vbcr april vol 2, no 2

VALUE PROPOSITIONS . . . . . . . . . . 4Unprecedented growth predicted for monoclonal antibodies

GOUT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Prophylaxis with colchicine often used inappropriately

ARTHRITIS UPDATE . . . . . . . . . . .12Rheumatologists warned to watch for serious infections in older patients

PSORIATIC ARTHRITIS . . . . . . . .13Apremilast shows promise in refractory PsAUstekinumab safe, effective in PsA

HEALTH ECONOMICS . . . . . . . . . .14Impact of specialty drugs on cost in the management of RAEconomic burden of osteoarthritis

Rheumatology PRACTICEMANAGEMENT™ . . . . . . . . . . . . . . . . . . 16Breach notification requirements

ANKYLOSING SPONDYLITIS . .18Early use of TNF inhibitors is beneficial

IN THE LITERATURE . . . . . . . . . .18Obesity a risk factor for developing RA

www.ValueBasedRheumatology.com

April 2013 VOl 2 • NO 2Value-Based

Care in RheumatologyFrOm the publishers OF AmericAn HeAltH & drug benefits®

TM

© 2013 Engage Healthcare Communications, LLC

i n s i d e

Hospitalizations or emergency department visits for serious infections are relatively

common in older adults with rheu

matoid arthritis (RA), according to a recent analysis (Widdifield J, et al. Arthritis Care Res. 2013;65:353-361).

The investigators documented

Rheumatologists Warned to Watch for Serious Infections in Older Patients with RARespiratory infections most common eventsBy Rosemary Frei, MSc

Continued on page 12


By analyzing information from the National Health and Nutrition Examination Survey

(NHANES) from 1988-1994 and 2007-2010, researchers have uncovered a 30% rate of gout prevalence among Americans with severe chronic kidney disease (CKD). They also found significantly higher rates of gout among individuals with lower average estimated glomerular filtration rates (eGFRs) or higher levels of albu

minuria, even after adjusting for uric acid levels (Juraschek SP, et al. Semin Arthritis Rheum. 2013 Jan 8 [Epub ahead of print]).

“Health practitioners treating patients with CKD who have newonset joint pain or swelling should be vigilant for undiagnosed gout,” noted Allan C. Gelber, MD, PhD, Associate Professor of Medicine at the Johns Hopkins Bloomberg School of Public Health, Baltimore, and his coauthors

Continued on page 5

Relationship between Chronic Kidney Disease and Gout Uncovered for the First TimeBy Rosemary Frei, MSc

Apremilast Improves Outcomes in Refractory Psoriatic Arthritis By Phoebe Starr

New classification criteria for systemic sclerosis have been developed and should allow

for more patients to be classified as having systemic sclerosis compared with the 1980 criteria, said Janet E. Pope, MD, MPH, FRCPC, Professor of Medicine and Division Head of Rheumatology at St Joseph’s Hospital and Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.

“There’s a need, because the old

criteria didn’t classify up to 20% of the people who clinicians thought had scleroderma, and in a rare disease with serious and sometimes lethal complications, they really should meet classification criteria,” Dr Pope said. “Also, we need new criteria for doing studies on these sorts of patients, who would not be allowed into randomized controlled trials.”

The 1980 major criteria still work well in classifying sclerodactyly that

New Classification Criteria for Systemic Sclerosis ProposedBy Wayne Kuznar


Apremilast, an oral investigational drug, significantly improved the signs and

symptoms of psoriatic arthritis (PsA) in patients whose disease failed to respond to previous diseasemodify

ing antirheumatic drugs (DMARDs), including biologic agents, according to the results of the phase 3 clinical trial, PALACE-1.

“This large, first phase 3 study of apremilast in PsA showed that the drug

© E

raxi

on/

big

sto

ck.c

om

www.ValueBasedRheumatology.com

Join Our Editorial Advisory Board

Your Information

_____________________________________________________________________________________First Name Last Name Credentials _____________________________________________________________________________________________________Title Company

_____________________________________________________________________________________________________Address

_______________________________________________________________________________________________________E-mail Phone

Value-Based Care in RheumatologyTM is looking for practicing rheumatologists with a wide range of experience who are interested in joining our Editorial Advisory Board.

Now in its second year of publication, Value-Based Care in RheumatologyTM covers key developments from rheumatology literature and from national and interna-tional rheumatology meetings. Editorial Advisory Board members provide expert commentaries and perspectives on value-based care in all rheumatic diseases and offer expert opinion on relevant topics and new developments in the field, including new and emerging drug therapies, managing patients with rheumatic diseases, practice management, as well as payers and policy issues affecting rheumatology practices.

Mission StatementValue-Based Care in RheumatologyTM provides a forum for payers, providers, and the entire rheumatology team to consider the cost-value issues particular to rheumatology treatments. This unique focus is achieved through news coverage from major rheumatology meetings and the rheumatic diseases literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care.

To be considered for the Editorial Advisory Board of this exciting

new publication, please complete

this form. Incomplete forms will

not be considered.

I would like to join the Editorial Advisory Board of Value-Based Care in RheumatologyTM. Fax to: 732-992-1881

In This Issue

Value-Based CareinRheumatology

FROM THE PUBLISHERS OF AMERICAN HEALTH & DRUG BENEFITS®

TM

Value-Based Care in Rheumatology, ISSN applied, is published 6 times a year by Engage Healthcare Com munications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2013 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Care in Rheumatology is a registered trademark of Engage Health care Communi cations, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

The ideas and opinions expressed in Value-Based Care in Rheumatology do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Value-Based Care in Rheumatology should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to per-sons or property arising out of or related to any use of the material mentioned in this publication.

VBCR Editorial Advisory Board

VALUE PROPOSITIONSUnprecedented growth predicted for

monoclonal antibodies to treat RA HHS announces agenda to lower costs and

improve quality with health ITMore…

GOUTRelationship between chronic kidney disease

and gout uncovered for the first timeProphylaxis with colchicine often used

inappropriately in patients with goutMore…

ARTHRITIS UPDATEStudy shines new light on deleterious dance

between B- and T-cells in RAMore…

PSORIATIC ARTHRITISApremilast improves outcomes in refractory

psoriatic arthritisUstekinumab shows promise

HEALTH ECONOMICSTransitioning from conventional to biologic

DMARDs a consistent trend in RA

VASCULITISRituximab the newest treatment for ANCA

vasculitis, but cyclophosphamide still a viable option

Rheumatology PRACTICEMANAGEMENT™

Breach notification requirements

ANKYLOSING SPONDYLITISEarly use of TNF inhibitors is beneficial in

ankylosing spondylitis

IN THE LITERATUREObesity a risk factor for developing rheumatoid

arthritisAdalimumab safe for patients with rheumatoid

arthritis and renal insufficiency

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

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

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

F. Randy Vogenberg, RPh, PhDPrincipalInstitute of Integrated HealthcareGreenville, SC

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

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

3 VOL. 2 I nO. 2 APRiL 2013 I www.ValueBasedRheumatology.com

PUBLISHING STAFFSenior Vice President/Group PublisherNicholas [email protected], Client ServicesZach CeretelleEditorial DirectorDalia [email protected] EditorLisa NeumanAssociate EditorLara J. LortonEditorial AssistantsJennifer BrandtCara GuglielmonSenior Production ManagerLynn HamiltonProduction ManagerMelissa Lawlor

THE LYNx GROUPPresident/CEOBrian Tyburski Chief Operating OfficerPam Rattanonont FerrisVice President of FinanceAndrea KellyAssociate Editorial Director, Projects DivisionTerri MooreDirector, Quality ControlBarbara MarinoDirector, Production & ManufacturingAlaina PedeDirector, Creative & DesignRobyn JacobsCreative & Design AssistantLora LaRoccaDirector, Digital MediaAnthony RomanoWeb Content ManagersDavid MaldonadoAnthony TraveanDigital ProgrammerMichael AmundsenSenior Project ManagerAndrea BoylstonProject CoordinatorsDeanna MartinezJackie LumaBusiness ManagerBlanche MarchittoExecutive AdministratorRachael BaranoskiOffice CoordinatorRobert Sorensen

Engage Healthcare Communications, LLC1249 South River Road, Ste 202ACranbury, NJ 08512Telephone: 732-992-1882Fax: 732-992-1881

Mission StatementValue-Based Care in Rheumatology provides a forum for payers, providers, and the entire rheumatology team to consider the cost-value issues particular to rheumatology treatments. This unique focus is achieved through news coverage from major rheumatology meetings and the rheumatic diseases literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care.

Contact Information:For subscription information please contact: Telephone: 732-992-1880 Fax: 732-992-1881 Permission requests to reprint all or part of any article published in this publication should be addressed to [email protected]. Address all editorial queries to: [email protected]. Telephone: 732-992-1882 Fax: 732-992-1881

POSTMASTER: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Care in Rheumatology, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

4 VALue-BAsed CARe in RheumAtOLOgy I APRiL 2013 VOL. 2 I nO. 2

Value Propositions

Unprecedented Growth Predicted for Monoclonal Antibodies to Treat Rheumatoid Arthritis

According to Global Business Intelligence (GBI) Research, a leading provider of business intelligence reports, the worldwide market for monoclonal antibodies (mAbs) is well positioned for unprecedented growth over the next 6 years. Currently, 8 mAbs are approved for the treatment of rheumatoid arthritis (RA), and 4 of those are in the top 10 best-selling drugs with 2011 worldwide sales of more than $23 billion.

The top mAbs earner across the entire industry is Remicade. Along with the other 2 mAbs that were first approved to treat RA, Humira and Enbrel, these 3 pharmaceuticals alone have dominated the RA drug market since their introduction. GBI believes that even with the impending patent cliff, the sales of these 3 drugs are unlikely to abate anytime soon. “Physicians are likely to exercise great caution when prescribing biologics, in part due to their potentially serious side-effects,” said one GBI analyst, Dominic Trewartha. “Rheumatologists in general are also quite conservative in their treatment patterns, which could explain why Remicade, Humira, and Enbrel are doing so well, being the first mAbs approved for RA. In contrast, biosimilars are less likely to be prescribed. For this reason, the growth of the global market is expected to continue in spite of the impending patent expiry of 3 of the 4 top-selling RA mAbs in the US.”

Mr Trewartha, citing the expense and approval difficulty associated with bringing new biosimilars to market, also predicts that none of the drugs currently poised to enter the market appear to offer significant improvements or advantages over the existing class of mAbs, which will leave Remicade, Humira, and Enbrel able to maintain their topselling status in the United States, Japan, Germany, France, United Kingdom, Italy, and Spain, growing from a combined $11.5 billion in sales in 2011 to $15.7 billion in 2018. www.gbiresearch.com; January 2013

HHS Announces Agenda to Lower Costs and Improve Quality with Health IT

The US Department of Health and Human Services (HHS) and the Centers for Medicare & Medicaid Services (CMS) announced a plan to accelerate implementation of the health information exchange and to build a seamless, secure information flow that will be essential to transforming the healthcare system in the United States.

“Thanks to the Affordable Care Act, we are improving the way care is delivered while lowering costs,” said the acting administrator of CMS, Marilyn Tavenner. “We are already seeing benefits, such as a reduction in hospital readmissions, due to these reforms. Health IT [information technology] and the secure exchange of information across providers are crucial to reforming the system, and must be a routine part of care delivery.”

HHS has stated that this year it will:• Set the goal of 50% of physician offices using electronic health records

(EHRs) and 80% of eligible hospitals receiving meaningful use incentive payments by the end of 2013

• Increase its emphasis on ensuring electronic exchange across providers by issuing a request for information seeking public input about a variety of policies that will strengthen the business case for electronic exchange across providers to ensure patients’ health information will follow them seamlessly and securely wherever they access care

• Enhance the use of EHRs through initiatives such as the Blue Button initiative, in which Medicare beneficiaries can access their full Medicare records online. HHS is working with the Veterans Administration and 450 other organizations to make healthcare information available to patients and health plan members

• Implement Meaningful Use Stage 2 by implementing rules that define

what data must be able to be exchanged between health IT systems, including how the data will be structured and coded so that providers will have a uniform way to format and send data securely

• Take new steps to ensure that the integrity of the program is sound. HHS is currently conducting extensive medical reviews and issuing comparative billing reports to identify providers.According to HHS, EHR adoption has tripled since 2010, increasing

44% in 2012 alone. www.HHS.gov; March 6, 2013

Optimizing 3 Tesla MRI of the Spine in Spondyloarthropathy

According to a group of researchers at Johns Hopkins Hospital and Johns Hopkins University School of Medicine, high-field imaging offers excellent capability for improved diagnosis and prognosis of spinal disorders, including those caused by rheumatic diseases such as spondyloarthropathy. With the promise of improved image quality, the use of 3 Tesla magnetic resonance imaging (MRI) is becoming more common in clinical rheumatology practice.

With its higher signaltonoise ratio, the images that can be captured using the 3 Tesla MRI offer higher spatial and contrast resolutions as well as higher temporal resolution, making it more advantageous from a clinical efficacy standpoint than lower-field MRI scanners.

However, with its advantages also come several disadvantages, namely its cost. The 3 Tesla MRI scanner is more expensive than a lower-field MRI scanner, and some artifacts that are caused by B1 field homogeneity can be exaggerated. Del Grande F, et al. J Musculoskelet Med; March 2012

Reminder Forms about Pneumococcal Vaccination Important for Immunosuppressed Patients

From a public health perspective, it is important for immunosuppressed patients to be up-to-date on pneumococcal vaccinations; how-ever, numerous studies have shown that most patients in this population group do not receive this vaccination, with some studies finding rates as low as 19%. In this cluster quality improvement (QI) trial, 14 rheumatologists at 5 ambulatory rheumatology practice sites affiliated with Brigham and Women’s Hospital gave 3717 patients (74% women; mean age, 53.7 years) who were taking immunosuppressive medications a pointofcare paper reminder form if they were not current on this vaccination. Of the total number of patients evaluated, 66% had rheumatoid arthritis.

The study and control patients chosen for inclusion in this QI intervention strategy were generated using the hospital’s electronic medical record (EMR) system. The rheumatologists were selected based on the volume of patients seen in their practices.

During the 38 months of follow-up, the rheumatologists who reminded their patients with the point-of-care paper reminder saw a significant increase in the number of patients who became current with the pneumococcal vaccination, improving from 67.6% before the paper reminder was given to 80% after being given the paper reminder (P = .006). In contrast, the vaccination rate in the control group, which did not receive a paper reminder, remained flat, with rates of 52.3% before the study and 52% after the study (P = .90).

The results of this study proved that with an information systems infrastructure, such as EMR, and regular updates and education for physicians, a simple pointofcare paper reminder can help improve compliance rates for the vaccination of immunosuppressed patients. Desai SP, et al. Arthritis Rheum; January 2013

in their write-up of the study. “Moreover, practitioners treating patients with gout should be wary of CKD as an underlying factor contributing to both hyperuricemia and gout risk, because many uratelowering medications require renal dosing or have associated nephrotoxicity.”

Dr Gelber and his colleagues looked at the signals produced by levels of albuminuria, serum uric acid, hyperuricemia, and eGFR among 15,132 adults in the 1988-1994 NHANES and 10,814 adults in the 2007-2010 NHANES.

The overall prevalence of gout among Americans was 2.7% in the 1988-1994 time frame and 3.7% during 2007-2010. In both periods, there was an inverse relationship between the proportion of patients with a reduced eGFR and gout or hyperuricemia, and a direct relationship between increased albuminuria and gout or hyperuricemia. The mean eGFR for patients with gout was 76 mL/min/1.73 m2 to 82 mL/min/1.73 m2, whereas for people without gout it was 97 mL/min/1.73 m2 to 102 mL/min/1.73 m2.

Similarly, in both NHANES timeframes, approximately 1% to 2% of people with eGFRs of ≥90 mL/min/1.73 m2 had gout compared with 30% among those with eGFRs of <30 mL/min/1.73 m2. The team observed

a similar pattern for albuminuria, even after adjusting for factors such as age, sex, race/ethnicity, hypertension, body mass index, and diabetes.

“One of the more impressive aspects of our findings is the dose- response relationship. Incremental changes in eGFR, albuminuria, and CKD are associated with a higher prevalence of gout. And these find

ings were not merely relegated to persons with severe CKD,” Stephen Juraschek, an MD/PhD student in epidemiology at Johns Hopkins Uni

versity, said. “Furthermore, we found that the relationship persisted even after accounting for multiple risk factors associated with both CKD and gout, including uric acid levels.” n


Gout

Relationship between Chronic Kidney Disease and Gout... Continued from cover

Colchicine is an effective prophylaxis against gout only when it is taken consistently over 14

days by patients who are prone to gout attacks, according to study results by researchers from Boston University.

A second study from the University of Pennsylvania and the Philadelphia VA Medical Center shows that prophylactic colchicine is used inappropriately—without concurrent urate lowering therapy—approximately 75% of the time, contributing to unnecessary expense.

The group, led by Tuhina Neogi, MD, PhD, FRCPC, Associate Professor of Medicine, Boston University School of Medicine, performed an Internet- based crossover study of 724 patients with at least 1 gout attack in the previous year, with each patient serving as his or her own control. They were followed for 1 year, during which time data on their medication use were collected. At the study entry, 38.4% of the patients were taking uratelowering therapy for gout. The most common uratelowering therapy was allopurinol (Zyloprim), the most common dose of colchicine (Colcrys) taken was 0.6 mg daily, and the most common non

steroidal antiinflammatory drug (NSAID) used for prophylaxis was ibuprofen.

Using patients with no colchicine use in the previous 14 days as a reference group, the adjusted odds of a gout attack were reduced by 54% when colchicine was taken every day for 14 days, whereas intermittent or shortterm use was found to be ineffective. The use of an NSAID in those 14 days did not decrease the risk of an attack, regardless of the consistency of its use.

The cost of colchicine has increased dramatically in the United States, and inappropriate use as a prophylaxis for gout would further increase the cost of using this therapy. To assess how colchicine was being pre

scribed at his institution for prophylaxis, Michael George, MD, a physician at the Philadelphia VA Medical Center, reviewed the prescription records for 126 patients who were prescribed the drug for ≥30 days as a prophylaxis for gout.

“All told, approximately 75% of the patients were being inappropriately treated with colchicine,” said Dr George. “One of the major differences between the appropriately treated group and the inappropriately treated group was the percentage of patients who had seen a rheumatologist in the past year. A rheumatology consult appears to have an impact on inappropriate colchicine prescribing.”

Colchicine use was considered to be inappropriate in 73.8% of the patients—27% were not prescribed urate-lowering therapy, 39.7% were not at their uric acid goal and had not had their uratelowering therapy intensified in the previous 3 months, and 7.1% were at their uric acid goal for more than 1 year with no flares or tophi.

Patients who were appropriate - ly prescribed colchicine (compared with inappropriate prescribing) were

younger (median age, 65 years vs 70 years, respectively), were receiving colchicine for a shorter period (median time, 1.12 years vs 3.26 years), and were more likely to be seen by a rheumatologist in the past year (57.6% vs 21.5%) or ever (75.8% vs 54.8%).

By instituting appropriateuse criteria, the Philadelphia VA Pharmacy estimated cost avoidance of $227,656 for colchicine in fiscal year 2013, said Dr George. n

Prophylaxis with Colchicine Often Used Inappropriately in Patients with Gout By Wayne Kuznar

“A rheumatology consult appears to have an impact on inappropriate colchicine prescribing.”

—Michael George, MD

at a glance➤ Colchicine is an effective

prophylaxis against gout when taken consistently over 14 days

➤ Prophylactic colchicine is used inappropriately in approximately 75% of patients

➤ Patients who were appropriately prescribed colchicine were younger, taking the drug for a shorter time, and were more likely to be seen by a rheumatologist

at a glance➤ The NHANES from 19881994

and 20072010 uncovered a 30% rate of gout prevalence among Americans with severe chronic kidney disease

➤ There was an inverse relationship between the proportion of patients with a reduced eGFR and gout or hyperuricemia, and a direct relationship between increased albuminuria and gout or hyperuricemia

“Practitioners treating patients with gout should be wary of CKD as an underlying factor contributing to both hyperuricemia and gout risk, since many urate-lowering medications require renal dosing or have associated nephrotoxicity.”

—Allan C. Gelber, MD, PhD

See also page 11

For adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to methotrexate (MTX)1

Learn more at XeljanzHCP.com

IMPORTANT SAFETY INFORMATIONWARNING: SERIOUS INFECTIONS AND MALIGNANCYSERIOUS INFECTIONSPatients treated with XELJANZ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.If a serious infection develops, interrupt XELJANZ until the infection is controlled. Reported infections include: • Activetuberculosis,whichmaypresentwithpulmonaryorextrapulmonarydisease.PatientsshouldbetestedforlatenttuberculosisbeforeXELJANZuseandduringtherapy.TreatmentforlatentinfectionshouldbeinitiatedpriortoXELJANZuse.

• Invasivefungalinfections,includingcryptococcosisandpneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.

• Bacterial,viral,andotherinfectionsduetoopportunisticpathogens.

TherisksandbenefitsoftreatmentwithXELJANZshouldbecarefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patientsshouldbecloselymonitoredforthedevelopmentofsigns and symptoms of infection during and after treatment with

XELJANZ,includingthepossibledevelopmentoftuberculosisinpatientswhotestednegativeforlatenttuberculosisinfectionpriorto initiating therapy. MALIGNANCIESLymphomaandothermalignancieshavebeenobservedinpatientstreatedwithXELJANZ.EpsteinBarrVirus-associatedpost-transplantlymphoproliferativedisorderhasbeenobservedatanincreased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications. SERIOUS INFECTIONSThe most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster and urinary tract infection. XELJANZ should not be initiated in patients with an active infection, including localized infections. Consider the risks and benefits of treatment before initiating XELJANZ in patients:• with chronic or recurrent infection;• who have been exposed to tuberculosis (TB);• with a history of a serious or an opportunistic infection;• who have lived or traveled in areas of endemic TB or mycoses; or• with underlying conditions that may predispose them to infection.Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ. XELJANZ should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis.

INDICATION• XELJANZ (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an

inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs).

• XELJANZ should not be used in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine.

References: 1. XELJANZ® (tofacitinib) Prescribing Information. New York, NY: Pfizer Inc. 2. Data on file. Pfizer Inc, New York, NY. 3. Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367(6):495-507.

Introducing XELJANZ

Powerful efficacy. First in a new class.2

Choose XELJANZforrobustefficacyasmonotherapyorincombinationwithMTX1-3

Results of a 6-month, randomized, double-blind, controlled, multicentermonotherapy study in which 610 patients with moderate to severe active RA who had an inadequate response to a biologic or nonbiologic DMARD due to lack of efficacy or toxicity received XELJANZ 5 mg twice daily (N=241) or placebo (N=120). At the month 3 visit, all placebo patients were advanced blindly to a second predetermined treatment of XELJANZ.

*P<0.05 vs placebo†P<0.0001 vs placebo

Results of a 12-month, randomized, double-blind, controlled, multicenter study in which 792 patients with moderate to severe active RA who had an inadequate response to a biologic or nonbiologic DMARD due to intolerance, toxicity, or inadequate response received XELJANZ 5 mg twice daily (N=311) or placebo (N=157) added to background nonbiologic DMARD treatment. At 3 months, nonresponding placebo patients were advanced blindly to a second predetermined treatment of XELJANZ. At 6 months, all placebo patients were advanced in the same fashion.

Consider a change to the way you treat moderate to severe RA.

Please see additional Important Safety Information and brief summary of full Prescribing Information, including boxed warning, on the following pages.

• XELJANZmonotherapyACR20/50/70responserates (month 3)1-3:-XELJANZ5mgtwicedaily:59%†,31%†,and15%*-Placebo:26%,12%,and6%

• XELJANZincombinationwithDMARDsACR20/50/70responserates(month6)1,2:-XELJANZ5mgtwicedaily+DMARDs:53%†,34%†,and13%†

-Placebo+DMARDs:31%,13%,and3%

TRA539315-01_VBCR.indd 1-2 3/22/13 10:43 AM

XELJANZ® (tofacitinib)

WARNING: SERIOUS INFECTIONS AND MALIGNANCY

SERIOUS INFECTIONS

Patients treated with XELJANZ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

If a serious infection develops, interrupt XELJANZ until the infection is controlled.

Reported infections include:

• Activetuberculosis,whichmaypresentwithpulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before XELJANZ use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ use.

• Invasivefungalinfections,includingcryptococcosisand pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.

• Bacterial,viral,andotherinfectionsduetoopportunistic pathogens.

The risks and benefits of treatment with XELJANZ 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 XELJANZ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

MALIGNANCIES

Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein BarrVirus-associatedpost-transplantlymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications.

INDICATIONS AND USAGE

• XELJANZ(tofacitinib)isindicatedforthetreatmentofadultpatientswithmoderatelytoseverelyactiverheumatoidarthritiswhohavehadaninadequateresponseorintolerancetomethotrexate.Itmaybeusedasmonotherapyorincombinationwithmethotrexateorothernonbiologicdisease-modifyingantirheumaticdrugs(DMARDs).

• XELJANZshouldnotbeusedincombinationwithbiologicDMARDsorwithpotentimmunosuppressantssuchasazathioprineandcyclosporine.

CONTRAINDICATIONS

None.

WARNINGS AND PRECAUTIONSSerious InfectionsSeriousandsometimesfatalinfectionsduetobacterial,mycobacterial,invasivefungal,viral,orotheropportunisticpathogenshavebeenreportedinrheumatoidarthritispatientsreceivingXELJANZ.ThemostcommonseriousinfectionsreportedwithXELJANZincludedpneumonia,cellulitis,herpeszosterandurinarytractinfection.Amongopportunisticinfections,tuberculosisandothermycobacterialinfections,cryptococcus,esophagealcandidiasis,pneumocystosis,multidermatomalherpeszoster,cytomegalovirus,andBKviruswerereportedwithXELJANZ.Somepatientshavepresentedwithdisseminatedratherthanlocalizeddisease,andwereoftentakingconcomitantimmunomodulatingagentssuchasmethotrexateorcorticosteroids.Otherseriousinfectionsthatwerenotreportedinclinicalstudiesmayalsooccur(e.g.,histoplasmosis,coccidioidomycosis,andlisteriosis).XELJANZshouldnotbeinitiatedinpatientswithanactiveinfection,includinglocalizedinfections.TherisksandbenefitsoftreatmentshouldbeconsideredpriortoinitiatingXELJANZinpatients:• withchronicorrecurrentinfection• whohavebeenexposedtotuberculosis• withahistoryofaseriousoranopportunisticinfection• whohaveresidedortraveledinareasofendemic

tuberculosisorendemicmycoses;or• withunderlyingconditionsthatmaypredispose

themtoinfection.PatientsshouldbecloselymonitoredforthedevelopmentofsignsandsymptomsofinfectionduringandaftertreatmentwithXELJANZ.XELJANZshouldbeinterruptedifapatientdevelopsaseriousinfection,anopportunisticinfection,orsepsis.ApatientwhodevelopsanewinfectionduringtreatmentwithXELJANZshouldundergopromptandcompletediagnostictestingappropriateforanimmunocompromisedpatient;appropriateantimicrobialtherapyshouldbeinitiated,andthepatientshouldbecloselymonitored.

BRIEFSUMMARYOFPRESCRIBINGINFORMATION.SEEPACKAGEINSERTFORFULLPRESCRIBINGINFORMATION.

TuberculosisPatientsshouldbeevaluatedandtestedforlatentoractiveinfectionpriortoadministrationofXELJANZ.Anti-tuberculosistherapyshouldalsobeconsideredpriortoadministrationofXELJANZinpatientswithapasthistoryoflatentoractivetuberculosisinwhomanadequatecourseoftreatmentcannotbeconfirmed,andforpatientswithanegativetestforlatenttuberculosisbutwhohaveriskfactorsfortuberculosisinfection.Consultationwithaphysicianwithexpertiseinthetreatmentoftuberculosisisrecommendedtoaidinthedecisionaboutwhetherinitiatinganti-tuberculosistherapyisappropriateforanindividualpatient.Patientsshouldbecloselymonitoredforthedevelopmentofsignsandsymptomsoftuberculosis,includingpatientswhotestednegativeforlatenttuberculosisinfectionpriortoinitiatingtherapy.PatientswithlatenttuberculosisshouldbetreatedwithstandardantimycobacterialtherapybeforeadministeringXELJANZ.ViralReactivation Viralreactivation,includingcasesofherpesvirusreactivation(e.g.,herpeszoster),wereobservedinclinicalstudieswithXELJANZ.TheimpactofXELJANZonchronicviralhepatitisreactivationisunknown.PatientswhoscreenedpositiveforhepatitisBorCwereexcludedfromclinicaltrials.Malignancy and Lymphoproliferative Disorder ConsidertherisksandbenefitsofXELJANZtreatmentpriortoinitiatingtherapyinpatientswithaknownmalignancyotherthanasuccessfullytreatednon-melanomaskincancer(NMSC)orwhenconsideringcontinuingXELJANZinpatientswhodevelopamalignancy.MalignancieswereobservedinclinicalstudiesofXELJANZ.Inthesevencontrolledrheumatoidarthritisclinicalstudies,11solidcancersandonelymphomawerediagnosedin3328patientsreceivingXELJANZwithorwithoutDMARD,comparedto0solidcancersand0lymphomasin809patientsintheplacebowithorwithoutDMARDgroupduringthefirst12monthsofexposure.Lymphomasandsolidcancershavealsobeenobservedinthelong-termextensionsstudiesinrheumatoidarthritispatientstreatedwithXELJANZ.InPhase2B,controlleddose-rangingtrialsinde-novorenaltransplantpatients,allofwhomreceivedinductiontherapywithbasiliximab,highdosecorticosteroids,andmycophenolicacidproducts,EpsteinBarrVirus-associatedpost-transplantlymphoproliferativedisorderwasobservedin5outof218patientstreatedwithXELJANZ(2.3%)comparedto0outof111patientstreatedwithcyclosporine.Gastrointestinal Perforations EventsofgastrointestinalperforationhavebeenreportedinclinicalstudieswithXELJANZinrheumatoidarthritispatients,althoughtheroleofJAKinhibitionintheseeventsisnotknown.XELJANZshouldbeusedwithcautioninpatientswhomaybeatincreasedriskforgastrointestinalperforation(e.g.,patientswithahistoryofdiverticulitis).Patientspresentingwithnewonsetabdominalsymptomsshouldbeevaluatedpromptlyforearlyidentificationofgastrointestinalperforation.Laboratory ParametersLymphocytesTreatmentwithXELJANZwasassociatedwithinitiallymphocytosisatonemonthofexposurefollowedbyagradualdecreaseinmeanlymphocytecountsbelowthebaselineofapproximately10%during12monthsoftherapy.Lymphocytecountslessthan500cells/mm3wereassociatedwithanincreasedincidenceoftreatedandseriousinfections.AvoidinitiationofXELJANZtreatmentinpatientswithalowlymphocytecount(i.e.,lessthan500cells/mm3).Inpatientswhodevelopaconfirmedabsolutelymphocytecountlessthan500cells/mm3treatmentwithXELJANZisnotrecommended.Monitorlymphocytecountsatbaselineandevery3monthsthereafter.NeutrophilsTreatmentwithXELJANZwasassociatedwithanincreasedincidenceofneutropenia(lessthan2000cells/mm3)comparedtoplacebo.AvoidinitiationofXELJANZtreatmentinpatientswithalowneutrophilcount(i.e.,ANClessthan1000cells/mm3).ForpatientswhodevelopapersistentANCof500-1000cells/mm3,interruptXELJANZdosinguntilANCisgreaterthanorequalto1000cells/mm3.InpatientswhodevelopanANClessthan500cells/mm3,treatmentwithXELJANZisnotrecommended.Monitorneutrophilcountsatbaselineandafter4-8weeksoftreatmentandevery3monthsthereafter.HemoglobinAvoidinitiationofXELJANZtreatmentinpatientswithalowhemoglobinlevel(i.e.lessthan9g/dL).TreatmentwithXELJANZshouldbeinterruptedinpatientswhodevelophemoglobinlevelslessthan8g/dLorwhosehemoglobinleveldropsgreaterthan2g/dLontreatment.Monitorhemoglobinatbaselineandafter4–8weeksoftreatmentandevery3monthsthereafter.Liver EnzymesTreatmentwithXELJANZwasassociatedwithanincreasedincidenceofliverenzymeelevationcomparedtoplacebo.MostoftheseabnormalitiesoccurredinstudieswithbackgroundDMARD(primarilymethotrexate)therapy.Routinemonitoringoflivertestsandpromptinvestigationofthecausesofliverenzymeelevationsisrecommendedtoidentifypotentialcasesofdrug-inducedliverinjury.Ifdrug-inducedliverinjuryissuspected,theadministrationof

XELJANZshouldbeinterrupteduntilthisdiagnosishasbeenexcluded.LipidsTreatmentwithXELJANZwasassociatedwithincreasesinlipidparametersincludingtotalcholesterol,low-densitylipoprotein(LDL)cholesterol,andhigh-densitylipoprotein(HDL)cholesterol.Maximumeffectsweregenerallyobservedwithin6weeks.Theeffectoftheselipidparameterelevationsoncardiovascularmorbidityandmortalityhasnotbeendetermined.Assessmentoflipidparametersshouldbeperformedapproximately4-8weeksfollowinginitiationofXELJANZtherapy.Managepatientsaccordingtoclinicalguidelines[e.g.,NationalCholesterolEducationProgram(NCEP)]forthemanagementofhyperlipidemia.VaccinationsNodataareavailableontheresponsetovaccinationoronthesecondarytransmissionofinfectionbylivevaccinestopatientsreceivingXELJANZ.LivevaccinesshouldnotbegivenconcurrentlywithXELJANZ.UpdateimmunizationsinagreementwithcurrentimmunizationguidelinespriortoinitiatingXELJANZtherapy.Hepatic Impairment TreatmentwithXELJANZisnotrecommendedinpatientswithseverehepaticimpairment.ADVERSEREACTIONSBecauseclinicalstudiesareconductedunderwidelyvaryingconditions,adversereactionratesobservedintheclinicalstudiesofadrugcannotbedirectlycomparedtoratesintheclinicalstudiesofanotherdrugandmaynotpredicttheratesobservedinabroaderpatientpopulationinclinicalpractice.ThefollowingdataincludestwoPhase2andfivePhase3double-blind,controlled,multicentertrials.Inthesetrials,patientswererandomizedtodosesofXELJANZ5mgtwicedaily(292patients)and10mgtwicedaily(306patients)monotherapy,XELJANZ5mgtwicedaily(1044patients)and10mgtwicedaily(1043patients)incombinationwithDMARDs(includingmethotrexate)andplacebo(809patients).AllsevenprotocolsincludedprovisionsforpatientstakingplacebotoreceivetreatmentwithXELJANZatMonth3orMonth6eitherbypatientresponse(basedonuncontrolleddiseaseactivity)orbydesign,sothatadverseeventscannotalwaysbeunambiguouslyattributedtoagiventreatment.ThereforesomeanalysesthatfollowincludepatientswhochangedtreatmentbydesignorbypatientresponsefromplacebotoXELJANZinboththeplaceboandXELJANZgroupofagiveninterval.ComparisonsbetweenplaceboandXELJANZwerebasedonthefirst3monthsofexposure,andcomparisonsbetweenXELJANZ5mgtwicedailyandXELJANZ10mgtwicedailywerebasedonthefirst12monthsofexposure.Thelong-termsafetypopulationincludesallpatientswhoparticipatedinadouble-blind,controlledtrial(includingearlierdevelopmentphasestudies)andthenparticipatedinoneoftwolong-termsafetystudies.Thedesignofthelong-termsafetystudiesallowedformodificationofXELJANZdosesaccordingtoclinicaljudgment.Thislimitstheinterpretationofthelong-termsafetydatawithrespecttodose.Clinical Trial Experience Themostcommonseriousadversereactionswereseriousinfections.Theproportionofpatientswhodiscontinuedtreatmentduetoanyadversereactionduringthe0to3monthsexposureinthedouble-blind,placebo-controlledtrialswas4%forpatientstakingXELJANZand3%forplacebo-treatedpatients.Overall Infections Inthesevencontrolledtrials,duringthe0to3monthsexposure,theoverallfrequencyofinfectionswas20%and22%inthe5mgtwicedailyand10mgtwicedailygroups,respectively,and18%intheplacebogroup.ThemostcommonlyreportedinfectionswithXELJANZwereupperrespiratorytractinfections,nasopharyngitis,andurinarytractinfections(4%,3%,and2%ofpatients,respectively).Serious InfectionsInthesevencontrolledtrials,duringthe0to3monthsexposure,seriousinfectionswerereportedin1patient(0.5eventsper100patient-years)whoreceivedplaceboand11patients(1.7eventsper100patient-years)whoreceivedXELJANZ5mgor10mgtwicedaily.Theratedifferencebetweentreatmentgroups(andthecorresponding95%confidenceinterval)was1.1(-0.4,2.5)eventsper100patient-yearsforthecombined5mgtwicedailyand10mgtwicedailyXELJANZgroupminusplacebo.Inthesevencontrolledtrials,duringthe0to12monthsexposure,seriousinfectionswerereportedin34patients(2.7eventsper100patient-years)whoreceived5mgtwicedailyofXELJANZand33patients(2.7eventsper100patient-years)whoreceived10mgtwicedailyofXELJANZ.TheratedifferencebetweenXELJANZdoses(andthecorresponding95%confidenceinterval)was-0.1(-1.3,1.2)eventsper100patient-yearsfor10mgtwicedailyXELJANZminus5mgtwicedailyXELJANZ.Themostcommonseriousinfectionsincludedpneumonia,cellulitis,herpeszoster,andurinarytractinfection.TuberculosisInthesevencontrolledtrials,duringthe0to3monthsexposure,tuberculosiswasnotreportedinpatientswhoreceivedplacebo,5mgtwicedailyofXELJANZ,or10mgtwicedailyofXELJANZ.Inthesevencontrolledtrials,duringthe0to12monthsexposure,tuberculosiswasreportedin0patientswhoreceived5mgtwicedailyofXELJANZand6patients(0.5eventsper100patient-years)whoreceived10mgtwicedaily

IMPORTANT SAFETY INFORMATIONWARNING: SERIOUS INFECTIONS AND MALIGNANCYSERIOUS INFECTIONSPatients treated with XELJANZ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.If a serious infection develops, interrupt XELJANZ until the infection is controlled. Reported infections include: • Activetuberculosis,whichmaypresentwithpulmonaryorextrapulmonarydisease.PatientsshouldbetestedforlatenttuberculosisbeforeXELJANZuseandduringtherapy.TreatmentforlatentinfectionshouldbeinitiatedpriortoXELJANZuse.

• Invasivefungalinfections,includingcryptococcosisandpneumocystosis.Patients with invasive fungal infections may present with disseminated, rather than localized, disease.

• Bacterial,viral,andotherinfectionsduetoopportunisticpathogens.TherisksandbenefitsoftreatmentwithXELJANZshouldbecarefullyconsidered prior to initiating therapy in patients with chronic or recurrent infection. Patientsshouldbecloselymonitoredforthedevelopmentofsignsandsymptoms of infection during and after treatment with XELJANZ, including thepossibledevelopmentoftuberculosisinpatientswhotestednegativeforlatenttuberculosisinfectionpriortoinitiatingtherapy.MALIGNANCIESLymphomaandothermalignancieshavebeenobservedinpatientstreatedwithXELJANZ.EpsteinBarrVirus-associatedpost-transplantlymphoproliferativedisorderhasbeenobservedatanincreasedratein renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications. SERIOUS INFECTIONSThe most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster and urinary tract infection. XELJANZ should not be initiated in patients with an active infection, including localized infections. Consider the risks and benefits of treatment before initiating XELJANZ in patients:• with chronic or recurrent infection;• who have been exposed to tuberculosis (TB);• with a history of a serious or an opportunistic infection;• who have lived or traveled in areas of endemic TB or mycoses; or• with underlying conditions that may predispose them to infection.Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ. XELJANZ should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. TuberculosisEvaluate and test patients for latent or active infection before administration of XELJANZ. Consider anti-TB therapy prior to administration of XELJANZ in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection. Treat patients with latent TB with standard therapy before administrating XELJANZ.ViralReactivationViral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster) were observed in clinical studies with XELJANZ. MALIGNANCYandLYMPHOPROLIFERATIVEDISORDERConsider the risks and benefits of XELJANZ treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ in patients who develop a malignancy. In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one lymphoma were diagnosed in 3328 patients receiving XELJANZ with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure. Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with XELJANZ. In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high dose corticosteroids, and mycophenolic acid products, Epstein Barr Virus-associated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of 111 patients treated with cyclosporine.

GASTROINTESTINAL PERFORATIONSGastrointestinal perforations have been reported in rheumatoid arthritis clinical trials, although the role of JAK inhibition is not known. XELJANZ should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). LABORATORYPARAMETERSLymphocytesTreatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean lymphocyte counts of approximately 10% during 12 months of therapy. Counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections. Avoid initiation of XELJANZ treatment in patients with a count less than 500 cells/mm3. In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3 treatment with XELJANZ is not recommended. Monitor lymphocyte counts at baseline and every 3 months thereafter. NeutrophilsTreatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo. Avoid initiation of XELJANZ treatment in patients with an ANC less than 1000 cells/mm3. For patients who develop a persistent ANC of 500- 1000 cells/mm3, interrupt XELJANZ dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with XELJANZ is not recommended. Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter. HemoglobinAvoid initiation of XELJANZ treatment in patients with a hemoglobin level less than 9 g/dL. Treatment with XELJANZ should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment. Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter. Liver EnzymesTreatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy.Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury. If drug-induced liver injury is suspected, the administration of XELJANZ should be interrupted until this diagnosis has been excluded.LipidsTreatment with XELJANZ was associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. Assess lipid parameters approximately 4-8 weeks following initiation of XELJANZ therapy, and manage patients according to clinical guidelines for the management of hyperlipidemia.VACCINATIONS Live vaccines should not be given concurrently with XELJANZ. Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ therapy.HEPATIC IMPAIRMENTTreatment with XELJANZ is not recommended in patients with severe hepatic impairment.ADVERSEREACTIONSThe most common serious adverse reactions were serious infections. The most commonly reported adverse reactions during the first 3 months in controlled clinical trials with XELJANZ 5 mg twice daily and placebo, respectively, (occurring in greater than or equal to 2% of patients treated with XELJANZ with or without DMARDs ) were upper respiratory tract infections (4.5%,3.3%), headache (4.3%,2.1%), diarrhea (4.0%,2.3%), and nasopharyngitis (3.8%,2.8%).USE IN PREGNANCYThere are no adequate and well-controlled studies in pregnant women. XELJANZ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Please see brief summary of full Prescribing Information, including boxed warning, on the following pages.

TRA539315-01 © 2013 Pfizer Inc. Printed in USA/March 2013 All rights reserved.

TRA539315-01_VBCR.indd 3-4 3/22/13 10:43 AM

of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ.Cases of disseminated tuberculosis were also reported. The median XELJANZ exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days).Opportunistic Infections (excluding tuberculosis) In the seven controlled trials, during the 0 to 3 months exposure, opportunistic infections were not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ.In the seven controlled trials, during the 0 to 12 months exposure, opportunistic infections were reported in 4 patients (0.3 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 4 patients (0.3 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ.The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days).Malignancy In the seven controlled trials, during the 0 to 3 months exposure, malignancies excluding NMSC were reported in 0 patients who received placebo and 2 patients (0.3 events per 100 patient-years) who received either XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 0.3 (-0.1, 0.7) events per 100 patient-years for the combined 5 mg and 10 mg twice daily XELJANZ group minus placebo.In the seven controlled trials, during the 0 to 12 months exposure, malignancies excluding NMSC were reported in 5 patients (0.4 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 7 patients (0.6 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.2 (-0.4, 0.7) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. One of these malignancies was a case of lymphoma that occurred during the 0 to 12 month period in a patient treated with XELJANZ 10 mg twice daily.The most common types of malignancy, including malignancies observed during the long-term extension, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma, and malignant melanoma.Laboratory Tests

Lymphocytes In the controlled clinical trials, confirmed decreases in lymphocyte counts below 500 cells/mm3 occurred in 0.04% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 months of exposure.Confirmed lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections.Neutrophils In the controlled clinical trials, confirmed decreases in ANC below 1000 cells/mm3 occurred in 0.07% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 months of exposure.There were no confirmed decreases in ANC below 500 cells/mm3 observed in any treatment group.There was no clear relationship between neutropenia and the occurrence of serious infections.In the long-term safety population, the pattern and incidence of confirmed decreases in ANC remained consistent with what was seen in the controlled clinical trials.Liver Enzyme Tests Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3x ULN) were observed in patients treated with XELJANZ. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of XELJANZ, or reduction in XELJANZ dose, resulted in decrease or normalization of liver enzymes.In the controlled monotherapy trials (0-3 months), no differences in the incidence of ALT or AST elevations were observed between the placebo, and XELJANZ 5 mg, and 10 mg twice daily groups.In the controlled background DMARD trials (0-3 months), ALT elevations greater than 3x ULN were observed in 1.0%, 1.3% and 1.2% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3x ULN were observed in 0.6%, 0.5% and 0.4% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively.One case of drug-induced liver injury was reported in a patient treated with XELJANZ 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3x ULN and bilirubin elevations greater than 2x ULN, which required hospitalizations and a liver biopsy.Lipids In the controlled clinical trials, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL

cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the first 3 months of exposure in the controlled clinical trials are summarized below:• MeanLDLcholesterolincreasedby15%intheXELJANZ

5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm.

• MeanHDLcholesterolincreasedby10%intheXELJANZ5 mg twice daily arm and 12% in the XELJANZ 10 mg twice daily arm.

• MeanLDL/HDLratioswereessentiallyunchangedinXELJANZ-treated patients.

In a controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy.In the long-term safety population, elevations in lipid parameters remained consistent with what was seen in the controlled clinical trials.Serum Creatinine

In the controlled clinical trials, dose-related elevations in serum creatinine were observed with XELJANZ treatment. The mean increase in serum creatinine was <0.1 mg/dL in the 12-month pooled safety analysis; however with increasing duration of exposure in the long-term extensions, up to 2% of patients were discontinued from XELJANZ treatment due to the protocol-specified discontinuation criterion of an increase in creatinine by more than 50% of baseline. The clinical significance of the observed serum creatinine elevations is unknown.

Other Adverse Reactions Adverse reactions occurring in 2% or more of patients on 5 mg twice daily or 10 mg twice daily XELJANZ and at least 1% greater than that observed in patients on placebo with or without DMARD are summarized in the table below.

Adverse Reactions Occurring in at Least 2% or More of Patients on 5 or 10 mg Twice Daily XELJANZ With or Without DMARD (0-3 months) and at Least 1% Greater Than That Observed in Patients on Placebo

Other adverse reactions occurring in controlled and open-label extension studies included:Blood and lymphatic system disorders: AnemiaMetabolism and nutrition disorders: DehydrationPsychiatric disorders: InsomniaNervous system disorders: ParesthesiaRespiratory, thoracic and mediastinal disorders: Dyspnea, cough, sinus congestionGastrointestinal disorders: Abdominal pain, dyspepsia, vomiting, gastritis, nauseaHepatobiliary disorders: Hepatic steatosisSkin and subcutaneous tissue disorders: Rash, erythema, pruritusMusculoskeletal, connective tissue and bone disorders: Musculoskeletal pain, arthralgia, tendonitis, joint swellingGeneral disorders and administration site conditions: Pyrexia, fatigue, peripheral edemaDRUG INTERACTIONS

Potent CYP3A4 Inhibitors Tofacitinib exposure is increased when XELJANZ is coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 (e.g., ketoconazole).Moderate CYP3A4 and Potent CYP2C19 Inhibitors Tofacitinib exposure is increased when XELJANZ is coadministered with medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole).Potent CYP3A4 Inducers Tofacitinib exposure is decreased when XELJANZ is coadministered with potent CYP3A4 inducers (e.g., rifampin).Immunosuppressive Drugs There is a risk of added immunosuppression when XELJANZ is coadministered with potent immunosuppressive drugs (e.g., azathioprine, tacrolimus, cyclosporine). Combined use of multiple-dose XELJANZ with potent immunosuppressives has not been studied in rheumatoid arthritis.

USE IN SPECIFIC POPULATIONS

Pregnancy

Teratogenic effects:

Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. XELJANZ

should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Tofacitinib has been shown to be fetocidal and teratogenic in rats and rabbits when given at exposures 146 times and 13 times, respectively, the maximum recommended human dose (MRHD).In a rat embryofetal developmental study, tofacitinib was teratogenic at exposure levels approximately 146 times the MRHD (on an AUC basis at oral doses of 100 mg/kg/day). Teratogenic effects consisted of external and soft tissue malformations of anasarca, and membranous ventricular septal defects, respectively, and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day). In the rabbit embryofetal development study, tofacitinib was teratogenic at exposure levels approximately 13 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day).Nonteratogenic effects:

In a peri- and postnatal rat study, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the MRHD (on an AUC basis at oral doses of 50 mg/kg/day). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day).Pregnancy Registry: To monitor the outcomes of pregnant women exposed to XELJANZ, a pregnancy registry has been established. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.Nursing Mothers Tofacitinib was secreted in milk of lactating rats. It is not known whether tofacitinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from tofacitinib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug for the mother.Pediatric Use The safety and effectiveness of XELJANZ in pediatric patients have not been established.Geriatric Use Of the 3315 patients who enrolled in Studies I to V, a total of 505 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older. The frequency of serious infection among XELJANZ-treated subjects 65 years of age and older was higher than among those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.Hepatic Impairment No dose adjustment is required in patients with mild hepatic impairment. XELJANZ dose should be reduced to 5 mg once daily in patients with moderate hepatic impairment. The safety and efficacy of XELJANZ have not been studied in patients with severe hepatic impairment or in patients with positive hepatitis B virus or hepatitis C virus serology.Renal Impairment No dose adjustment is required in patients with mild renal impairment. XELJANZ dose should be reduced to 5 mg once daily in patients with moderate and severe renal impairment. In clinical trials, XELJANZ was not evaluated in rheumatoid arthritis patients with baseline creatinine clearance values (estimated by the Cockroft-Gault equation) less than 40 mL/min.

OVERDOSAGE

Signs, Symptoms, and Laboratory Findings of Acute Overdosage in Humans There is no experience with overdose of XELJANZ.Treatment or Management of Overdose Pharmacokinetic data up to and including a single dose of 100 mg in healthy volunteers indicate that more than 95% of the administered dose is expected to be eliminated within 24 hours.There is no specific antidote for overdose with XELJANZ. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate treatment.

This brief summary is based on XELJANZ® (tofacitinib) Prescribing Information LAB-0445-1.0 Issued: November 2012

XELJANZ5 mg

Twice Daily

XELJANZ10 mg

Twice DailyPlacebo

Preferred Term N = 1336 (%)

N = 1349 (%)

N = 809 (%)

Diarrhea 4.0 2.9 2.3Nasopharyngitis 3.8 2.8 2.8Upper respiratory tract infection

4.5 3.8 3.3

Headache 4.3 3.4 2.1

Hypertension 1.6 2.3 1.1

N reflects randomized and treated patients from the seven clinical trials

TRA476916-01 © 2012 Pfizer Inc. All rights reserved. November 2012

TRA539315-01_VBCR.indd 5 3/22/13 10:43 AM


A careful analysis of educational resources for patients with gout indicates that there is

significant room for improvement in conveying the right messages to patients in the right ways (Robinson PC, Schumacher JR Jr. Clin Rheuma-tol. 2013 Jan 16 [Epub ahead of print]).

Researchers looked at 10 patient education guides, including the American College of Rheumatology’s Gout Patient Fact Sheet, the Mayo Clinic’s Gout Information Page, the United Kingdom Gout Society’s booklet “All About Gout: A Patient Guide to Managing Gout,” the Australian Rheumatology Association’s Arthritis/Gout Information Sheet, and the medical database UpToDate’s Patient Information: Gout (The Basics) and Gout (Beyond the Basics).

They parsed the texts’ readability, content, and whether they avoided

jargon, used pictures and/or diagrams; explained terms clearly; and had clear instructions regarding treatment options.

The median readability grade level of the resources was 8.5. The highest readability grade was 11.3, for the UpToDate Beyond the Basics pages, and the lowest was 5 for the UpToDate The Basics information. The Beyond the Basics resource also had the highest score on the Simple Measure of Gobbledygook index.

The team also drew up a list of criteria for content that ideally should be in goutrelated patient education materials, and found that the 2 items that were most frequently left out were the importance of treating serum uric acid to target, and of prophylaxis against acute flares during urate-lowering therapy.

Of the educational materials examined, 60% omitted these items. Half of

the materials also did not include the fact that chronic renal failure is associated with gout, nor did they name the

authors or their qualifications.Six sets of educational materials

avoided jargon, whereas another had only a few instances of jargon use. All 10 explained the terms that were used, 7 used pictures and/or diagrams, and 6 had clear instructions. However, only 4 stated the intended audience, only 2 had key messages at the beginning, and 7 had less than 2500 words.

“I hope this study will encourage people and organizations to examine not only the resources featured in the article but all gout education resources to see whether they communicate in an appropriate way, and whether they are sending all of the important messages that we think patients need to know,” said lead investigator Philip Robinson, MD, a practicing rheumatologist at the University of Queensland Diamantina Institute, Australia.—RF n

Educational Materials for Patients with Gout Have Room for Improvement

“I hope this study will encourage people and organizations to examine not only the resources featured in the article but all gout education resources to see whether they communicate in an appropriate way, and whether they are sending all of the important messages that we think patients need to know.”

—Philip Robinson, MD

Gout

Ottawa, Ontario—A simple questionnaire can help clinicians track adverse events (AEs) and plan medication adjustments in patients receiving biologic drug therapy, according to researchers at The Hospital for Sick Children in Toronto, Ontario, who presented at the recent Canadian Rheumatology Association annual meeting.

In the Safety in Patients Receiving Biologic Therapies (SPOT) study, the researchers analyzed the responses from children with rheumatic diseases or their parents to a standardized, selfadministered questionnaire between June and August 2012.

“This screening form helps to alert physicians to any potential adverse events in patients on biologics in a standardized fashion,” said lead investigator Shirley Tse, MD, Program Director in the hospital’s Division of Rheumatology. “After reviewing the forms, the physicians can see if further investigations or medication dose adjustments need to be done.”

Dr Tse and her team asked 22 fe

male and 21 male patients aged 3 to 18 years (mean age, 12.3 years) to complete the questionnaire.

The patients’ diagnoses included juvenile idiopathic arthritis, uveitis, childhood vasculitis, and childhood onset lupus. Of these patients, 81% had been exposed to anti–tumor necrosis factor agents, 14% had received rituximab (Rituxan), 12% had received anakinra (Kineret), and 5% had received abatacept (Orencia). In

addition, 19% had taken more than 1 biologic agent.

In total, 43 children and parents completed the questionnaire, with 88% completing the questionnaires without missing data. Only 3 patients needed help answering the questions. All of the responders said the questions were clear and easy to answer, and that enough space was provided for their responses.

The results showed that 33 patients

(77%) reported AEs from their biologic drug therapy, with the most common AE being pain (22 of 33). Among those complaining of pain, the most common forms were joint pain/arthralgias (20 of 22) and abdominal pain (3 of 22). Dr Tse believes that the joint pain that the children reported “may have been more reflective of their underlying disease than use of the biologic agents.”

Also, 13 respondents said that they had signs of infection, 8 reported allergic or anaphylactic reactions to the injections, 5 had rashes, and 4 had new neurologic issues, most often reported as headaches. The other complaints were 3 reports of new or recurrent uveitis and 3 reports of abnormal laboratory tests. None of the patients reported any malignancies.

Of the children who reported AEs, 36% (12 of 33) required medical intervention for their AEs, including 3 who were hospitalized and another 3 whose biologic therapy had to be temporarily or permanently stopped. n

Quick Questionnaire Can Elicit Information on Adverse Events Associated with Biologic TherapyBy Rosemary Frei, MSc

Biologic Drug Therapy

“This screening form helps to alert physicians to any potential adverse events in patients on biologics in a standardized fashion. After reviewing the forms, the physicians can see if further investigations or medication dose adjustments need to be done.”

—Shirley Tse, MD

of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ.Cases of disseminated tuberculosis were also reported. The median XELJANZ exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days).Opportunistic Infections (excluding tuberculosis) In the seven controlled trials, during the 0 to 3 months exposure, opportunistic infections were not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ.In the seven controlled trials, during the 0 to 12 months exposure, opportunistic infections were reported in 4 patients (0.3 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 4 patients (0.3 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ.The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days).Malignancy In the seven controlled trials, during the 0 to 3 months exposure, malignancies excluding NMSC were reported in 0 patients who received placebo and 2 patients (0.3 events per 100 patient-years) who received either XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 0.3 (-0.1, 0.7) events per 100 patient-years for the combined 5 mg and 10 mg twice daily XELJANZ group minus placebo.In the seven controlled trials, during the 0 to 12 months exposure, malignancies excluding NMSC were reported in 5 patients (0.4 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 7 patients (0.6 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.2 (-0.4, 0.7) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. One of these malignancies was a case of lymphoma that occurred during the 0 to 12 month period in a patient treated with XELJANZ 10 mg twice daily.The most common types of malignancy, including malignancies observed during the long-term extension, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma, and malignant melanoma.Laboratory Tests

Lymphocytes In the controlled clinical trials, confirmed decreases in lymphocyte counts below 500 cells/mm3 occurred in 0.04% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 months of exposure.Confirmed lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections.Neutrophils In the controlled clinical trials, confirmed decreases in ANC below 1000 cells/mm3 occurred in 0.07% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 months of exposure.There were no confirmed decreases in ANC below 500 cells/mm3 observed in any treatment group.There was no clear relationship between neutropenia and the occurrence of serious infections.In the long-term safety population, the pattern and incidence of confirmed decreases in ANC remained consistent with what was seen in the controlled clinical trials.Liver Enzyme Tests Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3x ULN) were observed in patients treated with XELJANZ. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of XELJANZ, or reduction in XELJANZ dose, resulted in decrease or normalization of liver enzymes.In the controlled monotherapy trials (0-3 months), no differences in the incidence of ALT or AST elevations were observed between the placebo, and XELJANZ 5 mg, and 10 mg twice daily groups.In the controlled background DMARD trials (0-3 months), ALT elevations greater than 3x ULN were observed in 1.0%, 1.3% and 1.2% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3x ULN were observed in 0.6%, 0.5% and 0.4% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively.One case of drug-induced liver injury was reported in a patient treated with XELJANZ 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3x ULN and bilirubin elevations greater than 2x ULN, which required hospitalizations and a liver biopsy.Lipids In the controlled clinical trials, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL

cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the first 3 months of exposure in the controlled clinical trials are summarized below:• MeanLDLcholesterolincreasedby15%intheXELJANZ

5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm.

• MeanHDLcholesterolincreasedby10%intheXELJANZ5 mg twice daily arm and 12% in the XELJANZ 10 mg twice daily arm.

• MeanLDL/HDLratioswereessentiallyunchangedinXELJANZ-treated patients.

In a controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy.In the long-term safety population, elevations in lipid parameters remained consistent with what was seen in the controlled clinical trials.Serum Creatinine

In the controlled clinical trials, dose-related elevations in serum creatinine were observed with XELJANZ treatment. The mean increase in serum creatinine was <0.1 mg/dL in the 12-month pooled safety analysis; however with increasing duration of exposure in the long-term extensions, up to 2% of patients were discontinued from XELJANZ treatment due to the protocol-specified discontinuation criterion of an increase in creatinine by more than 50% of baseline. The clinical significance of the observed serum creatinine elevations is unknown.

Other Adverse Reactions Adverse reactions occurring in 2% or more of patients on 5 mg twice daily or 10 mg twice daily XELJANZ and at least 1% greater than that observed in patients on placebo with or without DMARD are summarized in the table below.

Adverse Reactions Occurring in at Least 2% or More of Patients on 5 or 10 mg Twice Daily XELJANZ With or Without DMARD (0-3 months) and at Least 1% Greater Than That Observed in Patients on Placebo

Other adverse reactions occurring in controlled and open-label extension studies included:Blood and lymphatic system disorders: AnemiaMetabolism and nutrition disorders: DehydrationPsychiatric disorders: InsomniaNervous system disorders: ParesthesiaRespiratory, thoracic and mediastinal disorders: Dyspnea, cough, sinus congestionGastrointestinal disorders: Abdominal pain, dyspepsia, vomiting, gastritis, nauseaHepatobiliary disorders: Hepatic steatosisSkin and subcutaneous tissue disorders: Rash, erythema, pruritusMusculoskeletal, connective tissue and bone disorders: Musculoskeletal pain, arthralgia, tendonitis, joint swellingGeneral disorders and administration site conditions: Pyrexia, fatigue, peripheral edemaDRUG INTERACTIONS

Potent CYP3A4 Inhibitors Tofacitinib exposure is increased when XELJANZ is coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 (e.g., ketoconazole).Moderate CYP3A4 and Potent CYP2C19 Inhibitors Tofacitinib exposure is increased when XELJANZ is coadministered with medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole).Potent CYP3A4 Inducers Tofacitinib exposure is decreased when XELJANZ is coadministered with potent CYP3A4 inducers (e.g., rifampin).Immunosuppressive Drugs There is a risk of added immunosuppression when XELJANZ is coadministered with potent immunosuppressive drugs (e.g., azathioprine, tacrolimus, cyclosporine). Combined use of multiple-dose XELJANZ with potent immunosuppressives has not been studied in rheumatoid arthritis.

USE IN SPECIFIC POPULATIONS

Pregnancy

Teratogenic effects:

Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. XELJANZ

should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Tofacitinib has been shown to be fetocidal and teratogenic in rats and rabbits when given at exposures 146 times and 13 times, respectively, the maximum recommended human dose (MRHD).In a rat embryofetal developmental study, tofacitinib was teratogenic at exposure levels approximately 146 times the MRHD (on an AUC basis at oral doses of 100 mg/kg/day). Teratogenic effects consisted of external and soft tissue malformations of anasarca, and membranous ventricular septal defects, respectively, and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day). In the rabbit embryofetal development study, tofacitinib was teratogenic at exposure levels approximately 13 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day).Nonteratogenic effects:

In a peri- and postnatal rat study, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the MRHD (on an AUC basis at oral doses of 50 mg/kg/day). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day).Pregnancy Registry: To monitor the outcomes of pregnant women exposed to XELJANZ, a pregnancy registry has been established. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.Nursing Mothers Tofacitinib was secreted in milk of lactating rats. It is not known whether tofacitinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from tofacitinib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug for the mother.Pediatric Use The safety and effectiveness of XELJANZ in pediatric patients have not been established.Geriatric Use Of the 3315 patients who enrolled in Studies I to V, a total of 505 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older. The frequency of serious infection among XELJANZ-treated subjects 65 years of age and older was higher than among those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.Hepatic Impairment No dose adjustment is required in patients with mild hepatic impairment. XELJANZ dose should be reduced to 5 mg once daily in patients with moderate hepatic impairment. The safety and efficacy of XELJANZ have not been studied in patients with severe hepatic impairment or in patients with positive hepatitis B virus or hepatitis C virus serology.Renal Impairment No dose adjustment is required in patients with mild renal impairment. XELJANZ dose should be reduced to 5 mg once daily in patients with moderate and severe renal impairment. In clinical trials, XELJANZ was not evaluated in rheumatoid arthritis patients with baseline creatinine clearance values (estimated by the Cockroft-Gault equation) less than 40 mL/min.

OVERDOSAGE

Signs, Symptoms, and Laboratory Findings of Acute Overdosage in Humans There is no experience with overdose of XELJANZ.Treatment or Management of Overdose Pharmacokinetic data up to and including a single dose of 100 mg in healthy volunteers indicate that more than 95% of the administered dose is expected to be eliminated within 24 hours.There is no specific antidote for overdose with XELJANZ. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate treatment.

This brief summary is based on XELJANZ® (tofacitinib) Prescribing Information LAB-0445-1.0 Issued: November 2012

XELJANZ5 mg

Twice Daily

XELJANZ10 mg

Twice DailyPlacebo

Preferred Term N = 1336 (%)

N = 1349 (%)

N = 809 (%)

Diarrhea 4.0 2.9 2.3Nasopharyngitis 3.8 2.8 2.8Upper respiratory tract infection

4.5 3.8 3.3

Headache 4.3 3.4 2.1

Hypertension 1.6 2.3 1.1

N reflects randomized and treated patients from the seven clinical trials

TRA476916-01 © 2012 Pfizer Inc. All rights reserved. November 2012

TRA539315-01_VBCR.indd 5 3/22/13 10:43 AM

See also page 5


Researchers are finding tantalizing clues about how the immune system is thrown off bal

ance in diseases such as rheumatoid arthritis (RA).

In a recent study, a UK team found that regulatory Bcells are present in lower numbers in patients with active RA than they are in patients with inactive RA or in those without any immune disease, and that their remaining regulatory Bcells are less able to fend off an immune attack from within (Flores-Borja F, et al. Sci Transl Med. 2013;5:1-12).

“People with active rheumatoid arthritis have lower levels of regulatory Bcells in their peripheral blood, and their regulatory Bcells also are less able to prevent the development of autoreactive responses and inflammation—tipping the balance of the immune system toward the presence and action of pathogenic cells,” lead investigator Claudia Mauri, PhD, Professor of Immunology at University

College London, told Value-Based Care in Rheumatology.

Dr Mauri said that her team had already shown in previous studies that regulatory Bcells are very important for “restraining” RA and other auto

immune diseases, such as systemic lupus erythematosus. To gain an even greater understanding of what happens with autoimmune diseases, they compared the function of regulatory

B-cells in 97 healthy individuals versus 103 patients with active RA and 76 persons with inactive RA.

In a series of in vitro experiments, the researchers found that healthy people’s regulatory B-cells “maintain

the crucial balance” between the pool of regulatory Tcells and the Thelper 1 and T-helper 17 cell populations, thus maintaining the body’s tolerance to selfantigens without allowing au

toimmune diseases to develop. However, regulatory Bcells from patients with active RA failed to maintain this balance. In addition, the team found a lower titer of regulatory Bcells in the peripheral blood of people with active RA.

This helps to elucidate not only what is happening in RA, but it also uncovers more of the details of the regulatory functions within the immune system.

“The idea was to deepen our understanding of how regulatory Bcells work; eventually we hope to help develop a therapy that can restore their number and functioning to levels similar to those in healthy individuals,” said Dr Mauri.

“We have moved on to genetic work in our research, because we now have a good understanding of how regulatory Bcells work and how they interact with other cells in the immune system, and we have to take other steps to bring our work to the clinic.” n

Study Shines New Light on Deleterious Dance between B-Cells and T-Cells in Rheumatoid Arthritis By Rosemary Frei, MSc

“People with active rheumatoid arthritis have lower levels of regulatory B-cells in their peripheral blood, and their regulatory B-cells also are less able to prevent the development of autoreactive responses and inflammation—tipping the balance of the immune system toward the presence and action of pathogenic cells.”

—Claudia Mauri, PhD

Arthritis Update

Rheumatologists Warned to Watch for Serious Infections... Continued from cover

20,575 serious infections among 86,039 Canadian patients with RA aged ≥66 years, or a rate of 46.36 events per 1000 patient-years. These include not only the “usual suspects,” such as respiratory infections and bacterial pneumonia, but also fungal infections.

Predictors of serious infection in this population included:• Living in a rural area• Having a past infection• Having other serious conditions

(such as renal disease or chronic lung disease)

• Having extraarticular features of RA. Medications—including disease-

modi fying antirheumatic drugs (DMARDs), anti–tumor necrosis factor (TNF) agents, methotrexate, and glucocorticoids—also increased the rate of serious infections.

“The takehome message is that as physicians, we should be particularly careful about our management of medications and comorbidities among seniors with RA,” said investigator Sasha Bernatsky, MD, PhD, Assistant Professor of Medicine at McGill University in Montreal, Quebec.

Dr Bernatsky, along with other researchers, extracted data on patients with RA aged ≥66 years from health administrative data in Ontario from 1992 to 2010. They compared the information on patients with RA who were treated in a hospital for a primary diagnosis of infection with

matched patients with RA without such infections.

Serious respiratory infections—mostly bacterial pneumonia—occurred at a rate of >2 cases per 100 patients with RA who were followed

for 1 year. The rate for herpes zoster infections was almost 1 case per 100 patients with RA annually; similarly, there was almost 1 case of bacterial skin or soft-tissue infection per 100 patients with RA annually. The considerable number of serious fungal infections—0.09 per 1000 patient-years— which are “quite rare infections,”

was quite surprising, according to Dr Bernatsky.

Having a past infection conferred a 51% increased risk of developing a serious infection. Furthermore, a score of 1 on the Deyo-Charlson Comorbidity Index was associated with a 34% increased infection risk, whereas a score of ≤2 increased the risk by 44%.

The greatest increases in infection risk were associated with medications. For example, there was a >7.5-fold higher risk with a very high prednisone-equivalent dose. Overall infection risk was more than doubled with the use of methotrexate azathioprine, cyclophosphamide, or other DMARDs. An approximately 60% increased risk of infection was associated with current anti-TNF drug use.

“Our data, being unselected and populationbased, likely represent a somewhat different patient profile from that seen in clinical registries,” noted Dr Bernatsky. “[But] populationbased administrative data can generate precise, reasonably generalizable estimates for the risk of important events such as serious infections, including relatively uncommon ones, like significant fungal infections.” n

“The take-home message is that as physicians, we should be particularly careful about our management of medications and comorbidities among seniors with RA.”

—Sasha Bernatsky, MD, PhD

at a glance➤ Serious respiratory infections

occurred at a rate of >2 cases per 100 patients with RA who were followed for 1 year

➤ The greatest increases in infection risk were associated with medications

➤ Predictors of serious infection in older patients with RA include living in rural areas, having past infections, other serious conditions, or extraarticular features of RA

➤ Having a past infection conferred a 51% increased risk of developing a serious infection in senior patients with RA


Psoriatic Arthritis

was effective in DMARD- and/or biologic-experienced patients with PsA, and was well tolerated with acceptable safety,” stated lead investigator Arthur F. Kavanaugh, MD, Professor of Clinical Medicine and Director of the Center for Innovative Therapy at the University of California, San Diego. “These results are encouraging for both physicians and patients, with a potentially effective and safe oral therapy for patients with PsA,” including those who do not respond to other antirheumatic agents, he said.

Apremilast was effective in combination with other DMARDs, but was even more effective as a monotherapy and in biologic-naïve patients. No unexpected safety concerns were reported. Apremilast inhibits phosphodiesterase 4 and acts by decreasing proinflammatory mediators while increasing anti-inflammatory mediators, Dr Kavanaugh noted. Approximately 3000 patients have been treated with the drug to date.

The multicenter, doubleblind, placebo-controlled, parallel-group PALACE-1 trial randomized 168 patients (median age, 60 years) with moderate-to-severe PsA to receive apremilast 30 mg twice daily, apremilast 20 mg twice daily, or placebo. The study enrolled patients with active PsA (defined as at least 3 tender and 3 swollen joints) who had failed 1 to 3 previous DMARDs or biologics. During the trial, 66% of the patients received

concurrent DMARDs. At baseline, the patients’ median

duration of PsA was approximately 7 years. The median number of tender joints was approximately 22, and the median number of swollen joints was approximately 21. The patients who did not improve by week 16 were switched to one or the other of the active treatments. At week 24, all of the patients received active treatment for the extension phase of the study.

For overall study results, the primary end point of reaching the ACR 20% criteria for improvement (ACR20) in the signs and symptoms of PsA at week 16 was significant for both doses of apremilast versus placebo: 40% for the 30-mg dose and 31% for the 20-mg dose versus 19% for placebo (P = .001 for both comparisons with placebo).

Higher responses were seen in the patients receiving apremilast monotherapy compared with the overall

population. In the monotherapy group, ACR20 at week 16 was achieved by 50.8% of the patients taking the 30-mg dose and by 31.5% of the patients taking the 20-mg dose, versus by 10.5% of the patients in the placebo group (P = .001 for both comparisons with placebo).

Among the biologicnaïve patients treated with apremilast plus a DMARD, ACR20 at week 16 was achieved in 37% of the 30-mg group and in 33% of the 20-mg group versus in 27% of the placebo group. Among the biologic-naïve patients receiving apremilast monotherapy, ACR20 was achieved in 58%, 24%, and 12% of patients, respectively.

Significant responses favoring apre-milast were observed across all of the arthritisrelated secondary end points, including ACR50, ACR70, and the 28-joint Disease Activity Score.

The safety of apremilast was acceptable, with no new signals of concern observed in this study. Any serious adverse events (AEs) were reported in 5.2% of the group receiving apremilast 30 mg twice daily, in 4.8% of those receiving the 20-mg dose, and in 4.2% of the placebo group. AEs leading to drug discontinuation occurred in 7.1%, 6%, and 4.8% of the patients, respectively. One death was reported in a patient using apremilast 20 mg twice daily. No opportunistic infections, lymphoma, or cardiovascular events were reported.

PALACE-1 is 1 of 3 pivotal phase

3 clinical studies in the apremilast development program. Results of the PALACE-2 and PALACE-3 trials were reported in September 2012. Representatives of the drug manufacturer said that the company will submit a New Drug Application to the US Food and Drug Administration in the first half of 2013.

Scott J. Zashin, MD, a Clinical Assistant Professor of Internal Medicine, Division of Rheumatology, University of Texas Southwestern Medical School, Dallas, suggested that apremilast may find a role as a first-line therapy for patients with moderatetosevere rheumatoid arthritis who do not want to self-inject or receive an infusion. But until longerterm safety data are available, “apremilast should be reserved for those patients who have failed DMARDs and biologics because of a lack of efficacy or toxicity,” Dr Zashin commented. n

Ustekinumab Safe and Effective in PsA

Apremilast significantly improved the signs and symptoms of PsA in patients whose disease failed to respond to previous DMARDs, including biologic agents.

at a glance➤ Apremilast decreases

proinflammatory mediators while increasing antiinflammatory mediators

➤ The primary end point of reaching ACR20 by week 16 was significant for the apremilast 30mg and 20mg doses versus placebo

Apremilast Improves Outcomes in Refractory... Continued from cover

Phase 3 data for the PSUMMIT I and PSUMMIT II clinical trials show that ustekinumab (Stelara)

is safe and effective in patients with psoriatic arthritis (PsA), and that the improvement persists over 1 year of treatment.

Ustekinumab is the first new biologic agent in phase 3 clinical trials for the treatment of PsA. The drug is an interleukin (IL)-12 and IL-23 inhibitor, a mechanism that is thought to be specific to PsA and not to other autoimmune arthritic diseases. Ustekinumab is approved by the US Food and Drug Administration for the treatment of psoriasis, and is investigational for PsA. Approximately 20% of patients with psoriasis will develop PsA.

The only drugs currently approved by the FDA for the treatment of PsA are tumor necrosis factor (TNF) inhibitors. “TNF inhibitors are not universally effective, and there is a need for new treatments. The PSUMMIT II

data are promising,” said lead investigator Arthur F. Kavanaugh, MD, Professor of Clinical Medicine and Director of the Center for Innovative Therapy at the University of California, San Diego.

Week 24 Data from PSUMMIT IIThe phase 2, multicenter, ran-

domized, doubleblind, placebocontrolled PSUMMIT II trial evaluated 2 doses of ustekinumab given subcutaneously to patients with active PsA who were uncontrolled by 1 to 5 diseasemodifying antirheumatic drugs (DMARDs), nonsteroidal anti-inflammatory drugs (NSAIDs), and/or TNF inhibitors.

Patients were randomized to receive subcutaneous ustekinumab 45 mg or 90 mg, or placebo, at weeks 0 and 4, and then every 12 weeks.

At week 24, the primary end point of achieving at least the ACR 20% criteria for improvement (ACR20) in the

signs and symptoms of PsA was reached in 43.7% of the patients who received the 45-mg dose of ustekinumab and in 43.8% of the patients who received the 90-mg dose, versus 20.2% of the patients who received placebo (P <.001 for both comparisons with placebo).

Among the patients who were previously treated with a TNF inhibitor, 36.7% in the ustekinumab 45-mg group and 34.5% in the ustekinumab 90-mg group met the ACR20 criteria, versus 14.5% of the patients who were given placebo (P <.001 for both comparisons with placebo).

The percentage of patients who achieved at least ACR50 at week 24 was 17.5% for ustekinumab 45 mg and 22.9% for ustekinumab 90 mg, versus 6.7% for placebo (P = .018 for the 45-mg dose versus placebo, and P = .001 for the 90-mg dose versus placebo).

Significant improvements from

baseline to week 24 also were seen in physical function as measured by the Health Assessment Questionnaire Disability Index for both dosage levels of ustekinumab versus placebo.

Christopher Ritchlin, MD, Professor of Medicine and Director of the Rheumatology Fellowship Program and the Clinical Immunology Research Center at the University of Rochester Medical Center, NY, was the lead investigator of PSUMMIT II.

Week 52 Data from PSUMMIT IUstekinumab was superior to place

bo in patients with active PsA despite treatment with DMARDs and NSAIDs (but not a TNF inhibitor) at 24 weeks, according to results from the PSUMMIT I trial. New 52-week data from PSUMMIT I showed that this improvement persisted from 24 to 52 weeks in patients who were treated with ustekinumab versus placebo.—PS n


Health Economics

San Diego, CA—Rheumatoid arthritis (RA) is associated with significant economic and clinical burden on the US healthcare system as a result of its growing prevalence, the frequent disability and reduced work productivity associated with this chronic disease, and the overall impact on a patient’s quality of life. This clinical impact is directly linked to the increasing costs of managing patients with RA. In 2008, the average annual overall medical cost for a patient with RA was approximately $13,000.

The treatment of RA has evolved with the introduction of socalled traditional diseasemodifying antirheumatic drugs (DMARDs) in the past few decades and, more recently, biologic DMARDs. Lisa Mostovoy, PharmD, Clinical Advisor at CVS Caremark, and colleagues have investigated the impact of the growing availability of biologic DMARDs on the cost and utilization of RA therapies between January 1, 2006, and December 31, 2011; they presented their findings in a poster session at

the 2013 Academy of Managed Care Pharmacy annual meeting.

Dr Mostovoy and her team used CVS Caremark’s administrative claims data of prescription drugs for conventional and biologic DMARDs, which included anti–tumor necrosis factor (TNF) therapies and non–anti TNF therapies. This retrospective longitudinal study included approximately 381,000 members using DMARDs annually. During the study period, the use of conventional DMARDs decreased annually and the use of biologic DMARDs increased.

In 2006, the difference between the use of conventional DMARDs and the use of biologic agents was more than 50%, favoring the conventional agents. By 2011, that difference was reduced to just more than 10%, favoring the conventional DMARDs. Overall, the use of conventional versus biologic DMARDs, respectively, was:• 77.6% vs 22.4% in 2006 • 74.4% vs 25.6% in 2007• 70.8% vs 29.2% in 2008• 66.4% vs 33.6% in 2009• 59.0% vs 41.0% in 2010• 56.4% vs 43.6% in 2011.

Similarly, the permember peryear (PMPY) cost of conventional DMARDs decreased by 36%, and the PMPY cost of biologics increased by almost 24% during that period. Simultaneously, the per-utilizer per-year (PUPY) costs for biologic DMARDs grew by 9% over the study period, from $9083.07 in 2006 to $9884.40 in 2011, and by >41% for conventional DMARDs, from $525.23 in 2006 to $743.11 in 2011.

Although the cost of conventional DMARDs grew 4-fold more than the

cost of biologics, the absolute difference in cost between the 2 types of medications remains significant. According to the researchers, these results suggest that the annual costs per member are not fully explained by changes in the annual utilization costs per member. “We observed a significant shift to biologics, as a percentage of overall utilization, as well as an increase in the PMPY cost of 24%, while PUPY cost grew only 9%,” Dr Mostovoy and colleagues noted. “These findings suggest that an increasing number of patients are utilizing biologic DMARDs in 2011 as compared with 2006,” they concluded, which is in accordance with the 2008 clinical guidelines of the American College of Rheumatology (ACR).

Dr Mostovoy and colleagues suggest that, based on these results, as well as on the 2012 ACR recommendations and on the emerging treatments for RA, the growing use of biologic therapies for RA can be expected to continue, despite the greater costs associated with these agents. n

San Diego, CA—A recent report by the Institute of Medicine estimates that the treatment of noncancerous chronic pain costs the US healthcare system $635 billion annually. Using a commercial database from Humana, a national health insurance plan, Margaret K. Pasquale, PhD, Principal Researcher at Comprehensive Health Insights, and colleagues analyzed the economic burden of chronic versus acute pain in the general US population and in Medicare beneficiaries.

Dr Pasquale and colleagues selected 36 chronic pain conditions (eg, hip and spine fractures, back pain, gout, and osteoarthritis [OA]) and 14 noncancerous acute pain conditions (eg, hip and spinal fracture, childbirth, burns, and postoperative pain).

The study included 267,948 individuals. Of these, 137,166 had a chronic

pain condition and 130,792 had an acute pain condition.

Back pain was the most common chronic pain, followed by OA, in the commercial population.

In the Medicare population, the most common chronic pain was OA,

followed by back pain. The highest drivers for healthcare

utilization in patients with chronic pain included outpatient visits and prescriptions for pain medications. In

both cohorts, women were slightly more likely to have a chronic pain

condition than men, but men had more acute pain.

Overall, the cost for chronic pain was higher among the Medicare population than the commercial population.

Of the top 10 highest chronic pain conditions, back pain had the greatest adjusted annual costs, at $119,370,308, in the commercial cohort, followed by an annual cost of $98,312,233 for OA.

However, in the Medicare cohort, OA had the highest adjusted annual cost of $326,894,658, followed by an adjusted annual cost for back pain of $218,467,149.

This study highlights the significant economic impact of chronic pain on the US healthcare system and the need to manage chronic pain properly to minimize preventable healthcare utilization and its associated costs.—DB n

The Economic Burden of Chronic Pain on the US Healthcare SystemOsteoarthritis the greatest pain-related cost driver among Medicare patients

Of the top 10 highest chronic pain conditions, back pain had the greatest adjusted annual costs, at $119,370,308, in the commercial cohort, followed by an annual cost of $98,312,233 for OA. However, in the Medicare cohort, OA had the highest adjusted annual cost of $326,894,658, followed by an adjusted annual cost for back pain of $218,467,149.

These results suggest that the annual costs per member are not fully explained by changes in the annual utilization costs per member.

Transitioning from Conventional to Biologic DMARDs a Consistent Trend in the Treatment of Patients with Rheumatoid ArthritisBy Dalia Buffery


is continuous and proximal to the metacarpophalangeal joints, accord

ing to Dr Pope. But the American College of Rheumatology (ACR)’s 1980 Criteria for the Classification of Systemic Sclerosis failed to classify a significant proportion of patients with early systemic scleroderma and patients with the limited subtype of the disease, she said. Experienced clinicians believe that these patients should be classified as having systemic sclerosis.

The ACR and the European League Against Rheumatism established a committee to develop new criteria. The committee used an 8-step process, first testing the validity of 23 items selected in existing databases of systemic sclerosis cases and controls. Then, 20 cases that represented the spectrum of systemic sclerosis (low probability to high probability) were selected and ranked by experts and conjoint analysis to assign weights of importance to 17 preliminary items.

A provisional threshold was established to classify definite systemic

sclerosis based on the sum of the weights of the 17 items. To test the

provisional algorithm, data on the 17 items were collected from 605 cases and controls (possible mimickers) in North America and Europe.

The threshold was refined in a sub

set of 25 cases within the range of borderline probability of systemic sclerosis. Experts were then asked to confirm whether each case had “definite systemic sclerosis” or not, which led to a new threshold. From there, the final items with proposed weights were selected.

These 17 items were reduced to 9 during a facetoface meeting of the steering committee, while maintaining adequate sensitivity and specificity, as tested in a random sample of cases and controls (N = 200) from North America and Europe. In the validation cohort of 405 cases, a score of ≥9 showed a sensitivity of 91% and a specificity of 92%, whereas the 1980 criteria had a sensitivity of 75% and a specificity of 72% in this cohort.

“It’s better to classify the people who you think have the disease, especially when it’s a rare disease and you want to get them appropriate treatment or into research protocols,” said Dr Pope. n

Systemic Sclerosis

at a glance➤ The major criteria developed

in 1980 still work well in classifying sclerodactyly that is continuous and proximal to the metacarpophalangeal joints

➤ However, they fail to classify a significant proportion of patients with early systemic scleroderma or with the limited subtype of the disease

➤ In the current validation cohort, a score of ≥9 showed a sensitivity of 91% and a specificity of 92%

➤ The 1980 criteria had a sensitivity of 75% and a specificity of 72% in this cohort

“The old criteria didn’t classify up to 20% of the people who clinicians thought had scleroderma, and in a rare disease with serious and sometimes lethal complications, they really should meet classification criteria.”

—Janet E. Pope, MD, MPH, FRCPC

New Classification Criteria... Continued from cover

San Diego, CA—Specialty drugs have been gradually becoming the standard of care for many chronic diseases, including rheumatoid arthritis (RA), and their costs continue to rise faster than the cost of traditional, nonspecialty drugs, according to Patrick P. Gleason, PharmD, Director of Clinical Outcomes Assessment at Prime Therapeutics, and colleagues. In 2012, drugs used for the treatment of RA had an average cost of $2251 per prescription, a 12.1% cost increase from 2011. Dr Gleason and colleagues discussed the results of their study on specialty drugs as a cost driver in the management of RA at a poster presentation at the 2013 Academy of Managed Care Pharmacy annual meeting.

Integrated pharmacy and medical claims data from 1.2 million members in a commercial health plan showed that 4251 members had a diagnosis of RA in 2008, with an annual increase of RA diagnosis of 9.8% through 2010. During that period, the use of special

ty drugs for RA increased by 0.8%. The total cost of care per person per year (PPPY) increased from $19,830 in 2008 to $23,128 in 2010 (including those using or not using specialty drugs).

In 2008, specialty pharmacy drugs constituted 54.7% of the PPPY total cost of care of a patient using specialty drugs. That percentage decreased slightly, to 53.0%, in 2010. When considering only patients with RA who were using specialty drugs, the total annual cost of care for a patient with RA was $29,652 in 2008, which included $16,218 for specialty drugs (covered by the medical or the pharmacy benefit) compared with $11,252 for all medical costs.

Similarly, in 2010, the total cost of care for a patient with RA using specialty drugs was $34,164, which included $18,098 for specialty drugs covered by pharmacy and medical benefits compared with $13,710 for all other medical costs. These num

bers indicate a gradual increase in the spending on specialty drugs compared with the spending on all other medical services for patients with RA.

Between 2008 and 2010, the cost of specialty drugs for RA was growing at a rate of 6.9% annually, while the costs for other drugs remained stable. Furthermore, the wholesale acquisition

cost of the 2 most common specialty drugs used for the treatment of RA—adalimumab (Humira) and etanercept (Enbrel)—increased by an average of 9.2% during the past 5 years.

“Anticipating that these price increases will continue for the foreseeable future, it is forecasted that RA specialty drugs treatment cost will exceed $50,000 per person per year in 2022,” noted Dr Gleason and colleagues. This suggests, they added, that “the anticipated medical cost savings from RA specialty drug cannot offset their cost as RA specialty drug costs now exceed all medical costs.”

The investigators commented that these anticipated costs further suggest that many patients will require help toward paying for the ever growing costs of specialty drugs, whether from payers, from the drug manufacturer, or via other support systems, and it is not too soon to plan for these types of resource allocation mechanisms. n

Impact of Specialty Drugs on the Cost of Rheumatoid Arthritis ManagementBy Dalia Buffery

Many patients will require help toward paying for the ever-growing costs of specialty drugs, whether from payers, from the drug manufacturer, or via other support systems, and it is not too soon to plan for these types of resource allocation mechanisms.

Health Economics


Breach Notification RequirementsNew enforcement provisions go into effect this year By Jennifer Kirschenbaum, Esq

Rheumatology Practice Management™

It should be no surprise that medical practices have an obligation to maintain protected health infor

mation in certain ways, and to only use and disclose such protected health information as authorized by the patient or otherwise by law. Such requirements are set forth under the Privacy Rule.

What may surprise you is that when protected health information is not maintained by a medical practice in accordance with HIPAA, notification to the patient or other sources may be required pursuant to the Breach Notification Rule (45 CFR Part 164). You may not be aware of the Breach Notification Rule because it was part of proposed modifications set forth several years ago, and many practices did not adopt the requirements of the rule because the statute at that time had not been written with teeth.

However, the Final Rule promulgated on January 25, 2013, not only modifies the Breach Notification Rule, it incorporates significant enforcement provisions should a breach occur and not be dealt with appropriately by the practice. Effective September 23, 2013, every medical practice is required to notify an individual of an acquisition, access, use, or disclosure of protected health information in a manner not permitted under the Privacy Rule, otherwise known as a breach. Pursuant to the statute, a breach excludes:1. Any unintentional acquisition, ac

cess, or use of protected health information by a workforce member or person acting under the authority of the practice or a business associate, if such acquisition, access, or use was made in good faith and within the scope of authority and does not result in further use or disclosure in a manner not permitted under the practice’s privacy policy.

2. Any inadvertent disclosure by a person who is authorized to access protected health information at the practice, or a business associate, to another person authorized to access protected health information at the same practice, or business associate, or organized healthcare arrangement in which the practice participates, and the information received as a result of such disclosure is not further used or disclosed in a manner not permitted under the practice’s privacy policy.

3. A disclosure of protected health information where the practice, or

business associate, has a goodfaith belief that an unauthorized person to whom the disclosure was made would not reasonably have been able to retain such information.

4. Where the practice has demonstrated that there is a low probability that the protected health information has been compromised based on a risk assessment of at least the following factors:A. The nature and extent of the

protected health information involved, including the types of identifiers and the likelihood of re-identification

B. The unauthorized person who used the protected health information or to whom the disclosure was made

C. Whether the protected health information was actually acquired or viewed

D. The extent to which the risk to the protected health information has been mitigated (45 CFR 164.402).

Notification is required at several levels: (1) to the individual; (2) to the media; and (3) to the Secretary of the US Department of Health and Human Services (HHS). Each requirement is addressed in turn below.

To the IndividualNotification to the individual is re

quired where, after a risk assessment, it has been determined that protected health information has been—or is reasonably believed by the practice to have been—accessed, acquired, used, or disclosed as a result of a breach. A breach shall be treated as being discovered by the practice on the first day that the breach is actually known to the practice or, by exercising reasonable diligence, would have been known to the practice, meaning that, if such breach is known—or by exercising reasonable diligence would have been known—to any person who is a workforce member or agent of the covered entity other than the person committing the breach. Notification to the individual is required no later than 60 calendar days after the discovery of a breach, and in the notification the practice is required to provide, to the extent possible, the following information: • A brief description of what hap

pened, including the date of the breach and the date of the discovery of the breach, if the date is known

• A description of the types of unse

cured protected health information that were involved in the breach (such as whether the individual’s full name, social security number, date of birth, home address, account number, diagnosis, disability code, or other types of information were involved)

• Any steps that the individual should take to protect himself or herself from potential harm resulting from the breach

• A brief description of what the covered entity involved is doing to investigate the breach, to mitigate harm to the individual, and to protect against any further breaches

• Contact procedures for the individual to ask questions or learn additional information, which shall include a tollfree telephone number, an email address, website, and/or postal address.Notification is required to be sent

in writing by first-class mail to the individual at the last known address of the individual or, if the individual agrees to electronic notice and such agreement has not been withdrawn, by electronic mail. The notification may be provided in 1 or more mailings as information is available. If the practice knows that the individual is deceased and has the address of his or her next of kin or personal representative, written notification by first-class mail to either the next of kin or personal representative must be made. Again, the notification may be provided in 1 or more mailings as information is available.

In a case where there is insufficient or outofdate contact information that precludes written notification to the individual, substitute notice may be provided. In a breach where more than 10 individuals are affected, substitute notice may take the form of either a conspicuous posting on the home page of the practice’s website for a period of 90 days, or a conspicuous notice in major print and/or broadcast media outlets in the geographic areas where the affected individuals likely reside, that includes a tollfree phone number that remains active for at least 90 days where individuals can learn whether their unsecured protected health information may be included in the breach (45 CFR 164.404).

To the MediaWhen more than 500 residents of a

state or jurisdiction are involved in a

protected health information breach, the practice is required to notify prominent media outlets serving the state or jurisdiction within 60 calendar days after the discovery of the breach (45 CFR 164.406).

To the HHS SecretaryThe practice must also notify the

Secretary of HHS when a breach has occurred that involves 500 or more individuals, in the manner and form specified on the HHS website. For all breaches involving less than 500 individuals, the practice shall maintain a log or other documentation of such breaches and, no later than 60 days after the end of each calendar year, provide notification to the Secretary in the manner specified on the HHS website (45 CFR 164.408).

Additional ConcernsIn addition to the foregoing, busi

ness associates are required to report the discovery of a breach to the practice within 60 calendar days (45 CFR 164.410).

Failure to abide by the Breach Notification Rule may open up the practice to substantial liability. The recent modifications to HIPAA allow for the imposition of civil monetary penalties for any entity or individual in violation of any HIPAA requirement, including the Breach Notification Rule, which is why it is imperative to understand and implement the requirements of the rule. Implementation requires that the policies, procedures, and contracts of the practice reflect the requirements of the Breach Notification Rule.

To discuss your practice’s compliance needs to prepare for September 23, 2013, check out available HIPAA policies at www.healthcarepractice compliance.com, or contact Jennifer at 516-747-6700 x302 or [email protected]. Prior to September 2013, all practices will be required to adopt new Notice of Privacy Practices, as well as accompanying documents, such as a Breach Notification Policy.

Jennifer Kirschenbaum, Esq, manages Kirschenbaum & Kirschenbaum’s health-care department, which specializes in rep-resenting healthcare practitioners in regulatory compliance, audit defense, li-censure, and transactional matters. She may be reached at 516-747-6700 x302 or by e-mail at [email protected]. n


Vasculitis

Rituximab (Rituxan) is the most recent and the only treatment approved by the US Food and

Drug Administration (FDA) for antineu trophil cytoplasmic autoantibody (ANCA)associated vasculitis, but there is still a role for cyclophosphamide in these diseases, especially in patients with more severe forms, according to several researchers.

Traditional immunosuppressive drugs have improved treatment outcomes for patients with ANCAassociated vasculitis, but the development of biologic agents and a better understanding of the pathogenesis of the disease have contributed to the discovery of rituximab as an effective alternative to the immunosuppressive drug cyclophosphamide.

“This is an exciting period in which we now have 2 options for remission induction for severe GPA [granulomatosis with polyangiitis] and MPA [microscopic polyangiitis],” said Carol Langford, MD, MHS, FACP, Director of the Center for Vasculitis Care and Research, Cleveland Clinic, OH.

Targeting B-Cells Enhances Remission

B lymphocytes have been a target in GPA since cyclophosphamide demonstrated a profound effect on suppressing Blymphocyte function in patients with the disease, said Ulrich Specks, MD, Professor of Medicine, Mayo Clinic, Rochester, MN. The activity and extent of GPA is directly linked to the frequency of activated peripheral blood B lymphocytes.

Rituximab was approved by the FDA in 2011 for the treatment of patients with GPA or MPA based on the results of the Ri tuximab for ANCA-Associated Vasculitis (RAVE) study. The study included 197 patients with active, severe GPA or MPA who were randomized to rituximab 375 mg/m2 once weekly for 4 weeks or to oral cyclophosphamide 2 mg/kg daily for 3 to 6 months.

The primary end point was the percentage of patients who achieved clinical remission, defined as a Birmingham Vasculitis Activity Score for Wegener’s granulomatosis of 0 and complete tapering of the prednisone dose at 6 months. In the rituximab group, 64% of the patients

achieved the primary end point compared with 53% of the patients in the cyclophosphamide group, which met the criterion for noninferiority, said Dr Specks.

“RAVE demonstrated that rituximab is a proven alternative to cyclophosphamide for induction of remission in patients with severe ANCA associated vasculitis, which is of particular importance for patients who have a severe disease flare that requires treatment, and for patients who want to preserve their fertility,” because infertility is a potential side effect of cyclophosphamide, Dr Specks said.

Sustained remission was also equivalent between rituximab and cyclophosphamide in a second randomized controlled trial known as RITUXVAS, an open-label study of 44 patients who were randomized in a 3:1 ratio to rituximab plus 2 infusions of cyclophosphamide or to intravenous (IV) cyclophosphamide for 6 months followed by oral azathioprine. All of the patients were newly diagnosed with ANCAassociated vasculitis at entry; all had severe renal disease; all were, on average, 10 years older than the patients enrolled in the RAVE study; and 25% had received a plasma exchange immediately before randomization.

The primary end point of RITUXVAS, sustained remission at 12 months, was achieved by 76% of the rituximab group versus 82% of the cyclophosphamide group on an intent-to-treat analysis. The RITUXVAS trial demonstrated that over 12 months, a single course of ri tuximab achieved the same results as a 6-month course of cyclophosphamide followed by azathioprine.

Remission maintenance was again shown to be similar between the

2 strategies in an analysis of the 18-month follow-up of RAVE par- tici pants.

Cyclophosphamide Still an Option in Some Cases

Cyclophosphamide is a much betterunderstood agent now than it was nearly 40 years ago. It continues to have a role in inducing remission in patients with GPA and MPA, particularly in patients who have severe forms of these diseases, Dr Langford explained.

The additional learning experience with cyclophosphamide has led to improved patient outcomes and improved strategies to reduce its side effects. In a German cohort of 445 patients who were observed for 4 decades, mortality rates declined over time, as a result, in part, to the improved use of cy clophosphamide.

Toxicity ProfileThe toxicity profile of these agents

involves not only acute toxicities, such as infection, bone marrow suppression, and cystitis, “but also longterm complications, including infertility for both men and women, myelodysplasia that can lead to lymphoma and leukemia, and the potential for bladder cancer,” Dr Langford pointed out.

The risk of bladder cancer with cyclophosphamide use is related to the total dose and the duration of the ex

posure, with a 5% risk at 10 years from the first cyclophosphamide dose, to a 15% risk at 16 years from the first dose.

Improved TreatmentBetter use of cyclophosphamide has

evolved, Dr Langford said. Strategies by the treatment of ANCAassociated vasculitis is now considered in 2 phases—the induction of remission, followed by maintenance. Azathioprine maintenance after 3 to 6 months of cyclophosphamide therapy maintains remission without increasing the relapse rate. Methotrexate maintenance is similarly as effective as azathioprine in maintaining remission.

Other strategies include limiting the duration of exposure from 3 to 4 months, avoiding its use in nonsevere disease, and using it as prophylaxis for Pneumocystis, as well as for urothelial protection.

Careful Monitoring RecommendedThe time to remission is equivalent

between intermittent IV dosing and daily oral cyclophosphamide at a median of 3 months; however, intermittent therapy is associated with a higher rate of relapse.

Patients who receive daily therapy, however, have a higher rate of leukopenia, leading to the recommendation that the complete blood count should be monitored every 1 to 2 weeks for the duration of daily therapy. n

“This is an exciting period in which we now have 2 options for remission induction for severe GPA and MPA.”

—Carol Langford, MD, MHS, FACP

at a glance➤ Rituximab is the only treatment

approved by the FDA for ANCAassociated vasculitis

➤ There is still, however, a substantial role for cyclophosphamide in patients with severe forms of this disease

➤ In the RAVE study, 64% of the patients in the rituximab group achieved clinical remission compared with 53% of those receiving cyclophosphamide

➤ In the RITUXVAS trial, a 12month single course of rituximab achieved the same sustained remission levels as a 6month course of cyclophosphamide

“RAVE demonstrated that rituximab is a proven alternative to cyclophosphamide for induction of remission in patients with severe ANCA-associated vasculitis, which is of particular importance for patients who have a severe disease flare that requires treatment, and for patients who want to preserve their fertility.”

—Ulrich Specks, MD

Rituximab the Newest Treatment for Patients with ANCA-Associated Vasculitis, but Cyclophosphamide Still a Viable Option in Severe Disease By Wayne Kuznar


Ankylosing Spondylitis

In the Literature

Ottawa, Ontario—Patients with ankylosing spondylitis who take tumor necrosis factor (TNF) inhibitors are 70% less likely to experience radiographic disease progression, according to a cohort study presented at the Canadian Rheumatology Association’s 2013 annual meeting.

Nigil Haroon, MD, PhD, DM, FACR, at the University Health Network/Mt Sinai Hospital and Assistant Professor in the Department of Medicine at the University of Toronto, and Lianne Gensler, MD, Health Sciences Assistant Clinical Professor at the University of California, San Francisco, co-led the 5-center study, in which they followed 334 patients with ankylosing spondylitis for an average of 2.5 years.

The patients were recruited by team members at the University Health Network in Toronto; Cedars-Sinai Medical Center in Los Angeles; the National Institutes of Health’s National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethes

da, MD; the University of Texas Health Science Center at Houston; and the University of California, San

Francisco. The study was not funded by any pharmaceutical companies.

The patients’ mean age at study entry was approximately 41 years and their average disease duration was 16

years. Of the total number of patients, 30% were progressors, which was defined by an increase in 2 modified

Stoke Ankylosing Spondylitis Spinal Score (mSASSS) units over 2 years.

The multivariate analysis revealed that there are only 4 factors that are independent predictors of disease

progression—baseline disease severity, smoking, level of inflammation, and exposure to TNF inhibitors.

Patients with ankylosing spondylitis who had used TNF inhibitors were 70% less likely to progress than patients who had never taken this type of medication. In addition, the patients who started taking TNF inhibitors within 10 years of disease onset had a 3-fold lower probability of disease progression than those who started taking these types of medications later.

“This is the first time that anybody has been able to show conclusively that damage progression in ankylosing spondylitis can be prevented by using TNF inhibitors. The key is to use them early and for sufficiently long periods in patients who need them. Considering the cost of the medications, the decision to start these medications and how to continue them should be based on proper guidelines and the response observed,” concluded Dr Haroon. n

Obesity a Risk Factor for Developing Rheumatoid Arthritis

Researchers have sought to discover whether there is a plausible link between obesity and the development of rheumatoid arthritis (RA), with 2 large US studies finding no such evidence and 2 European studies showing significant evidence to suggest the link.

A recent study investigated the influence of obesity on the development of RA to determine whether obesity is a possible risk factor that could help to explain the annual increase in the incidence of RA in the United States since 1995, after a 4-decade de cline (Crowson CS, et al. Arthritis Care Res [Hoboken]. 2013;65:71-77).

The study included 1626 patients who were evenly split between patients having RA (N = 813) and controls (N = 813), with approximately 30% of each group classified as obese (body mass index of ≥30 kg/m2) at the index date. The patients who were classified as obese were found to have

a higher risk of developing RA during the study period (odds ratio, 1.24; 95% confidence interval, 1.01-1.53). Furthermore, the investigators found that the incidence of RA rose by an increment of 9.2 per 100,000 among women, and obesity accounted for 52% of this increase (4.8 per 100,000).

The results of this study suggest that obesity is associated with a modest risk for the development of RA, which may account for some of the rise in the prevalence of obesity.

Although the mechanisms by which obesity may put patients at risk for RA are mostly unknown, this study suggests that, in addition to the environmental elements that are known to be risk factors, the association between obesity and chronic inflammation, as well as their influence on the devel-opment of RA, should be further investigated.

Adalimumab Safe for Patients with RA and Renal Insufficiency

A common comorbidity in patients

with RA, renal insufficiency is caused by agents such as nonsteroidal anti inflammatory drugs, disease-modifying antirheumatic drugs, and methotrexate. Some of these drugs may even have toxic side effects when used in patients with only mild renal insufficiency. Methotrexate, an anchor drug for the treatment of RA, can cause severe con sequences at very low doses (ie, 2.5 mg once weekly), and in some cases, can even be fatal.

A recent study showed that adalimumab did not worsen renal function or have other serious adverse events in patients with RA and renal insufficiency, including patients with endstage renal disease who were undergoing hemodialysis (Sumida K, et al. Arthritis Care Res [Hoboken]. 2013;65: 471-475).

In the study, 65 patients with RA (in cluding 2 patients who were undergoing hemodialysis) were treated with adalimumab 40 mg subcutaneously every other week in the Nephrology Center of Toranomon Hospital in Toyko, Japan, from December

2008 to June 2011. The 2 patients who were undergo

ing hemodialysis received adalimumab on nonhemodialysis days. The patients’ renal function was evaluated using the estimated glomerular filtration rate (eGFR). Changes in eGFR were compared between patients with renal insufficiency (N = 39) and patients without renal insufficiency (N = 26). Renal insufficiency was defined as an eGFR of <60 mL/minute/1.73 m2.

No significant differences were found between the 2 groups in the proportion of patients who discontinued or who changed adalimumab treatment (51.3% vs 50%; P = .53). The mean changes in eGFR between the patients with renal insufficiency and the patients without renal insufficiency were not significant (P = .92 and P = .78, respectively).

These results indicate that adalimumab does not adversely affect renal function or cause serious adverse events in patients with RA who have renal insufficiency, including patients who are undergoing hemodialysis. n

Early Use of TNF Inhibitors Is Beneficial in Ankylosing Spondylitis By Rosemary Frei, MSc

“This is the first time that anybody has been able to show conclusively that damage progression in ankylosing spondylitis can be prevented by using TNF inhibitors....Considering the cost of the medications, the decision to start these medications and how to continue

them should be based on proper guidelines and the response observed.”

—Nigil Haroon, MD, PhD, DM, FACR

CALL FOR PAPERS

American Health & Drug Benefits offers an open forum for all healthcare participants to exchangeideas and present their data, innovations, and initiatives to facilitate patient-centered healthcare and benefit designmodels that meet the needs of all stakeholders—Distributors, Employers, Manufacturers, Patients, Payers,Providers, Purchasers, Regulators, and Researchers.

Readers are invited to submit articles that aim at improving the quality of patient care and patient well-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.comFor more information, call 732-992-1892 or e-mail [email protected]

Areas of High Interest Include:

• Adherence Concerns

• Benefit Design

• Case Studies

• Comorbidities and Cost Issues

• Comparative Effectiveness Research

• Cost Analyses

• Decision-Making Tools

• Ethics in Medicine

• Health Economics Research

• Health Plan Initiatives

• Health Information Technology

• Industry Trends

• Innovations in Healthcare

• Literature Reviews

• Medicare/Medicaid

• Patient Advocacy/Patient Care

• Pharmacoeconomics

• Policy Issues

• Prevention Initiatives

• Reimbursement Strategies

• Social Media and Health

• Survey Results

• Value-Based Healthcare

• Wellness Programs

Trends in Biologic Therapies for RA

91

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

Vol 5, No 2 l March/April 2012

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

Value has been defined as the relationship between

benefits and costs.

Using mathematical concepts,

value has been described as “value = benefits/cost” o

r

the units of benefit d

erived from a given number of

units of costs. A

pplying this definition, if we wish to

maximize the value of a therapy, there are only 2 ways

to achieve it: either by increasing the benefits

obtained from the therapy, or by decreasing the cost

paid for that therapy.

Value in healthcare is also a function of perspective.

What may be considered valuable to an individual

patient undergoing treatment or to a physician pre-

scribing that treatment to a sim

ilar group of patients

may not necessarily be considered valuable to the same

extent by a payer, who must not only pay for that indi-

vidual’s treatment but who also has to manage the

needs of multiple groups of patients and/or members

with equally compelling medical conditions and prior-

ities. Optimizing value within the healthcare system

means that physicians and payers must be aligned in

the way they view the various benefits and costs o

f a

given treatment.

Achieving such optimization is where the article by

Ms Greenapple in this issue of America

n Health & Drug

Benefitsfits in. In her article, Ms Greenapple shows

that providers and payers, at least when it comes to the

use of biologics for the treatment of rheumatoid arthri-

tis, have much more in common than not when look-

ing at value within this drug class. The findings fro

m

this survey have several important implications to

providers, payers, and patients/plan members.

PROVIDERS: Providers can practice more

autonomously in addressing the needs of the patient

with rheumatoid arthritis. They can do this by follow-

ing evidence-based guidelines as they initiate treat-

ment with disease-modifying antirheumatic drugs, and

only progress to more costly biologic therapies when

they need to improve treatment benefits, thereby opti-

mizing the value of treatment. Such staged manage-

ment is aligned with payer coverage policies.

PAYERS: For payers, this iss

ue is a matter of expec-

tation. Knowing that providers practice using the same

specialty guidelines that payers follow will allow payers

to expect that their contracted providers will “do the

right thing” when it comes to promoting evidence-

based medicine when treating patients with rheuma-

toid arthritis.

PATIENTS/PLAN MEMBERS: When provider

practice is aligned with plan policy, patients or plan

members are the ultimate winners. As is d

escribed in

this article, with 84% of providers reporting approval

rates of at least 61% of requests for rheumatoid arthritis

biologics (and 55% reporting approvals of at least 81%

of such requests), patients who need more intensive

treatment for their arthritis can receive it in

a more

timely and coordinated manner.

MEDICAL DIRECTORS: Does this mean that

payers should stop enforcing step therapies or other

such strategies? Regretfully, n

ot yet; complete buy-in

to evidence-based medicine has not yet been

achieved, and we continue to see treatment irregular-

ities for certain disease states. Perhaps one day soon,

with the advancement of meaningful use parameters

by providers, along with electronic medical records

and decision support systems promoting evidence-

based medicine, we will be able to get there. After all,

reaching such a goal for rheumatoid arthritis, or any

other significant condition, would not only be

admirable, but more important, it would provide great

value in healthcare.

Albert Tzeel,

MD, MHSA, FACPE

National Medical Director, HumanaOne

Milwaukee, WI

STAKEHOLDER PERSPECTIVE

Continued

BUSINESS

83

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

Vol 5, No 2 l March/April 2012

R heumatoid arthritis (RA) is a chronic systemic

autoimmune disorder and the most common form

of inflammatory arthritis. 1 RA affects 1% of the

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

Recent epidemiologic data indicate that the incidence of

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

affects many individuals who are of working age and

remains a major cause of disability, the economic burden

of RA adds a significant cost not only to patients and

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

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

and substantial healthcare utilization are factors that

must be considered in RA management.4,5

Because complications of RA may begin to develop

within months of disease onset, early and aggressive

treatment is considered clinically necessary to manage

immediate symptoms of pain associated with inflamma-

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

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

Ms Greenapple is President, Reimbursement Intelligence,

LLC, Madison, NJ.

Trends in Biologic Therapies 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

AHDB Call to Papers_2012_AHDB Call to Papers 4/17/12 12:32 PM Page 1

Contact us at [email protected] for subscription rates and information on how to subscribe, or call us at 973.805.2300.

Featuring

2 Shunpike Road, 3rd Floor, Madison, NJ 07940 p: 973.805.2300 e: [email protected] www.reimbursementintelligence.com

Subscribe today to the essential roadmap to navigating reimbursement in one of today’s most challenging and competitive markets

Updated a minimum of six times per year

Based on ongoing parallel surveys of 100 rheumatologists and 50 managed care decision makers

Delivers concise and insightful commentary focused on implications for current and emerging immunology brands

Subscribers receive:

1. The 2012 Rheumatology Reimbursement Report

2. Quarterly updates on key topics including biosimilars, manufacturer and sales force reimbursement effectiveness, and rheumatology practice and specialty pharmacy trends – topics tailored to meet subscribers’ key interests and strategic issues

3. Updates throughout the year driven by market and competitive events

Premium subscribers also have access to customized, fast-turnaround research with members of the Reimbursement Intelligence Network, our panel of leading managed care decision makers

The Rheumatology Insights Service

vbcr april vol 2, no 2

Documents