Patients with fibromyalgia hadsignificant improvement in pain,sleep, and quality-of-life mea -

sures when treated with pregabalin

(Lyrica) versus placebo, according tothe results of the first clinical trial ofthis condition in Japan (Ohta H, et al.Arthritis Res Ther. 2012;14:R217 [Epub

www.ValueBasedRheumatology.com

OCTOBER 2012 VOL 1• NO 5Value-Based

Care inRheumatologyFROM THE PUBLISHERS OF AMERICAN HEALTH & DRUG BENEFITS®

TM

First-Ever ACR Guidelinesfor the Management of Patients with GoutBy Neil Canavan

Patients with FibromyalgiaImprove Rapidly withPregabalinFirst Japanese clinical trial for this conditionBy Charles Bankhead

© 2012 Engage Healthcare Communications, LLC

For the first time in its 78-year history, the American College ofRheumatology (ACR) has issued guidelines for the management ofgout in October, which were published in 2 parts (Khanna D, et al.

Arthritis Care Res. 2012;64:1431-1461).

Systemic Lupus Erythematosus:New Genetic Risk Factors forThrombosis Identified Can inform clinical decision-makingBy Alice Goodman

Thrombosis is more common inpatients with systemic lupuserythematosus (SLE) than in the

general population and is associatedwith increased mortality. Researchershave recently identified specific genet-ic risk factors for thrombosis in pa -

tients with SLE, and results of theirstudy suggest that these risk factorsdiffer among ethnic groups (Kaiser R,et al. J Rheumatol. 2012;39:1603-1610).

These findings may help predictwhich patients with SLE are at in -

GOUT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6Gout management often inappropriateLead in blood associated with gout

FIBROMYALGIA . . . . . . . . . . . . . . . . .10Motivation interviewing in patientsprovides mixed results

FDA UPDATE . . . . . . . . . . . . . . . . . . . .14Actemra indicated for RAHumira approved for ulcerative colitisProlia indicated for men with OA

PERSONALIZED MEDICINE inRheumatology™ . . . . . . 15

New osteoarthritis biomarker

ECONOMIC ISSUES IN RHEUMATOLOGY . . . . . . . . . . . . . . .17Cost-effectiveness of biologics influenced by RA severity

RHEUMATOLOGY UPDATE . . . .18TNF inhibitors not linked to cancer

OSTEOARTHRITIS . . . . . . . . . . . . . .20Physicians’ bias in knee replacement

Rheumatology PRACTICEMANAGEMENT™ . . . . . . . . . . . . . . . . . .22

I N S I D EContinued on page 10

Continued on page 5

Continued on page 15

High EmergencyDepartment Utilization andCosts for Gout Detailed forFirst TimeIncreasing incidence, expendituresBy Rosemary Frei, MSc

The incidence of gout is on therise, and with it the cost of care.Between 2006 and 2008, gout

was associated with >280 million visitsto the emergency department in theUnited States, with median costsincreasing annually. In 2008, nearly175,000 emergency department visitswere made by patients with gout astheir primary complaint, totaling $166

million, according to the first-everanalysis of gout-related utilization andcost of care in US emergency depart-ments (Garg R, et al. Arthritis Care Res[Hoboken]. 2012 Sep 4 [Epub ahead ofprint]).

These findings, the researchersnote, confirm that gout, which is themost common inflammatory arthritis,

Continued on page 16

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Ted R. Mikuls, MD

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CALL FOR PAPERS

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Readers are invited to submit articles that aim at improving the quality of patient care and patient well-beingwhile reducing or controlling costs, enhancing the health of communities and patient populations, as well as othertopics relevant to benefit design with specific implications to policymakers, payers, and employers.

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

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Trends in Biologic Therapies for RA

91

www.AH

DBonline

.com l Am

erican He

alth & Dr

ug Benef

its l

Vol 5, N

o 2 l Ma

rch/Apri

l 2012

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

Value has

been defi

ned as th

e relation

ship betw

een

benefits

and costs

. Using

mathemat

ical conc

epts,

value ha

s been de

scribed as

“value =

benefits/

cost” or

the units

of benefit

derived

from a gi

ven num

ber of

units of c

osts. App

lying this

definitio

n, if we w

ish to

maximize

the valu

e of a ther

apy, there

are only 2

ways

to achie

ve it: ei

ther by

increasing

the ben

efits

obtained

from the

therapy, o

r by decr

easing the

cost

paid for t

hat thera

py.

Value in h

ealthcare

is also a fu

nction of

perspectiv

e.

What ma

y be con

sidered v

aluable to

an indiv

idual

patient u

ndergoin

g treatme

nt or to

a physici

an pre-

scribing t

hat treatm

ent to a s

imilar gro

up of pat

ients

may not n

ecessarily

be consid

ered valua

ble to the

same

extent by

a payer, w

ho must n

ot only pa

y for that

indi-

vidual’s t

reatment

but who

also has

to manag

e the

needs of

multiple

groups of

patients

and/or m

embers

with equa

lly compel

ling medi

cal condi

tions and

prior-

ities. Opt

imizing v

alue with

in the he

althcare s

ystem

means tha

t physici

ans and p

ayers mus

t be align

ed in

the way th

ey view t

he variou

s benefits

and costs

of a

given trea

tment.

Achievin

g such op

timization

is where

the artic

le by

Ms Green

apple in th

is issue of

American Health & Drug

Benefitsfits i

n. In her

article,

Ms Green

apple sho

ws

that prov

iders and

payers, at

least whe

n it comes

to the

use of bio

logics for

the treatm

ent of rhe

umatoid a

rthri-

tis, have m

uch more

in comm

on than n

ot when

look-

ing at val

ue within

this drug

class. Th

e finding

s from

this surve

y have s

everal im

portant im

plications

to

providers

, payers, a

nd patien

ts/plan me

mbers.

PROVIDERS: Providers

can p

ractice

more

autonom

ously in a

ddressing

the need

s of the p

atient

with rheu

matoid ar

thritis. T

hey can d

o this by

follow-

ing evide

nce-based

guideline

s as they

initiate

treat-

ment wit

h disease-

modifyin

g antirheu

matic dru

gs, and

only prog

ress to m

ore costly

biologic

therapies

when

they need

to improv

e treatme

nt benefit

s, thereby

opti-

mizing the

value of

treatmen

t. Such st

aged man

age-

ment is a

ligned wit

h payer c

overage p

olicies.

PAYERS: For paye

rs, this iss

ue is a ma

tter of exp

ec-

tation. Kn

owing tha

t provider

s practice

using the

same

specialty g

uidelines

that paye

rs follow w

ill allow p

ayers

to expect

that their

contract

ed provid

ers will “d

o the

right thin

g” when

it comes

to promo

ting evide

nce-

based med

icine whe

n treating

patients

with rheu

ma-

toid arthr

itis.

PATIENTS/PLAN MEMBERS: When

provider

practice i

s aligned

with plan

policy, p

atients or

plan

members

are the u

ltimate w

inners. A

s is descri

bed in

this artic

le, with 8

4% of pro

viders rep

orting app

roval

rates of at

least 61%

of reques

ts for rheu

matoid ar

thritis

biologics (

and 55%

reporting

approvals

of at least

81%

of such r

equests),

patients w

ho need

more inte

nsive

treatmen

t for thei

r arthriti

s can rece

ive it in

a more

timely an

d coordina

ted manne

r.

MEDICAL DIRECTORS: Does th

is mean

that

payers sh

ould stop

enforcing

step the

rapies or

other

such stra

tegies? Re

gretfully,

not yet; c

omplete

buy-in

to evide

nce-base

d medic

ine has

not yet

been

achieved

, and we c

ontinue to

see treat

ment irre

gular-

ities for c

ertain dis

ease state

s. Perhap

s one day

soon,

with the

advancem

ent of me

aningful

use param

eters

by provid

ers, alon

g with e

lectronic

medical

records

and decis

ion supp

ort system

s promoti

ng evide

nce-

based me

dicine, we

will be a

ble to get

there. Af

ter all,

reaching s

uch a go

al for rhe

umatoid

arthritis,

or any

other sig

nificant

condition

, would

not only

be

admirabl

e, but mo

re importa

nt, it wou

ld provid

e great

value in

healthca

re.

Albert Tzeel,

MD, MHSA, FACPE

National

Medical D

irector, H

umanaOn

e

Milwauke

e, 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 for

Rheumatoid 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.comDisclosures 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

In This Issue

PublisherNicholas Englezosnick@engagehc.com732-992-1884

Editorial DirectorDalia Bufferydalia@engagehc.com732-992-1889

Associate PublisherAmerican Health & Drug BenefitsMaurice Nogueiramaurice@engagehc.com732-992-1895

Associate EditorLara J. Lortonlara@engagehc.com732-992-1892

Editorial AssistantJennifer Brandtjbrandt@the-lynx-group.com732-992-1536

Director, Client ServicesZach 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: 732-992-1880 Fax: 732-992-1881

Permission requests to reprint all or part of any articlepublished in this magazine should be addressed to editorial@engagehc.com.

Address all editorial queries to: editorial@engagehc.comTelephone: 732-992-1536 Fax: 732-992-1881

Value-Based Care in Rheumatology, ISSN applied, is published 6 times a year by Engage HealthcareCom munications, LLC, 1249 South River Road,Suite 202A, Cranbury, NJ 08512. Copyright © 2012by Engage 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,1249 South River Road, Suite 202A, Cranbury, NJ08512. Fax: 732-992-1881. Yearly subscription rates:1 year: $99.00 USD; 2 years: $149.00 USD; 3 years:$199.00 USD.

VBCR Advisory Editorial Board

GOUTFirst-ever ACR guidelines for gout management Only 50% of physicians treat gout according to ACR guidelinesPoorly managed gout major driver in increasedhealthcare utilization for veteransMore….

FIBROMYALGIAMotivation interviewing to encourage exerciseprovides mixed resultsMore….

PSORIATIC ARTHRITISApremilast shows promising results in 3 pivotal trials

FDA UPDATEExpanded indication for Actemra for RAHumira approved for ulcerative colitisProlia indicated for men with osteoarthritis

PERSONALIZED MEDICINE inRheumatology™

New genetic risk factors for thrombosis inpatients with lupus Biomarker may lead to blood test to measureosteoarthritis severity

ECONOMIC ISSUES INRHEUMATOLOGYHigh emergency department utilization andcost for gout Cost-effectiveness of biologics affected by RAdisease severityMore….

RHEUMATOLOGY UPDATEDisease activity trajectory important in patients’ willingness to change RA medicationNo link between TNF inhibitors for RA and cancerMore….

OSTEOARTHRITISEffect of walking program on exercise adherence and physical activityPhysician bias uncovered in knee replacementsurgery recommendationsSocioeconomic burden of OA-related hip and knee replacement reached “remarkable” levelsMore….

Rheumatology PRACTICEMANAGEMENT™

Accountable care organizations

Value-Based CareinRheumatology

FROM THE PUBLISHERS OF AMERICAN HEALTH & DRUG BENEFITS®

TM

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 ServicesCatamaran Center of ExcellenceNorthwest RegionPortland, 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

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, Jr, RPh, MBA Pharmacy Operations ManagerHarvard Pilgrim Health CareWellesley, MA

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

3VOL. 1 I NO. 5 OCTOBER 2012 I www.ValueBasedRheumatology.com

Immune Response BioPharma Applies for OrphanDesignation for Its New Juvenile RheumatoidArthritis Vaccine

Immune Response BioPharma, Inc, has submitted an application to theUS Food and Drug Administration for an orphan designation for its newvaccine, Ravax, which targets the immune system of patients with juve-nile rheumatoid arthritis (RA).

“RAVAX is a first in class and best in class vaccine for rheumatoidarthritis, which works by down regulating aberrant T cells and treatingthe underlining causes of the RA disease. Orphan designation will allowfor a more speedy development of RAVAX and will give us further flexi-bility in trial design and expand the RA vaccine use into the rare disease,JRA [juvenile RA], said David Buswell, Chief Operating Officer andInterim Chief Executive Officer of Immune Response BioPharma. Thedrug’s manufacturer believes that through vaccination with T-cell recep-tor peptides specific to the autoreactive T-cells, the patient’s immune sys-tem may be stimulated to downregulate and turn off the aberrant T-cellswithout involving normal cells. Ravax provides specific treatment with-out total immunosuppression, and, at the same time, uses typical path-ways of self-regulating the immune system.

The filing of the new application is seen as a step forward in the devel-opment of this unique vaccine for patients with juvenile RA, charting anew approach to therapy for this patient population.

Immune Response BioPharma believes that the new vaccine may inhibitthe T-cells that cause RA, which could prevent the development of or thedeterioration of RA. The company has completed two phase 2 clinical tri-als with Ravax in patients with RA. A phase 2b trial with the vaccineinvolving 340 patients with RA showed a significant treatment responseafter the third injection using the American College of Rheumatology 20%response rate criteria (ACR20) in reducing swollen joint counts. ImmuneResponse BioPharma, Inc, press release, October 23, 2012

Gout Can Be Cured If Properly Managed Gout is a common inflammatory arthritis with appropriate treatments

and a well-understood disease mechanism, yet many patients are notreceiving appropriate therapy; therefore, a disease that is curable is onlyseldom cured. The recent guidelines issued by the ACR for the manage-ment of this disease highlight the need for early treatment, including thetreatment of acute gouty attacks within 24 hours, reducing serum uratelevels to below 6 mg/dL, and prescribing appropriate pharmacotherapywith currently available medications that can control serum urate levelsin these patients.

In addition to the guidelines that are discussed in this issue of Value-Based Care in Rheumatology (page 1), another article also mentioned in thisissue (page 6) highlights the current reality that only approximately 50%of physicians manage patients with gout according to the recent ACR rec-ommendations, leaving much room for improvement to change the faceof this disease by adhering to evidence-based practice guidelines.

Discussing the question of why a curable disease is so seldom cured,Michael Doherty, MD, and colleagues note in a recent article that“Doctors often focus on managing acute attacks rather than viewing goutas a chronic progressive crystal deposition disease. Urate-lowering treat-ment is underprescribed and often underdosed. Appropriate educationof patients and doctors…may help to overcome these barriers andimprove management of this easily diagnosed and curable form of poten-tially severe arthritis.” Ann Rheum Dis. 2012;71:1765

New Questionnaire Helps Rheumatologists andPatients Identify Foot and Ankle Problems in RA

The majority of patients with RA have disabilities related to their footor ankle; however, these problems are often being ignored by physiciansand are not always properly managed. Now a new and simple question-naire, which is available to the public free of charge, can help physiciansand patients to detect foot and ankle problems in patients with RA.

What makes this questionnaire different from many other generalquestionnaires is that it was specifically designed by rheumatologists inthe United Kingdom to be directed toward patients with RA and not allpatients with disabilities or pain. Most questionnaires that are designedto assess the foot in persons with musculoskeletal conditions do notinvolve the ankle in the assessment, even though the ankle is often affect-ed in RA. The new questionnaire, called the Swindon Foot and AnkleQuestionnaire, includes 10 quick questions, with accompanying illustra-tions of the foot, that can help patients to identify the exact location oftheir problem. This questionnaire can even be used by those patients whoare not well-versed in medical terminology. The team that developed thequestionnaire suggests that patients should be able to complete it in lessthan a minute. Waller R, et al. The Swindon Foot and Ankle Question -naire. ISRN Rheumatology. 2012

Novel Approach to Autoimmune DiseasesMay Lead to New Therapies

Researchers at Duke University Medical Center have found that repro-ducing a rare type of B-cell and infusing it back into the body may poten-tially be an effective way of treating autoimmune diseases, such as RAand multiple sclerosis.

“Regulatory B-cells are a fairly new finding that we’re just beginning to understand,” said coauthor Thomas F. Tedder, PhD, Professor ofImmunology, Duke University Medical Center. “B10 cells are important,because they make sure an immune response doesn’t get carried away,resulting in autoimmunity or pathology. This study shows for the firsttime that there is a highly controlled process that determines when andwhere these cells produce IL-10.”

Dr Tedder and colleagues have been studying the reproduction of B10cells in mice, showing that B10 cells only respond to specific antigens.Using this information, the researchers set out to see if B10 cells could beused as a cell-based therapy to regulate the immune response in patientswith autoimmune diseases.

“Autoimmune diseases are very complicated, so creating a single ther-apy that allows us to go after multiple disease targets without causingimmunosuppression has proven difficult. Here we are hoping to takewhat Mother Nature has already created, improve on it by expanding thecells outside of the body, and then put them back in to let Mother Naturego back to work.”

More research is needed to understand how to expand B10 cells andhow they work in humans before B10-based therapies can be developedfor patients with RA. Yoshizaki A, et al. Nature. 2012 Oct 14

Value Propositions

4 VALUE-BASED CARE IN RHEUMATOLOGY I OCTOBER 2012 VOL. 1 I NO. 5

The first part, titled “SystematicNonpharmacologic and Pharma -cologic Therapeutic Approaches toHyperuricemia,” addresses severalkey considerations for treating pa -tients with gout, including:➤The need for lowering serum uric

acid levels to <6 mg/dL➤The appropriate dosing for first-

and second-line treatment options,including guidance on the recentlyUS Food and Drug Administration(FDA)-approved drugs febuxostat(Uloric) and pegloticase (Krystexxa)➤Dietary recommendations➤Recommendation that patients

who are at high risk for severeallopurinol (Zyloprim) sensitivityundergo genetic testing for theHLA-B*5801 allele.“Acute gout attacks can be debili-

tating and [can] adversely affectpatients’ quality of life,” said one ofthe lead authors of the guidelines,John D. Fitzgerald, MD, PhD, Act -ing Rheumatology Division Chief atthe University of California, LosAngeles, in a September 28, 2012,press release on the guidelines(www.wiley.com/WileyCDA/PressRelease/pressReleaseId-105332.html?print=true). “In order to improve pa -tient care, the ACR funded this col-laborative effort among US re -searchers to produce guidelines,outlining pharmacological therapiesand nondrug treatments to managegout,” Dr Fitzgerald said.

Answering the Need

Gout is the most common inflam-matory arthritis representing a meta-bolic disorder that is characterized byinadequate elimination of uric acidfrom the blood; uric acid is a break-down product of purines, which areessential components for makingDNA and RNA. Elevated serum lev-els of uric acid (ie, hyperuricemia)lead to eventual precipitation and todeposition of urate crystals in thejoints of the extremities, therebycausing severe inflammation and,often, debilitating pain.

Gout affects an estimated 8.3 mil-lion adults in the United States, andits prevalence has been increasing inthe past 20 years. Factors driving thisincrease include more incidences ofcomorbidities that promote hyper-uricemia (eg, hypertension and type2 diabetes), the use of diuretics forcardiovascular disease, and dietarytrends.

Although the number of patientswith gout is rising, the authors of the new ACR guidelines state that,“Despite advanced understanding ofthe molecular bases of hyperuricemiaand gouty inflammation and theextensive practice experience of manyproviders, substantial quality of caregaps exist in gout management.”

The new guidelines were request-ed by the ACR and reflect the conclu-

sions of recent clinical research ingout mechanisms and management,including recommendations regard-ing new pharmacologic agents forgout.

To formulate the ACR recommen-dations, Dr Fitzgerald and colleaguesreviewed medical literature publishedfrom the 1950s to the present. A taskforce panel of experts in the field,including 7 rheumatologists, 2 pri-mary care physicians, 1 nephrologist,and 1 patient representative, thenranked and voted on the key findings.

The recommendations reflect therole of a genetic component in goutin relation to testing for the HLA-B*5801 allele before the initiation oftherapy with the xanthine oxidaseinhibitor allopurinol, acknowledgingthe potential role of personalizedmedicine in gout.

Core Recommendations

1. Patient education on diet, life -style, and the management of comor-bidities is a recommended core thera -peutic measure in patients with gout

Clinicians are urged to look forcomorbid conditions that may becausing hyperuricemia (ie, renal dis-ease); a checklist of these conditions is provided in the guidance. Accord -ingly, agents used to treat such comor-bidities should be considered for theirurate-elevating potential (ie, thiazidesand loop diuretics). Those medicinesdeemed nonessential to the manage-ment of comorbid conditions shouldbe reduced or eliminated.

Regarding diet, the task force pan -el has provided a table of itemsgrouped into the 3 recommendationcategories of “avoid,” “limit,” and “en -courage.” Examples include avoidingorgan meats that have a high purinecontent, high fructose corn syrup,and, during a gout attack, any con-sumption of alcohol; limiting intakeof most meats, sugar, salt, and alco-hol; and encouraging a low-fat dietwith vegetables.

2. Serum urate level should be low-ered sufficiently to durably improvethe signs and symptoms of gout,with the target of <6 mg/dL at min-imum, and often <5 mg/dL

The panel recommends a serumuric acid target of <6 mg/dL in allpatients with gout, and a target of <5 mg/dL in patients who remainunable to achieve a durable reduc-tion in gout episodes or symptoms,including tophi that are palpable orvisible by physical examination.

During the titration period after

treatment initiation, the panel recom-mends monitoring serum uric acidevery 2 to 5 weeks. After target levelsare achieved, serum uric acid levelsshould be assessed every 6 months.

3. Xanthine oxidase inhibitor (XOI)therapy with allopurinol or withfebuxostat is recommended as thefirst-line pharmacologic urate-lower-ing therapy (ULT) approach

In cases where XOIs are contraindi-cated as a result of concurrent medica-tions or conditions or because of XOIintolerance, probenecid (Benemid) isrecommended as an alternative first-line ULT. Regarding timing, ULTmay be initiated during an acutegout attack, as long as effective anti-inflammatory management has beeninstituted as well.

4. The starting dosage of allopurinolshould be ≤100 mg daily and up to80 mg daily in patients with moder-ate-to-severe chronic kidney disease(CKD), followed by gradual upwardtitration of the maintenance dose,which can exceed 300 mg daily,even in patients with CKD

These recommendations are con-sistent with the previous guidelinesfrom the FDA and the EuropeanLeague Against Rheumatism. Thepanel’s rationale for starting with thislower dose is to mitigate the potentialfor a severe allopurinol hypersensi-tivity reaction.

Prescribing allopurinol in a dose of<300 mg daily is deemed valid by thetask force panel in consideration ofdata showing that roughly 50% of allpatients with gout fail to achieve tar-get serum uric acid levels below thatthreshold. As the task force panelstates, “Maintenance dosage of allo -purinol can be raised above 300 mgper day, even in those with renalimpairment, provided there is ade-quate patient education and regularmonitoring for drug hypersensitivityand other adverse events.” The max-imum FDA-approved dose of allo -purinol is 800 mg/day.

The maximum dose for febuxostatis 80 mg/day; however, the task forcepanel has found data to support amaximum dosing level of 120mg/day. This dose level is approvedin many countries outside of theUnited States in the setting of activedisease refractory to appropriatelydosed oral ULT.

5. Before the initiation of allopuri-nol, HLA-B*5801 screening should

5VOL. 1 I NO. 5 OCTOBER 2012 I www.ValueBasedRheumatology.com

First-Ever ACR Guidelines for... Continued from cover

Gout

Continued on page 6

“To improve patient care,the ACR funded thiscollaborative effort amongUS researchers to produceguidelines, outliningpharmacological therapiesand nondrug treatments tomanage gout.”

—John D. Fitzgerald, MD, PhD

at a glance

� Target serum urate level to<6 mg/dL

� Initiate allopurinol 100 mg/dayfor early disease (<50 mg/dayfor patients with advancedkidney disease)

� Febuxostat (up to 80 mg/day)can be used to controlhyperuricemia

� If these therapies fail, considerthe use of probenecid,fonofibrate, losartan, orpegloticase

� Counsel patients about theimportance of diet, uratecontrol, risk for kidney andcardiovascular disease, anddrug use that can affect uratelevels (ie, diuretics)

The new ACR guidelines for goutrecommend:

Only Half of Physicians Treat Gout According to New ACR Guideline Recommendations By Neil Canavan

Gout

6 VALUE-BASED CARE IN RHEUMATOLOGY I OCTOBER 2012 VOL. 1 I NO. 5

be considered in subpopulationswhere the allele is frequently elevat-ed and where allele-positive sub-jects are at high risk for severeallopurinol sensitivity reactions (eg,Koreans with ≥stage 3 CKD and allpatients of Han Chinese and Thaidescent)

The panel recommends that HLA-B*5801 screening be performed withthe rapid, widely available poly-merase chain reaction–based ap -proach. For inconclusive results, HLA-B*5801 sequencing is advised. If apatient tests HLA-B*5801–positive,alternatives to allopurinol should beprescribed.

The panel did not recommend uni-versal HLA-B*5801 screening, citingdata that indicate a prevalence of<2% of the allele for individuals out-side of the highlighted risk groups.

6. Combination oral ULT with 1XOI agent and 1 uricosuric agent isappropriate when the serum uratetarget has not been met by appropri-ate dosing of an XOI

The panel recommends the urico-suric agents probenecid, fenofibrate(TriCor; off-label use), or losartan(Cozaar; off-label use) as adjunctivetherapy in a comprehensive ULTprogram in the refractory diseasesetting. Nine refractory disease casescenarios are described within theguidance.

7. Pegloticase is appropriate forpatients with severe gout diseaseburden and refractoriness to, or in -tolerance of, appropriately dosedoral ULT options

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

ULT was not recommended for anypatient with gout.

Safety and Quality of Care

Commenting on the effort overall,Dr Fitzgerald stated in the pressrelease, “The ACR gout guidelinesare designed to emphasize safety,quality of therapy, and to reflect bestpractice based upon medical evi-dence available at this time. Our goalis that these guidelines, along witheducating gout patients in effectivetreatment, will improve adherence,quality of care, and management ofthis painful and potentially chroni-cally debilitating condition.”

Part 2 of the guidelines, titled“Therapy and Antiinflammatory Pro -phylaxis of Acute Gouty Arthritis,”will be discussed in the Decemberissue of this publication. �

First-Ever ACR Guidelines Issued for... Continued from page 5

Cincinnati, OH—Results of a newstudy suggest that despite the availabil-ity of urate-lowering treatments (ULTs)and the newly published AmericanCollege of Rheumatology (ACR) guide-lines for the treatment of gout, whichwere initially introduced at last year’sACR annual meeting, no more than50% of physicians are currently follow-ing these recommendations.

“The take-home message here isthat adherence to the guidelines is notvery good for any physician type,”lead investigator Robert J. Morlock,PhD, Head of Global Market Accessand Health Economics Consultant,Ardea Biosciences, San Diego, CA,and Adjunct Faculty at Henry FordHospital, Detroit, MI, told Value-BasedCare in Rheumatology. “Rheumatol -ogists are slightly better than primarycare providers, but neither group istreating enough of their patients to theguidelines.”

The study was presented at theOctober 2012 meeting of the Academyof Managed Care Pharmacy. In theirstudy, Dr Morlock and colleagues con-ducted a retrospective chart review ofpatients who were diagnosed withgout and were being seen by arheumatologist or by a primary carephysician (PCP).

To be included in the study, patientshad to be initiated with gout treatmentwith 1 of 2 xanthine oxidase inhibitors

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

All treating physicians had to haveat least 50 patients with a diagnosis ofgout in their practice within the pastyear. There were 125 rheumatologypractices (500 patients) and 124 PCPs (358 patients) included in theanalysis. Chart reviews were per-formed on the last 5 patients treatedwithin a given practice.

The patient cohort was assessed foradherence to the ACR guidelinesaccording to the following criteria:timely prophylaxis with a ULT, titra-tion to a target serum uric acid level of<6 mg/dL, and the number of assess-

ments of serum uric acid in 12months.

Results of the analysis were strik-ing. A key component of the guide-lines—frequent monitoring of thepatient—was routinely ignored. Afteran initial baseline measurement ofserum uric acid, only 68% of rheuma-tologists, and 53% of PCPs performeda second assessment within the first12 months after initiating treatment.

“After 2 or more gout episodes in ayear, the guidelines recommend treat-ing with a ULT,” explained DrMorlock. “That’s step 1. Step 2 asksthat you then follow urate levels—butif [physicians] aren’t taking anotherlaboratory value for a year or more,how can they say if the drug is opti-mally working or not?”

Reflecting the lack of recommendedfollow-up, the majority of patients inthis cohort did not achieve the sug-gested serum uric acid treatment goalof <6 mg/dL; only 50% of patients inrheumatology practices reached thistarget versus 36% of patients beingtreated by a PCP.

The cut-off point is not arbitrary—the goal of long-term ULT is to reduceserum uric acid levels below the satu-ration point of monosodium urate sothat new crystals do not form and soexisting crystals are dissolved. Yet,lacking the data for serum uric acidlevels, in this study 32% of rheumatol-

ogists and 57% of PCPs did not adjusttheir patients’ ULT dose to this treat-ment goal.

Given the evidence that it takes sev-eral years for physicians to incorpo-rate national guidelines into theirdaily practice, what can be done toimprove guideline adherence soonerin face of the significant disease bur-den on patients?

“What I’d like to see managedcare do is put metrics in place tomeasure or grade clinicians on fol-lowing the guideline,” Dr Morlocksuggested. Lacking that, he advisedphysicians to simply do a bit moretesting. “If you have the laboratoryassessments, you can adjust thetreatment accordingly.” �

“The take-home messagehere is that adherence tothe guidelines is not verygood for any physician type.Rheumatologists are slightlybetter than primary careproviders, but neither groupis treating enough of theirpatients to the guidelines.”

—Robert J. Morlock, PhD

“What I’d like to seemanaged care do is putmetrics in place to measureor grade clinicians onfollowing the guideline. Ifyou have the laboratoryassessments, you can adjustthe treatment accordingly.”

—Robert J. Morlock, PhD

“Our goal is that theseguidelines, along witheducating gout patients ineffective treatment, willimprove adherence, qualityof care, and management ofthis painful and potentiallychronically debilitatingcondition.”

—John D. Fitzgerald, MD, PhD

ORENCIA® (abatacept) for injection for intravenous use injection, for subcutaneous useBrief Summary of Prescribing Information. For completeprescribing information, please consult official packageinsert.INDICATIONS AND USAGEAdult Rheumatoid Arthritis (RA) - ORENCIA® (abatacept) isindicated for reducing signs and symptoms, inducing majorclinical response, inhibiting the progression of structuraldamage, and improving physical function in adult patients withmoderately to severely active rheumatoid arthritis. ORENCIA maybe used as monotherapy or concomitantly with disease-modifying antirheumatic drugs (DMARDs) other than tumornecrosis factor (TNF) antagonists.Juvenile Idiopathic Arthritis - ORENCIA is indicated forreducing signs and symptoms in pediatric patients 6 years ofage and older with moderately to severely active polyarticularjuvenile idiopathic arthritis. ORENCIA may be used asmonotherapy or concomitantly with methotrexate (MTX).Important Limitations of Use - ORENCIA should not beadministered concomitantly with TNF antagonists. ORENCIA isnot recommended for use concomitantly with other biologicrheumatoid arthritis (RA) therapy, such as anakinra.CONTRAINDICATIONSNone.WARNINGS AND PRECAUTIONSConcomitant Use with TNF Antagonists - In controlled clinicaltrials in patients with adult RA, patients receiving concomitantintravenous ORENCIA and TNF antagonist therapy experiencedmore infections (63%) and serious infections (4.4%) comparedto patients treated with only TNF antagonists (43% and 0.8%,respectively) [see Adverse Reactions]. These trials failed todemonstrate an important enhancement of efficacy withconcomitant administration of ORENCIA with TNF antagonist;therefore, concurrent therapy with ORENCIA and a TNFantagonist is not recommended. While transitioning from TNFantagonist therapy to ORENCIA therapy, patients should bemonitored for signs of infection.Hypersensitivity - Of 2688 patients with adult RA treated withORENCIA intravenously in clinical trials, there were two cases ofanaphylaxis or anaphylactoid reactions. Other events potentiallyassociated with drug hypersensitivity, such as hypotension,urticaria, and dyspnea, each occurred in less than 0.9% ofORENCIA-treated patients. Of the 190 patients with juvenileidiopathic arthritis treated with ORENCIA in clinical trials, therewas one case of a hypersensitivity reaction (0.5%). Appropriatemedical support measures for the treatment of hypersensitivityreactions should be available for immediate use in the event ofa reaction [see Adverse Reactions].Infections - Serious infections, including sepsis and pneumonia,have been reported in patients receiving ORENCIA. Some ofthese infections have been fatal. Many of the serious infectionshave occurred in patients on concomitant immunosuppressivetherapy which in addition to their underlying disease, couldfurther predispose them to infection. Physicians should exercisecaution when considering the use of ORENCIA in patients with ahistory of recurrent infections, underlying conditions which maypredispose them to infections, or chronic, latent, or localizedinfections. Patients who develop a new infection whileundergoing treatment with ORENCIA should be monitoredclosely. Administration of ORENCIA should be discontinued if apatient develops a serious infection [see Adverse Reactions].A higher rate of serious infections has been observed in adult RApatients treated with concurrent TNF antagonists and ORENCIA[see Warnings and Precautions].Prior to initiating immunomodulatory therapies, includingORENCIA, patients should be screened for latent tuberculosisinfection with a tuberculin skin test. ORENCIA has not beenstudied in patients with a positive tuberculosis screen, and thesafety of ORENCIA in individuals with latent tuberculosisinfection is unknown. Patients testing positive in tuberculosisscreening should be treated by standard medical practice priorto therapy with ORENCIA.Antirheumatic therapies have been associated with hepatitis Breactivation. Therefore, screening for viral hepatitis should beperformed in accordance with published guidelines beforestarting therapy with ORENCIA. In clinical studies with ORENCIA,patients who screened positive for hepatitis were excluded fromstudy. Immunizations - Live vaccines should not be given concurrentlywith ORENCIA or within 3 months of its discontinuation. No dataare available on the secondary transmission of infection frompersons receiving live vaccines to patients receiving ORENCIA.The efficacy of vaccination in patients receiving ORENCIA is not

known. Based on its mechanism of action, ORENCIA (abatacept)may blunt the effectiveness of some immunizations.It is recommended that patients with juvenile idiopathic arthritisbe brought up to date with all immunizations in agreementwith current immunization guidelines prior to initiating ORENCIA therapy.Use in Patients with Chronic Obstructive Pulmonary Disease(COPD) - Adult COPD patients treated with ORENCIA developedadverse events more frequently than those treated with placebo,including COPD exacerbations, cough, rhonchi, and dyspnea. Useof ORENCIA in patients with RA and COPD should be undertakenwith caution and such patients should be monitored forworsening of their respiratory status [see Adverse Reactions].Immunosuppression - The possibility exists for drugs inhibitingT cell activation, including ORENCIA, to affect host defensesagainst infections and malignancies since T cells mediatecellular immune responses. The impact of treatment withORENCIA on the development and course of malignancies is notfully understood [see Adverse Reactions ]. In clinical trials inpatients with adult RA, a higher rate of infections was seen inORENCIA-treated patients compared to placebo [see AdverseReactions].ADVERSE REACTIONSClinical Studies Experience in Adult RA Patients Treatedwith Intravenous ORENCIA - Because clinical trials areconducted under widely varying and controlled conditions,adverse reaction rates observed in clinical trials of a drug cannotbe directly compared to rates in the clinical trials of another drugand may not predict the rates observed in a broader patientpopulation in clinical practice.The data described herein reflect exposure to ORENCIAadministered intravenously in patients with active RA in placebo-controlled studies (1955 patients with ORENCIA, 989 withplacebo). The studies had either a double-blind, placebo-controlled period of 6 months (258 patients with ORENCIA, 133with placebo) or 1 year (1697 patients with ORENCIA, 856 withplacebo). A subset of these patients received concomitantbiologic DMARD therapy, such as a TNF blocking agent (204patients with ORENCIA, 134 with placebo).The majority of patients in RA clinical studies received one or more of the following concomitant medications with ORENCIA: MTX, nonsteroidal anti-inflammatory drugs (NSAIDs),corticosteroids, TNF blocking agents, azathioprine, chloroquine,gold, hydroxychloroquine, leflunomide, sulfasalazine, andanakinra.The most serious adverse reactions were serious infections andmalignancies.The most commonly reported adverse events (occurring in ≥10%of patients treated with ORENCIA) were headache, upperrespiratory tract infection, nasopharyngitis, and nausea.The adverse events most frequently resulting in clinicalintervention (interruption or discontinuation of ORENCIA) weredue to infection. The most frequently reported infections resultingin dose interruption were upper respiratory tract infection (1.0%),bronchitis (0.7%), and herpes zoster (0.7%). The most frequentinfections resulting in discontinuation were pneumonia (0.2%),localized infection (0.2%), and bronchitis (0.1%).Infections - In the placebo-controlled trials, infections werereported in 54% of ORENCIA-treated patients and 48% ofplacebo-treated patients. The most commonly reportedinfections (reported in 5-13% of patients) were upper respiratorytract infection, nasopharyngitis, sinusitis, urinary tract infection,influenza, and bronchitis. Other infections reported in fewer than5% of patients at a higher frequency (>0.5%) with ORENCIAcompared to placebo, were rhinitis, herpes simplex, andpneumonia [see Warnings and Precautions ].Serious infections were reported in 3.0% of patients treated withORENCIA and 1.9% of patients treated with placebo. The mostcommon (0.2-0.5%) serious infections reported with ORENCIAwere pneumonia, cellulitis, urinary tract infection, bronchitis,diverticulitis, and acute pyelonephritis [see Warnings andPrecautions].Malignancies - In the placebo-controlled portions of the clinicaltrials (1955 patients treated with ORENCIA for a median of 12 months), the overall frequencies of malignancies were similarin the ORENCIA- and placebo-treated patients (1.3% and 1.1%,respectively). However, more cases of lung cancer wereobserved in ORENCIA-treated patients (4, 0.2%) than placebo-treated patients (0). In the cumulative ORENCIA clinical trials(placebo-controlled and uncontrolled, open-label) a total of 8 cases of lung cancer (0.21 cases per 100 patient-years) and 4 lymphomas (0.10 cases per 100 patient-years) were observedin 2688 patients (3827 patient-years). The rate observed forlymphoma is approximately 3.5-fold higher than expected in anage- and gender-matched general population based on theNational Cancer Institute’s Surveillance, Epidemiology, and End

Results Database. Patients with RA, particularly those with highlyactive disease, are at a higher risk for the development oflymphoma. Other malignancies included skin, breast, bile duct,bladder, cervical, endometrial, lymphoma, melanoma,myelodysplastic syndrome, ovarian, prostate, renal, thyroid, anduterine cancers [see Warnings and Precautions]. The potentialrole of ORENCIA (abatacept) in the development of malignanciesin humans is unknown.Infusion-Related Reactions and Hypersensitivity Reactions -Acute infusion-related events (adverse reactions occurringwithin 1 hour of the start of the infusion) in Studies III, IV, and V[see Clinical Studies (14.1) in Full Prescribing Information] weremore common in the ORENCIA-treated patients than the placebopatients (9% for ORENCIA, 6% for placebo). The most frequentlyreported events (1-2%) were dizziness, headache, andhypertension.Acute infusion-related events that were reported in >0.1% and≤1% of patients treated with ORENCIA included cardiopulmonarysymptoms, such as hypotension, increased blood pressure, anddyspnea; other symptoms included nausea, flushing, urticaria,cough, hypersensitivity, pruritus, rash, and wheezing. Most ofthese reactions were mild (68%) to moderate (28%). Fewer than1% of ORENCIA-treated patients discontinued due to an acuteinfusion-related event. In controlled trials, 6 ORENCIA-treatedpatients compared to 2 placebo-treated patients discontinuedstudy treatment due to acute infusion-related events.Of 2688 patients treated with ORENCIA in clinical trials, therewere two cases of anaphylaxis or anaphylactoid reactions. Otherevents potentially associated with drug hypersensitivity, such ashypotension, urticaria, and dyspnea, each occurred in less than0.9% of ORENCIA-treated patients and generally occurred within24 hours of ORENCIA infusion. Appropriate medical supportmeasures for the treatment of hypersensitivity reactions shouldbe available for immediate use in the event of a reaction [seeWarnings and Precautions].Adverse Reactions in Patients with COPD - In Study V [seeClinical Studies (14.1) in Full Prescribing Information], therewere 37 patients with chronic obstructive pulmonary disease(COPD) who were treated with ORENCIA and 17 COPD patientswho were treated with placebo. The COPD patients treated withORENCIA developed adverse events more frequently than thosetreated with placebo (97% vs 88%, respectively). Respiratorydisorders occurred more frequently in ORENCIA-treated patientscompared to placebo-treated patients (43% vs 24%,respectively) including COPD exacerbation, cough, rhonchi, anddyspnea. A greater percentage of ORENCIA-treated patientsdeveloped a serious adverse event compared to placebo-treatedpatients (27% vs 6%), including COPD exacerbation (3 of 37 patients [8%]) and pneumonia (1 of 37 patients [3%]) [seeWarnings and Precautions].Other Adverse Reactions - Adverse events occurring in 3% ormore of patients and at least 1% more frequently in ORENCIA-treated patients (n=1955) versus placebo (n=989) duringplacebo-controlled RA studies were: Headache (18%, 13%);Nasopharyngitis (12%, 9%); Dizziness (9%, 7%); Cough (8%,7%); Back pain (7%, 6%); Hypertension (7%, 4%); Dyspepsia(6%, 4%); Urinary tract infection (6%, 5%); Rash (4%, 3%); Painin extremity (3%, 2%), respectively. The ORENCIA group included204 patients on concomitant biologic DMARDs (adalimumab,anakinra, etanercept, or infliximab). The placebo group included134 patients on concomitant biologic DMARDs (adalimumab,anakinra, etanercept, or infliximab).Immunogenicity - Antibodies directed against the entireabatacept molecule or to the CTLA-4 portion of abatacept wereassessed by ELISA assays in RA patients for up to 2 yearsfollowing repeated treatment with ORENCIA. Thirty-four of 1993(1.7%) patients developed binding antibodies to the entireabatacept molecule or to the CTLA-4 portion of abatacept.Because trough levels of abatacept can interfere with assayresults, a subset analysis was performed. In this analysis it wasobserved that 9 of 154 (5.8%) patients that had discontinuedtreatment with ORENCIA for over 56 days developed antibodies.Samples with confirmed binding activity to CTLA-4 wereassessed for the presence of neutralizing antibodies in a cell-based luciferase reporter assay. Six of 9 (67%) evaluablepatients were shown to possess neutralizing antibodies.However, the development of neutralizing antibodies may beunderreported due to lack of assay sensitivity.No correlation of antibody development to clinical response oradverse events was observed.The data reflect the percentage of patients whose test resultswere positive for antibodies to abatacept in specific assays. Theobserved incidence of antibody (including neutralizing antibody)positivity in an assay is highly dependent on several factors,including assay sensitivity and specificity, assay methodology,sample handling, timing of sample collection, concomitantmedication, and underlying disease. For these reasons,

Trim Size: 11” x 14.125” Pub:

comparison of the incidence of antibodies to abatacept with theincidence of antibodies to other products may be misleading.Clinical Experience in MTX-Naive Patients - Study VI was anactive-controlled clinical trial in MTX-naive patients [see ClinicalStudies (14.1) in Full Prescribing Information]. The safetyexperience in these patients was consistent with Studies I-V.Clinical Experience in Adult RA Patients Treated withSubcutaneous ORENCIA (abatacept) - Because clinical trialsare conducted under widely varying and controlled conditions,adverse reaction rates observed in clinical trials of a drug cannotbe directly compared to rates in the clinical trials of another drugand may not predict the rates observed in a broader patientpopulation in clinical practice.Study SC-I was a randomized, double-blind, double-dummy,non-inferiority study that compared the efficacy and safety ofabatacept administered subcutaneously (SC) and intravenously(IV) in 1457 subjects with rheumatoid arthritis, receivingbackground MTX, and experiencing an inadequate response toMTX (MTX-IR) [see Clinical Studies (14.1) in Full PrescribingInformation]. The safety experience and immunogenicity forORENCIA administered subcutaneously was consistent withintravenous Studies I-VI. Due to the route of administration,injection site reactions and immunogenicity were evaluated inStudy SC-I and two other smaller studies discussed in thesections below.Injection Site Reactions in Adult RA Patients Treated withSubcutaneous ORENCIA - Study SC-I compared the safety ofabatacept including injection site reactions followingsubcutaneous or intravenous administration. The overallfrequency of injection site reactions was 2.6% (19/736) and2.5% (18/721) for the subcutaneous abatacept group and theintravenous abatacept group (subcutaneous placebo),respectively. All these injection site reactions (includinghematoma, pruritus, and erythema) were mild (83%) tomoderate (17%) in severity, and none necessitated drugdiscontinuation.Immunogenicity in Adult RA Patients Treated withSubcutaneous ORENCIA - Study SC-I compared theimmunogenicity to abatacept following subcutaneous orintravenous administration. The overall immunogenicityfrequency to abatacept was 1.1% (8/725) and 2.3% (16/710) forthe subcutaneous and intravenous groups, respectively. The rateis consistent with previous experience, and there was nocorrelation of immunogenicity with effects on pharmacokinetics,safety, or efficacy.Immunogenicity and Safety of Subcutaneous ORENCIAAdministration as Monotherapy without an IntravenousLoading Dose - Study SC-II was conducted to determine theeffect of monotherapy use of ORENCIA on immunogenicityfollowing subcutaneous administration without an intravenousload in 100 RA patients, who had not previously receivedabatacept or other CTLA4Ig, who received either subcutaneousORENCIA plus MTX (n=51) or subcutaneous ORENCIAmonotherapy (n=49). No patients in either group developed anti-product antibodies after 4 months of treatment. The safetyobserved in this study was consistent with that observed in theother subcutaneous studies.Immunogenicity and Safety of Subcutaneous ORENCIA uponWithdrawal (Three Months) and Restart of Treatment - StudySC-III in the subcutaneous program was conducted toinvestigate the effect of withdrawal (three months) and restart ofORENCIA subcutaneous treatment on immunogenicity in RApatients treated concomitantly with MTX. One hundred sixty-seven patients were enrolled in the first 3-month treatmentperiod and responders (n=120) were randomized to eithersubcutaneous ORENCIA or placebo for the second 3-monthperiod (withdrawal period). Patients from this period thenreceived open-label ORENCIA treatment in the final 3-monthperiod of the study (period 3). At the end of the withdrawalperiod, 0/38 patients who continued to receive subcutaneousORENCIA developed anti-product antibodies compared to 7/73(9.6%) of patients who had subcutaneous ORENCIA withdrawnduring this period. Half of the patients receiving subcutaneousplacebo during the withdrawal period received a singleintravenous infusion of ORENCIA at the start of period 3 and halfreceived intravenous placebo. At the end of period 3, when allpatients again received subcutaneous ORENCIA, theimmunogenicity rates were 1/38 (2.6%) in the group receivingsubcutaneous ORENCIA throughout, and 2/73 (2.7%) in thegroup that had received placebo during the withdrawal period.Upon reinitiating therapy, there were no injection reactions andno differences in response to therapy in patients who werewithdrawn from subcutaneous therapy for up to 3 monthsrelative to those who remained on subcutaneous therapy,whether therapy was reintroduced with or without anintravenous loading dose. The safety observed in this study wasconsistent with that observed in the other studies.

Clinical Studies Experience in Juvenile Idiopathic Arthritis -In general, the adverse events in pediatric patients were similarin frequency and type to those seen in adult patients [seeWarnings and Precautions, Adverse Reactions].ORENCIA (abatacept) has been studied in 190 pediatric patients,6 to 17 years of age, with polyarticular juvenile idiopathicarthritis. Overall frequency of adverse events in the 4-month,lead-in, open-label period of the study was 70%; infectionsoccurred at a frequency of 36% [see Clinical Studies (14.2) inFull Prescribing Information]. The most common infections wereupper respiratory tract infection and nasopharyngitis. Theinfections resolved without sequelae, and the types of infectionswere consistent with those commonly seen in outpatientpediatric populations. Other events that occurred at a prevalenceof at least 5% were headache, nausea, diarrhea, cough, pyrexia,and abdominal pain.A total of 6 serious adverse events (acute lymphocytic leukemia,ovarian cyst, varicella infection, disease flare [2], and joint wear)were reported during the initial 4 months of treatment withORENCIA.Of the 190 patients with juvenile idiopathic arthritis treated withORENCIA in clinical trials, there was one case of ahypersensitivity reaction (0.5%). During Periods A, B, and C,acute infusion-related reactions occurred at a frequency of 4%,2%, and 3%, respectively, and were consistent with the types ofevents reported in adults.Upon continued treatment in the open-label extension period,the types of adverse events were similar in frequency and typeto those seen in adult patients, except for a single patientdiagnosed with multiple sclerosis while on open-label treatment.Immunogenicity - Antibodies directed against the entireabatacept molecule or to the CTLA-4 portion of abatacept wereassessed by ELISA assays in patients with juvenile idiopathicarthritis following repeated treatment with ORENCIA throughoutthe open-label period. For patients who were withdrawn fromtherapy for up to 6 months during the double-blind period, therate of antibody formation to the CTLA-4 portion of the moleculewas 41% (22/54), while for those who remained on therapy therate was 13% (7/54). Twenty of these patients had samples thatcould be tested for antibodies with neutralizing activity; of these, 8 (40%) patients were shown to possess neutralizing antibodies.The presence of antibodies was generally transient and titerswere low. The presence of antibodies was not associated withadverse events, changes in efficacy, or an effect on serumconcentrations of abatacept. For patients who were withdrawnfrom ORENCIA during the double-blind period for up to 6 months,no serious acute infusion-related events were observed upon re-initiation of ORENCIA therapy.Postmarketing Experience - Adverse reactions have beenreported during the postapproval use of ORENCIA. Because thesereactions are reported voluntarily from a population of uncertainsize, it is not always possible to reliably estimate their frequencyor establish a causal relationship to ORENCIA. Based on thepostmarketing experience in adult RA patients, the followingadverse reaction has been identified during postapproval usewith ORENCIA.• Vasculitis (including cutaneous vasculitis and leukocytoclastic

vasculitis)DRUG INTERACTIONSTNF Antagonists - Concurrent administration of a TNFantagonist with ORENCIA has been associated with an increasedrisk of serious infections and no significant additional efficacyover use of the TNF antagonists alone. Concurrent therapy withORENCIA and TNF antagonists is not recommended [seeWarnings and Precautions].Other Biologic RA Therapy - There is insufficient experience toassess the safety and efficacy of ORENCIA administeredconcurrently with other biologic RA therapy, such as anakinra,and therefore such use is not recommended.Blood Glucose Testing - Parenteral drug products containingmaltose can interfere with the readings of blood glucosemonitors that use test strips with glucose dehydrogenasepyrroloquinolinequinone (GDH-PQQ). The GDH-PQQ basedglucose monitoring systems may react with the maltose presentin ORENCIA for intravenous administration, resulting in falselyelevated blood glucose readings on the day of infusion. Whenreceiving ORENCIA through intravenous administration, patientsthat require blood glucose monitoring should be advised toconsider methods that do not react with maltose, such as thosebased on glucose dehydrogenase nicotine adenine dinucleotide(GDH-NAD), glucose oxidase, or glucose hexokinase testmethods.ORENCIA for subcutaneous administration does not containmaltose; therefore, patients do not need to alter their glucosemonitoring.

USE IN SPECIFIC POPULATIONSPregnancy - Pregnancy Category C: There are no adequateand well-controlled studies of ORENCIA (abatacept) use inpregnant women. Abatacept has been shown to cross theplacenta in animals, and in animal reproduction studiesalterations in immune function occurred. ORENCIA should beused during pregnancy only if the potential benefit to the motherjustifies the potential risk to the fetus.Abatacept was not teratogenic when administered to pregnantmice at doses up to 300 mg/kg and in pregnant rats and rabbitsat doses up to 200 mg/kg daily representing approximately 29 times the exposure associated with the maximumrecommended human dose (MRHD) of 10 mg/kg based on AUC(area under the time-concentration curve). Abatacept administered to female rats every three days duringearly gestation and throughout the lactation period, produced noadverse effects in offspring at doses up to 45 mg/kg,representing 3 times the exposure associated with the MRHD of10 mg/kg based on AUC. However, at 200 mg/kg, 11 times theMRHD exposure, alterations in immune function were observedconsisting of a 9-fold increase in T-cell dependent antibodyresponse in female pups and thyroid inflammation in one femalepup. It is not known whether these findings indicate a risk fordevelopment of autoimmune diseases in humans exposed in utero to abatacept. However, exposure to abatacept in thejuvenile rat, which may be more representative of the fetalimmune system state in the human, resulted in immune systemabnormalities including inflammation of the thyroid andpancreas [see Nonclinical Toxicology (13.2) in Full PrescribingInformation]. Pregnancy Registry: To monitor maternal-fetal outcomes ofpregnant women exposed to ORENCIA, a pregnancy registry hasbeen established. Healthcare professionals are encouraged toregister patients and pregnant women are encouraged to enrollthemselves by calling 1-877-311-8972. Nursing Mothers - It is not known whether ORENCIA is excretedinto human milk or absorbed systemically after ingestion by anursing infant. However, abatacept was excreted in rat milk.Because many drugs are excreted in human milk, and becauseof the potential for serious adverse reactions in nursing infantsfrom ORENCIA, a decision should be made whether todiscontinue nursing or to discontinue the drug, taking intoaccount the importance of the drug to the mother. Pediatric Use - ORENCIA is indicated for reducing signs andsymptoms in pediatric patients with moderately to severelyactive polyarticular juvenile idiopathic arthritis ages 6 years andolder. ORENCIA may be used as monotherapy or concomitantlywith MTX. Studies in juvenile rats exposed to ORENCIA prior to immunesystem maturity have shown immune system abnormalitiesincluding an increase in the incidence of infections leading todeath as well as inflammation of the thyroid and pancreas [seeNonclinical Toxicology (13.2) in Full Prescribing Information].Studies in adult mice and monkeys have not demonstratedsimilar findings. As the immune system of the rat is undevelopedin the first few weeks after birth, the relevance of these resultsto humans greater than 6 years of age (where the immunesystem is largely developed) is unknown.ORENCIA is not recommended for use in patients below the ageof 6 years.The safety and effectiveness of ORENCIA in pediatric patientsbelow 6 years of age have not been established. The safety andefficacy of ORENCIA in pediatric patients for uses other thanjuvenile idiopathic arthritis have not been established.Geriatric Use - A total of 323 patients 65 years of age and older,including 53 patients 75 years and older, received ORENCIA inclinical studies. No overall differences in safety or effectivenesswere observed between these patients and younger patients, butthese numbers are too low to rule out differences. The frequencyof serious infection and malignancy among ORENCIA-treatedpatients over age 65 was higher than for those under age 65.Because there is a higher incidence of infections andmalignancies in the elderly population in general, caution shouldbe used when treating the elderly.OVERDOSAGE Doses up to 50 mg/kg have been administered intravenouslywithout apparent toxic effect. In case of overdosage, it isrecommended that the patient be monitored for any signs orsymptoms of adverse reactions and appropriate symptomatictreatment instituted.

427US08PBS01104 B5-B0001A2-09-111292618A0/1294018 Rev September 2011

Trim Size: 11” x 14.125” Pub:

Physicians should consider leadin the blood as a cause of gout inpatients who do not appear to

have other causes for their condition,according to researchers whose articleon the topic was recently published(Krishnan E, et al. Ann Intern Med.2012;157:233-241).

The investigators found that peoplewith a blood lead level between 2.6and 26.8 mcg/dL had a 3.6-fold high-er risk of gout than did those with ablood lead level of 0.18 to 1.2 mcg/dL.These individuals also had a nearly 2-fold higher likelihood of havinghyperuricemia.

The Centers for Disease Controland Prevention and the World HealthOrganization both consider a bloodlead level of <25 mcg/dL to be non -elevated. This study challenges thatthreshold, and also points to the needfor measurement of blood lead levelsas a routine part of the search for sec-ondary causes of gout.

“In all cases of gout, clinicians

should first try to identify an obviouscause—sometimes it is alcohol use,and sometimes it is a concomitantsickle-cell trait,” advised lead investi-gator Eswar Krishnan, MD, MPhil,Assistant Professor of Medicine at theStanford School of Medicine, PaloAlto, CA, in an interview with Value-Based Care in Rheumatology. “If none isfound, they should consider perform-ing a blood lead level test.”

The study included 6153 patients(aged ≥40 years) from the NationalHealth and Nutrition ExaminationSurvey (NHANES).

In an accompanying editorial,Ashwini Sehgal, MD, DuncanNeuhauser Professor of CommunityHealth Improvement and Professor ofEpidemiology and Biostatistics, Bio -ethics, and Medicine at Case WesternReserve University, Cleveland, OH,noted that the study has significantmerit because of its large nationalsample size.

Dr Sehgal believes the current

thresholds for safe blood lead levelsshould be lowered, and healthcareproviders “should obtain lifetimeexposure histories from their patients

and consider checking blood levels,bearing in mind that lead accumulat-ed in the bones long ago might still

Cincinnati, OH—Patients with goutwho have uncontrolled serum uricacid levels are much more likely toutilize healthcare resources, such ashospitalizations and outpatient ser -vices, compared with patients withgout whose serum uric acid levelsare being effectively managed,according to data from a large studyof veterans conducted by EswarKrishnan, MD, MPhil, AssistantProfessor of Medi cine at the StanfordSchool of Medi cine, Palo Alto, CA,and colleagues. The study was pre-sented in a poster at the October 2012meeting of the Academy of ManagedCare Pharmacy.

Several previous, smaller studieshave suggested the relationshipbetween uncontrolled gout andincreased healthcare utilization; how-ever, the impact of uncontrolledserum uric acid on “healthcare utiliza-tion among veterans with gout hasnot been well documented,” Dr

Krishnan and colleagues suggested.They undertook this investigation inresponse to the vast number of indi-viduals in the Veterans Affairs systemand the rising incidence of gout as thepopulation ages.

The data came from medicalrecords from the Veterans IntegratedServices Network between January2002 and January 2011. The timecourse was divided into 6-monthcycles. Mean serum uric acid levelswere estimated for each 6-monthcycle, with linear extrapolation usedto estimate serum uric acid for any 6-month period in which no measure-ment was taken.

To qualify for the analysis, patientshad to be aged >18 years, have had atleast 2 diagnoses of gout, have a min-imum of 2 serum uric acid measureswithin the eligibility period, have atleast 1 year of follow-up, and have nocomorbid inflammatory diseases.

A total of 2553 veterans with gout

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

Uncontrolled serum uric acid wasdefined as ≥7 mg/dL. The averageduration of follow-up was approxi-mately 6 years.

The results showed that 50% of the6-month cycles recorded values of

serum uric acid in the uncontrolledrange (>7 mg/dL), whereas only 30%of patients had a serum uric acid levelat or below the American College ofRheumatology–recommended thresh-old of 6 mg/dL.

In addition, patients with uncon-trolled serum uric acid were atincreased risk for all-cause and gout-related hospitalizations (hazard ratios[HRs], 1.25 and 1.49, respectively), aswell as an elevated risk for all-causeand gout-related outpatient visits(HRs, 1.32 and 1.09, respectively) ver-sus those with controlled gout.

The numbers of gout-related andnon–gout-related hospitalization andoutpatient visits were also higher forveterans with uncontrolled gout (HRs,1.47, 1.12, 1.23, and 1.00, respectively)versus those with controlled gout.

Healthcare utilization was similarlyincreased, even when the cut-off pointwas reduced to a less stringent level of>6 mg/dL. �

Patients with uncontrolledserum uric acid were atincreased risk for all-causeand gout-relatedhospitalizations, as well as an elevated risk for all-cause and gout-relatedoutpatient visits.

Continued on page 10

9VOL. 1 I NO. 5 OCTOBER 2012 I www.ValueBasedRheumatology.com

Gout

“In all cases of gout,clinicians should first try toidentify an obvious cause—sometimes it is alcohol use,and sometimes it is aconcomitant sickle-cell trait.If none is found, they shouldconsider performing a bloodlead level test.”

—Eswar Krishnan, MD, MPhil

� Patients with gout who do nothave other causes for thiscondition should be tested forlead in their blood

� People with blood lead levelsbetween 2.6 and 26.8 mcg/dLhave a 3.6-fold increased riskfor gout and an almost doublerisk for hyperuricemia

� Current blood lead levelthresholds should likely belowered, because even 1.2mcg/dL of lead in the blood isassociated with increasedincidence of gout

� Physicians should obtainlifetime lead exposure historiesfrom patients, because leadaccumulates in the bones andcan affect patients long afterexposure

at a glance

Poorly Managed Gout a Driver for Increased HealthcareUtilization for VeteransHospitalization rates rise with uncontrolled uric acid levelsBy Neil Canavan

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

ahead of print]). Significant pain reliefoccurred within the first week of treat-ment with pregabalin and persistedover the 15-week duration of the trial.Significantly more patients reportedbeing “very much improved” or“much improved” with pregabalinthan with placebo (P = .078).

Quality of sleep improved signifi-cantly in the pregabalin arm within thefirst week of treatment and remainedsignificantly improved versus placebothrough the end of the study.

“In this, the first clinical trial infibromyalgia patients in Japan, pre-gabalin demonstrated significant effi -cacy in pain reduction and alsoimproved measures of sleep andfunctioning,” Hiroyoshi Ohta, MS, ofPfizer Japan in Tokyo, and colleaguesconcluded. “The drug was generallywell tolerated, and adverse events[AEs] were consistent with prior tri-als and current product labeling.These data suggest that pregabalinmay be an effective treatment optionfor the relief of pain and sleep prob-lems in Japanese patients withfibromyalgia.”

Approved in the United States forthe treatment of fibromyalgia, prega-balin has not been evaluated exten-

sively in controlled trials of Asianpatients, and there have not been anyclinical trials of patients with fi -bromyalgia in Japan. For this study,investigators at 44 centers in Japan

enrolled patients aged ≥18 years whomet the 1990 American College ofRheumatology diagnostic criteria forfibromyalgia.

A total of 498 patients (mean age,approximately 47 years) were ran-

domized to placebo or to pregabalinat a starting dose of 150 mg daily,which was titrated over 3 weeks to amaintenance dose of 300 mg or 450mg daily, and was continued for anadditional 12 weeks.

The mean duration of fibromyalgiawas 62 months in the placebo groupand 69.6 months among those receiv-ing pregabalin.

The primary end point was themean pain score at the end of thestudy, as recorded daily by patients,who rated their pain over the previ-ous 24 hours from 0 (no pain) to 10(worst possible pain). The mean painscore was evaluated weekly duringthe trial.

Secondary end points consisted ofpatient assessment of pain by visualanalog scale (VAS; 0-100 mm), thePatient Global Impression of Change(PGIC), the Fibromyalgia ImpactQuestionnaire (FIQ), the 36-Item ShortForm Health Survey (SF-36), theHospital Anxiety and DepressionScale, self-rated sleep quality, and theMedical Outcomes Study (MOS)Sleep Scale.

Encouraging Results

The baseline pain score averagedbetween 6.4 and 6.5 in the 2 groups.When the trial ended, the pregabalinarm had a mean reduction of 1.48 frombaseline compared with a reduction of1.03 in the placebo group (P = .046).

The proportions of patients with a≥50% reduction in mean pain score atfinal assessment were 22.8% in the pre-gabalin group and 12.1% in the place-bo group (P = .017). In addition, 40.4%of the patients treated with pregabalinhad a ≥30% reduction in mean painscore compared with 30.6% of patientsin the placebo group (P = .023).

The VAS pain score averagedbetween 67 and 68 at baseline. Atfinal assessment, the mean score was47.42 with pregabalin, a reduction of6.19 versus the placebo group (P =.013). PGIC results showed that38.6% of the pregabalin group was“very much improved” or “muchimproved” at final assessment com-pared with 26.7% of the placebogroup (P = .078).

There was a significant improve-ment in FIQ total score, which was3.33 lower in the pregabalin groupversus in the placebo group (P = .014).The FIQ subscales of feeling good,pain, fatigue, and morning tirednessall showed significant differences infavor of the pregabalin arm.

The physical functioning and vitali-

ty scales of the SF-36 were significant-ly improved with pregabalin (P = .006and P = .052, respectively) versus withplacebo.

The mean change in quality-of-sleep score also showed significantlygreater improvement with pregabalinat the last assessment (P <.001) and atevery time point from week 1 throughweek 15 (P ≤.001).

Multiple items on the MOS SleepScale improved significantly morewith pregabalin, such as sleep distur-bance (P <.001), sleep adequacy (P<.001), sleep quantity (P = .007), andawakening with shortness of breath orheadache (P = .049). In addition, thecomposite MOS Sleep Scale score wassignificantly improved in the prega-balin group (P = .013).

Adverse Events

AEs and treatment-emergent AEsoccurred more often in the pregabalinarm (90.0% and 82.4%, respectively)than in the placebo group (70.6% and51.6%, respectively). The most com-mon AEs in the pregabalin arm weresomnolence, dizziness, nasopharyngi-tis, weight gain, and constipation. Theauthors reported that 9.6% of patientsin the pregabalin arm withdrewbecause of AEs compared with 3.6%in the placebo arm. �

Fibromyalgia

Patients with Fibromyalgia Improve Rapidly... Continued from cover

10 VALUE-BASED CARE IN RHEUMATOLOGY I OCTOBER 2012 VOL. 1 I NO. 5

“The drug was generallywell tolerated, and adverseevents were consistent withprior trials and currentproduct labeling. These datasuggest that pregabalin maybe an effective treatmentoption for the relief of painand sleep problems inJapanese patients withfibromyalgia.”

—Hiroyoshi Ohta, MS

at a glance� The first Japanese study

investigating the effect ofpregabalin in patients withfibromyalgia showedsignificant improvements inpain, sleep, and quality of life

� The impact was quick, withinthe first week of treatment,and lasted throughout the trial

� Of the patients receivingpregabalin, 40.4% had a≥30% reduction in mean pain score

� By the end of the study,22.8% of those receivingpregabalin had a ≥50%reduction in mean pain score

� More adverse events werereported in the pregabalin armthan in the placebo group; the most common weresomnolence, dizziness,nasopharyngitis, weight gain,and constipation

be able to cause harm.”Dr Krishnan and colleagues used a

cross-sectional analysis of individualsfrom 2 cycles of NHANES, 2005-2006and 2007-2008. People who wereundergoing dialysis or who had a his-tory of renal disease or an estimatedglomerular filtration rate <10 mL/min, because of the associationbetween kidney disease, hyper-uricemia, and gout.

The 290 patients with gout in theNHANES sample were significantlyolder than the 5863 persons withoutgout (average age, 56.65 years vs62.49 years, respectively). They alsohad greater renal impairment andwere more likely to have comorbidi-ties, such as obesity, hypertension, ordiabetes.

Mean blood lead level was 2.64mcg/dL in the group with goutcompared with 1.95 mcg/dL forthose without gout. In addition, the

prevalence of gout and the meanconcentration of serum urateincreased linearly with higher bloodlead levels, and people with hyper-uricemia had a worse cardiovascularrisk factor profile than those withoutthe condition. Blood levels of cadmi-um and mercury were not correlatedwith gout.

Furthermore, blood lead levels aslow as approximately 1.2 mcg/dLwere associated with increased goutprevalence, independent of othermajor risk factors.

A multivariate logistic regressionanalysis, adjusting for confoundingfactors, showed that patients in thehighest blood lead level quartile hadgreater risk for gout or hyperuricemia(range, 2.6-26.8 mcg/dL; odds ratio,3.62 for gout, 1.84 for hyperuricemia)compared with those in the lowestblood lead level quartile (range, 0.18-1.20 mcg/dL). �

Lead in Blood Associated with Gout... Continued from page 9

Gout

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12 VALUE-BASED CARE IN RHEUMATOLOGY I OCTOBER 2012 VOL. 1 I NO. 5

Apremilast, an investigationaloral, small-molecule inhibitorof phospho diesterase (PDE)-4

that mod ulates an intracellular net-work of proinflammatory and anti-inflammatory mediators, is currentlyin phase 3 clinical trials (known as thePALACE trials) for the treatment ofpatients with psoriatic arthritis.

PDE-4 is a cyclic adenosine mono -phosphate (cAMP)-specific PDE andthe dominant PDE in inflammatorycells. PDE-4 inhibition elevates intra-cellular cAMP levels, which, in turn,downregulates the inflammatory re -sponse by modulating the expressionof tumor necrosis factor (TNF)-alpha,interleukin-23, and other inflammato-ry cytokines. Elevation of cAMP alsoincreased other anti-inflammatorycytokines.

The PALACE 2 and PALACE 3 tri-als met their primary end point,demonstrating a statistically signifi-cant improvement from baseline inthe percentage of patients with psori-atic arthritis who were treated withapremilast and achieved at least a 20%improvement in American College ofRheumatology (ACR20) criteria. These2 studies join PALACE 1, which alsomet the primary end point of ACR20in the groups treated with apremilast,according to a September 6, 2012,press release from the manufacturer(http://ir.celgene.com/phoenix.zhtml?c=111960&p=irol-newsArticle&ID=1732178&highlight=).

Together, the 3 PALACE studiescomprise the most comprehensivepsoriatic arthritis program to dateintended for regulatory submission to

the US Food and Drug Admin is -tration (FDA). PALACE 1, 2, and 3 areeach pivotal phase 3, multicenter,double-blind, placebo-controlled, par-allel-group studies with 2 active treat-ment arms.

Approximately 1500 patients with awide spectrum of psoriatic arthritiswere randomized in the combinedPALACE trials in a 1:1:1 manner to re -ceive apremilast 20 mg twice daily, 30mg twice daily, or identically appearingplacebo for 24 weeks, with an extensionphase running through 52 weeks withall patients receiving apremilast.

Patients included in the trialscould have had previous treatmentwith oral disease-modifying anti -rheumatic drugs (DMARDs), biolog-ic DMARDs, as well as previous fail-ure with a TNF blocker therapy.

In each of the trials, apremilast wasused alone or in combination withoral DMARDs. PALACE-3 includes alarge subset of patients with signifi-cant skin involvement with psoriasis.

In all 3 studies, significant improve-ment in ACR20 was maintainedthrough week 24. In addition, consis-tent significant and clinically mean-ingful responses were observed invarious measures of signs and symp-toms of psoriatic arthritis and in phys-ical function of patients receivingapremilast therapy through week 24.

All 3 studies are currently ongoing,and the study extensions are blindeduntil all patients complete 52 weeks of treatment.

A New Drug Application for ap -remilast is expected to be submitted tothe FDA early next year. �

Psoriatic Arthritis

Fibromyalgia

An intense program of tele-phone support does not havea significant effect on the moti-

vation of patients with fibromyalgiato exercise or on their disease symp-toms, according to the first random-ized study to expressly address exer-cise in this patient population (AngDC, et al. Clin J Pain. 2012 Oct 5 [Epubahead of print]).

Motivational interviewing, whichwas the modality tested in this study,involves trained professionals helpingpeople resolve ambivalence about abehavior change—in this case, adher-ence to a regular exercise regimen.

This approach was compared over12 weeks with people in an educationcontrol group who had an equal num-ber of fibromyalgia-relevant educa-tion sessions, all of which were con-ducted over the phone. Participantswere assessed at baseline, immediate-ly after the treatment sessions, andafter 3 and 6 months.

The investigators were surprisedthat the results did not show a higherpercentage of patients in the motiva-tional interview group who reported

an increase of at least 30 minutes per week in moderate-to-vigorousphysical activity or a reduction inphysical impairment resulting fromfibromyalgia.

“I did not expect for the educationcontrol group to improve, but it did—likely because education control sub-jects may have consciously or sub -consciously increased their physicalactivity level, given that they wereinvolved in an exercise trial,” saidlead investigator Dennis C. Ang, MD,MS, Chief, Section on Rheumatology& Immunology, Wake Forest BaptistMedical Center, Winston-Salem, NC,in an interview with Value-Based Carein Rheumatology.

Dr Ang conducted the study while

he was at Indiana University-PurdueUniversity, Indianapolis, IN. He andhis colleagues randomized 107 peoplewith fibromyalgia to 6 motivationalinterviewing sessions and another 109people to 6 education sessions onfibromyalgia self-management.

The motivational interview thera-pists who participated in the studyhad received roughly 24 hours of ini-tial training in motivational interviewsand approximate 60 hours of ongoingtraining before and during the study.

The first 2 motivational interviewsessions focused on increasing patientmotivation to exercise, and the next 2 were devoted to strategies thatstrengthen commitment to exercise.The last 2 calls focused on follow-through strategies to prevent relapseto inactivity.

For their part, participants in theeducation control group received edu-cational health information on fibro -myalgia, pain, fatigue, sleep, stress,and living well with fibromyalgia.

There were no significant differ-ences at any of the time pointsbetween the 2 groups in the primary

outcomes of increase in exercise andimprovement in the scores on theFibromyalgia Impact Questionnaire(FIQ)-Physical Impairment scale.

However, more patients who hadmotivational interviewing than edu-cation control had meaningful im -provements in FIQ scores (globalsymptom severity) at their 6-monthfollow-up (62.9% vs 49.5%; P = .06).Furthermore, those in the motivation-al interview group made greater gainson the 6-minute walk test comparedwith the education control groupmembers.

The motivational interview cohortalso had a greater increase in the num-ber of hours of physical activityimmediately postintervention and agreater reduction in pain severityimmediately postintervention and attheir 3-month follow-up.

Dr Ang said that his team intends todelve further into this approach. “Wewould like to know if motivationalinterviewing therapists’ degree ofadherence to the principle of motiva-tional interviewing was associatedwith increased physical activity.” �

Motivation Interviewing of Patients with Fibromyalgia toEncourage Exercise Provides Mixed ResultsBy Rosemary Frei, MSc

“I did not expect for theeducation control group toimprove, but it did.”

—Dennis C. Ang, MD, MS

Apremilast Shows Promising Results in 3 Pivotal Trialsof Patients with Psoriatic ArthritisBy Alice Goodman

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 bene� 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 in� 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 concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections in patients with rheumatoid arthritis (RA); therefore, the concomitant use of HUMIRA and these biologic products is not recommended in the treatment of patients with RA [see Warnings and Precautions and Drug Interactions]. Treatment with HUMIRA should not be initiated in patients with an active infection, including localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. The risks and bene� 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 con� 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 bene� 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% con� 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 signi� 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% con� 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 in� 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, � xed drug reaction, non-speci� 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 identi� ed as carriers of HBV. Adequate data are not available on the safety or ef� 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 signi� 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 con� rmed signi� 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 bene� 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 Failure Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. Cases of worsening CHF have also been observed with HUMIRA. Physicians should exercise caution when using HUMIRA in patients who have heart failure and monitor them carefully. Autoimmunity Treatment with HUMIRA may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with HUMIRA, treatment should be discontinued [see Adverse Reactions].Immunizations In a placebo-controlled clinical trial of patients with rheumatoid arthritis, no difference was detected in anti-pneumococcal antibody response between HUMIRA and placebo treatment groups when the pneumococcal polysaccharide vaccine and in� 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 bene� 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 proportion of patients who discontinued treatment due to adverse reactions during the double-blind, placebo-controlled portion of Studies RA-I, RA-II, RA-III and RA-IV was 7% for patients taking HUMIRA and 4% for placebo-treated patients. The most common adverse reactions leading to discontinuation of HUMIRA were clinical � 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 � rst eight months after initiation of therapy and may re� 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 Precautions].AutoantibodiesIn the rheumatoid arthritis controlled trials, 12% of patients treated with HUMIRA and 7% of placebo-treated patients that had negative baseline ANA titers developed positive titers at week 24. Two patients out of 3046 treated with HUMIRA developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms. The impact of long-term treatment with HUMIRA on the development of autoimmune diseases is unknown. Liver Enzyme Elevations There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of HUMIRA (40 mg SC every other week) in patients with RA, PsA, and AS with control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULN occurred in 3.5% of HUMIRA-treated patients and 1.5% of control-treated patients. Since many of these patients in these trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between HUMIRA and the liver enzyme elevations is not clear. In controlled Phase 3 trials of HUMIRA (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on Days 1 and 15, respectively, followed by 40 mg every other week) in patients with Crohn’s disease with control period duration ranging from 4 to 52 weeks, ALT elevations ≥ 3 x ULN occurred in 0.9% of HUMIRA-treated patients and 0.9% of control-treated patients. In controlled Phase 3 trials of HUMIRA (initial dose of 80 mg then 40 mg every other week) in patients with plaque psoriasis with control period duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of HUMIRA-treated patients and 1.8% of control-treated patients. 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 identi� 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 re� ect exposure to HUMIRA in 2468 patients, including 2073 exposed for 6 months, 1497 exposed for greater than one year and 1380 in adequate and well-controlled studies (Studies RA-I, RA-II, RA-III, and RA-IV). HUMIRA was studied primarily in placebo-controlled trials and in long-term follow up studies for up to 36 months duration. The population had a mean age of 54 years, 77% were female, 91% were Caucasian and had moderately to severely active rheumatoid arthritis. Most patients received 40 mg HUMIRA every other week. Table 1 summarizes reactions reported at a rate of at least 5% in patients treated with HUMIRA 40 mg every other week compared to placebo and with an incidence higher than placebo. In Study RA-III, the types and frequencies of adverse reactions in the second year open-label extension were similar to those observed in the one-year double-blind portion.

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

HUMIRA 40 mg subcutaneous Every

Other Week

Placebo

(N=705) (N=690)

Adverse Reaction (Preferred Term)

Respiratory

Upper respiratory infection 17% 13%

Sinusitis 11% 9%

Flu syndrome 7% 6%

Gastrointestinal

Nausea 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%

Other

Headache 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-treated pediatric patients in the juvenile idiopathic arthritis (JIA) trial were similar in frequency and type to those seen in adult patients [see Warnings and Precautions, Adverse Reactions]. Important � 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 adverse reactions reported in the study included neutropenia, streptococcal pharyngitis, increased aminotransferases, herpes zoster, myositis, metrorrhagia, appendicitis. Serious infections were observed in 4% of patients within approximately 2 years of initiation of treatment with HUMIRA and included cases of herpes simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster. A total of 45% of children experienced an infection while receiving HUMIRA with or without concomitant MTX in the � 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 � rst 48 weeks of treatment, non-serious hypersensitivity reactions were seen in approximately 6% of children and included primarily localized allergic hypersensitivity reactions and allergic rash. Isolated mild to moderate elevations of liver aminotransferases (ALT more common than AST) were observed in children with JIA exposed to HUMIRA alone; liver enzyme test elevations were more frequent among those treated with the combination of HUMIRA and MTX than those treated with HUMIRA alone. In general, these elevations did not lead to discontinuation of HUMIRA treatment. In the JIA trial, 10% of patients treated with HUMIRA who had negative baseline anti-dsDNA antibodies developed positive titers after 48 weeks of treatment. No patient developed clinical signs of autoimmunity during the clinical trial. Approximately 15% of children treated with HUMIRA developed mild-to-moderate elevations of creatine phosphokinase (CPK). Elevations exceeding 5 times the upper limit of normal were observed in several patients. CPK levels decreased or returned to normal in all patients. Most patients were able to continue HUMIRA without interruption.

3:56 PM

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 bene� 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 in� 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 concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections in patients with rheumatoid arthritis (RA); therefore, the concomitant use of HUMIRA and these biologic products is not recommended in the treatment of patients with RA [see Warnings and Precautions and Drug Interactions]. Treatment with HUMIRA should not be initiated in patients with an active infection, including localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. The risks and bene� 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 con� 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 bene� 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% con� 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 signi� 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% con� 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 in� 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, � xed drug reaction, non-speci� 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 identi� ed as carriers of HBV. Adequate data are not available on the safety or ef� 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 signi� 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 con� rmed signi� 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 bene� 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 Failure Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. Cases of worsening CHF have also been observed with HUMIRA. Physicians should exercise caution when using HUMIRA in patients who have heart failure and monitor them carefully. Autoimmunity Treatment with HUMIRA may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with HUMIRA, treatment should be discontinued [see Adverse Reactions].Immunizations In a placebo-controlled clinical trial of patients with rheumatoid arthritis, no difference was detected in anti-pneumococcal antibody response between HUMIRA and placebo treatment groups when the pneumococcal polysaccharide vaccine and in� 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 bene� 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 proportion of patients who discontinued treatment due to adverse reactions during the double-blind, placebo-controlled portion of Studies RA-I, RA-II, RA-III and RA-IV was 7% for patients taking HUMIRA and 4% for placebo-treated patients. The most common adverse reactions leading to discontinuation of HUMIRA were clinical � 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 � rst eight months after initiation of therapy and may re� 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 Precautions].AutoantibodiesIn the rheumatoid arthritis controlled trials, 12% of patients treated with HUMIRA and 7% of placebo-treated patients that had negative baseline ANA titers developed positive titers at week 24. Two patients out of 3046 treated with HUMIRA developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms. The impact of long-term treatment with HUMIRA on the development of autoimmune diseases is unknown. Liver Enzyme Elevations There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of HUMIRA (40 mg SC every other week) in patients with RA, PsA, and AS with control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULN occurred in 3.5% of HUMIRA-treated patients and 1.5% of control-treated patients. Since many of these patients in these trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between HUMIRA and the liver enzyme elevations is not clear. In controlled Phase 3 trials of HUMIRA (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on Days 1 and 15, respectively, followed by 40 mg every other week) in patients with Crohn’s disease with control period duration ranging from 4 to 52 weeks, ALT elevations ≥ 3 x ULN occurred in 0.9% of HUMIRA-treated patients and 0.9% of control-treated patients. In controlled Phase 3 trials of HUMIRA (initial dose of 80 mg then 40 mg every other week) in patients with plaque psoriasis with control period duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of HUMIRA-treated patients and 1.8% of control-treated patients. 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 identi� 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 re� ect exposure to HUMIRA in 2468 patients, including 2073 exposed for 6 months, 1497 exposed for greater than one year and 1380 in adequate and well-controlled studies (Studies RA-I, RA-II, RA-III, and RA-IV). HUMIRA was studied primarily in placebo-controlled trials and in long-term follow up studies for up to 36 months duration. The population had a mean age of 54 years, 77% were female, 91% were Caucasian and had moderately to severely active rheumatoid arthritis. Most patients received 40 mg HUMIRA every other week. Table 1 summarizes reactions reported at a rate of at least 5% in patients treated with HUMIRA 40 mg every other week compared to placebo and with an incidence higher than placebo. In Study RA-III, the types and frequencies of adverse reactions in the second year open-label extension were similar to those observed in the one-year double-blind portion.

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

HUMIRA 40 mg subcutaneous Every

Other Week

Placebo

(N=705) (N=690)

Adverse Reaction (Preferred Term)

Respiratory

Upper respiratory infection 17% 13%

Sinusitis 11% 9%

Flu syndrome 7% 6%

Gastrointestinal

Nausea 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%

Other

Headache 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-treated pediatric patients in the juvenile idiopathic arthritis (JIA) trial were similar in frequency and type to those seen in adult patients [see Warnings and Precautions, Adverse Reactions]. Important � 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 adverse reactions reported in the study included neutropenia, streptococcal pharyngitis, increased aminotransferases, herpes zoster, myositis, metrorrhagia, appendicitis. Serious infections were observed in 4% of patients within approximately 2 years of initiation of treatment with HUMIRA and included cases of herpes simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster. A total of 45% of children experienced an infection while receiving HUMIRA with or without concomitant MTX in the � 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 � rst 48 weeks of treatment, non-serious hypersensitivity reactions were seen in approximately 6% of children and included primarily localized allergic hypersensitivity reactions and allergic rash. Isolated mild to moderate elevations of liver aminotransferases (ALT more common than AST) were observed in children with JIA exposed to HUMIRA alone; liver enzyme test elevations were more frequent among those treated with the combination of HUMIRA and MTX than those treated with HUMIRA alone. In general, these elevations did not lead to discontinuation of HUMIRA treatment. In the JIA trial, 10% of patients treated with HUMIRA who had negative baseline anti-dsDNA antibodies developed positive titers after 48 weeks of treatment. No patient developed clinical signs of autoimmunity during the clinical trial. Approximately 15% of children treated with HUMIRA developed mild-to-moderate elevations of creatine phosphokinase (CPK). Elevations exceeding 5 times the upper limit of normal were observed in several patients. CPK levels decreased or returned to normal in all patients. Most patients were able to continue HUMIRA without interruption.

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FDA Update

with a TNF blocker. There is insuf� 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 Precautions].USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B - There are no adequate and well-controlled studies in pregnant women. Because animal reproduction and developmental studies are not always predictive of human response, HUMIRA should be used during pregnancy only if clearly needed. Pregnancy Registry: To monitor outcomes of pregnant women exposed to HUMIRA, a pregnancy registry has been established. Physicians are encouraged to register patients by calling 1-877-311-8972. Nursing Mothers It is not known whether adalimumab is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from HUMIRA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and ef� cacy of HUMIRA in pediatric patients for uses other than juvenile idiopathic arthritis (JIA) have not been established. Juvenile Idiopathic ArthritisIn the JIA trial, HUMIRA was shown to reduce signs and symptoms of active polyarticular JIA in patients 4 to 17 years of age. HUMIRA has not been studied in children less than 4 years of age, and there are limited data on HUMIRA treatment in children with weight <15 kg. The safety of HUMIRA in pediatric patients in the JIA trial was generally similar to that observed in adults with certain exceptions [see Adverse Reactions]. Post-marketing cases of malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers including HUMIRA [see Warnings and Precautions]. Geriatric Use A total of 519 rheumatoid arthritis patients 65 years of age and older, including 107 patients 75 years of age and older, received HUMIRA in clinical studies RA-I through IV. No overall difference in effectiveness was observed between these subjects and younger subjects. The frequency of serious infection and malignancy among HUMIRA treated subjects over 65 years of age was higher than for those under 65 years of age. Because there is a higher incidence of infections and malignancies in the elderly population in general, caution should be used when treating the elderly.

OVERDOSAGE Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies of HUMIRA have not been conducted to evaluate the carcinogenic potential or its effect on fertility. No clastogenic or mutagenic effects of HUMIRA were observed in the in vivo mouse micronucleus test or the Salmonella-Escherichia coli (Ames) assay, respectively.

PATIENT COUNSELING INFORMATION Patients or their caregivers should be provided the HUMIRA “Medication Guide” and provided an opportunity to read it and ask questions prior to initiation of therapy. The healthcare provider should ask the patient questions to determine any risk factors for treatment. Patients developing signs and symptoms of infection should seek medical evaluation immediately. Patient Counseling Patients should be advised of the potential bene� ts and risks of HUMIRA. Physicians should instruct their patients to read the Medication Guide before starting HUMIRA therapy and to reread each time the prescription is renewed. • Infections Inform patients that HUMIRA may lower the ability of their immune system to � ght infections. Instruct

patients of the importance of contacting their doctor if they develop any symptoms of infection, including tuberculosis, invasive fungal infections, and reactivation of hepatitis B virus infections.

• Malignancies Patients should be counseled about the risk of malignancies while receiving HUMIRA. • Allergic Reactions Patients should be advised to seek immediate medical attention if they experience any symptoms of severe

allergic reactions. Advise latex-sensitive patients that the needle cap of the pre� lled syringe contains latex. • Other Medical Conditions Advise patients to report any signs of new or worsening medical conditions such as congestive heart

failure, neurological disease, autoimmune disorders, or cytopenias. Advise patients to report any symptoms suggestive of a cytopenia such as bruising, bleeding, or persistent fever.

Ref: 03–A608-R28Rev. May, 2012

64C-894702 MASTER

64M-896403

Psoriatic Arthritis and Ankylosing Spondylitis Clinical StudiesHUMIRA has been studied in 395 patients with psoriatic arthritis (PsA) in two placebo-controlled trials and in an open label study and in 393 patients with ankylosing spondylitis (AS) in two placebo-controlled studies. The safety pro� le for patients with PsA and AS treated with HUMIRA 40 mg every other week was similar to the safety pro� le seen in patients with RA, HUMIRA Studies RA-I through IV. Crohn’s Disease Clinical StudiesHUMIRA has been studied in 1478 patients with Crohn’s disease in four placebo-controlled and two open-label extension studies. The safety pro� le for patients with Crohn’s disease treated with HUMIRA was similar to the safety pro� 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 pro� le for patients with plaque psoriasis treated with HUMIRA was similar to the safety pro� 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. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to HUMIRA exposure. Gastrointestinal disorders: Diverticulitis, large bowel perforations including perforations associated with diverticulitis and appendiceal perforations associated with appendicitis, pancreatitis Hepato-biliary disorders: Liver failureImmune system disorders: SarcoidosisNervous system disorders: Demyelinating disorders (e.g., optic neuritis, Guillain-Barré syndrome), cerebrovascular accidentRespiratory disorders: Interstitial lung disease, including pulmonary � brosis, pulmonary embolism Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening psoriasis (all sub-types including pustular and palmoplantar), alopecia Vascular disorders: Systemic vasculitis, deep vein thrombosis

DRUG INTERACTIONS Methotrexate Although methotrexate (MTX) reduces the apparent adalimumab clearance, the data do not suggest the need for dose adjustment of either HUMIRA or MTX. Biologic Products In clinical studies in patients with RA, an increased risk of serious infections has been seen with the combination of TNF blockers with anakinra or abatacept, with no added bene� 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

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14 VALUE-BASED CARE IN RHEUMATOLOGY I OCTOBER 2012 VOL. 1 I NO. 5

Expanded Indication forActemra for RheumatoidArthritis

The US Food and Drug Admin -istration (FDA) has approved anexpanded indication for tocilizumab(Actemra; Genentech), a humanizedin terleukin-6 receptor–inhibiting mon o clonal antibody, for the treat-ment of adults with moderate-to-severe rheumatoid arthritis (RA) whohave had an inadequate response totherapy with ≥1 disease-modifyinganti rheumatic drugs (DMARDs).

Tocilizumab can be used as a single-agent therapy or in combination withmethotrexate or with other DMARDsin this patient population. Theexpanded indication reinforces thesafety and efficacy profile of this medication.

This expanded indication is basedon newly presented efficacy and safe-ty data from the previous phase 3clinical trials—OPTION, TOWARD,and LITHE; safety data from thepostmarketing experience with to -cilizumab since its initial FDAapproval in 2010; as well as data fromother clinical studies, including trialsthat evaluated this medication in areal-world setting.

Tocilizumab is administered byinjection. In the OPTION trial, 59% ofpatients who received tocilizumaband 48% of those receiving methotrex-ate achieved American College ofRheumatology 20% improvement cri-

teria (ACR20) at week 24 comparedwith 27% of patients receiving place -bo plus methotrexate. Similarly, inLITHE, 56% of those receivingtocilizumab and 51% of those receiv-ing a combination of tocilizumab plusmethotrexate reached ACR20 at 24weeks compared with 27% of theplacebo plus methotrexate group.

In addition, tocilizumab 4 mg/kgand 8 mg/kg slowed or inhibited theprogression of structural damage inpatients with RA compared withplacebo plus methotrexate at week 52.Tocilizumab is already approved forthe treatment of active systemic juve-nile idiopathic arthritis in patientsaged ≥2 years. (October 11, 2012)

Humira Approved for Ulcerative Colitis

The FDA has approved a new in -dication for adalimumab (Humira;Abbott Laboratories) for the treatmentof moderate-to-severe ulcerative colitis in adults, to control ulcerativecolitis when immunosuppressantmedicines, such as corticosteroids,azathioprine, and 6-mercaptopurine,have not worked.

Adalimumab is an anti–tumornecrosis factor (TNF) that blocks pro-teins involved in abnormal inflamma-tory and immune responses. Ulcer -ative colitis is a chronic disease thatcauses inflammation and ulcers in theinner lining of the large intestine.

“Each patient with ulcerative colitis

experiences the disease differently,and treatment must be adjusted tomeet each individual’s needs,” saidDonna Griebel, MD, Director of theDivision of Gastroenterology andInborn Errors Products in the FDA’sCenter for Drug Evaluation andResearch. This “approval provides animportant new treatment option forpatients who have had an inadequateresponse to conventional therapy.”

Adalimumab is already approvedfor the treatment of RA, psoriaticarthritis, ankylosing spondylitis,Crohn’s disease, plaque psoriasis,and juvenile idiopathic arthritis.

Adalimumab’s safety and effec-tiveness for ulcerative colitis wereestablished in 2 clinical trials involv-ing 908 patients who had never beentreated with a TNF blocker, or wholost response to or were intolerant toTNF blockers.

The approved dosing regimen forulcerative colitis includes an initialdose of 160 mg, a second dose 2weeks later of 80 mg, and a mainte-nance dose of 40 mg every otherweek thereafter. The drug shouldonly be continued in patients whoshow evidence of clinical remissionby 8 weeks of therapy.

No new side effects were identi-fied during clinical studies. Com -mon side effects of adalimumabinclude infections, reactions at theinjection site, headache, and rash.(September 28, 2012)

Prolia Receives NewIndication for Men withOsteoporosis

The FDA approved a new indica-tion for the subcutaneous RANK li -gand inhibitor denosumab (Prolia)for the treatment of bone mass loss inmen with osteoporosis who are athigh risk for fracture. Denosumab, 60mg, is administered as a single injec-tion by a healthcare provider every 6months.

The approval was based on 12-month data from the pivotal phase 3clinical trial ADAMO. The trialincluded 242 men (age, 30-85 years)with low bone mineral density (BMD)and who have had a major osteo-porotic fracture. Treatment with deno-sumab resulted in significant increas-es in lumbar spine T-scores comparedwith placebo (5.7% vs 0.9%, respec-tively). In addition, in creases in BMDwere seen in all skeletal sites com-pared with placebo.

The safety profile was similar toprevious studies with denosumab inpostmenopausal women. The mostcommon adverse reactions reported(>5%) were back pain, arthralgia, andnasopharyngitis.

Denosumab is already approvedfor the treatment of osteoporosis in postmenopausal women at highrisk for fracture, and for patients whohave failed or are intolerant of othertherapies for osteoporosis. (Septem -ber 20, 2012) �

15VOL. 1 I NO. 5 OCTOBER 2012 I www.ValueBasedRheumatology.com

Personalized Medicine in Rheumatology™

creased risk for potentially fatal throm-botic events, allowing the provider totailor treatments and prevention forthe individual patient. In addition, theresults further expand the understand-ing of a genetic basis for ethnic differ-ences associated with thrombosis inpatients with SLE.

“In the future, genetic informationmay help predict which patients withSLE are at greatest risk for thromboticevents….Examining genetic risk fac-tors for thrombosis in SLE may notonly help to understand pathogenesisbut also inform prediction of this SLEcomplication,” wrote Rachel Kaiser,MD, The Rosalind Russell MedicalRe search Center for Arthritis, Uni -versity of California, San Francisco(UCSF), and coauthors.

Increased Risk for Thrombosis

Patients with SLE are at increasedrisk for thrombosis, and thrombosisgenerally occurs at younger ages, withmore significant morbidity. Womenaged 18 to 44 years who have SLE arehospitalized with myocardial infarc-tion or stroke 9 times more often thanthe general population. The need forlifetime anticoagulation for the pre-vention of thrombosis has severaldrawbacks, including an increasedrisk for bleeding. Therefore, it is im -portant to identify better predictors ofthrombosis to enable prevention, theauthors noted.

Established risk factors—includingthe presence of antiphospholipid anti-

bodies, smoking, longer disease dura-tion, older age at SLE diagnosis, anddisease activity—do not completelyexplain excess thrombosis in patientswith SLE. For example, only 10% ofthe 40% of patients with SLE who pro-

duce antiphospholipid antibodieshave a thrombotic event, and 40% ofthose who have a thrombotic event areantiphospholipid antibody negative.

Genetic Risk Factors

Most known genetic risk factors forthrombosis in the general populationare found mainly in whites, althoughthere are striking ethnic differences inthrombosis in both the general popu-lation and in patients with SLE thathave not been well studied. Blacks

have a 3- to 5-fold lower risk of deep-vein thrombosis and pulmonaryembolism compared with whites;however, blacks have a higher rate ofvenous thromboembolism. Under -standing the genetics might explainsome of the variations in thrombosisoutcomes among patients with SLE ofdifferent ethnicities.

The genetic variants fibrinogengamma (FGG) rs2066865, methylene -tetrahydrofolate reductase (MTHFR)rs1801133 and rs1801131, and factor VLeiden (FVL) rs6025 are associatedwith a risk for thrombosis amongwhite patients with SLE, and FGGrs2066865 may be a risk factor forthrombosis in Hispanic patients withSLE. These and genetic risk factors forthrombosis may contribute to the dif-ference in risk among patients withSLE beyond traditional explanations.

The authors examined the singlenucleotide polymorphisms that havebeen associated with thrombosis in thegeneral population of whites or havebeen implicated in thrombosis andcoagulation in 2 multiethnic cohorts ofpatients with SLE. The first was a mul-tiethnic cohort of 1698 patients withSLE from UCSF. A replication cohortconsisted of 1361 patients with SLEfrom the PROFILE cohort who wererecruited from Northwestern Uni -versity, Johns Hopkins University, theUniversity of Alabama at Birmingham,the University of Texas Health ScienceCenter at Houston, and the Universityof Puerto Rico.

In the discovery cohort, 92% werewomen and 60% were white (thecohort also included 15% Hispanics,13% Asian Americans, and 12%blacks). The mean age at SLE diagno-sis was 33 years, and the mean diseaseduration was 9 years. Approximately23% of patients had at least 1 throm-bosis. Of all the patients, 35% wereantiphospholipid antibody positive.

In the replication cohort, character-istics were similar for age at diseaseonset and proportion of women, butthere were fewer whites and AsianAmericans and more blacks than inthe discovery cohort. Only 12% of per-sons in the replication cohort experi-enced a thrombotic event. The authorsattribute this difference in the percent-age of thrombotic events between thecohorts in part to differences in re -cording thrombotic events. �

SLE: New Genetic Risk Factors for Thrombosis... Continued from cover

“In the future, geneticinformation may helppredict which patients withSLE are at greatest risk forthrombotic events….Examining genetic riskfactors for thrombosis in SLE may not only help tounderstand pathogenesisbut also inform prediction ofthis SLE complication.”

—Rachel Kaiser, MD, et al

A rash on the leg of a 45-year-oldwoman, caused by systemic lupus erythematosus

Developing new strategies forthe prevention of osteoarthri-tis (OA) and its significant

clinical burden is largely based on bet-ter understanding of the mechanismof OA disease and identification ofpotential biomarkers that may beinvolved in the progressive deteriora-tion of the joints, including knee andhip. Researchers in Shanghai, China,have uncovered a new biomarker, themolecule fetuin-A, which their newstudy indicates is an excellent surro-gate to gauge the severity of disease inpatients with primary knee OA (XiaoJ, et al. Serum fetuin-A levels areinversely associated with clinicalseverity in patients with primary knee

osteoarthritis. Biomarkers. 2012 Oct 16[Epub ahead of print]).

If these observations are validated,the result would be the developmentof a simple blood test that wouldserve as a guide to therapy, includingpharmacologic, joint-saving treatmentdecisions.

As lead author, Jie Xiao, MD,Department of Anesthesiology, RenjiHospital, Shanghai Jiaotong Univer -sity School of Medicine, China, andcolleagues, state in the article, “Riskassessment and the development ofpreventive or therapeutic interven-tions at the early stages of the diseasecould remarkably improve clinical out -comes and reduce healthcare costs.”

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

knee OA in particular because it is themost prevalent form of the disease, aswell as a major cause of physical dis-ability and impaired quality of life inelderly patients.

The rationale for investigating thediagnostic utility of fetuin-A in OAstems from observations made in thesetting of rheumatoid arthritis (RA),which found that fetuin-A levels weresignificantly lower in patients with RA.

On further investigation, fetuin-A, aglycoprotein that is synthesized andsecreted from human liver cells, wasdiscovered to be a mediator of chronicinflammatory disease.

To assess the viability of fetuin-A asa diagnostic biomarker in patientswith OA, the laboratory values for 215patients with knee OA were measured

“The identification of novelbiomarkers measurable inperipheral circulation andcapable of predictingrelevant outcomes in earlyOA is a critical issue for thedevelopment of preventivestrategies and early-stageinterventions.”

—Jie Xiao, MD, et al

Biomarker May Lead to Blood Test to Measure Osteoarthritis SeverityBy Neil Canavan

Continued on page 16

See also Osteoarthritis

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is also very costly to the US healthcaresystem.

Another, surprising, main findingof this study is that emergency depart-ment visit–related charges are signifi-cantly lower with gout as the primarydiagnosis than with gout as a second-ary diagnosis or not a diagnosis at all.

“I was a little surprised by this find-ing, but not shocked,” lead investiga-tor Ted R. Mikuls, MD, Professor ofInternal Medicine at the University ofNebraska Medical Center and OmahaVA Medical Center, NE, told Value-Based Care in Rheumatology. “It’s veryimportant to remember that goutoften keeps ‘bad company,’ whichincludes other chronic health condi-tions, such as diabetes and heart dis-ease. So, in cases where these latter

illnesses are the primary cause of[emergency department] visits, andgout is a secondary diagnosis, per-haps it’s not too surprising that costswould be even higher.”

Utilization and Cost Rates

These findings are based on ananalysis of data from the NationwideEmergency Department Sample(NEDS) between 2006 and 2008.NEDS tracks patient-related informa-tion and charges generated fromemergency department visits forbetween 24 and 28 states in the UnitedStates.

Between 2006 and 2008, gout wasthe primary or secondary diagnosisassociated with >280 million visits tothe emergency department, represent-ing 0.7% of all emergency department

visits; it was the primary diagnosis forapproximately 0.2% of those visits,annually.

The median cost for a visit to theemergency department—with gout asthe primary diagnosis—was $540 in2006 and $667 in 2008, which corre-sponded to $128 million and $166 mil-lion in total emergency department–related charges, respectively.

The median per-visit charges withgout as a secondary diagnosis were$960 and $1187 in 2006 and in 2008,respectively, representing a 23.6%increase within the span of 3 years.

Gout-Related Characteristics

The researchers examined individ-ual patient characteristics, showingthat after adjustment for an array ofvariables, men were 79% more likelythan women to have a gout-relatedvisit to the emergency departmentthan a non–gout-related visit. Otherpatient characteristics associated witha propensity toward an emergencydepartment visit for gout were age, anannual household income of <$38,000,and being treated in a hospital in thesouthern United States or in a non-metropolitan area.

Conversely, having Medicare as thepayer was associated with a signifi-cantly lower propensity for a gout-related emergency department visitthan for those with private healthinsurance coverage.

The researchers noted that factorssuch as having a median annualincome of <$38,000 and being treatedin rural or southern areas of theUnited States may be surrogates forpoor healthcare access. They suggest-ed another possibility that thesedynamics are associated with otherconfounding factors that were nottaken into account in the analysis, suchas the prevalence of gout, race and eth-

nicity, and differences in diet and alco-hol intake.

The Future

“I think providers need to reallythink about novel ways of deliveringgout care, because there are growingdata to suggest that our current prac-tices are failing a majority of gout suf-ferers,” said Dr Mikuls.

The researchers suggest that gout-

related utilization of the emergencydepartment is likely to increase “in theabsence of effective interventions”that are focused on shifting gout careaway from the emergency departmentand into the primary care setting.Furthermore, “the availability of high-ly novel but often more expensivediagnostic imaging modalities andurate-lowering therapies may addfurther to escalations in gout-related”overall cost of gout “in the nearfuture.”

Dr Mikuls and colleagues hope tocontinue to explore utilization trendsrelated to gout and to investigatepractice strategies to improve thequality of gout care and lower the sig-nificant cost and clinical burden itplaces on patients and on the UShealthcare system. �

Economic Issues in Rheumatology

16 VALUE-BASED CARE IN RHEUMATOLOGY I OCTOBER 2012 VOL. 1 I NO. 5

at a glance� Gout is a common condition

with a heavy economic toll onthe US healthcare system

� In this first US analysis ofgout-related emergencydepartment utilization, goutwas associated with 0.7% ofall visits to the emergencydepartment between 2006and 2008

� The median cost of gout-related visits to the emergencydepartment was $540 in 2006 and $667 in 2008,corresponding to $128 millionand $166 million, respectively

� The median per-visit chargesfor gout as a secondarydiagnosis were $960 in 2006and $1187 in 2008—a 23.6%increase in 3 years

High Emergency Department Utilization and Costs... Continued from cover

“It’s very important toremember that gout oftenkeeps ‘bad company,’ whichincludes other chronic healthconditions, such as diabetesand heart disease.”

—Ted R. Mikuls, MD

and then compared with the laborato-ry results from 76 healthy individuals.

Serum fetuin-A levels were mea -sured by an enzyme-linked immuno -sorbent assay. These results werethen correlated with imaging analy-ses that were obtained from patientswho underwent weight-bearing an -tero posterior radiographs of theaffected knee.

The severity of the disease symp-toms was assessed with the WesternOntario and McMaster UniversitiesOs teo arthritis Index.

Results of this comparison demon-strated—for the first time—thatserum fetuin-A levels independentlyand negatively correlated with greaterclinical severity in patients with OA.When compared with radiographic

data, the relative levels for this circu-lating serum biomarker also showed asignificant decrease in advanced-stagedisease compared with early-stagedisease.

As stated by the authors, theseresults indicate that fetuin-A may beprotective against the developmentand progression of OA, and, on amechanistic level, may reflect specific

biologic processes of OA. As to the clinical relevance, “The

iden tification of novel biomarkersmeasurable in peripheral circulationand capable of predicting relevantoutcomes in early OA is a criticalissue for the development of preven-tive strategies and early-stage inter-ventions,” Dr Xiao and colleagueswrote. �

Biomarker May Lead to Blood Test... Continued from page 15

“Providers need to reallythink about novel ways ofdelivering gout care,because there are growingdata to suggest that ourcurrent practices are failinga majority of goutsufferers.”

—Ted R. Mikuls, MD

Personalized Medicine

Economic Issues in Rheumatology

Phoenix, AZ—Cost-effectiveness val-ues for biologics in patients withrheumatoid arthritis (RA) are half ashigh—indicating much lower valuefor money—when using real-life datarather than using results of random-ized controlled trials (RCTs), a newmeta-analysis that was presented atthe 2012 annual meeting of the Societyfor Medical Decision Making hasshown.

Lead investigator Hawre J. Jalal,MD, MSc, from the School of PublicHealth at the University of Minnesota,Minneapolis, and colleagues from theNational Data Bank for RheumaticDiseases in Wichita, KS, and theUniversity of Nebraska MedicalCenter in Omaha, conducted themeta-analysis to compare the use ofRCT data in cost-effectiveness analy-ses versus pa tient outcomes in real-world settings.

“Most cost-effectiveness analysisstudies are based on medications’ effi-cacy in RCTs rather than on their real-life effectiveness. However, RCTs inRA have many documented limita-tions, including highly selectivepatient groups,” explained Dr Jalal.

“These have been studied extensivelyin the literature.”

The team identified 9 RCT-basedcost-effectiveness studies of biologicscompared with nonbiologics inpatients with RA that were publishedbetween 2000 and 2006. They thenconstructed 9 mathematical modelsusing the sensitivity analysis resultsreported in the studies.

This is the first time such anapproach has been used in a meta-analysis. Sensitivity analyses areexaminations of how the results arealtered when study parameters arechanged. They then calculated howthe resulting incremental cost-effec-tiveness ratios (ICERs) for biologicsand nonbiologics differ when datawere used from RCTs or from real-lifeobservational data from the large USNational Data Bank for RheumaticDiseases.

The results showed that when effec-tiveness estimates are based on obser-vational data rather than RCT efficacyestimates, the ICERs doubled. Thistranslates into a halving of the cost-effectiveness, because higher ICERsindicate lower cost-effectiveness (ie,

less value for the money spent).Nearly half (48%) of the total

increase in ICER with observationaldata versus RCT data was a result ofthe initial disability improvement withthe use of biologics, based on scores inthe Health Assessment Questionnaire(HAQ) Disability Index.

The initial disability improvementis significantly lower in real-life datathan in RCTs. Other factors that signif-icantly contributed to an increase in

the ICER for biologics with RCT datacompared with observational datawere the way the health-related quali-ty of life associated with the HAQ wasmeasured, HAQ progression amongtherapy nonresponders, and HAQprogression for nonbiologics.

HAQ progression for biologics wasthe one factor that favored a lowerICER with RCT data. “What the latterfinding means is that, following theshort-term decrease in HAQ with bio-logics, HAQ values increase at a high-er rate in RCTs than in real-life set-tings. This may be because RCTs are generally of short duration,”explained Dr Jalal. “This was the onlyinput from our initial analysis thatmade biologics appear more cost-effective based on efficacy data fromRCTs than with effectiveness datafrom the observational database.”

The bottom line is that biologicsmay be less cost-effective than initial-ly thought, noted Dr Jalal. However,this analysis did not account for theindirect costs that may be affected bylower efficacy of nonbiologic thera-pies in RA, such as reduced produc-tivity and absence from work. �

Cost-Effectiveness for Biologics in RA Lower withReal-Life Data than with Randomized Trials Data By Rosemary Frei, MSc

Cost-Effectiveness of Biologics Affected by RA DiseaseSeverity in a New Decision Model Using various patients’ willingness-to-pay thresholds

17VOL. 1 I NO. 5 OCTOBER 2012 I www.ValueBasedRheumatology.com

“Most cost-effectivenessanalysis studies are based onmedications’ efficacy in RCTsrather than on their real-lifeeffectiveness. However, RCTs in RA have manydocumented limitations,including highly selectivepatient groups.”

—Hawre J. Jalal, MD, MSc

Phoenix, AZ—A novel mathematicalmodel can help to pinpoint when bio-logics become most cost-effective forvarious disease categories of patientswith rheumatoid arthritis (RA).

Researchers have found that with awillingness to pay of up to $100,000per additional quality-adjusted life-year (QALY) gained from therapy,biologics could be cost-effective formildly disabled elderly patients iftheir costs were cut by 60%.

When the willingness-to-pay thres -hold is bumped up to $300,000 perQALY gained, biologics become cost-effective for younger and more dis-abled patients.

The researchers presented theirfindings at the 2012 annual meeting of the Society for Medical DecisionMaking.

“We are finding that there may be a

‘window of opportunity’ duringwhich biologics are most cost-effec-tive,” said lead investigator Hawre J.Jalal, MD, MSc, of the School of PublicHealth at the University of Minnesota,Minneapolis, when asked by Value-Based Care in Rheumatology aboutdetails of the study. He said, however,that the analysis of this research is attoo early of a stage for him to be ableto share all of the results.

The model constructed by Dr Jalaland colleagues was a Markov decisionprocesses model. Their goal was toidentify the decision sequences ofhypothetical RA patients that maxi-mize the net health benefit. A spec-trum of patient ages and quintile oflevels of disability, as measured byHealth Assessment Questionnaire-Disability Index (HAQ-DI) scores,were assessed.

The data for the study came fromthe National Data Bank for Rheu -matic Diseases to define patients’propensity to use biologic or nonbio-logic therapies. The team also esti-mated direct and indirect costs—associated with productivity losses—from the literature, and calculated anaverage quality of life using theEuroQol 5D (EQ-5D) instrument foreach HAQ-DI quartile. The re -searchers discounted both costs andbenefits by 3% annually.

Besides finding that biologics couldbe cost-effective either in mildly dis-abled elderly people with RA whohave a willingness to pay of up to$100,000 per QALY, when the cost ofbiologics was reduced by 60%, or inyounger and more disabled individu-als with a willingness to pay of up to$300,000 per QALY, the researchers

also found that biologics are cost-effective for patients who are diag-nosed within the 2 previous years andwho are more disabled.—RF �

at a glance� With a willingness to pay of up

to $100,000 per additionalQALY gained, biologics couldbe cost-effective for mildly dis-abled elderly patients with RAif their costs were cut by 60%

� When the willingness-to-paythreshold is $300,000 perQALY gained, biologicsbecome cost-effective foryounger and more disabledpatients

Rheumatology Update

18 VALUE-BASED CARE IN RHEUMATOLOGY I OCTOBER 2012 VOL. 1 I NO. 5

Anew, large meta-analysis indi-cates that at least 6 months ofbiologic therapy for rheuma-

toid arthritis (RA) does not increase therisk of cancer (Lopez-Olivo MA, et al.JAMA. 2012;308:898-908).

The one exception found was a dou-bling of malignancy risk for patientswith RA compared with controls after52 weeks of treatment with tumornecrosis factor (TNF) inhibitors plusmethotrexate. The absolute increasedrisk, however, was only 6 per 1000patients and was not present at earlieror later time points, up to 156 weeks, orwith any of the TNF inhibitors beingused as monotherapy.

Conflicting results from differenttypes of studies, including observa-tional studies, have been published,suggesting the potential for an associa-tion between the different biologictherapies used in RA and the poten -tialfor malignancy. The US Food and DrugAdministration (FDA) has recom-mended adding a warning to thateffect to all TNF inhibitors.

This large meta-analysis sought toresolve these conflicting reports, and itis the first systematic review investigat-ing malignancy risk using evidencefrom randomized clinical trials (RCTs)only and in patients with RA only,based on data on all the available

biologic response modifiers. The team systematically reviewed 63

RCTs involving 29,423 patients withRA who were receiving biologic thera-

py for at least 24 weeks. Although theresearchers have faith in their findings,they caution that a carcinogenic effectcannot be entirely excluded.

They point out that the only signifi-cant increase in risk for malignancythat was found disappeared when amore conservative effect measure wasused in the statistical analysis; there-

fore, this positive result was not con-sistent and could have just happenedby chance. However, further monitor-ing from observational studies isneeded to better understand thelonger-term toxicity implications ofthese biologic agents.

Maria A. Lopez-Olivo, MD, MSc,PhD, Instructor, Department ofGeneral Internal Medicine-Research,Division of Internal Medicine, at TheUniversity of Texas M.D. AndersonCancer Center, Houston, and col-leagues conducted the meta-analysis totake a close look at this area of contro-versy. They examined studies on all 9biologic response modifiers that areapproved by the FDA.

Dr Lopez-Olivo and colleagues ana-lyzed results from 71 publications on63 different trials. All of the trials weremulticenter, and 42 trials were multi-national. The smallest number ofpatients in a trial was 20, and thelargest was 1399. Follow-up rangedfrom 24 to 156 weeks, and dosing ofthe biologic response modifiers rangedfrom below the recommended doses toabove them. Most of the patients (N = 15,989) were assigned to biologicresponse modifiers plus methotrexateand/or other disease-modifyingantirheumatic drugs (DMARDs), 3615to biologic response modifiers alone,

and 9819 to control groups.Only 4 of the trials were compar-

isons between biologic response modi-fiers. Pharmaceutical companies spon-sored 56 of the trials, and theresearchers of 3 others did not disclosethe source of funding.

The team expressed the results asboth Peto odds ratios (ORs) and rela-tive risks, and stated that “the Peto ORis preferred for uncommon events.”

For all cancer types combined, theonly significant increase in Peto OR,2.1, was for a comparison of all TNFinhibitor plus DMARD combinationsversus a DMARD alone at 52 weeks.The only significant decrease in PetoOR, 0.11, was for the non-TNF inhib -itor anakinra plus methotrexate versusplacebo plus methotrexate at 24 weeks.

“The data available appear to sug-gest that there is no cumulative riskover time, but these data are also sub-ject to bias. Clinical trials, however,are less subject to bias and, in thecontext of malignancies, are appro-priate to evaluate rapid developmentof cancer,” Dr Lopez-Olivo and col-leagues wrote.

They caution that “clinicians shouldbe aware that closer monitoring is rec-ommended for patients who arereceiving these types of drugs and whohave had malignancies in the past.” �

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

For patients who have failed ther-apy with a tumor necrosis factor(TNF) inhibitor, switching to

B-cell–depleting rituximab (Rituxan)may be a similar treatment option toswitching to a different anti-TNFagent in terms of control of rheuma-toid arthritis (RA), according to theresults of a recent multicenter trial(Gomez-Reino JJ, et al. Ann RheumDis. 2012;71:1861-1864).

Patients had similar disease activityscores at 6, 9, and 12 months whetherthey received another TNF inhibitoror the B-cell–depleting drug. Analysisof individual anti-TNF agents, how-ever, showed that switching to ritux-imab led to significantly better diseasecontrol than did a change to a mono-

clonal TNF inhibitor, such as inflix-imab (Remicade) or adalimumab(Humira).

“Our results show that, in patientswith RA who fail on treatment with a

TNF antagonist, switching to ritux-imab is perhaps more efficacious thanswitching to an alternative TNFantagonist,” noted Juan J. Gomez-Reino, MD, of Universidad deSantiago de Compostela in Barcelona,Spain, and colleagues in the article.Rituximab, in combination withmethotrexate (Trexall), is indicated forthe treatment of patients with moder-ate-to-severe RA who have had aninadequate response to one or more ofthe TNF antagonists.

Observational studies have sug-gested that switching to rituximabmight lead to control of RA that issimilar to or better than what mightbe achieved by switching to a differ-ent TNF inhibitor after failure of ini-

tial anti-TNF therapy. Moreover, dataare lacking on the efficacy of switch-ing from one anti-TNF agent toanother, as well as on the influence ofanti-TNF sequencing on a subsequentchange to rituximab, Dr Gomez-Reino and colleagues pointed out intheir introduction.

To learn more about the options forswitching after anti-TNF failure,investigators at 100 centers through-out Spain conducted a prospectiveobservational clinical trial involvingpatients who had received inadequatedisease control or who lost diseasecontrol during anti-TNF therapy.

The trial included 1124 patients, 591of whom received rituximab and 533

B-Cell Depletion Matches TNF Inhibition as SwitchingOption for Patients with RA Who Have Failed TNF TherapyBy Charles Bankhead

“The data available appearto suggest that there is no cumulative risk over time,but these data are alsosubject to bias. Clinical trials,however, are less subject to bias and, in the context of malignancies, areappropriate to evaluaterapid development of cancer.”

—Maria A. Lopez-Olivo, MD, MSc,

PhD, et al

Continued on page 19

“In patients with RA whofail on treatment with a TNFantagonist, switching torituximab is perhaps moreefficacious than switching toan alternative TNFantagonist.”

—Juan J. Gomez-Reino, MD, et al

19VOL. 1 I NO. 5 OCTOBER 2012 I www.ValueBasedRheumatology.com

Phoenix, AZ—New data indicate thatclinicians and researchers should takeinto account the overall disease trajec-tory of patients with rheumatoidarthritis (RA), not only their diseaseactivity at a given point, when recom-mending medication changes.

The analysis presented at the 2012annual meeting of the Society forMedical Decision Making showed asignificant relationship betweenpatients’ willingness to change theircurrent treatment, illness trajectory,and disease activity.

For example, people who overallhave fluctuating or worsening RA aremuch more willing to change medica-tions when they are experiencing aflare than when they are near remis-sion, the findings indicate.

“Studies using only contemporane-ous assessments do not fully capturehow disease activity influences will-ingness to change [medication],” saidLiana Fraenkel, MD, MPH, AssociateProfessor of Medicine (Rheuma -tology), at Yale School of Medicine,New Haven, CT, and her colleagues.This is important, because “unwilling-ness of patients to change their cur-rent treatment can impede efforts toprovide the best available care.”

Dr Fraenkel and her colleaguesrecruited 156 volunteer patients with

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

ticipants dropped out of the baselineinterview, and thus the researchersexcluded them from the analysis. All 4interviews were completed by 94patients; 28 patients completed 3interviews, and 21 patients completed2 interviews.

In each interview, the patients’ dis-ease activity was assessed using theRoutine Assessment of Patient Index

Data (RAPID)4, a validated 40-pointself-report measure (score of 5.67, nearremission; 6.46, low disease activity;6.82, moderate disease activity; 7.75,high disease activity). They alsoassessed the gap between the patients’current and desired health state. Inaddition, an 11-point scale was usedto gauge the patients’ willingness tochange medications, which rangedfrom zero for “not willing” to 10 for“extremely willing.”

Not surprisingly, the worse thepatients’ disease activity was, thegreater the discrepancy was betweentheir current and desired health states.

The researchers then put each sub-ject’s disease trajectory into 1 of 4 cat-egories, depending on the diseaseactivity at each of the 4 time points (ie,stable, improving, declining, or fluc-tuating). The characteristics ofpatients in each of the 4 groups weresimilar, except there were significantlymore females than males in the fluctu-ating and the improving groups, andsignificantly more males in the declin-ing group.

The results revealed that thepatients’ willingness to change med-ication differed significantly, depend-ing on their category of disease activi-ty. This was the case despite the factthat there were only small differences

in RAPID4 scores between the 4 dis-ease activity categories.

Analysis of the interactionsbetween disease trajectory category,disease activity at each time point,and willingness to change medicationshowed that disease activity alone,and disease trajectory together withdisease activity, both significantlyinfluenced willingness to changemedication. The 2 factors combinedhad a stronger influence than diseaseactivity alone. �

Disease Activity Trajectory Important Factor inPatients’ Willingness to Change Their RA Medication By Rosemary Frei, MSc

“Studies using onlycontemporaneousassessments do not fullycapture how disease activityinfluences willingness tochange [medication].Unwillingness of patients tochange their currenttreatment can impedeefforts to provide the bestavailable care.”

—Liana Fraenkel, MD, MPH

Analysis of the interactionsbetween disease trajectorycategory, disease activity ateach time point, andwillingness to changemedication showed thatdisease activity alone, anddisease trajectory togetherwith disease activity, bothsignificantly influencedwillingness to changemedication.

who received an alternative TNFinhibitor. The primary outcome waschange in the Disease Activity Score in28 joints (DAS28). Follow-up assess-ments occurred at 6, 9, and 12 months,and investigators will continue fol-low-up for 3 years.

Patients treated with rituximab hadlonger disease duration (>5 years,79.3% vs 67.4%; P <.001), more extra-articular manifestations (36.7% vs27.7%; P < .001), more incidences of atreatment history with >1 prior anti-TNF agent (37.0% vs 11.4%; P <.001),and a higher DAS28 score at baseline(5.5 vs 5.0; P <.001).

Overall, the treatment groupsobtained similar disease control, asrepresented by DAS28 scores at 6, 9,and 12 months. Analysis of the data by

mechanism of TNF inhibition revealedsignificant differences. Etanercept andrituximab had similar disease controlat all assessments. In contrast, pooledresults showed significant differencesin DAS28 reductions that favored rit-uximab versus an adalimumab andinfliximab combination at 6 months (–1.61 vs –1.04, respectively; P = .001)and at 12 months (–1.81 vs –1.55,respectively; P = .05).

The absence of a significant differ-ence between rituximab and the ada -limumab and infliximab combinationgroups at 9 months “could reflect how[rituximab] is used in clinical practice(ie, retreatment when worsening),”the authors noted in the discussion oftheir findings. “In fact, this blunting ofresponse to [rituximab] disappears at

12 months when the response is againbetter than in the TNF antagonist

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

ture has been reported by others.”A greater proportion of patients

treated achieved a good response byEuropean League Against Rheuma -tism criteria at 6 months with ritux-imab than with the alternative TNFinhibitors (59% vs 45%; P = .025).Thereafter, the proportion of patientswith good, moderate, or no responsedid not differ between the treatmentgroups.

“Optimal treatment for patientswith RA failing on TNF antagonistsmay include [rituximab],” Dr Gomez-Reino and colleagues concluded.“Our work further suggests that theimprovement in DAS28 is larger inpatients treated with [rituximab] thanin those treated with monoclonal anti-TNF antibodies.” �

Rheumatology Update

“Our work further suggeststhat the improvement inDAS28 is larger in patientstreated with [rituximab]than in those treated withmonoclonal anti-TNFantibodies.”

—Juan J. Gomez-Reino, MD, et al

B-Cell Depletion Matches TNF Inhibition... Continued from page 18

Osteoarthritis

Effect of a Walking Program on Exercise Adherenceand Physical Disability in Patients with OsteoarthritisBy Rosemary Frei, MSc

Promoting physical activity inpatients with osteoarthritis(OA) is important. Interventions

that may motivate patients with OA to adhere to an exercise regimen toreduce the risk of physical disabilityrelated to this chronic disease cantherefore be helpful for providers andfor patients. New research has shownthat it is possible to use an evidence-based aerobic walking program tohelp patients with OA minimize theirsymptoms (Brosseau L, et al. BMCPublic Health. 2012;12:871).

The investigators successfully im -ple mented a supervised community-based aerobic walking program(SCAWP) and combined it with edu-cation and counseling to boost ad -herence.

In addition, they compared the out-comes from this combination withSCAWP alone or with self-directedwalking. The combination approachdid not result in increased exerciseadherence over the year’s length ofthe study, but it did produce greateradherence over the short-term.

“Our results indicated that if anolder individual is adherent to a self-management walking program for along time, simple incentives, such as apedometer, logbooks, and periodic 3-month assessment, seem to be suc-cessful in maintaining the good habitsof regular walking in order to reduceknee pain, [increase] functional activi-ties, and enhance quality of life,”Lucie Brosseau, PhD, Professor and

Research Chair of RehabilitationSciences at the University of Ottawa,Ontario, Canada, who led the project,told Value-Based Care in Rheumatology.

The SCAWP Program

The researchers randomized 69 par-ticipants with mild-to-moderate OAto SCAWP and a behavioral interven-tion, 79 to SCAWP alone, and 74 to a self-directed walking program.Members of all 3 groups also receivedan educational pamphlet describingthe positive effects on OA of walking.

The researchers were blinded towhich group each participant wasrandomized to, and they followedparticipants for 12 months, as well asfor an additional 6-month, unsuper-vised period.

Participants took part in SCAWPvia walking clubs in the Ottawa area.There were 3 weekly walking sessions

over a 12-month period, with eachsession beginning with a 10-minutewarm-up followed by 45 minutes ofaerobic walking and a 10-minute cool-down. The program was structured tofirst progressively increase exerciseduration and heart-rate intensity, andthen to maintain these.

The behavioral intervention com-prised one 2-hour group session week-ly for 20 weeks. At the sessions, partic-ipants discussed short-term goalsetting, and they received education onarthritis-related topics. Participantsalso had monthly face-to-face meetingsfor the first 6 months of the study. Inthe last 6 months, they received tele-phone counseling on both long-termgoals and on strategies to stay with thewalking program rather than drop out.

Members of all 3 groups were pro-vided with pedometers and logbooksto measure their daily walking timeand any additional physical activity.They also received compensation fortheir participation in the study.

Women (mean age, 63.4 years) com-prised the majority of the study par-ticipants; their mean disease durationwas 10.3 years.

The dropout rate at 12 months was40.6% in the combination group,43.1% in the SCAWP-only group, and49.3% in the self-directed group.

Adherence Rates

Adherence rates at 3 months were80.2% for the combination cohort, 77%for the SCAWP-alone cohort, and 65.2%

for the self-directed walking cohort (P<.012 for combination vs self-directed).However at 6, 9, and 12 months, therates were lower and similar in all 3groups, producing an overall adherenceof 60.4% in the combination group,57.6% in the SCAWP-only group, and55.1% in the self-directed group.

The researchers also measured par-ticipants’ results on the StanfordPatient Education Research Center’sArthritis Self-Efficacy Scale and foundthe only difference was significantlyhigher scores at 18 months in the self-directed group’s “confidence aboutdoing things.”

An explanation for this result maybe that participants in the self-directedgroup who did not drop out developedstrategies to motivate them to walkalone during the 12-month phase andto continue during the 6-month follow-up phase, suggested Dr Brosseau. Incontrast, participants in the other 2groups were accustomed to beingsupervised by exercise therapists at thewalking club during the 12-monthstudy, and therefore they would havehad to develop new behavioral strate-gies to motivate them to continuewalking without supervision.

“What is very interesting with thisproject is that individuals with mild-to-moderate osteoarthritis of the knee‘smile’ when they walk regularly fol-lowing the progressive and effectiveprescribed program. When theystopped walking regularly, the paincame back,” remarked Dr Brosseau. �

20 VALUE-BASED CARE IN RHEUMATOLOGY I OCTOBER 2012 VOL. 1 I NO. 5

“If an older individual isadherent to a self-management walkingprogram for a long time,simple incentives...seem tobe successful in maintainingthe good habits of regular walking.”

—Lucie Brosseau, PhD

Phoenix, AZ—Among the surprisingfindings of a survey presented at the34th Annual Meeting of the Societyfor Medical Decision Making werethat orthopedic surgeons are signifi-cantly more likely to recommend totalknee arthroplasty (TKA) to men thanto women, and that rheumatologistsworking in academic settings aremuch more likely to recommend suchsurgery than those working in non -academic environments.

The survey investigated what fac-tors influence physicians’ recommen-

dations for or against TKA in youngerpatients with mild or moderateosteoarthritis (OA).

The survey was given to 896 physi-cians—494 rheumatologists attend -ing the 2011 American College ofRheumatology’s annual meeting and406 orthopedic surgeons attending the2012 American Academy of Ortho -pedic Surgeons annual meeting.

“TKA rates are expected to vary,because the decision to undergo TKAis strongly influenced by patient pref-erences,” said lead investigator Liana

Fraenkel, MD, MPH, Associate Pro -fessor of Medicine (Rheumatology), atYale School of Medicine, New Haven,

CT. “Nonetheless, our results demon-strate that rates of TKA are also influ-enced by physician bias.” Dr Fraenkelcalled for the development of objec-tive criteria for the appropriateness ofTKA to reduce such bias.

More than half (54%) of the sur-geons performed more than 25 kneereplacement surgeries annually. Morethan half (54%) of the rheumatologistssee more than 20 patients monthlywith knee OA.

Each physician was presented withvariants of a scenario of a 62-year-oldperson with knee OA who has moder-ate knee pain that limits strenuous

“The decision to undergoTKA is strongly influenced bypatient preferences.Nonetheless, our resultsdemonstrate that rates ofTKA are also influenced byphysician bias.”

—Liana Fraenkel, MD, MPH

Physician Bias Uncovered in Recommendations forKnee Replacement SurgeryMen more likely candidates than women

Continued on page 21

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

Osteoarthritis (OA) is a majorcause of impaired mobility,with significant impact espe-

cially on the joints, often leading tototal hip or knee replacement, whichreduces the patient’s quality of life inaddition to having significant eco-nomic costs. The socioeconomic bur-den of total hip and knee replacementhas soared to “remarkable” levels,according to Italian researchers(Piscitelli P, et al. Arthritis Care Res[Hoboken]. 2012;64:1320-1327).

In this new study conducted in Italybetween 2001 and 2005, the number ofhip arthroplasties increased by 5.4%annually, and the number of kneearthroplasties increased by 13.4%.Among younger patients, lost workdays exceeded 1 million in 2005.

Hospital costs for these proceduressurpassed €1 billion annually in Italy,and rehabilitation costs increased bymore than 40%.

“Our study confirms that thesocioeconomic burden of total jointarthroplasties (TJAs), including revi-

sion surgery, due to hip and kneeosteoarthritis is growing and heavilyaffecting the working population,”Prisco Piscitelli, MD, of the Universityof Florence, and coauthors wrote intheir article.

“The socioeconomic burden of TJAsperformed for symptomatic OA inItaly is remarkable and calls for theadoption of proper preventive meas-ures,” they noted.

An aging population and the grow-ing obesity epidemic have helpeddrive increases in the prevalence andincidence of OA, which has becomethe sixth leading cause of disabilityworldwide, according to the WorldHealth Organization. OA alreadyaccounts for more than 50% of hospi-tal admissions related to rheumatol-ogy. The estimated medical costs forpatients with OA are double those ofpatients without the condition.

Increasing Incidence

The investigators searched theItalian Ministry of Health database toidentify hip and knee arthroplastiesperformed in Italy between 2001 and2005 as a result of a diagnosis of OA.

They excluded records related to hiparthroplasty in patients aged <25years, because the reason for the sur-gery was unlikely to be OA.

“The incidence of total hip replace-ment in Europe varies between 50 and140 procedures per 100,000 inhabi-tants, with OA being the main causefor intervention,” noted Dr Piscitelliand colleagues.

The results showed that the numberof hip arthroplasties increased from34,006 in 2001 to 41,816 in 2005, repre-senting a change in incidence from80.0 per 100,000 persons to 94.8 per100,000 persons. Women accountedfor more than 50% (almost 26,000) ofthe procedures.

The number of knee arthroplastiesrose from 26,751 in 2001 to 44,051 in2005. The rate of the surgical proce-dure increased from 62.9 per 100,000persons in 2001 to 99.9 per 100,000persons in 2005. Women accountedfor approximately 66% of the totalnumber of procedures (N = 32,185).

The largest proportion of total jointreplacement was for people aged ≥65years. However, the rate of growth inthe number of procedures was highestfor patients aged <65 years.

The number of knee-prosthesisrevisions increased from 1146 in 2001to 2295 in 2005, representing an annu-alized growth rate of 17.4%.

Productivity Loss and Costs

OA-related healthcare costs are sub-stantial, driven by arthroplasty proce-dures, nonsteroidal anti-inflammato-ry drugs (NSAIDs), agents to preventNSAID-induced gastrointestinal sideeffects, and rehabilitation. Few studieshave quantified the direct and indirectcosts of TJA, particularly amongmembers of the European Union.

Direct costs were estimated on thebasis of a particular country’s diagno-sis-related groups. For patients aged<65 years, the estimated indirect costswere associated with the loss of workproductivity.

The estimated number of workdays lost as a result of TJA increasedfrom 805,347 in 2001 to 1,017,937 in2005. Hip arthroplasties accounted fora majority of the procedures (631,351),but the annualized growth rate wasgreater for knee procedures (12.0% vs4.1%).

Estimated total costs included hos-pital costs, rehabilitation, venousthromboembolism, and postoperativeinfection. The total cost increasedfrom €972 million in 2001 to €1.381 billion in 2005. The estimated totalcost for the 5-year period was almost€6 billion.

Over the 5-year period, the averageper-patient cost was €16,835 for hipreplacement and €15,358 for kneereplacement. �

21VOL. 1 I NO. 5 OCTOBER 2012 I www.ValueBasedRheumatology.com

at a glance� OA has become the sixth

leading cause of disabilityworldwide

� Hospital costs for theseprocedures surpassed €1 billion annually in Italy, andrehabilitation costs increasedby more than 40%

� Between 2001 and 2005, theaverage per-patient cost was€16,835 for hip replacementand €15,358 for kneereplacement

“The socioeconomic burden of total jointarthroplasties, includingrevision surgery, due to hipand knee osteoarthritis isgrowing and heavilyaffecting the workingpopulation.”

—Prisco Piscitelli, MD, et al

Lateral x-ray of a right total kneereplacement.

Osteoarthritis

activity despite medical management. Each physician was asked to rate

his or her recommendation for kneereplacement surgery on a 6-point scaleranging from very strongly recom-mended for TKA to very strongly rec-ommended against TKA.

Overall, 51% of the surgeons andrheu matologists recommended the pro - cedure. The proportion recommendingTKA ranged from 30% to 55% when the

patient had mild radio graphic OA andmoderate pain, and from 39% to 71%when the patient had moderate radi-ographic OA and moderate pain.

The survey results revealed that theaverage age of rheumatologists or sur-geons who recommended TKA wassignificantly lower than those whodid not recommend TKA.

US surgeons were much more likelythan their European counterparts to

recommend surgery (the majority ofthe physicians in both groups werepracticing in the United States).

As can be expected, both groupsrecommended the procedure morefrequently for severe than for mildradiographic OA, but the differencewas more pronounced among rheu -ma tologists (60% vs 41%, P <.001) thansurgeons (56% vs 47%, P = .05).

Surgeons were much more likely to

recommend TKA when the patient wasmale than female (59% vs 44%, P= .002),and rheumatologists had a higherpropensity to recommend TKA forretired patients than for those who werestill working (56% vs 42%, P = .002).

The study was funded by theArthritis Foundation and the NationalInstitute of Health’s National Instituteof Arthritis and Musculoskeletal andSkin Diseases.—RF �

Physician Bias Uncovered... Continued from page 20

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As healthcare reform changesthe face of medical practice aswe know it, certain initiatives

are likely to play a prominent role inemerging practice structures. Amongthe programs predicted to take centerstage are those offered by Medicare’sShared Savings Program, in particu-lar, accountable care organizations(ACOs).

Understanding the ACO Concept

An ACO is defined by the Centersfor Medicare & Medicaid Services(CMS) as “an organization of health-care providers that agrees to beaccountable for the quality, cost, andoverall care of the Medicare benefici-aries who are enrolled in the tradition-al fee-for-service program who areassigned to it.”

A stated goal of the ACO model isone that “promotes accountability fora patient population and coordinatesitems and services under parts A andB [of Medicare] and encouragesinvestment in infrastructure andredesigned care processes for highquality and efficient service delivery”(42 USC § 1395jjj[a][1]). With the com-bined aims of reducing cost whileincreasing the quality of care, themodel seems to be an efficient mecha-nism to navigate the changing health-care landscape.

The ACO model has existed for sev-eral years as a test program adminis-tered by CMS, and rapid growth ofthis model is anticipated. Of course,the concept of accountable care is notnew, because the idea of coordinatedcare, increased quality, and decreasedcost has been a shared goal of manydifferent aspects of the healthcareindustry for decades. If you are won-dering what authority is out there toindicate this developing trend, lookno further than healthcare reformitself. The Patient Protection andAffordable Care Act has identifiedACOs as one of the waves of thefuture that will improve quality ofcare by encouraging physicians to col-laborate with one another.

At its core, an ACO is an entityformed to tabulate patient care data ina way that Medicare may then deter-mine cost-savings, which the ACOwould be eligible to share in. By wayof a simplified example, if an ACOwere able to evidence a lower rate ofhospital admissions as a result of preventive care initiatives, the ACO

would allegedly be entitled to a por-tion of the shared savings.

The beauty of the ACO model isthat this structure does not require apractitioner to lose ownership or con-trol over his/her practice. Instead, apractitioner may elect to participatewith an ACO, sharing patient caredata with the ACO, and to participatewith shared savings. The ACO wouldbe a separate entity, apart from yourpractice. ACOs may be physicianowned, hospital and physicianowned, owned by a hospital employ-ing physicians, owned by a networkof individual practices of physicians,or owned by others, as specified bythe Secretary of Health and HumanServices (42 USC § 1395jjj[b][1]).

For specialists, membership may bea “no-brainer,” because specialistsmay join as many ACOs as will havethem. Any such membership wouldlikely be cemented by a contractdefining the relationship.

A barrier to the ACO model hasbeen start-up cost. Because an ACOrelies on, at its core, integration of dataand patient care, all participantsshould be operable on collab orativeelectronic medical record (EMR) sys-tems. Reading the previous statementmay leave little to the imagination asto why large hospital systems andlarge practice groups are better suitedto ACO formation than individual,smaller groups coming together andforming an ACO. The large hospitalsystems and large medical practicesare presumably integrated and pre-sumably better suited to absorbing thecost for hardware, software, training,and lag time, with the EMR integra-tion required for the ACO model.

Also, the start-up cost makes anACO creation less desirable for spe-cialists, such as oncologists, whoarguably may have less to gain fromthis structure than primary careproviders, the intended core of themodel—each ACO is required to haveprimary care providers, accounting

for more than 5000 Medicare benefici-aries at any given time.

Although start-up costs may requirea significant financial investment,there are financial advantages to theACO model. The current paymentstructure, as practitioners are wellaware, is untenable and is bankrupt-ing Medicare. Medicare has had tofind ways to incentivize physicians tokeep costs down, and the ACO modelis one of the answers to this dilemma.Under the Shared Savings Program,the model includes reimbursement forfee-for-service, plus a percentage ofshared savings. The intended impactof this model is to provide for a modelthat enables reimbursement to shiftfrom quantity to quality, with the ulti-mate aim of reducing costs to thehealthcare system.

Choosing “Accountable” Care

For betting individuals, a safe bet isthat our current care delivery system isnot sustainable, and changes will becoming. We are headed toward a mod-ified system, where quality over quan-tity and preventive over reactive arevalued. To ensure your practice keepspace with anticipated changes in ourhealthcare delivery system, regardlessof whether you intend to participate inan ACO or similar model, you maywish to consider the concepts set forthherein and better position your prac-tice for accountability, includingadopting EMRs and understandingnew initiatives such as ACOs.

ACO creation takes a village—ACOcreation begins with doctors, lawyers,managers, billers, EMR companies,chief executive officers, accountants,and consultants, and requires signifi-cant start-up capital, as discussedabove. For those interested in theACO model, ACO participants mustmake a 3-year commitment to the pro-gram when they sign on; a structuremust be implemented for receivingand distributing shared savings;processes must be in place to coordi-nate care, such as having remotepatient monitoring; and the ACOmust have at least 5000 beneficiarieswho will all receive their primary carecoverage through the ACO (42 USC §1395jjj[b][2]). In order to receive finan-cial incentives, quality-of-care mea -sures must be in place, such as thosefor clinical processes and outcomes,and experience of care, and, in addi-tion, there are numerous otherrequirements that must be in place inorder to be eligible to participate in anACO (42 USC § 1395jjj[b][2]).

It is also relevant to note that ACOsmust be formed and operated in com-pliance with antitrust re quirements.Those looking to participate in anACO need to be wary of the fact thatACOs may be considered harmful toconsumers by reducing competition.To assist ACOs, the Department ofJustice and the Federal Trade Com -mission have created a procedure forvoluntary expedited review. Beforebeing admitted into the SharedSavings Program, newly formedACOs may apply to both agencies foran antitrust analysis (www.justice.gov/atr/public/health_care/aco.html).It is advisable to consult with yourhealthcare counsel to ensure compli-ance with relevant antitrust laws andpolicies and to offer your ACO thebest protection possible.

Although the climb for an ACO cre-ation is certainly uphill, it is notunhikable. And, with rolling admis-sions for ACO participants by CMS,the next application period being for a2014 start date, the number of Noticeof Intent to Apply letters is predictedto increase dramatically over the com-ing years. It is not being suggestedthat this system is going to be perfectand be the solution to all things wrongwith our healthcare system as itstands today. In fact, a lot of informa-tion is still unavailable, and it appearsthat the Secretary of Health andHuman Services is going to have a lotof authority over what payments aremade. What is clear moving forwardis that providers who fail to readytheir practices now and leaders in theindustry who do not get on board willfall to the back of the pack in themarathon that is healthcare today. �

This article is for education and discussionpurposes only and does not constitute legaladvice.

Jennifer Kirschenbaum, Esq, managesKirschenbaum & Kirschenbaum’s health -care department, which specializes in rep-resenting healthcare practitioners in regulatory compliance, audit defense,licen sure, 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 discussaccountable care organizations, Jennifermay be reached at 516-747-6700 x302 orby e-mail at Jennifer@kirschenbaumesq.com. For more information aboutKirschenbaum & Kirschenbaum’s health -care practice, visit www.nyhealthcareattorneys.com.

For specialists, membershipmay be a “no-brainer,”because specialists may joinas many ACOs as will have them.

Rheumatology Practice Management™

22 VALUE-BASED CARE IN RHEUMATOLOGY I OCTOBER 2012 VOL. 1 I NO. 5

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

Healthy knee anatomy, degenerative arthritis of the knee

and replacement surgery. Digital illustration.

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

An X-ray Of A Knee Replacement

Bionic Knee - lateral x-ray of a right total knee replacement.

X-ray Of The Knee Of A 83 Year Old Woman Showing

Degenerative Arthritis.

Systemic Lupus Erythematosus

Systemic Lupus Erythematosus

Systemic Lupus Erythematosus

Systemic Lupus Erythematosus

Systemic Lupus Erythematosus

Systemic Lupus Erythematosus

Systemic Lupus Erythematosus