inactive disease by 6months are achievable goals. One ofthe most remarkable findings was theimportance of early treatment. Theredoes appear to be a window of oppor-tunity for JIA as there is for rheuma-toid arthritis,” stated lead authorCarol Wallace, MD, Professor of Pedi -atric Rheumatology at Children’sHospital and Regional Medical Center,and the University of WashingtonSchool of Medicine, Seattle.

TREAT was a multicenter, prospec-tive, double-blind, placebo-controlledtrial conducted in 15 centers; 85 chil-

dren with polyarticular JIA were ran-domized to methotrexate (Trexall,Rheumatrex), etanercept (Enbrel),

plus prednisolone (MEP arm, giving abiologic upfront) or methotrexate,etanercept placebo, and prednisoloneplacebo (MTX arm) for up to 12months. At enrollment, median agewas 11.1 years and median diseaseduration was 4.1 months.

At 4 months, patients who achievedat least a 70% response as assessed bythe ACR pediatric 70 were continuedon their blinded treatment; those whodid not reach this end point weregiven open-label MEP. At 6 months,patients who reached the primaryend point of clinically inactive disease

were continued on their treatment.Patients who did not achieve clinical-ly inactive disease at 6 monthsreceived unblinded etanercept andprednisone in addition to methotrex-ate until 12 months.

At 4 months, ACR pediatric 70 wasachieved in 30 of the 42 patients (71%)in the MEP arm versus 19 of the 43patients (44%) in the MTX arm. At 6months, clinically inactive disease wasachieved in 17 of the 42 patients (40%)in the MEP arm versus 10 of the 43patients (23%) randomized to MTX.

According to Dr Wallace, the defi-nition of clinically inactive diseaseused in this study had stringent crite-ria that included no affected joints,no symptoms, no eye involvement,normal sedimentation rate, andphysician’s global assessment of noactive arthritis.

“Nearly one third of patients over-all achieved clinical inactive diseaseby 6 months of therapy, which isremarkable,” she stated.

The strongest predictor of achievingclinically inactive disease at 6 monthswas disease duration. The odds ofachieving clinically inactive diseaseincreased by 30% for each month ear-lier that treatment was initiated after

the onset of symptoms (P = .011).Patients in both arms of the study

showed significant improvement at 6months on physicians’ global assess-ments of disease activity, parents’global assessments of well-being,number of joints with arthritis, andnumber of joints with limited motion.

At 12 months, clinical remission(defined as 6 months of inactive dis-ease on medication at 12 months)was achieved in 21% of those in theMEP arm versus 7% of those ran-domized to the MTX arm.

The frequency of grade 3 or higheradverse events was similar in botharms of the study.

In a separate interview, Stacy Ardoin,MD, Assistant Professor, Divi sion ofRheumatology and Immunology, atOhio State University Medical Centerin Columbus, said that not all childrenwith JIA should have early aggressivetreatment, but that the study is reas-suring regarding safety and diseasecontrol with this approach. “We needmore data on optimal therapy for JIA.It is not clear [yet] whether it is best toinitiate treatment with less-intensivetherapy and then add biologics, or tostart with our strongest therapies,”she said. �

Early Aggressive Therapy Effective in... Continued from cover

“This studysets a newstandard fortreatment,response, and

outcomes for children withpolyarticular JIA.”

—Carol Wallace, MD

Chicago, IL—An excellent response toetanercept (Enbrel) in patients withjuvenile idiopathic arthritis (JIA) wassignificantly associated with youngerage and less disability at disease onset,as well as less use of antirheumaticdrugs before initiating etanercept. Apoor response was significantly associ-ated with onset of systemic JIA andwith female sex.

The results from an observationalstudy by Marieke H. Otten, MD, MSc,of the Department of Pediatrics/ Pedi -atric Rheumatology, Erasmus MedicalCenter Sophia Children’s Hospital,Rotterdam, the Netherlands, and col-leagues will be useful for selectingpatients with JIA who are likely torespond to etanercept and for avoidinguse of this expensive drug in patientsunlikely to benefit from receiving it.

The use of disease-modifying anti -rheumatic drugs (DMARDs) earlier inthe course of disease has improvedoutcomes in patients with JIA. “A treat-ment goal of reaching inactive disease

now seems realistic. However, inactivedisease is still not achieved in a sub-stantial number of patients, and cur-rent approaches need to be optimizedeven more,” said Dr Otten, lead authorof the study.

The study was published online(Otten MH, et al. JAMA. 2011; 306:2340-2347) to coincide with its presen-tation at the 2011 American College ofRheumatology meeting.

Although etanercept has beenapproved in Europe and the UnitedStates for approximately a decade, nostudies have explored predictors ofresponse in children. The study wasbased on the Arthritis and Biologicalsin Children Register that includes allpatients with JIA in the Netherlandswho are currently or were previouslyreceiving treatment with biologicagents since 1999, when biologics werefirst introduced. The study populationincluded 262 pa tients with JIA whowere previously biologically naïvewhen they initiated treatment with

etanercept. Of the participants, 71%were female, the median age at JIAonset was 6.9 years, and the medianage at the start of etanercept was 12.4years; 46 (18%) patients had systemic-onset JIA, and the median age at initia-tion of etanercept was 12.4 years.

Responses evaluated at 15 monthswere categorized as excellent, interme-diate, and poor. An excellent response(defined as inactive disease or discon-tinuation as a result of disease remis-sion) was observed in 85 patients (32%).An intermediate re sponse (defined as>50% improvement from baseline butno evidence of inactive disease) wasseen in 92 patients (46%). A poorresponse (defined as <50% improve-

ment from baseline or discontinuationbecause of ineffectiveness or intoler-ance) was seen in 85 patients (32%).

During the first 15 months of thestudy, 1 or more adverse events (AEs)were reported in 119 patients, includ-ing infectious, noninfectious, and seri-ous AEs. AEs were reported in 37patients with an excellent response, 36patients with an intermediate response,and 46 patients with a poor response.

A secondary analysis was per-formed in 262 patients with a medianfollow-up of 35.6 months after initia-tion of etanercept. Over a period of 4 to7 years, 37% to 49% of patientsachieved inactive disease. Only 39patients (15%) tried to discontinueetanercept (of which 15 relapsed andneeded to restart etanercept).

There were no head-to-head com-parisons with other DMARDs, so it isnot known whether patients with asuboptimal response could have had abetter response to another agent, DrOtten stated. �

Factors Identified for Improved Response to Treatment for Juvenile Idiopathic ArthritisBy Phoebe Starr

Juvenile Idiopathic Arthritis

“A treatment goal ofreaching inactive diseasenow seems realistic.”

—Marieke H. Otten, MD, MSc


Ameta-analysis of studies ofmalignancies associated withtumor necrosis factor (TNF)

inhibitors indicates the drugs areassociated with a 45% increased riskfor developing a nonmelanoma skincancer but not with a significantlyincreased risk for lymphoma (MarietteX, et al. Ann Rheum Dis. 2011;70:1895-1904). The combined studies com-prise more than 40,000 patients andalmost 150,000 patient-years of expo-sure to TNF inhibitors.

“This analysis brings together thelatest information on malignancy asso-ciated with rheumatoid arthritis [RA]among people taking TNF inhibitors,”commented Edward Keystone, MD,FRCP, a senior consultant in rheuma-tology at Mount Sinai Hospital, andProfessor of Medicine, University ofToronto, Ontario. “And it shows thatwhile nonmelanoma skin cancer isincreased, solid malignancies are not.These agents have become the main-stay of treatment in people who failmethotrexate, and their benefits out-weigh the risks, but clinicians shouldbe aware of the fact that nonmelanomaskin cancer can occur.”

The European team that undertookthe meta-analysis analyzed 21 papersand 8 abstracts published or present -ed since 1998 that included data onmalignancies among people with RAreceiving TNF inhibitors. The investi-gators determined that the relative riskfor malignancy was not increased in

patients receiving TNF inhibitors com-pared with controls treated with dis-ease-modifying antirheumatic drugs(DMARDs), even among those takingTNF inhibitors for a long duration.

By analyzing the data of 3 rheuma-tology-related databases, the investi-gators found that the relative risk of

melanoma was not significantly ele-vated with TNF inhibitor therapy(1.79; 95% confidence interval [CI],0.92-2.67). The relative risk of lym-phoma also was not significantly ele-vated in people with RA receivingTNF inhibitors compared with thosereceiving classic DMARDs (1.11; 95%CI, 0.70-1.51). However, the standard-ized incidence ratio for lymphoma inpeople taking TNF inhibitors was sig-nificantly elevated, at 2.55 (95% CI,1.93-3.17), compared with people with -out RA in the general population.

“This meta-analysis provides clearevidence that treatment with TNF[inhibitors] results in a 45% increased

risk of nonmelanoma skin cancer,”stated lead investigator XavierMariette, MD, and colleagues.

They note that their results contrastwith those from 2 meta-analyses thatshow an odds ratio of 3.3 for develop-ing malignancies among patients withRA being treated with infliximab,

adalimumab, or etanercept (BongartzT, et al. JAMA. 2006;295:2275-2285;Bongartz T, et al. Ann Rheum Dis. 2009;68:1177-1183). How ever, the investiga-tors state that possible differences inexposure to the interventions andcomparators were not taken intoaccount, and that the increased riskoccurred only among people takinghigher doses of TNF inhibitors.

These findings follow another re centmeta-analysis that showed a 2-foldincreased risk for nonmelanoma skincancer but not for other cancers withthe use of TNF inhibitors in patientswith RA (Askling J, et al. Pharmacoepi -demiol Drug Saf. 2011;20:119-130).

“This systematic review and meta-analysis provides reassurance tophysicians and patients that the treat-ment of RA patients with TNFinhibitors does not increase the risk ofmalignancy, particularly lymphoma,”the authors concluded. “However, itdoes appear to increase the risk of skincancer, including melanoma.”

They encourage researchers to pub-lish additional studies to add to thesolidity of the evidence base, particu-larly for individual malignancies. �

TNF Inhibitors Associated with Increased Risk ofNonmelanoma Skin Cancer but Not LymphomaBy Rosemary Frei, MSc

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

Chicago, IL—Patients who initiate treat-ment with tumor necrosis factor (TNF)inhibitors for autoimmune diseases arenot as likely to develop serious infec-tions as those who start treatment withnonbiologic drugs, according to a studypresented at the 2011 American Collegeof Rheumatology meeting.

In a retrospective cohort study com-paring TNF inhibitors with nonbio -logic therapies, Carlos G. Grijalva,MD, MPH, Assistant Professor of Pre -ventive Medicine, Division of Phar -macoepidemiology, Vanderbilt Uni -versity, Nashville, TN, and colleaguesfound the rate of serious infections tobe approximately 8 per 100 person-years with each type of treatment.

Most previous safety studies of

TNF inhibitors had small samplesizes, short follow-up periods, andgrouped TNF inhibitors in a singlecategory. The investigators used amulti-institution collaboration of 4large databases (Kaiser PermanenteNorthern California, New Jersey andPennsylvania Pharmaceutical Assis -tance programs, Tennessee Medicaid,and national Medicare/Medicaid),together known as the Safety Assess -ment of Biologic Therapies (SABER),to assemble cohorts of patients withrheumatoid arthritis (RA), inflamma-tory bowel disease (IBD), and psori-atic arthritis, and matched controlsfor each group.

The databases were examined forthe incidence of hospitalization for

serious infections. The sample includ-ed 10,484 comparator pairs with RA,2323 pairs with IBD, and 3215 pairswith psoriasis and spondyloarthrop -athies. A propensity score matchinganalysis was used to control for poten-tial confounders. Follow-up lasted fora maximum of 1 year.

A total of 1172 infections thatrequired hospitalization occurredbetween 1998 and 2007, with 53%being pneumonia or skin and soft-tissue infections.

Among patients with RA who start-ed treatment with a TNF inhibitor, therate of serious infection requiring hos-pitalizations was 8.16 per 100 person-years, which was not significantly dif-ferent from the rate of 7.78 per 100

person-years among patients with RAwho started therapy with a regimenof a nonbiologic disease-modifyingantirheumatic drug.

Differences in the rates of hospital-ization for serious infections emergedbetween the TNF inhibitors. Amongthe patients with RA, the rate ofserious infection with infliximab(Remicade) was 26% higher than foretanercept (Enbrel) and 23% higherthan for adalimumab (Humira), com-mented Dr Grijalva.

Among patients with RA, baselineuse of corticosteroids was associatedwith a dose-dependent increase inrisk for infections, ranging from a 32%increase in risk with baseline dosages

TNF Inhibitors Are Not Linked to Serious Infection RiskBy Wayne Kuznar

Drug Therapy


“These agents have become themainstay of treatment in people whofail methotrexate, and their benefitsoutweigh the risks, but clinicians shouldbe aware of the fact that nonmelanomaskin cancer can occur.”

—Edward Keystone, MD, FRCP


Although completely misun-derstood and often maligned,fibromyalgia (FM) is a func-

tional somatic syndrome estimatedto affect 2% to 4% of the population,with a female to male incidence ratioof approximately 4:1. Onset is typical-ly between the ages of 20 and 60 years,with a mean age of 49 years. The puz-zling symptoms of FM may includeany number of signs and symptoms—chronic (>3 months) and widespreador localized pain and allodynia,hyperesthesia, fatigue, sleep distur-bance, joint stiffness, difficulty swal-lowing, functional bowel abnor -malities (especially irritable bowelsyndrome), numbness, tingling, cog-nitive dysfunction, depression, anxi-ety, and comorbid rheumatologicconditions. Affected patients reportincreased difficulty with activities ofdaily living, including walking andclimbing stairs. FM has a profoundimpact on the affected patient’s quali-ty of life. It can interfere with the abil-ity to work, thereby resulting in loss ofproductivity, and it can result in emo-tional problems.

FM is a controversial diagnosis thatlacks scientific consensus. The diag-nostic criteria for FM were firstreleased in 1990 and are currentlybeing updated by the AmericanCollege of Rheumatology (ACR); theyinclude evaluation of the major clini-cal symptoms and a focus on chronicwidespread pain with at least 11 of 18predefined tender points throughoutthe musculoskeletal system.

However, recent studies emphasizethe degree and number of somaticsymptoms rather than tender pointsas indicators. The ACR preliminarydiagnostic criteria use the WidespreadPain Index and the Symptom Severity

Scale, which both have a score range of0 to 12; scores of >6 on either scale areconsidered diagnostic of FM. There issignificant debate regarding the valueof clinical and radiologic workup ofthese patients, especially because FMis primarily a diagnosis of exclusion. If

FM is suspected, autonomic dysfunc-tion questionnaires and the Fibro -myalgia Impact Ques tionnaire mayaid in diagnosing it and monitoringpatients’ responses to therapy.

Recent research on scientific andclinical hypotheses for the pathophys-iology and etiology of FM include:• Genetic predisposition• External triggers, such as psycho-

logical stress trauma or infection• Disruption of normal dopamine-

related neurotransmission• Abnormal serotonin metabolism• Deficient growth hormone secretion• Psychological factors, such as major

depression• Autonomic dysfunction• Aberrant immune response to intes -

tinal bacteria.Optimal, value-based approaches

to FM therapies are also the subject ofintense debate. For example, there isthe question of the appropriate health-care provider to manage patients withFM—is it the rheumatologist, neurolo-gist, psychiatrist, or primary carephysician?

Currently the US Food and DrugAd ministration (FDA)-approved phar -macologic approaches to managingFM include pregabalin (Lyrica),duloxetine (Cymbalta), and mil-nacipran (Savella). The comparativesafety and efficacy of these 3 agentshave been studied in 17 randomizedcontrolled trials involving a total of7739 patients with FM. All 3 drugswere found to be superior to placebofor fatigue, with milnacipran and pre-gabalin being superior to duloxetine.Improvements in sleep disturbancewere found only with milnacipran,and only pregabalin was found to besuperior to placebo in treatingdepressed mood. In terms of painmanagement, all 3 agents were associ-ated with an approximate 30% reduc-tion in pain, with no significant differ-ences among them. This suggests thatdrug choice should primarily besymptom-based. Other therapies, in -cluding aerobic exercise, hydrotherapy,and multicomponent therapy, shouldbe offered as adjunctive therapy.

There are also anecdotal data onnon–FDA-approved medications, in -cluding tricyclic antidepressants, tra-madol (Ultram), opioids, and combina-tion therapies (eg, trazodone [Desyrel]plus pregabalin), each of which is

associated with specific cautionsregarding their use (eg, some opioidsmay worsen symptoms of FM).

Nonpharmacologic approaches totreatment have also been studied,including cognitive behavioral thera-py (eg, mindfulness-based stressreduction) and complementary andalternative medicine therapies, in -cluding meditative movement therapy,massage therapy, acupuncture, andtraditional Chinese medicine.

There is ongoing active researchregarding FM to further our under-standing of the disease, including useof functional magnetic resonanceimaging, investigation of opioidreceptors in the brain, and somaticanalyses. Further study will berequired before these efforts impactclinical practice. �

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

Fibromyalgia

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

FM is a functional somaticsyndrome estimated toaffect 2% to 4% of thepopulation, with a female-to-male incidence ratio ofapproximately 4:1.

There is significant debateregarding the value ofclinical and radiologicworkup of these patients,especially because FM isprimarily a diagnosis of exclusion.

<5 mg daily to nearly triple the riskwith dosages >10 mg daily.

“The findings were consistentacross diseases,” said Dr Grijalva.

Among patients with psoriasis orspondyloarthropathy, the risk ofinfections was higher for patientsreceiving glucocorticoid doses of 5 to10 mg daily (hazard ratio [HR] 2.01;95% confidence interval [CI], 1.08-3.73) and >10 mg daily (HR 2.77; 95%CI, 1.44-5.32) compared with no glu-cocorticoid use.

The data provide reassurance forpatients and providers that TNF

inhibitors did not increase the risk ofserious infections when compared

with other nonbiologic treatments, DrGrijalva said.

In an editorial that accompaniedthe publication of the study (GrijalvaCD, et al. JAMA. 2011;306:2331-2339),Will Dixon, PhD, of the University ofManchester, England, and David T.Felson, MD, MPH, of Boston Uni -versity School of Medicine, wrote,“These intriguing findings need rep -lication in other studies. Neverthe -less, the report by Dr Grijalva et alraises important questions about thecomparative safety of immunosup-pressant and biologic therapy andmay prompt a reevaluation of anti-TNF safety.” �

TNF Inhibitors... Continued from page 21

Differences in the rates of hospitalizationfor serious infections emerged betweenthe TNF inhibitors. Among the patientswith RA, the rate of serious infectionwith infliximab was 26% higher than foretanercept and 23% higher than foradalimumab.

—Carlos G. Grijalva, MD, MPH

vbcr may vol 1, no 2

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