VBCR Dec 2013

december 2013 VOL 2 • NO 6

www.ValueBasedRheumatology.com

Triple Therapy or Biologics as Preferred Treatment for RA? ACR 2013 “Great Debate”

By Wayne Kuznar

Ronald van Vollenhoven

Professor of Medicine and Chief, Division of Rheumatology and Immunology, University of Nebraska Medical Center, Omaha. The 3 components

Continued on page 8

2013 Select Top Studies with Significant Implications for Patient Management

By Alice Goodman San Diego, CA—It was a Herculean task to review 2900 abstracts from the 2013 American College of Rheumatology (ACR) annual meeting to select the studies most likely to impact clinical practice, but Arthur F. Kava­naugh,

By Phoebe Starr

Laura C. Coates

San Diego, CA—Using a “treat-to-target” strategy (ie, tight control) was superior to the standard approach in reducing disease activity in the skin and joints of patients with newly diagnosed psoriatic arthritis in the randomized Tight Control of Psoriatic Arthritis (TICOPA) trial. Treat to target has been successful in controlling

James R. O’Dell

San Diego, CA—The most appropriate choice to treat rheumatoid arthritis (RA) should incorporate value into the decision, said James R. O’Dell, MD,

“Treat to Target” Superior to Standard Care for Patients with Psoriatic Arthritis

MD, Director, Center for In­novative Therapy, University of California, San Diego, and John J. Cush, MD, Director of Clinical Rheumatology, Baylor Research Institute, Dallas, TX, took up the challenge. Following are some Continued on page 9

Continued on page 21

Selective JAK3 Inhibitor Improves the Symptoms of Rheumatoid Arthritis Impressive response rates seen with VX-509

By Wayne Kuznar San Diego, CA—An investigational oral selective Janus kinase (JAK) 3 inhibitor was superior to placebo in response rate and changes in disease activity in an ongoing phase 2b study in patients with rheumatoid arthritis (RA).

Twelve-week results from the 24week study were reported by Mark C. Genovese, MD, Professor of Medicine, Immunology and Rheumatology, Stan-

ford University, Palo Alto, CA, at the 2013 American College of Rheumatology (ACR) meeting.

The study compared VX-509, a selective inhibitor of JAK3, with placebo in a double-blind fashion in 358 patients with RA who had active disease despite treatment with methotrexate. Patients were randomized to placebo or to 1 of 4 doses of VX-509 (100 mg once daily, 150 mg once daily, Continued on page 13

inside VALUE PROPOSITIONS. . . . . . . . . . .

A new model for value-based physician reimbursement FDA UPDATE. . . . . . . . . . . . . . . . . . . . . .

Otrexup, first subcutaneous methotrexate approved RHEUMATOLOGY UPDATE . . .

Apremilast clears ulcers in Behçet’s disease LUPUS . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Challenges in lupus management HEALTH ECONOMICS. . . . . . . . . .

Allopurinol a cost-saving uratelowering therapy for gout

© 2013 Engage Healthcare Communications, LLC

disease activity in patients with rheumatoid arthritis, and TICOPA provides evidence in support of this approach in psoriatic arthritis.

“Treating to a specific objective target [tight control] has as its goal excellent disease control. Aiming for this high bar improved outcomes for patients with psoriatic arthritis in TICOPA, the

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10 11 12

RHEUMATOID ARTHRITIS. . . . 14 Triple therapy superior to monotherapy methotrexate, cost-effective PSORIATIC ARTHRITIS. . . . . . . . 21 Ustekinumab slows joint destruction in active disease Personalized Medicine in Rheumatology™ . . . . . . . . . . . . . . . . . .

Osteoarthritis biomarkers fraught with challenges

IN THE LITERATURE . . . . . . . . . .

Survey reveals rheumatologists’ ethical concerns DRUG UPDATE. . . . . . . . . . . . . . . . . .

Stelara for active psoriatic arthritis

22 23 25

Join Our Editorial Advisory Board 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 international 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 Statement Value-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.

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In This Issue

Publishing Staff Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Director, Client Services Zach Ceretelle zceretelle@the-lynx-group.com Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Senior Production Manager Lynn Hamilton Production Manager Melissa Lawlor The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Director, Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean Digital Programmer Michael Amundsen Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen

VALUE PROPOSITIONS

RHEUMATOID ARTHRITIS

A new model for value-based physician reimbursement More…

RA-related joint surgery declines in the era of biologics More…

FDA UPDATE

PSORIATIC ARTHRITIS

Otrexup, first subcutaneous methotrexate approved

Ustekinumab slows joint destruction in active psoriatic arthritis More…

RHEUMATOLOGY UPDATE Rituximab effective for IgG4-related disorders More…

LUPUs Challenges in lupus management More…

Potential biomarkers for preeclampsia in pregnant women with lupus More…

HEALTH ECONOMICS

OSTEOARTHRITIS

Comparing of urate-lowering therapies for gout More…

In the article “AMPLE: Head-to-head comparison of adalimumab and abatacept shows similar efficacy, safety,” in VBCR, August 2013, page 9, the first sentence was wrong. This study was a comparison of 2 biologics, not 2 anti-TNF agents (abatacept is not a TNF inhibitor).

We regret the error.

Stelara receives new indication for active psoriatic arthritis

James T. Kenney, Jr, RPh, MBA

Lynn Nishida, RPh

Scott Breidbart, MD

Muhammad Asim Khan, MD

Gary M. Owens, MD

Gary R. Feldman, MD, FACR

John Kolstoe, MD Kolstoe Rheumatology: Musculoskeletal Medicine East Lansing, MI Assistant Clinical Professor of Medicine Michigan State University

Rheumatology Associates of Long Island Smithtown, NY Chief Medical Officer Empire BlueCross BlueShield New York, NY Private Practice, Pacific Rheumatology, Los Angeles, CA Gary L. Johnson, MD, MS, MBA

Regional Medical Director Humana, Inc., Madison, WI

Shelly P. Kafka, MD, FACR

NO. 6

DRUG UPDATE

Howard B. Blumstein, MD

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 Communi­cations, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

I

Survey reveals ethical concerns of rheumatologists Long-term golimumab beneficial in RA

VBCR Editorial Advisory Board

Atheer A. Kaddis, PharmD

VOL. 2

Regular physical activity in osteoarthritis can improve health, save money

IN THE LITERATURE

Correction

Engage Healthcare Communications, LLC 1249 South River Road, Ste 202A Cranbury, NJ 08512 Telephone: 732-992-1882 Fax: 732-992-1881

The ideas and opinions expressed in Value-Based Care in Rheumatology do not necessarily reflect those of the editorial board, the editors, or the publisher.

Publication of an advertisement or other product mentioned in Value-Based Care in Rheumatology should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned.

Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

Personalized Medicine in Rheumatology™

Vice President, Managed Markets Diplomat Specialty Pharmacy Swartz Creek, MI Rheumatologist, Mountain State Rheumatology, Medical Director, Mountain State Clinical Research, Clarksburg, WV Clinical Assistant Professor West Virginia University School of Medicine, Morgantown, WV

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

Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA

Professor of Medicine Case Western Reserve University Cleveland, OH

Randall Krakauer, MD, FACP, FACR

National Medical Director Medicare, Aetna, Princeton, NJ

Kim A. Papp, MD, PhD

Founder and President Probity Medical Research Waterloo, Ontario, Canada Jeffrey S. Peller, MD

Practicing Rheumatologist Harbin Clinic/Rheumatology Rome, GA Edmund J. Pezalla, MD, MPH

Joel M. Kremer, MD

Pfaff Family Professor of Medicine Albany Medical College Director of Research, Center for Rheumatology, Albany, NY Alan Menter, MD

Director, Baylor Psoriasis Research Center, Dallas, TX Matthew Mitchell, PharmD, MBA

Manager, Pharmacy Services SelectHealth, Murray, UT

President, Gary Owens Associates Philadelphia, PA

National Medical Director for Pharmacy Policy and Strategy Aetna, Hartford, CT

Ronald van Vollenhoven, MD, PhD

Associate Professor Karlinska University Hospital Solna Stockholm, Sweden F. Randy Vogenberg, RPh, PhD

Principal, Institute of Integrated Healthcare, Greenville, SC

Mission Statement

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

Contact Information: For subscription information please contact: Telephone: 732-992-1880 Fax: 732-992-1881.

Permission requests to reprint all or part of any article published in this publication should be addressed to editorial@engagehc.com.

Address all editorial queries to: editorial@engagehc.com. 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.

december 2013

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www.ValueBasedRheumatology.com

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Value Propositions New Hepatitis C Therapy Can Help Some Patients with Rheumatic Disease

The US Food and Drug Administration (FDA) approved oral sofosbuvir (Sovaldi; Gilead) in a once-daily dosing for the treatment of chronic hepatitis C virus (HCV) infection. This is the first treatment for HCV infection that can be used without concomitant interferon injection, which could lead to severe flulike symptoms. This is also the first FDA-approved treatment for HCV infection that can be used by patients whose rheumatic disease prevents them from using interferon. Sofosbuvir is a nucleotide analog inhibitor that was designated by the FDA as a “breakthrough therapy,” which allows for a rapid approval process. The drug can be used in combination with interferon and with ribavirin, depending on the HCV infection genotype. For patients with genotype 2 and 3, it can be used with ribavirin, without interferon. Gilead Sciences, Inc; December 6, 2013

A New Model for Value-Based Physician Reimbursement

Value-based care is becoming central to the attempt to reform the US healthcare delivery system and patient care. The model of physician payment using relative-value units (RVUs) was developed a few decades ago to provide a uniform formula to pay for medical services. With the enhanced focus on value-based care, Eric C. Stecker, MD, and Steven A. Schroeder, MD, have recently suggested that “creating a new RVU-based system that incorporates value considerations has important advantages over pay-for-performance programs, salaries that are not tied to incentives, and physician-level capitation.”

They add that RVU-based physician measures “are proven, potent, and efficient motivators of physician behavior. Simple fixes to promote value could rapidly align physicians’ practice patterns with other elements of a value-focused health care system. Value-based RVUs could thereby serve as a bridge for physicians in the transition away from feefor-service payments, promote important primary care services, and improve the integration of specialty care into new delivery models. A reformed RVU system could remain central beyond fee for service, since methods such as global and bundled payments do not account for or direct the distribution of physicians’ work efforts within health systems.”

N Engl J Med. 2013;369:2176-2179

Physicians’ Role in Payment Reform

American physicians in different specialties are taking the initiative in testing new payment and delivery models. Several of these groups described their efforts at a recent forum on physician payment reform that was held by the Brookings Institution in November 2013. The current fee-for-service model is fraught with problems for physicians, from a payment and a quality-of-care perspective, which is presenting obstacles

in creating new payment and care delivery models, said Harold D. Miller, President and CEO of the Center for Healthcare Quality and Payment Reform, during the Brookings Institute forum.

Mr Miller discussed new payment models for physician reimbursement that would offset the new Medicare cuts to physician reimbursement that will take effect in January 2014. If these new models were implemented, he said, “they would more than pay for the offsets of $150 billion over 10 years needed to pay for the SGR [sustainable growth rate].” He added that physicians need support to bring about a new payment system. Healthcare Finance News; November 25, 2013

Efficacy of Hyaluronic Acid Injections Similar to NSAIDs for Knee OA

Results of a new meta-analysis of 5 randomized controlled studies show that intra-articular hyaluronic acid (IAHA) may be an appropriate alternative to nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of patients with knee osteoarthritis (OA), especially in patients who are at an increased risk for NSAID-related adverse reactions. The results showed no significant differences between IAHA and ongoing use of oral NSAIDs in relief of pain and stiffness, as well as in improved physical function among patients with knee OA at weeks 4 and 12. The most common adverse event of IAHA was injection-site pain. As can be expected, serious gastrointestinal (GI) events, such as drug-related GI bleeding, were more common with NSAIDs compared with IAHA injection. Overall, the investigators reported that “IAHA is not significantly different from continuous oral NSAIDs at 4 and 12 weeks.” Bannuru RR, et al. Semin Arthritis Rheum. 14 October, 2013; Epub ahead of print

Mayo Clinic Moving from FFS to Value-Based Care

Administrators at the Mayo Clinic are working to “bend the cost curve” and optimize resource utilization efficiency, according to Kari Bunkers, MD, Chief Medical Information Officer, Mayo Clinic Health System, and Medical Director, Mayo Clinic Office of Population Health Management.

The goal is to transform their community and regional practices from feefor-service (FFS) care to value-based care within the next 2 or 3 years.

Mayo Clinic providers are now focusing on a data-driven, team-based approach to coordinate care based on each patient’s unique needs.

Mayo Clinic has identified 10 key components related to value-based care, including prevention, community engagement, wellness, teambased care, patient engagement, access optimization, care coordination, smooth care transitions, and effective chronic disease management and palliative care. “We are determined to deliver better-coordinated care for patients, with a better overall experience through engaging them in ways that work for them, and by focusing on health, wellness, and outcomes,” said Dr Bunkers. 2013 AMGA Institute for Quality Leadership Conference; September 25-27, 2013

FDA Update FDA Approves Otrexup, First Subcutaneous Formulation of Methotrexate

The US Food and Drug Administration (FDA) approved a subcutaneous delivery formulation of methotrex­ ate (Otrexup; Antares Pharma) for once-weekly self-administration of the drug, with an easy-to-use, single-dose, disposable auto injector.

This new subcutaneous formulation is indicated for adults with severe active rheumatoid arthritis (RA) whose disease has an inadequate response to or who are intolerant of an adequate

4

trial of first-line therapy for RA, includ­ ing nonsteroidal anti-inflammatory agents, as well as for children with active polyarticular juvenile idiopathic arthritis (pJIA). The FDA also approved Otrexup for adults for the symptomatic control of severe recalcitrant and disabling psoriasis that is not adequately responsive to other forms of therapy.

Methotrexate is already available as an oral treatment for these same indications and is used by many patients with RA and pJIA. “This new delivery system for meth-

value-based CARE in Rheumatology

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December 2013

otrexate provides a welcome option for physicians and their patients to continue effective use of methotrexate. Otrexup can be used when a response is inadequate or there are tolerability issues with oral methotrexate, before adding or switching to costlier therapies,” said Michael H. Schiff, MD, Clinical Professor of Medicine, Rheumatology Division, University of Colorado School of Medicine, Denver. “The availability of an easy and safe way to administer subcutaneous methotrexate may overcome some of the current barriers to parenteral ad-

ministration which could enable more patients to realize the possibility of continued disease control and therefore benefit from subcutaneous methotrexate.”

The clinical data submitted to the FDA with the application for approval of the new formulation demonstrate the increased bioavailability of subcutaneous methotrexate compared with the oral formulation at every dose. These results highlight the limitations of oral methotrexate because of its reaching a bioavailability plateau at the 15-mg dose. n VOL. 2

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NO. 6

In the fight against active, autoantibody-positive systemic lupus erythematosus (SLE) in adult patients receiving standard therapy

Add BENLYSTA to Help Make SLE More Manageable When added to standard therapy, BENLYSTA significantly reduced disease activity vs standard therapy alone at Week 521

•

BENLYSTA 10 mg/kg + standard therapy demonstrated superior efficacy vs placebo + standard therapy in reducing disease activity at Week 52 in 2 Phase III trials (Total N=1684)1-3

•

The primary endpoint was the percentage of patients meeting the SLE Responder Index (SRI) at Week 52. The SRI components measure reduction in disease activity defined as clinical improvement (SELENA-SLEDAI*) with no significant worsening in any organ system (BILAG†) and no worsening in overall patient condition (PGA‡)1 – A Phase II trial (Total N=449) did not meet the prespecified co-primary endpoints of percent change in SELENA-SLEDAI at Week 24 and

time to first flare over 52 weeks. The Phase II trial led to the selection of a targeted autoantibody-positive population in the Phase III trials (28% of the Phase II trial population was autoantibody negative at baseline)4

•

In Phase II and III clinical trials, 1458 patients with SLE have been exposed to BENLYSTA for a total of 1516 patient-years2-5

* SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus: National Assessment Version of the Systemic Lupus Erythematosus Disease Activity Index). † BILAG (British Isles Lupus Assessment Group). ‡ PGA (Physician’s Global Assessment).

Indication BENLYSTA is indicated for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy.

Limitations of Use: The efficacy of BENLYSTA has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus. BENLYSTA has not been studied in combination with other biologics or intravenous cyclophosphamide. Use of BENLYSTA is not recommended in these situations.

How supplied: BENLYSTA is available as 120 mg in a 5-mL single-use vial and 400 mg in a 20-mL single-use vial for injection, for intravenous use only.

Important Safety Information for BENLYSTA CONTRAINDICATION BENLYSTA is contraindicated in patients who have had anaphylaxis with belimumab.

WARNINGS AND PRECAUTIONS MORTALITY There were more deaths reported with BENLYSTA than with placebo during the controlled period of the clinical trials. Out of 2133 patients in 3 clinical trials, a total of 14 deaths occurred in the following groups: 3/675 in placebo, 5/673 in BENLYSTA 1 mg/kg, 0/111 in BENLYSTA 4 mg/kg, and 6/674 in BENLYSTA 10 mg/kg. No single cause of death predominated. Etiologies included infection, cardiovascular disease, and suicide.

SERIOUS INFECTIONS Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including BENLYSTA. Caution should be exercised when considering use in patients with a history of chronic infections. Patients receiving therapy for a chronic infection should not receive BENLYSTA. Consider interrupting BENLYSTA therapy in patients who develop a new infection while receiving BENLYSTA. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis.

Please see additional Important Safety Information for BENLYSTA on following page.

Please see Brief Summary of Prescribing Information for BENLYSTA on adjacent pages.

www.GSKSource.com

Important Safety Information for BENLYSTA (cont’d) WARNINGS AND PRECAUTIONS (cont’d) MALIGNANCY The impact of treatment with BENLYSTA on the development of malignancies is not known. As with other immunomodulating agents, the mechanism of action of BENLYSTA could increase the risk of malignancies.

HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS) AND INFUSION REACTIONS Hypersensitivity reactions, including anaphylaxis and death, have been reported with BENLYSTA. Delay in the onset of acute hypersensitivity reactions has been observed. Patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. Some patients received premedication; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of these reactions.

Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely. Manifestations of hypersensitivity included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea. In the event of a serious hypersensitivity reaction, discontinue BENLYSTA immediately and administer appropriate medical therapy. Infusion-associated adverse events were also reported. Serious infusion reactions included bradycardia, myalgia, headache, rash, urticaria, and hypotension.

In the event of an infusion reaction, the infusion rate may be slowed or interrupted.

Patients should be informed of the signs and symptoms of a hypersensitivity reaction and instructed to seek immediate medical care should a reaction occur.

DEPRESSION In clinical trials, psychiatric events (primarily depression, insomnia, and anxiety) were reported more frequently with BENLYSTA than with placebo. Serious psychiatric events, serious depression, and two suicides were also reported. It is unknown if BENLYSTA treatment is associated with increased risk for these events. Instruct patients to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other mood changes.

IMMUNIZATION Live vaccines should not be given for 30 days before or concurrently with BENLYSTA. BENLYSTA may interfere with the response to immunizations.

USE WITH BIOLOGIC THERAPIES OR IV CYCLOPHOSPHAMIDE BENLYSTA has not been studied in combination with other biologic therapies, including B-cell targeted therapies, or IV cyclophosphamide.

Therefore, use of BENLYSTA is not recommended in combination with these therapies.

ADVERSE REACTIONS The most commonly reported adverse reactions (≥5%) were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, and pharyngitis.

Other Important Information for BENLYSTA USE IN SPECIFIC POPULATIONS Pregnancy: Category C. BENLYSTA should be used during pregnancy only if the potential benefit outweighs the risk. Women of childbearing potential should use adequate contraception during BENLYSTA treatment and for at least 4 months after the last dose.

Pregnancy Registry: Healthcare professionals are encouraged to register patients and pregnant women are encouraged to enroll themselves by calling 1-877-681-6296.

Effect in black/African American patients: In exploratory analyses of 2 Phase III trials, response rates were lower for black patients (N=148) in the BENLYSTA group relative to black patients in the placebo group. In the Phase II trial, black patients (N=106) in the BENLYSTA group did not appear to have a different response than the rest of the study population. Although no definitive conclusions can be drawn from these analyses, caution should be used when considering BENLYSTA for black/African American patients.

References: 1. BENLYSTA [package insert]. Rockville, MD: Human Genome Sciences, Inc; 2012. 2. Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9767):721-731. 3. Furie R, Petri M, Zamani O, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011;63(12):3918-3930. 4. Wallace DJ, Stohl W, Furie RA, et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum. 2009;61(9):1168-1178. 5. Data on file, Human Genome Sciences, Inc.

Please see Brief Summary of Prescribing Information for BENLYSTA on adjacent page.

©2013 GlaxoSmithKline group of companies.

All rights reserved. Printed in USA. BN2410R1 August 2013

BRIEF SUMMARY BENLYSTA® (belimumab) for injection, for intravenous use only.

The following is a brief summary only; see full Prescribing Information for complete product information.

INDICATIONS AND USAGE BENLYSTA® (belimumab) is indicated for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy.

Limitations of Use The efficacy of BENLYSTA has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus. BENLYSTA has not been studied in combination with other biologics or intravenous cyclophosphamide. Use of BENLYSTA is not recommended in these situations.

CONTRAINDICATIONS BENLYSTA is contraindicated in patients who have had anaphylaxis with belimumab.

WARNINGS AND PRECAUTIONS Mortality There were more deaths reported with BENLYSTA than with placebo during the controlled period of the clinical trials. Out of 2133 patients in 3 clinical trials, a total of 14 deaths occurred during the placebo-controlled, double-blind treatment periods: 3/675 (0.4%), 5/673 (0.7%), 0/111 (0%), and 6/674 (0.9%) deaths in the placebo, BENLYSTA 1 mg/kg, BENLYSTA 4 mg/kg, and BENLYSTA 10 mg/kg groups, respectively. No single cause of death predominated. Etiologies included infection, cardiovascular disease and suicide.

Serious Infections Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including BENLYSTA. Physicians should exercise caution when considering the use of BENLYSTA in patients with chronic infections. Patients receiving any therapy for chronic infection should not begin therapy with BENLYSTA. Consider interrupting BENLYSTA therapy in patients who develop a new infection while undergoing treatment with BENLYSTA and monitor these patients closely.

In the controlled clinical trials, the overall incidence of infections was 71% in patients treated with BENLYSTA compared with 67% in patients who received placebo. The most frequent infections (>5% of patients receiving BENLYSTA) were upper respiratory tract infection, urinary tract infection, nasopharyngitis, sinusitis, bronchitis, and influenza. Serious infections occurred in 6.0% of patients treated with BENLYSTA and in 5.2% of patients who received placebo. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis. Infections leading to discontinuation of treatment occurred in 0.7% of patients receiving BENLYSTA and 1.0% of patients receiving placebo. Infections resulting in death occurred in 0.3% (4/1458) of patients treated with BENLYSTA and in 0.1% (1/675) of patients receiving placebo.

Malignancy The impact of treatment with BENLYSTA on the development of malignancies is not known. In the controlled clinical trials, malignancies (including non-melanoma skin cancers) were reported in 0.4% of patients receiving BENLYSTA and 0.4% of patients receiving placebo. In the controlled clinical trials, malignancies, excluding non-melanoma skin cancers, were observed in 0.2% (3/1458) and 0.3% (2/675) of patients receiving BENLYSTA and placebo, respectively. As with other immunomodulating agents, the mechanism of action of BENLYSTA could increase the risk for the development of malignancies.

Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions, including anaphylaxis and death, have been reported in association with BENLYSTA. Delay in the onset of acute hypersensitivity reactions has been observed. Limited data suggest that patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. In the controlled clinical trials, hypersensitivity reactions (occurring on the same day of infusion) were reported in 13% (191/1458) of patients receiving BENLYSTA and 11% (76/675) of patients receiving placebo. Anaphylaxis was observed in 0.6% (9/1458) of patients receiving BENLYSTA and 0.4% (3/675) of patients receiving placebo. Manifestations included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see Warnings and Precautions]. Some patients (13%) received premedication, which may have mitigated or masked a hypersensitivity response; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of hypersensitivity reactions.

BENLYSTA should be administered by healthcare providers prepared to manage anaphylaxis. In the event of a serious reaction, administration of BENLYSTA must be discontinued immediately and appropriate medical therapy administered. Patients should be monitored during and for an appropriate period of time after administration of BENLYSTA. Patients should be informed of the signs and symptoms of a hypersensitivity reaction and instructed to seek immediate medical care should a reaction occur.

Infusion Reactions In the controlled clinical trials, adverse events associated with the infusion (occurring on the same day of the infusion) were reported in 17% (251/1458) of patients receiving BENLYSTA and 15% (99/675) of patients receiving placebo. Serious infusion reactions (excluding hypersensitivity reactions) were reported in 0.5% of patients receiving BENLYSTA and 0.4% of patients receiving placebo and included bradycardia, myalgia, headache, rash, urticaria, and hypotension. The most common infusion reactions (≥ 3% of patients receiving BENLYSTA) were headache, nausea, and skin reactions. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see Warnings and Precautions]. Some patients (13%) received premedication, which may have mitigated or masked an infusion reaction; however there is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion reactions [see Adverse Reactions].

BENLYSTA should be administered by healthcare providers prepared to manage infusion reactions. The infusion rate may be slowed or interrupted if the patient develops an infusion reaction. Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely.

Depression In the controlled clinical trials, psychiatric events were reported more frequently with BENLYSTA (16%) than with placebo (12%), related primarily to depression-related events (6.3% BENLYSTA and 4.7% placebo), insomnia (6.0% BENLYSTA and 5.3% placebo), and anxiety (3.9% BENLYSTA and 2.8% placebo). Serious psychiatric events were reported in 0.8% of patients receiving BENLYSTA (0.6% and 1.2% with 1 and 10 mg/kg, respectively) and 0.4% of patients receiving placebo. Serious depression was reported in 0.4% (6/1458) of

patients receiving BENLYSTA and 0.1% (1/675) of patients receiving placebo. Two suicides (0.1%) were reported in patients receiving BENLYSTA. The majority of patients who reported serious depression or suicidal behavior had a history of depression or other serious psychiatric disorders and most were receiving psychoactive medications. It is unknown if BENLYSTA treatment is associated with increased risk for these events.

Patients receiving BENLYSTA should be instructed to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other mood changes.

Immunization Live vaccines should not be given for 30 days before or concurrently with BENLYSTA as clinical safety has not been established.

No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving BENLYSTA or the effect of BENLYSTA on new immunizations. Because of its mechanism of action, BENLYSTA may interfere with the response to immunizations.

Concomitant Use with Other Biologic Therapies or Intravenous Cyclophosphamide BENLYSTA has not been studied in combination with other biologic therapies, including B-cell targeted therapies, or intravenous cyclophosphamide. Therefore, use of BENLYSTA is not recommended in combination with biologic therapies or intravenous cyclophosphamide.

ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials Experience The data described below reflect exposure to BENLYSTA plus standard of care compared with placebo plus standard of care in 2133 patients in 3 controlled studies. Patients received BENLYSTA at doses of 1 mg/kg (N=673), 4 mg/kg (N=111; Trial 1 only), or 10 mg/kg (N=674) or placebo (N=675) intravenously over a 1-hour period on Days 0, 14, 28, and then every 28 days. In two of the studies (Trial 1 and Trial 3), treatment was given for 48 weeks, while in the other study (Trial 2) treatment was given for 72 weeks [see Clinical Studies]. Because there was no apparent dose-related increase in the majority of adverse events observed with BENLYSTA, the safety data summarized below are presented for the 3 doses pooled, unless otherwise indicated; the adverse reaction table displays the results for the recommended dose of 10 mg/kg compared with placebo.

The population had a mean age of 39 (range 18-75), 94% were female, and 52% were Caucasian. In these trials, 93% of patients treated with BENLYSTA reported an adverse reaction compared with 92% treated with placebo.

The most common serious adverse reactions were serious infections (6.0% and 5.2% in the groups receiving BENLYSTA and placebo, respectively) [see Warnings and Precautions].

The most commonly-reported adverse reactions, occurring in ≥5% of patients in clinical trials were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, and pharyngitis.

The proportion of patients who discontinued treatment due to any adverse reaction during the controlled clinical trials was 6.2% for patients receiving BENLYSTA and 7.1% for patients receiving placebo.

The most common adverse reactions resulting in discontinuation of treatment (≥1% of patients receiving BENLYSTA or placebo) were infusion reactions (1.6% BENLYSTA and 0.9% placebo), lupus nephritis (0.7% BENLYSTA and 1.2% placebo), and infections (0.7% BENLYSTA and 1.0% placebo).

Table 1 lists adverse reactions, regardless of causality, occurring in at least 3% of patients with SLE who received BENLYSTA 10 mg/kg and at an incidence at least 1% greater than that observed with placebo in the 3 controlled studies.

Table 1. Incidence of Adverse Reactions Occurring in at Least 3% of Patients Treated With BENLYSTA 10 mg/kg Plus Standard of Care and at Least 1% More Frequently Than in Patients Receiving Placebo plus Standard of Care in 3 Controlled SLE Studies BENLYSTA 10 mg/kg Placebo + Standard of Care + Standard of Care (n = 674) (n = 675) Preferred Term % % 12 Nausea 15 Diarrhea 12 9 Pyrexia 10 8 Nasopharyngitis 9 7 Bronchitis 9 5 Insomnia 7 5 6 4 Pain in extremity Depression 5 4 4 Migraine 5 Pharyngitis 5 3 Cystitis 4 3 Leukopenia 4 2 Gastroenteritis viral 3 1 Immunogenicity In Trials 2 and 3, anti-belimumab antibodies were detected in 4 of 563 (0.7%) patients receiving BENLYSTA 10 mg/kg and in 27 of 559 (4.8%) patients receiving BENLYSTA 1 mg/kg. The reported frequency for the group receiving 10 mg/kg may underestimate the actual frequency due to lower assay sensitivity in the presence of high drug concentrations. Neutralizing antibodies were detected in 3 patients receiving BENLYSTA 1 mg/kg. Three patients with anti-belimumab antibodies experienced mild infusion reactions of nausea, erythematous rash, pruritus, eyelid edema, headache, and dyspnea; none of the reactions was life-threatening. The clinical relevance of the presence of anti-belimumab antibodies is not known.

The data reflect the percentage of patients whose test results were positive for antibodies to belimumab in specific assays. The observed incidence of antibody positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to belimumab with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS Formal drug interaction studies have not been performed with BENLYSTA. In clinical trials of patients with SLE, BENLYSTA was administered concomitantly with other drugs, including

corticosteroids, antimalarials, immunomodulatory and immunosuppressive agents (including azathioprine, methotrexate, and mycophenolate), angiotensin pathway antihypertensives, HMG-CoA reductase inhibitors (statins), and NSAIDs without evidence of a clinically meaningful effect of these concomitant medications on belimumab pharmacokinetics. The effect of belimumab on the pharmacokinetics of other drugs has not been evaluated [see Pharmacokinetics].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. There are no adequate and well-controlled clinical studies using BENLYSTA in pregnant women.

Immunoglobulin G (IgG) antibodies, including BENLYSTA, can cross the placenta. Because animal reproduction studies are not always predictive of human response, BENLYSTA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Women of childbearing potential should use adequate contraception during treatment with BENLYSTA and for at least 4 months after the final treatment.

Nonclinical reproductive studies have been performed in pregnant cynomolgus monkeys receiving belimumab at doses of 0, 5 and 150 mg/kg by intravenous infusion (the high dose was approximately 9 times the anticipated maximum human exposure) every 2 weeks from gestation day 20 to 150. Belimumab was shown to cross the placenta. Belimumab was not associated with direct or indirect teratogenicity under the conditions tested. Fetal deaths were observed in 14%, 24% and 15% of pregnant females in the 0, 5 and 150 mg/kg groups, respectively. Infant deaths occurred with an incidence of 0%, 8% and 5%. The cause of fetal and infant deaths is not known. The relevance of these findings to humans is not known. Other treatmentrelated findings were limited to the expected reversible reduction of B cells in both dams and infants and reversible reduction of IgM in infant monkeys. B-cell numbers recovered after the cessation of belimumab treatment by about 1 year post-partum in adult monkeys and by 3 months of age in infant monkeys. IgM levels in infants exposed to belimumab in utero recovered by 6 months of age.

Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to BENLYSTA, a pregnancy registry has been established. Healthcare professionals are encouraged to register patients and pregnant women are encouraged to enroll themselves by calling 1-877-681-6296.

Nursing Mothers It is not known whether BENLYSTA is excreted in human milk or absorbed systemically after ingestion. However, belimumab was excreted into the milk of cynomolgus monkeys.

Because maternal antibodies are excreted in human breast milk, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of breastfeeding to the infant and the importance of the drug to the mother.

Pediatric Use Safety and effectiveness of BENLYSTA have not been established in children.

Geriatric Use Clinical studies of BENLYSTA did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Use with caution in elderly patients.

Race In Trial 2 and Trial 3, response rates for the primary endpoint were lower for black subjects in the BENLYSTA group relative to black subjects in the placebo group [see Clinical Studies]. Use with caution in black/African-American patients.

OVERDOSAGE There is no clinical experience with overdosage of BENLYSTA. Two doses of up to 20 mg/kg have been given by intravenous infusion to humans with no increase in incidence or severity of adverse reactions compared with doses of 1, 4, or 10 mg/kg.

PATIENT COUNSELING INFORMATION See Medication Guide.

Advice for the Patient Patients should be given the Medication Guide for BENLYSTA and provided an opportunity to read it prior to each treatment session. It is important that the patient’s overall health be assessed at each infusion visit and any questions resulting from the patient’s reading of the Medication Guide be discussed.

Mortality: Patients should be advised that more patients receiving BENLYSTA in the main clinical trials died than did patients receiving placebo treatment [see Warnings and Precautions].

Serious Infections: Patients should be advised that BENLYSTA may decrease their ability to fight infections. Patients should be asked if they have a history of chronic infections and if they are currently on any therapy for an infection [see Warnings and Precautions]. Patients should be instructed to tell their healthcare provider if they develop signs or symptoms of an infection.

Hypersensitivity/Anaphylactic and Infusion Reactions: Educate patients on the signs and symptoms of anaphylaxis, including wheezing, difficulty breathing, peri-oral or lingual edema, and rash. Patients should be instructed to immediately tell their healthcare provider if they experience symptoms of an allergic reaction during or after the administration of BENLYSTA [see Warnings and Precautions].

Depression: Patients should be instructed to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts or other mood changes [see Warnings and Precautions].

Immunizations: Patients should be informed that they should not receive live vaccines while taking BENLYSTA. Response to vaccinations could be impaired by BENLYSTA [see Warnings and Precautions].

Pregnancy and Nursing Mothers: Patients should be informed that BENLYSTA has not been studied in pregnant women or nursing mothers so the effects of BENLYSTA on pregnant women or nursing infants are not known. Patients should be instructed to tell their healthcare provider if they are pregnant, become pregnant, or are thinking about becoming pregnant [see Use in Specific Populations].

Patients should be instructed to tell their healthcare provider if they plan to breastfeed their infant [see Use in Specific Populations].

BENLYSTA is a registered trademark of Human Genome Sciences, Inc., used under license by GlaxoSmithKline.

Manufactured by: Human Genome Sciences, Inc. Rockville, Maryland 20850 U.S. License No. 1820 Marketed by:

Human Genome Sciences, Inc. Rockville, MD 20850

GlaxoSmithKline Research Triangle Park, NC 27709

Controversies in Rheumatology

Triple Therapy or Biologics as Preferred Treatment for RA?... to value are efficacy, toxicity, and cost, and in this regard, triple disease-modifying antirheumatic drug (DMARD) therapy beats treatment with a bio­ logic response modifier, argued Dr O’Dell in a debate conducted at the 2013 American College of Rheumatology (ACR) annual meeting.

His opponent, Ronald van Vollenhoven, MD, PhD, Professor and Head, Unit for Clinical Therapy Research, Inflammatory Diseases, Karolinska Institutet, Stockholm, Sweden, countered that biologic agents have revolutionized the treatment of patients with RA and are clearly the more effective choice when used with methotrexate.

“Although triple DMARD therapy and biologics are both effective strategies, conventional therapy is far more cost-effective.”

—James R. O’Dell, MD

O’Dell: If You Treat to Target, Triple Therapy Is Just as Good...

Emphasizing a treat-to-target strategy, “conventional DMARD therapy should be started before biologics as initial treatment for RA, and conventional DMARDs should be combined with existing methotrexate before biologics are added,” said Dr O’Dell.

Major studies during the past decade in support of DMARDs are TEAR, RACAT, BeST, Swefot, and TICORA. As initial therapy, improvements in disease activity were at least as good with triple DMARD therapy as with a biologic, and at 2 years in the BeST study, less than 15% of patients who were started on conventional DMARD therapy required a step up to a biologic. In an observational study conducted in 2 Nordic hospitals (Sokka T, et al. Clin Exp Rheumatol. 2013;31:409-414), remission/low disease activity was achieved numerically (but not signifi-

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cantly) more often at hospitals that used conventional antirheumatic drugs compared with biologic drugs as a treatment strategy, while drug costs were half with conventional DMARDs. TEAR (Moreland LW, et al. Arthritis Rheum. 2012;64:2824-2835) was conducted in patients with poor prognosis, a group often selected for biologics; but even in this trial, disease activity scores were identical between triple therapy and biologic strategies by 36 weeks and onward.

“If patients with new-onset RA are treated with strategies that start with conventional DMARD combinations, they have equivalent outcomes to strategies that employ early biologics,” said Dr O’Dell. “And a lot of money is saved,” a point he would hammer home later in the debate. …Even After Methotrexate Failure In examining the best strategy after methotrexate failure, Dr O’Dell cited his own study—RACAT—published earlier this year (O’Dell JR, et al. N Engl J Med. 2013;369:307-318). In the RACAT study, triple DMARD therapy was noninferior to etanercept plus methotrexate on the end point of disease activity in patients with RA who had active disease despite methotrexate therapy. He also pointed to the Swefot trial (van Vollenhoven RF, et al. Lancet. 2012;379:1712-1720), in which the investigators concluded that there was no convincing clinical difference at 2 years between adding DMARDs or biologics after initial methotrexate failure.

“If we treat to target, it doesn’t matter which agents we use,” Dr O’Dell said. van Vollenhoven: More Rapid Response with Biologics, Better Radiographic Outcomes Biologic agents are numerically better than conventional agents on the end point of disease activity, act more quickly than conventional agents, and are significantly superior to conventional agents on radiographic end points, argued Dr van Vollenhoven.

In the Swefot trial, the rate of good responses was better with the addition of infliximab (Remicade) than with the addition of sulfasalazine and hydroxychloroquine after methotrexate failure at 12 months (39% vs 25%) and 24 months (43% vs 31%), although the difference at 24 months failed to achieve significance, because the high number of dropouts left the study underpowered. Radiographic progression was significantly less in the biologic arm at 24 months, said Dr van Vollenhoven.

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cal difference cannot be detected until there is a 22-point difference on the TSS, he insisted.

As initial therapy, “despite small differences in radiographic progression in the first year, there is no clinically important difference [between strategies] in year 2,” Dr O’Dell declared.

“Biologics, as a class, are much better tolerated than conventional agents.”

—Ronald van Vollenhoven, MD, PhD

Response is faster with biologics than with conventional DMARDs, continued Dr van Vollenhoven. The RACAT study showed a trend toward a more rapid response in patients assigned to etanercept-methotrexate compared with conventional combinations of DMARDs. It also demonstrated strong trends that favored etanercept in the change in the 28joint Disease Activity Score (DAS28) by 24 weeks, the percentage of patients who achieved a DAS28 ≤3.2 and ≤2.6 at 24 weeks, an ACR50 response at 24 weeks, and an ACR70 response at 48 weeks, with a significant improvement (P = .001) in the percentage who achieved an ACR70 response at 24 weeks.

By 2 Years, Clinical Outcomes Equal Dr O’Dell reminded the audience that although the TEAR study (Moreland LW, et al. Arthritis Rheum. 2012; 64:2824-2835) did indeed show a faster response to biologics in patients with poor prognosis, patients receiving triple therapy did as well as those who received biologics from week 36 to year 2. Similar results were obtained in the BeST trial of patients with early RA. In RACAT, patients were permitted to switch therapies with insufficient response to their original therapy, but by the end of the trial, outcomes were identical regardless of initial therapy or secondary therapy.

Furthermore, the small radiographic differences in favor of biologics, although statistically significant, are not clinically significant, said Dr O’Dell.

The advantage is typically on the order of one-half point on the 488point Total Sharp Score (TSS). A clini-

Tangling over Toxicity: Fewer Withdrawals with Biologics In terms of toxicity, infliximab and adalimumab (Humira) were associated with twice the rate of serious infections and triple the rate of malignancies compared with placebo in a meta-analysis (Bongartz T, et al. JAMA. 2006;295:2275-2285), Dr O’Dell said.

But Dr van Vollenhoven noted the higher rates of gastrointestinal and other complaints with conventional therapies. In the TEAR study, the withdrawal rate due to adverse events was more than double in patients assigned to conventional agents compared with biologics. Statistically significant higher rates of cardiovascular events and serious respiratory/thoracic/mediastinal events were also recorded among the patients assigned to conventional DMARDs. “Biologics, as a class, are much better tolerated than conventional agents,” Dr van Vollenhoven said.

Value: Triple Therapy the Clear Winner Dr O’Dell then turned to the cost component of the value equation. “I strongly believe that quality cost-effective care is important for all of us,” he said. In the TEAR study, every quality-adjusted life-year gained in patients receiving biologics cost $837,100. Although triple DMARD therapy and biologics are both effective strategies, conventional therapy is far more cost-effective, Dr O’Dell said.

In the future healthcare scenario in which health systems will receive bundled payments to care for patients with RA, and will be judged on quality, “are you going to aggressively use conventional therapy before biologics?” he asked Dr van Vollenhoven.

To which Dr van Vollenhoven replied, “While economic considera­ tions are legitimate, the fact is that all other things being equal, biologic therapy is the most effective treatment for rheumatoid arthritis today.”

But Dr O’Dell returned to the evidence from the 5 investigator-initiated trials in concluding that “conventional DMARD therapy should be the first option in the initial treatment of RA, and in patients with active disease despite methotrexate.” n VOL. 2

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Rheumatology Update

2013 Select Top Studies with Significant Implications... of their best “picks,” highlighting the prac­tical implications for patients with rheumatic diseases.

Juvenile Idiopathic Arthritis A longitudinal study followed a cohort of 171 patients with juvenile idiopathic arthritis (JIA) in Norway for 30 years. Of these patients, 59% were in clinical remission off medications, 34% had persistently active disease, and 7% were in remission but still receiving medications. Predictors of persistently active disease were polyarticular onset, short time in remission, and not being in remission at 15 years. At 30 years, 33% of the patients had unacceptable symptoms, and 33% were not in remission regardless of whether they took medications or not.

“The important message from this abstract is that JIA doesn’t go away.

When you treat children, you have to think about longer-term consequences of our modern treatments,” Dr Kavanaugh said.

Ankylosing Spondylitis A study of patients with ankylosing spondylitis showed that Routine Assessment of Patient Index Data (RAPID)3 scores correlated with Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in the assessment of disease activity and in monitoring the progression of the disease.

“BASDAI is mostly subjective and is useful in the clinic, but RAPID3 is easy to do in the office, and gives you something to track over time. It makes sense to use RAPID3 as a measure of activity in ankylosing spondylitis,” Dr Cush told listeners.

Vitamin D and Systemic Sclerosis This study, which was also presented at a plenary session, showed impaired vitamin D receptor signaling in patients with systemic sclerosis. The investigators found that the vitamin D receptor is important in Smad3 signaling, which promotes fibrosis. The results of this study suggest that upregulating the vitamin D receptor may reduce fibrosis and collagen deposition, but further studies are needed to replicate and support these findings, the investigators suggest.

“I am a naysayer with most vitamin D research. Vitamin D correlates with everything but doesn’t fix anything, but this novel research suggests that vitamin D may be a therapeutic target,” Dr Cush said.

Tight Control of Psoriatic Arthritis The randomized controlled study Tight Control of Psoriatic Arthritis VOL. 2

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(TICOPA) demonstrated that tight control of early psoriatic arthritis was statistically superior to standard care.

This new study was modeled after a similar study called TICORA, which showed that tight control improved outcomes in rheumatoid arthritis (RA).

At the end of 1 year, patients randomized to tight control did significantly better based on the ACR20 response measurement: 62% of patients reached ACR20 versus 45% with standard therapy. Skin responses, enthesitis, and dactylitis were improved in the tight control arm. However, more patients in the tight control arm were stepped up to biologic therapy.

The unifying thread in all these studies is the important implications the findings have to patient management, encompassing a large set of rheumatologic conditions.

“These data showed that those in the tight control arm had slightly more adverse events. The study shows risk versus benefit and provides data that can inform clinical practice. In psoriatic arthritis, we can say it would be best to evaluate patients at regular intervals [as done in the trial], and find the treatment that gets them to low disease activity,” Dr Kavanaugh commented.

“You don’t really know from this trial if tight control or biologics accounted for improved outcomes,” Dr Cush noted.

Immunoglobulin-Related Disorders The diagnostic category of immunoglobulin (Ig)G4-related disease explains a lot of previously undiagnosed patients with a collection of disorders.

The prospective open-label trial of patients representing the full spectrum of organ involvement showed that rituximab was effective in 85% of patients. The study also suggests that plasmablasts followed over time may be a biomarker. This is important because serum levels of IgG4 may not be elevated in all patients with these uncommon, but problematic, disorders.

“This paper is a major advance.

Treatment with rituximab makes sense, but this is the first time it’s been studied. In the absence of data, we might treat with rituximab, but this study gives us support for that, and we look forward to more data,” Dr Kavanaugh said (see full article, page 10).

Pregnancy and Arthritis This study prospectively followed a cohort of 245 patients (mean age, 31 years) with RA who wanted to become pregnant. Patients were followed from 2002 to 2010 to determine if fertility was impaired, and how long it took patients to get pregnant, as measured by the time to pregnancy. A time to pregnancy of less than 12 months was considered desirable; 42% of patients had a time to pregnancy of more than 12 months. Factors associated with longer time to pregnancy included older age, nulliparity, a high Disease Activity Score (DAS), prednisone use of >7.4 mg daily, and nonsteroidal anti-inflammatory drug use. Patients with the lowest DAS scores had the shortest time to pregnancy.

“This abstract speaks to the importance of the rheumatologist’s role in guiding patients and getting them ready for pregnancy. Patients with active RA are less successful at getting pregnant. I think the reason is systemic inflammation. This segues into medication. If you want to get pregnant, you have to bring disease activity down, but the patient may be trying to get pregnant on these med­ications.

This is where the rubber hits the road,” Dr Kavanaugh said.

Oral Ulcers in Behçet’s Disease In a recent study, apremilast was successful in clearing oral ulcers in patients with Behçet’s disease (see article, page 10). This is a relatively rare disease in the United States, with relatively few treatment options.

“Behçet’s disease is an unmet need.

We rely on anecdotal evidence to treat this relatively rare disorder with colchicine, azathioprine, and steroids.

We don’t have a lot of choices specifically for oral ulcers. If apremilast is approved by the FDA, we will have a new tool,” Dr Kavanaugh said.

“I don’t know why apremilast works, but it seems to be easier to take than other drugs that we use to manage Beh­ çet’s. If this study could be replicated and the drug taken to market, it would be a major advance,” Dr Cush said.

Pneumococcal Vaccine An inactivated heptavalent pneumococcal conjugate vaccine reduced the risk of serious pneumococcal infection by approximately 45% in this observational cohort study of 505 patients with RA and spondyloarthritis taking methotrexate, anti–tumor necrosis factor agents, and a combination of the 2 types of medications.

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biologic therapy. A conjugate vaccine is better immunologically,” Dr Kavanaugh said. “It looks like this vaccine is effective in decreasing serious infections, which is a major issue.”

“The number needed to treat to prevent 1 serious infection was 95. I would take those odds,” Dr Cush said.

Vasculitis-Related Mutations This study was elegant experimental research from the National Institutes of Health, showing a loss of mutations in adenosine deaminase2 in children with vasculitis. The investigators used whole genome sequencing and a zebra fish model to study the effect of mutations in adenosine deaminase2 on vascular integrity.

“This represents scientific study from the bedside to the bench, and then back to the bedside,” Dr Kavanaugh said. “This work may eventually lead to a drug to target this rare condition.”

Ultrasound for Joint Damage This study suggests how to incorporate ultrasound into clinical practice. The study included patients with moderate-to-severe active RA receiving methotrexate 15 mg who were given adalimumab and were randomized to higher or lower doses of methotrexate. Ultrasound was used to evaluate joint damage. The results were comparable in the 2 groups.

“Using ultrasound provides reassurance that a remission is indeed complete, and that patients do not have smoldering disease. The study shows it is possible to decrease the dose of methotrexate to 7.5 mg in some patients, but there are almost certainly patients who need a higher dose,” Dr Kavanaugh commented.

Sepsis-Related Death This population-based study showed that sepsis is the leading cause of in-hospital death in patients with polymyositis or dermatomyositis. The study included more than 3300 patients admitted to the hospital for polymyositis or dermatomyositis identified in 5 different claims databases from 5 states.

Inpatient mortality was 3.8% (N = 128).

Deaths occurred mostly in older female patients: 66% of deaths occurred in patients with dermatomyositis, and 33% in those with polymyositis. An infectious cause of death was found in 45% of cases.

“Infections are a major problem in managing patients on steroids. Steroids are the dominant drugs to control rheumatic disease. We are stuck here. We need newer therapies,” Dr Cush said. n

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Rheumatology Update

Apremilast Clears Ulcers in Behçet’s Disease

By Phoebe Starr San Diego, CA—Apremilast, a firstin-class oral targeted phosphodiesterase-4 inhibitor, achieved rapid, sustained clinically meaningful resolution of oral ulcers in patients with Behçet’s disease. Apremilast also reduced disease activity and improved patients’ quality of life (QOL) and pain compared with placebo.

“Apremilast is effective in the treatment of oral ulcers, and the study suggests that it is effective in the treatment of genital ulcers, a difficult-to-treat manifestation of Behçet’s disease. The improvement in disease activity was statistically significant and clinically meaningful for patients,” stated lead

American College of Rheumatology (ACR) meeting.

ACR President Audrey B. Uknis, MD, Professor of Medicine, Temple University, Philadelphia, commented on this study, “Behçet’s is a painful and difficult-to-manage syndrome that negatively affects quality of life.

The state-of-the-art treatment is inadequate. This study suggests that providing therapy that works via a different mechanism improves the ability to manage this disease.”

The prevalence of Behçet’s disease is highest in the Middle East, Asia, and Japan, and approximately 10,000 people in the United States suffer from this disease.

“Apremilast is effective in the treatment of oral ulcers, and the study suggests that it is effective in the treatment of genital ulcers, a difficultto-treat manifestation of Behçet’s disease.”

The BCT-001 Trial Results The BCT-001 trial was a phase 2, multicenter, randomized, placebocontrolled, double-blind, parallelgroup study that included 111 patients (mean age, 34.5 years; 69% women) with active oral ulcers, and the mean disease duration was approximately 5 years.

Patients were randomized to treatment with apremilast 30 mg twice daily or to placebo for 12 weeks. Patients were stratified according to sex.

At the end of 12 weeks, all patients were allowed to cross over to apremi-

—Gulen Hatemi, MD investigator Gulen Hatemi, MD, Associate Professor, Cerrahpasa Medical School, Istanbul, Turkey, at the 2013

“Behçet’s is a painful and difficultto-manage syndrome that negatively affects quality of life. The state-of-the-art treatment is inadequate.

This study suggests that providing therapy that works via a different mechanism improves the ability to manage this disease.”

—Audrey B. Uknis, MD last and were observed for 4 additional weeks. A total of 95 patients completed 12 weeks of the study, and 91 patients completed 24 weeks.

Apremilast was significantly superior to placebo in achieving complete response (ie, ulcer-free) at week 12 versus placebo; the complete response rate was 70.9% with apremilast versus 28.6% with placebo (P <.001). The 10 patients

with genital ulcers at baseline in the apremilast group achieved complete response; of the 6 patients in the placebo group with genital ulcers at baseline, 3 had a complete response at week 12 (P = .036). However, the oral and gen­ital ulcers recurred when the drug was stopped, Dr Hatemi told attendees.

Disease activity, as measured by the Behçet’s Disease Current Activity Form and the Behçet’s Disease Activity Index, was significantly improved with apremilast. “These responses were clinically meaningful,” Dr Hatemi said.

Pain associated with oral ulcers was assessed by the visual analog scale (VAS, 0-100) score, with 100 being the most severe; negative results reflect improvement. Apremilast significantly improved pain versus placebo based on the VAS score of –44.7 versus –16, respectively (P <.001). Patient-reported QOL was also significantly improved in patients receiving apremilast, as measured by the Behçet’s Disease QOL questionnaire (P = .039).

Overall, ≥1 adverse events were similar among the 2 cohorts: 89.3% with apremilast versus 89.1% with placebo.

The most common adverse event in both groups was headache; nausea, vomiting, and diarrhea were seen more frequently with apremilast, but the nausea was mild to moderate. n

Rituximab Effective in Treating IgG4-Related Disorders Elevated plasmablast levels potential new diagnostic biomarker San Diego, CA—The spectrum of immunoglobulin (Ig)G4-related disorders responds to treatment with rituximab, according to results of a new study, suggesting that elevated plasmablasts are a sensitive marker for these disorders. Lead investigator John H. Stone, MD, MPH, Director, Clinical Rheumatology, Massachusetts General Hospital, Boston, presented at the 2013 American College of Rheumatology meeting.

Despite its small size, this is the first study to demonstrate that a treatment is effective for this relatively recently described collection of diseases, said Dr Stone, who is one of the first researchers to describe IgG4-related disorders and their diagnoses.

“New therapeutic strategies are needed for IgG4-related disease,” Dr Stone said. “Glucocorticoids can be effective in many cases, but do not cure IgG4-related disease or lead to long-standing remissions in most cases.”

“Physicians might have used ritux-

10

imab to treat IgG4-related disorders,” commented Arthur F. Kavanaugh, MD, Director, Center for Innovative Therapy, University of California, San Diego. “This is the first evidence we have that it works.”

“New therapeutic strategies are needed for IgG4-related disease. Glucocorticoids can be effective in many cases, but do not cure IgG4-related disease or lead to long-standing remissions in most cases.”

—John H. Stone, MD, MPH Diagnosing IgG4-Related Disorders The diagnosis of IgG4-related disorders encompasses a collection of approximately 12 different multiorgan

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rheumatic diseases that baffled doctors, who overall treated these conditions empirically with anti-inflammatory drugs. IgG4-related disorders can mimic Sjogren’s syndrome, granulomatosis with polyangiitis, systemic lupus erythematosus, and sarcoidosis, as well as infections and malignancies.

The prospective open-label trial enrolled 28 patients, mostly men (median age, 63 years) with confirmed IgG4-related disorders that affected various organ systems, including the eyes, salivary glands, hypopharynx, lungs, lymph nodes, pericardium, pancreas, biliary tract, retroperitoneum, kidneys, and prostate. All patients received rituximab 1000 mg on day 1 and day 15, along with methylprednisolone 100 mg.

Follow-up assessments were planned for 1, 3, 5, 6, 8, 10, and 12 months after the first rituximab dose. The primary end point was disease response, as measured by at least a 2-point decrease in the IgG4-Related Disease

Responder Index, and by the ability to remain off of prednisone. Overall, 24 of 26 patients (92%) achieved the primary end point; they had no disease flares and no steroid requirement for 6 months. The mean Physician Global Assessment was 0 in 73% of the patients followed for ≥6 months.

Two participants required an increase in methylprednisolone after month 1. Two patients were hospitalized: 1 for Legionnaires’ disease, which was present at baseline, and 1 for autoimmune hemolytic anemia.

No serious unexpected side effects were attributed to rituximab.

Dr Stone and colleagues found that elevated plasmablasts are a potential biomarker for IgG4-related disorders, which would help to identify these conditions, which are difficult to diagnose. If confirmed as a biomarker, using elevated plasmablast levels as a diagnostic tool may allow patients with IgG4-related disorders to forego prolonged steroid treatment.—PS­ n VOL. 2

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Lupus

Challenges in Lupus Management

Easy on the prednisone, maximize immunomodulators, look for noncalcified plaque

By Wayne Kuznar San Diego, CA—Expanded use of hydroxychloroquine and limited use of prednisone are 2 strategies in the management of patients with systemic lupus erythematosus (SLE), said Michelle A. Petri, MD, MPH, Professor of Medicine, Johns Hopkins University, Baltimore, MD, at the 2013 American College of Rheumatology meeting.

Dr Petri also emphasized the increased cardiovascular risk in patients with SLE, calling for the identification of noncalcified coronary plaque.

New validated classification criteria for SLE were issued in 2012 (Petri M, et al. Arthritis Rheum. 2012;64:2677-2686) to address new developments, including a substantial redefinition of the arthritis criteria, and the recognition of a large number of detectable autoantibodies in arthritis. The new criteria do not require a radiograph to define arthritis. The presence of joint line tenderness with 30 minutes of mor­­ning stiffness qualifies as arthritis.

According to the Systemic Lupus International Collaborating Clinics, which published the new classification criteria, SLE is a clinical disease based on autoantibodies and built on 2 principles: patients need at least 1 clinical criterion plus 1 immunologic criterion (for a total of 4) or have lupus nephritis diagnosed by kidney biopsy.

“Anti-C1q performed very well in the regression analyses,” said Dr Petri.

“It was left out, because there are not validated assays available to most of

“My first take-home message is, the ‘P’ in prednisone stands for poison….My second take-home message is, ‘hydroxychloroquine for all.’ There are so many reasons hydroxychloroquine should be universally used in lupus….My third take-home message is that vitamin D is another safe immunomodulator, and it can modestly benefit disease activity.”

—Michelle A. Petri, MD, MPH us. It turned out that anti-C1q is 1 of the 3 most important lab tests associated with lupus nephritis, and it’s the only autoantibody that tracks with renal activity over time. So I think there’s more to come on anti-C1q.”

Prednisone Is Poison in Lupus “My first take-home message is, the ‘P’ in prednisone stands for poison,” Dr Petri said. Prednisone increases cardiovascular risk, and high-dose prednisone is now defined as >6 mg daily. With a daily dose of >6 mg, the risk of permanent organ damage has been shown to increase by 50%.

A 10-mg prednisone dose increases the risk for a cardiovascular event over the next 3 months by 2.4-fold, and at 20 mg, this risk increases 5-fold. “This is independent of the disease activity for which the prednisone was prescribed, and also independent of all the tradi-

tional cardiovascular risk factors,” Dr Petri said.

In the case of severe lupus, a new study reported that a steroid-free regimen for lupus nephritis was associated with a 72% complete remission rate and a 90% complete/partial remission rate for proliferative nephritis after treatment with rituximab (Condon MB, et al.

Ann Rheum Dis. 2013;72:1280-1286).

Immunomodulators for All To keep patients with mild-to-moderate lupus off of prednisone, the use of safe immunomodulators needs to be maximized, said Dr Petri.

“My second take-home message is, ‘hydroxychloroquine for all.’ There are so many reasons hydroxychloroquine should be universally used in lupus,” she said.

Hydroxychloroquine reduces flares, organ damage, lipids, and thrombo-

sis, and also improves survival, triples mycophenolate response, and prevents seizures.

“My third take-home message is that vitamin D is another safe immunomodulator, and it can modestly benefit disease activity,” Dr Petri said.

If the 25-hydroxy vitamin D dose increases by 20 ng/mL, what will the patient gain? A 13% decrease in the odds of having moderately active lupus, a 21% decrease of having moderate lupus on a Systemic Lupus Erythematosus Disease Activity Index, and a 15% decrease in the odds of having a urine creatinine and protein level of >0.5 mg/dL, which is the threshold for having a kidney biopsy.

Look for Noncalcified Plaque Inflammation also matters in the coronary arteries, Dr Petri noted. She is a firm believer in the use of computed tomography angiography for risk assessment, because it shows noncalcified plaque. This early inflammatory, vulnerable plaque is the most likely to rupture and cause a cardiovascular event, and is greatly increased in patients with lupus.

“Most important, we can prove that it is associated with current disease activity,” Dr Petri said.

Quantified noncalcified plaque increases with obesity, hypertension, and levels of homocysteine. “This is the link between lupus activity and the heart,” Dr Petri said. n

The Lupus Initiative Helps Eliminate Disparities in Patient Care San Diego, CA—Inadequate lupusspecific education and a lack of autoimmune centers are leading to a delay in the diagnosis of lupus, especially among ethnic minorities, who are disproportionately affected by lupus.

Compared with Caucasians, ethnic minorities in the United States have higher rates of lupus, earlier disease onset, more severe clinical mani­ festations, delay in diagnosis, increased work disability, and higher mortality rates.

The imbalance in lupus prevalence and patient outcomes has led a broad, inclusive consortium to launch The Lupus Initiative to reduce and eliminate the health disparities among patients with lupus.

The Lupus Initiative is a model program from the Office of Minority Health, in partnership with the Office VOL. 2

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of Women’s Health and the Office of the Surgeon General. Its goal is to educate healthcare providers and to improve the diagnosis and treatment of lupus in populations that are disproportionately affected by the disease based on race, ethnicity, and sex.

“First and foremost, it is a medical education initiative to reach out to those students and providers who do not have as good as a resource as many of us are fortunate to have,” said S. Sam Lim, MD, MPH, Associate Professor of Medicine, Emory University, Atlanta, GA, and Consortium Chair of the Lupus Initiative, at the 2013 American College of Rheumatology meeting.

Its curriculum contains 3 major components: a lecture kit, which includes a module of slides and audio; teaching videos; and pools of cases (available

online at TheLupusInitiative.org).

Additional components of the initiative include professional development and patient resources. Professional development includes online continuing medical education series, cases, toolkits, and short videos on specific topics.

“We are really trying to reach out to those who are practicing internal medicine, emergency medicine, and others who have initial visits with patients,” Dr Lim said. Educating these providers on lupus can increase the diagnosis of the disease among minorities.

Also in the curriculum are unique ways to leverage other needs, particularly of cultural competence, which is a set of congruent behaviors, knowledge, and policies that come together to enable effective work in cross-cultural situations. It combines december 2013

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the tenets of patient- and family-centered care, with an understanding of social and cultural influences that affect the quality of health services and treatment.

“Lupus is a wonderful vehicle to teach cultural competence, and it is mandated in medical education,” Dr Lim said. “Medical education is a right field to address health disparities,” he continued. There are logistical barriers of what we can do in terms of the data we collect, but we certainly want feedback as we disseminate this information.”

Dr Lim’s broad, inclusive consortium of government, patient advocacy groups, academia, industry, volunteers, disparities organizations, and medical organizations represents motivated people who volunteered their time.—WK n

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Health Economics

Cost-Effectiveness Comparison of Urate-Lowering Strategies for Gout Shows Superiority of Allopurinol

By Wayne Kuznar San Diego, CA—Allopurinol single therapy for the treatment of patients with gout is cost-saving, and sequential allopurinol-febuxostat dose-escalation therapy appears to be cost-effective, said Hyon K. Choi, MD, DrPH, Professor of Medicine, Boston University School of Medicine, MA, at the 2013 American College of Rheumatology (ACR) meeting.

In contrast, febuxostat single ther­ apy and febuxostat-allopurinol sequential therapy are unlikely to be cost-effective.

The 2012 ACR guidelines for the management of gout provided updated recommendations for using uratelowering therapies (ULTs) but did not consider the associated costs. “Nevertheless, it acknowledged the need for cost-effectiveness studies of new and emerging therapies,” said Dr Choi.

His group assessed the cost-effectiveness of 5 first-line ULT strategies, incorporating a dose-escalation strategy to reflect real practice conditions, for the management of gout over a lifetime. Dr Choi and colleagues developed a Markov model to calculate the lifetime health benefits, the costs, and the incremental cost-effectiveness ratios (ICERs) of the following strategies: • No ULT • Allopurinol used as single therapy

• Febuxostat as single therapy • Allopurinol-febuxostat sequential therapy • Febuxostat-allopurinol sequential therapy.

Two ULT dosing schemes were investigated: (1) fixed dosing with febuxostat 80 mg daily and allopurinol 300 mg daily, and (2) dose escalation (febuxostat up to 120 mg daily and allopurinol up to 800 mg daily).

The health states in the model reflected those that could occur during the lifetime of a patient with gout: controlled (serum urate acid [sUA] <6.0 mg/dL) or uncontrolled (sUA ≥6.0 mg/dL). Within each state, gout flares and ULT-associated adverse events, including allopurinol hypersensitivity syndrome, were accounted for and assigned a disutility.

The costs were evaluated from a payer perspective. Cost and utility estimates were obtained from the literature and discounted by 3% annually.

Based on the published literature, the fixed-dose efficacy was assumed to be 39% for allopurinol and 80% for febuxostat. The escalating-dose efficacy was assumed to be 78% for allopurinol and 82% for febuxostat. The allopurinol hypersensitivity syndrome incidence was assumed to be 0.4% and the fatality rate, 26.7%.

The quality-of-life utility measure, scored as 0 (death) to 1 (perfect health), was assumed to be 0.75 for patients with controlled sUA levels on ULT, 0.70 for those with uncontrolled sUA on ULT, and 0.66 for those with uncontrolled sUA off of ULT. The allopurinol hypersensitivity syndrome disutility was –0.35.

“If you’re willing to pay $47,000 or less, your preferred option would be allopurinol dose escalation, but if your range is $47,000 to half a million dollars, then your preferred option becomes sequential therapy with allopurinol followed by febuxostat.”

—Hyon K. Choi, MD, DrPH

Allopurinol was found to be cost-saving, said Dr Choi. Allopurinol fixed-dose treatment was associated with lifetime costs that were lower than no treatment ($11,851 vs $13,395,

respectively) while producing more quality-adjusted life-years (QALYs; 13.03 vs 12.63, respectively).

Fixed-dose febuxostat had lifetime costs of $36,114 with a 13.55 QALY, for an ICER of $46,700.

In the dose-escalation scenario, allopurinol again dominated and was cost-saving, with lower lifetime costs than no treatment ($10,827 vs $13,395, respectively) and a superior QALY (13.46 vs 12.63, respectively) compared with febuxostat’s lifetime costs of $40,157 and a QALY of 13.52, for an ICER of $488,800.

Sequential therapy with allopurinol-febuxostat had an ICER of $29,900, and sequential therapy with febuxostat-allopurinol had an ICER of $215,800. With the dose-escalation strategy, allopurinol only again dominated the model; however, allopurinol-febuxostat dose escalation had an ICER of $48,100 and febuxostat-allopurinol dose escalation had an ICER in excess of $500,000.

“If you’re willing to pay $47,000 or less, your preferred option would be allopurinol dose escalation, but if your range is $47,000 to half a million dollars, then your preferred option becomes sequential therapy with allopurinol followed by febuxostat,” said Dr Choi. n

High Discontinuation Rates of Triple Therapy in Patients with Rheumatoid Arthritis Starting patients on triple therapy more cost-effective than methotrexate plus a biologic

By Alice Goodman San Diego, CA—Only approximately 1% of patients with rheumatoid arthritis (RA) are receiving triple therapy consisting of methotrexate, sulfa­ salazine, and hydroxychloroquine, and these patients have very high rates of discontinuation, according to poster results presented at the 2013 American College of Rheumatology meeting.

According to Sofia Pedro, MS, of the National Data Bank for Rheumatic Diseases, Wichita, KS, and Kaleb Michaud, PhD, Assistant Professor of Internal Medicine, University of Nebraska Medical Center, Omaha, “This is the first study to provide discontinuation rates of TT [triple therapy] using

12

“This is the first study to provide discontinuation rates of TT using community experience in the biologic era, and we found discontinuation rates to be high and patients tended to switch between several combinations of methotrexate, sulfasalazine, and hydroxychloroquine.”

—Sofia Pedro, MS, and colleagues community experience in the biologic era, and we found discontinuation

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rates to be high and patients tended to switch between several combinations

of methotrexate, sulfasalazine, and hydroxychloroquine.” They noted that more studies are needed to see how results of large randomized trials, such as TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) and RACAT (CSP 551 RA: Comparison of Active Therapies), will affect triple therapy rates.

In addition, a group of Dutch researchers presented 2 analyses of the treatment strategies in the Treatment in the Rotterdam Early Arthritis Cohort (tREACH) trial; one analysis showed that triple therapy was more effective than methotrexate monotherapy in patients with early RA at 1 year, and the second analysis of Continued on page 13

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Rheumatoid Arthritis

Selective JAK3 Inhibitor Improves the Symptoms...

200 mg once daily, or 100 mg twice daily) for 24 weeks. All patients continued to take methotrexate.

In vitro data and clinical studies demonstrate that VX-509 has a high level of selectivity for the inhibition of JAK3 compared with JAK1- and JAK2-dependent assays. According to Dr Genovese, the JAK3 selectivity of VX-509 may have advantages over other JAK inhibitory approaches.

“Selective inhibition of JAK3 will not affect JAK1 signals mediated by other JAK1 pairs controlling a diverse set of physiologies,” he said. In addition, avoiding JAK2 inhibition may circumvent an impact on hematopoietic growth factor–signaling pathways.

In the study, patients with a <30% improvement in total joint count, swollen joint count, and pain could enter an escape arm, which consisted of therapy with VX-509, 150 mg twice daily or 200 mg once daily. Of the patients randomized to placebo, 31% entered the escape arm compared with only 6.9% to 16.9% of patients randomized to the VX-509 arms.

Efficacy The coprimary end points were the proportion of patients who achieved an ACR 20% symptom improvement (ACR20) response and the change from baseline in the Disease Activity Scale for 28 joints (DAS28)–C-reactive protein (CRP) at 12 weeks.

“The onset of response was rapid. Significant differences versus placebo were seen as early as week 1 for ACR20.”

—Mark C. Genovese, MD

Compared with placebo, all doses of VX-509 showed statistically significant ACR20 and ACR50 responses and a significant improvement from baseline in DAS28, said Dr Genovese.

An ACR20 response was achieved by 68%, 58%, 67%, and 47% of patients randomized to VX-509 at 100 mg twice daily, 200 mg once daily, 150 mg once daily, and 100 mg once daily,

respectively, all significantly superior to the 18% ACR20 response rate among patients randomized to placebo (P <.001 for all comparisons).

“The onset of response was rapid,” noted Dr Genovese. “Significant differences versus placebo were seen as early as week 1 for ACR 20.”

The 3 highest dose groups also showed significant ACR70 responses compared with placebo.

The DAS28 improvement from baseline was: • 0.70 in the placebo group • 2.04 in the VX-509 100-mg once-daily group (P <.001 vs placebo) • 2.2 in the VX-509 150-mg once-daily group (P <.001 vs placebo) • 2.51 in the VX-509 200-mg once-daily group (P <.001 vs placebo) • 2.42 in the VX-509 100-mg twice-­daily group (P <.001 vs placebo).

Only 1% of patients in the placebo group achieved a DAS28-CRP of <2.6 (indicative of remission) at week 12, compared with 17%, 29%, 24%, and 31% in the VX-509 100-mg once-­ daily, 150-mg once-daily, 200-mg once-daily, and 100-mg twice-daily

Continued from page 1

dosage groups (all P <.001).

Safety VX-509 demonstrated good tolerability, said Dr Genovese. The discontinuation rates resulting from adverse events were 6.6% in the pooled VX509 group and 8.5% in the placebo group. Adverse events occurred in 51.2% of patients in the pooled VX509 group and in 38% of patients in the placebo group, and most adverse events were mild to moderate.

The most common adverse events observed with VX-509 were headache (8%), hypercholesterolemia (3.8%), and nasopharyngitis (3.5%). The safety profile was comparable across all VX-509 dosage groups.

The rate of serious adverse events was not significantly different between the VX-509 and placebo (5.6%) cohorts, including infection (22% vs 15.5%, respectively) and serious infection (2.8% vs 1.4%, respectively). The VX-509 groups had generally mild elevations in transaminase levels and mild decreases in median neutrophil and lymphocyte counts. n

Health Economics

High Discontinuation Rates of Triple Therapy... Continued from page 12 tREACH showed that triple therapy was more cost-effective than methotrexate monotherapy.

Cost Effective Analysis A third study from the United States showed that triple therapy was more cost-effective compared with methotrexate and a biologic as upfront therapy for RA with comparable clinical outcomes. Viewed in this context, it is surprising that the study by Dr Pedro and colleagues showed that

at a glance ➤ Early use of triple therapy has been shown to be more effective than methotrexate monotherapy in patients with rheumatoid arthritis ➤ This new analysis shows that only a few patients (approximately 1%) are using triple therapy early on

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only approximately 1% of all patients with RA receive triple therapy to begin with.

The study identified 10,156 patients with RA who were taking biologics and disease-modifying antirheumatic drugs (DMARDs) from the National Data Bank for Rheumatic Diseases.

Between 1998 and 2012, 388 patients (3.8%) initiated triple therapy at some point in time. At first, discontinuation was defined as occurring when all 3 agents were no longer taken or if an➤ Furthermore, discontinuation rates are high among patients using various combinations of methotrexate, sulfasalazine, and hydroxychloroquine ➤ Triple therapy has also been shown to be more cost-effective than methotrexate plus a biologic ➤ Large randomized trials are needed to evaluate the rates of triple therapy use

other DMARD or biologic was added (definition I). According to this definition, 304 patients (78.4%) discontinued triple therapy, including 121 (39.8%) who switched to or added another DMARD immediately and 183 (60.2%) who stopped taking 1 or 2 of the 3 drugs. The total discontin­ uation of triple therapy by this first definition was 408 cases per 1000 person-years.

Discontinuation Rates Because the research team could not verify if triple therapy was purposely prescribed, they refined and added definitions of discontinuation as follows: • Definition IA: interruption periods of less than 3 months • Definition II: when a patient was no longer receiving any combination of the 3 DMARDs, or if a biologic agent was added • Definition III: the same as definition II, but with time starting from any combination of 2 drugs in the triple-therapy combination. december 2013

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Using definition I, the mean time receiving triple therapy was 1 year; using definition II, the mean time receiving triple therapy was 1.5 years.

The discontinuation rate for definitions II and III was 55.7% (N = 216).

The probabilities of discontinuing triple therapy after 2 years were 33.4% for definition I, 53.8% for definition II, and 60.7% for definition III. The median length of time receiving triple therapy was twice as high among patients in the definition II group as in the definition I group: 28 months (interquartile range [IQR], 10-112 months) versus 14 months (IQR, 6-45 months), respectively.

At 12 months, the probabilities of discontinuation for definitions I, II, and III were 50.1% (95% confidence interval [CI], 44.9%-55.1%), 62.7% (95% CI, 62.1%-71.9%), and 71.7% (95% CI, 66.8%-76.1%), respectively. At 24 months, the probabilities of discontinuation were 39.1%, 53.8%, and 60.7%, respectively. At 36 months, the probabilities of discontinuation were 29.1%, 43.8%, and 50.3%, respectively. n

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Rheumatoid Arthritis

Joint Surgery Declines in Patients with Rheumatoid Arthritis in the Era of Biologics

By Alice Goodman San Diego, CA—The rates of all types of joint surgery, except knee surgery, declined by more than 20% in patients with rheumatoid arthritis (RA) during the period from 1998 to 2011, as shown in a large population-based study presented at the 2013 American College of Rheumatology meeting. Although the study was done in Sweden, several studies show a similar decline in the United States.

“We proved our hypothesis that the incidence of joint replacement surgery is declining in RA. More disability at baseline and female gender were predictors of orthopedic surgery. We assume that the decline is related to better disease control with more aggressive therapy and newer biologics,” stated lead investigator Korosh Hekmat, MD, a rheumatologist and a PhD fellow at Malmö University, Sweden.

The study was based on a large patient registry in Sweden and included

patient-reported outcomes for 2342 patients with RA on visual analog scales for general health and pain and the Health Assessment Questionnaire

“The incidence of joint replacement surgery is declining in RA….We assume that the decline is related to better disease control with more aggressive therapy and newer biologics.”

—Korosh Hekmat, MD

(HAQ) in 1997, 2002, 2005, and 2009.

Response rates to the questionnaires ranged from 62% to 74%. The patient-reported outcomes were linked

to Swedish registries for inpatient and outpatient surgeries, as well as for the use of biologics.

The rates of orthopedic surgery were divided into 3 time periods: 1998-2001, 2002-2006, and 2007-2011.

Between 1998 and 2011, the incidence of all orthopedic surgeries was 82.3 per 1000 person-years. The incidence of any orthopedic surgery was 94.6 per 1000 person-years in the first time period, 82.6 per 1000 person-years in the second time period, and 71.8 per 1000 person-years in the third time period (P <.001 for both comparisons with the first time period).

The incidence of hip surgery declined from 27.8 per 1000 person-years in the first time period to 17.6 per 1000 person-years in the third time period (P <.001). Small-joint (ie, hands, wrists, feet, and ankles) surgery declined from 43.8 per 1000 person-years in the 1998-2001 period to 30.5 per

1000 person-years in the 2007-2011 period (P <.001).

The rate of knee surgery, however, increased slightly (but not significantly), from 12.3 per 1000 person-years in the first time period to 12.9 per 1000 patient-years in the third time period.

Female sex (hazard ratio [HR], 1.50) was a predictor of small-joint surgery, and greater disability on the HAQ (HR, 1.37) was a predictor of small- or large-joint surgery.

“The rates of surgery declined from 2002 to 2011, and this affects cost. We used to refer patients [to] orthopedic surgeons quite often, but now I see much less need for referral. We need to consider the expense of biologic therapy in the context of the expense of long-term disability and the financial and personal cost of joint replacement,” commented Fehmida Zahabi, MD, of Texas Rheumatology Care, Plano, during a press conference. n

Initial Triple Therapy Superior to Monotherapy on Disease Measures, Cost-Effectiveness

By Wayne Kuznar San Diego, CA—As initial treatment for rheumatoid arthritis (RA), therapy with 3 disease-modifying antirheu­ matic drugs (DMARDs) is superior to methotrexate monotherapy on measures of disease activity, and is also the more cost-effective strategy, said Pascal H.P. de Jong, PhD, of the Department of Rheumatology, Erasmus University Medical Center, Rotterdam, the Netherlands. The 2 treatment strategies were compared in a multicenter, stratified, single-blind trial in adults with early RA. Guidelines issued by the European League Against Rheumatism (2010) and the American College of Rheumatology (ACR; 2012) did not favor triple therapy for all patients with newly diagnosed RA, noted Dr de Jong at the 2013 ACR meeting.

The study included 281 adults with recent-onset RA who had a high probability of progressing to persistent RA, based on the Visser prediction model.

At baseline, the patients had a mean symptom duration of 166 days and a mean disease activity score (DAS) that ranged from 3.28 to 3.40.

The patients were randomized to 1

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of 3 induction therapy arms: • Arm A: triple DMARD therapy (methotrexate, sulfasalazine, and hydroxychloroquine) with 1-time administration of 120 mg of intramuscular glucocorticoids • Arm B: triple DMARD therapy with an oral glucocorticoid tapering scheme, starting at 15 mg daily • Arm C: methotrexate with oral glucocorticoids as in arm B. The patients were followed every 3 months for disease activity, with treatment decisions designed to maintain a DAS of ≤2.4. The medication regimen was intensified to include biologic agents in the event of treatment failure, which was defined as a DAS of >2.4. In cases of sustained remission, defined as a DAS of ≤1.6 at 2 consecutive visits, the medication intensity was tapered.

Clinical Results “Treatment goals were attained faster with triple therapy and maintained with 40% fewer biologicals,” said Dr de Jong.

The difference in disease activity over time, as measured by the area under the curve (AUC) for a mean

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December 2013

DAS, was 2.39 in favor of the triple DMARD strategy (P = .05). The largest difference in disease activity between the groups occurred at 3 months, indicating that treatment goals were achieved faster with triple DMARD therapy. The difference in disease ac-

“Treatment goals were attained faster with triple therapy and maintained with 40% fewer biologicals.”

—Pascal H.P. de Jong, PhD

tivity after 3 months diminished, because a treat-to-target approach was used in all groups, necessitating the intensification of treatment in arm C, Dr de Jong explained.

Functional ability, as measured by the AUC for mean scores on the Health Assessment Questionnaire, was superior at 3 months with triple DMARD therapy versus methotrexate monotherapy (difference, 1.67; P = .05). Oral

and intramuscular glucocorticoids were equally as effective as bridging strategies.

Radiographic progression after 1 year occurred in 19%, 23%, and 21% of patients in arms A, B, and C, respectively.

At 3 months, there were fewer treatment failures in the triple DMARD therapy groups, resulting in the prescription of approximately 40% fewer biologic medications; this difference remained over time.

Economic Implications In a cost analysis, direct and indirect costs were higher for methotrexate monotherapy versus triple therapy because of the 40% increase in the use of biologics in the monotherapy group, said Dr de Jong. The total cost per quality-adjusted life-year was €17,357 for arm C compared with €12,710 for arm A and €10,371 for arm B—the 2 triple-therapy groups.

Monotherapy also resulted in more loss of employment and long-term sickness, as well as a larger decrease in the number of hours worked compared with triple therapy. n VOL. 2

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Now this is novel.

Janus kinase inhibitor

IMPORTANT SAFETY INFORMATION Patients treated with XELJANZ速 (tofacitinib citrate) 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. Lymphoma and other malignancies have also been observed in patients treated with XELJANZ. Please see Indication, Important Safety Information, and brief summary of full Prescribing Information, including boxed warning, on the following pages.

First in a New Class Oral JAK Inhibitor

1,2

XELJANZ — Powerful Efficacy XELJANZ significantly reduces RA signs and symptoms alone or with MTX2 In 2 separate studies, XELJANZ achieved similar ACR response rates as monotherapy and in combination with DMARDs at 6 months1,2 MONOTHERAPY Oral Solo (Study I) 1,2 6 months

*P<0.001 vs. placebo † P<0.05 vs. placebo NRI‡

75

69 50

42

25

100

Patient Response Rates (%)

Patient Response Rates (%)

100

COMBINATION THERAPY Oral Sync (Study II)2 6 months

*P<0.0001 vs. placebo NRI‡

75

75

50

50

53

*

34*

25

22 0

(167/241)

ACR20

(101/241)

ACR50

(53/241)

ACR70

XELJANZ 5 mg BID results at 3 months: 59%*, 31%*, 15%† Placebo results at 3 months: 26%, 12%, 6% ACR20 was a secondary end point at 6 months and a primary end point at 3 months.

Results of a 6-month, randomized, double-blind, controlled, multicenter monotherapy study of 610 moderate to severe RA patients with lack of efficacy or toxicity on a biologic or nonbiologic DMARD who received XELJANZ 5 mg twice daily (N=241) or placebo (N=120). At month 3, all placebo patients advanced blindly to a predetermined XELJANZ dose. ‡ NRI: Nonresponder imputation.

100

25

13* 0

(164/311)

ACR20

(105/311)

ACR50

(41/311)

0

ACR70

Placebo results at 6 months: 31%, 13%, 3% ACR20 at 6 months was a primary end point.

Results of a 12-month, randomized, double-blind, controlled, multicenter study of 792 moderate to severe active RA patients with lack of efficacy or toxicity on a biologic or nonbiologic DMARD who received XELJANZ 5 mg twice daily (N=311) or placebo (N=157) added to background nonbiologic DMARD therapy. At month 3 nonresponding placebo patients advanced blindly to a predetermined XELJANZ dose; at 6 months all remaining placebo patients advanced.

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.

• Active tuberculosis, which may present with pulmonary IMPORTANT SAFETY INFORMATION or extrapulmonary disease. Patients should be tested for WARNING: SERIOUS INFECTIONS AND latent tuberculosis before XELJANZ use and during therapy.

MALIGNANCY Treatment for latent infection should be initiated prior to XELJANZ use.

SERIOUS INFECTIONS • Invasive fungal infections, including cryptococcosis and Patients treated with XELJANZ are at increased risk for developing serious infections that may lead to hospitalization or pneumocystosis. Patients with invasive fungal infections may death. Most patients who developed these infections were taking present with disseminated, rather than localized, disease. concomitant immunosuppressants such as methotrexate or • Bacterial, viral, and other infections due to opportunistic corticosteroids. pathogens.

If a serious infection develops, interrupt XELJANZ until the The risks and benefits of treatment with XELJANZ should be infection is controlled. carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

Reported infections include:

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

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

Alone or in Combination

In your MTX-IR patients, discover powerful efficacy with XELJANZ IMPORTANT SAFETY INFORMATION continued 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 Barr Virus-associated posttransplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications.

SERIOUS INFECTIONS The 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: References: 1. XELJANZ® (tofacitinib) Prescribing Information. New York, NY: Pfizer Inc. 2. Data on file. Pfizer Inc, New York, NY.

• 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.

Learn more at XeljanzHCP.com

IMPORTANT SAFETY INFORMATION 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: • Active tuberculosis, which may present with pulmonary 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.

• Invasive fungal infections, including cryptococcosis and pneumocystosis.

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

• Bacterial, viral, and other infections due to opportunistic 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 Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications.

SERIOUS INFECTIONS The 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.

Tuberculosis Evaluate 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. Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster) were observed in clinical studies with XELJANZ. MALIGNANCY and LYMPHOPROLIFERATIVE DISORDER Consider 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 Virusassociated 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.

TRA595505-02

© 2013 Pfizer Inc.

GASTROINTESTINAL PERFORATIONS Gastrointestinal 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).

LABORATORY PARAMETERS Lymphocytes Treatment 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.

Neutrophils Treatment 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 5001000 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.

Hemoglobin Avoid 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 Enzymes Treatment 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.

Lipids Treatment 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 IMPAIRMENT Treatment with XELJANZ is not recommended in patients with severe hepatic impairment.

ADVERSE REACTIONS The 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 PREGNANCY 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.

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

Printed in USA/October 2013

All rights reserved.

XELJANZ® (tofacitinib) BRIEF SUMMARY OF PRESCRIBING INFORMATION. SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION. 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: • Active tuberculosis, which may present with pulmonary 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.

• Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.

• Bacterial, viral, and other infections due to opportunistic 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 Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications.

INDICATIONS AND USAGE • 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.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Serious Infections Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving XELJANZ. The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster and urinary tract infection. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcus, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus, and BK virus were reported with XELJANZ. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids.

Other serious infections that were not reported in clinical studies may also occur (e.g., histoplasmosis, coccidioidomycosis, and listeriosis).

XELJANZ should not be initiated in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating XELJANZ in patients: • with chronic or recurrent infection • who have been exposed to tuberculosis • with a history of a serious or an opportunistic infection • who have resided or traveled in areas of endemic tuberculosis or endemic 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. A patient who develops a new infection during treatment with XELJANZ should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.

Tuberculosis Patients should be evaluated and tested for latent or active infection prior to administration of XELJANZ. Anti-tuberculosis therapy should also be considered prior to administration of XELJANZ in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient.

Patients should be closely monitored for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering XELJANZ. Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with XELJANZ. The impact of XELJANZ on chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or C were excluded from clinical trials.

Malignancy and Lymphoproliferative Disorder Consider 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. Malignancies were observed in clinical studies of XELJANZ. 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 extensions 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 Perforations Events of gastrointestinal perforation have been reported in clinical studies with XELJANZ in rheumatoid arthritis patients, although the role of JAK inhibition in these events 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). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation.

Laboratory Parameters Lymphocytes Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean lymphocyte counts below the baseline of approximately 10% during 12 months of therapy.

Lymphocyte 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 low lymphocyte count (i.e., 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.

Neutrophils Treatment 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 a low neutrophil count (i.e., 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.

Hemoglobin Avoid initiation of XELJANZ treatment in patients with a low hemoglobin level (i.e. 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 Enzymes Treatment 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.

Lipids Treatment 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. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.

Assessment of lipid parameters should be performed approximately 4-8 weeks following initiation of XELJANZ therapy.

Manage patients according to clinical guidelines [e.g., National Cholesterol Education Program (NCEP)] for the management of hyperlipidemia.

Vaccinations No data are available on the response to vaccination or on the secondary transmission of infection by live vaccines to patients receiving XELJANZ. Live vaccines should not be given concurrently with XELJANZ. Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ therapy.

Hepatic Impairment Treatment with XELJANZ is not recommended in patients with severe hepatic impairment.

ADVERSE REACTIONS Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.

The following data includes two Phase 2 and five Phase 3 double-blind, controlled, multicenter trials. In these trials, patients were randomized to doses of XELJANZ 5 mg twice daily (292 patients) and 10 mg twice daily (306 patients) monotherapy, XELJANZ 5 mg twice daily (1044 patients) and 10 mg twice daily (1043 patients) in combination with DMARDs (including methotrexate) and placebo (809 patients). All seven protocols included provisions for patients taking placebo to receive treatment with XELJANZ at Month 3 or Month 6 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Therefore some analyses that follow include patients who changed treatment by design or by patient response from placebo to XELJANZ in both the placebo and XELJANZ group of a given interval.

Comparisons between placebo and XELJANZ were based on the first 3 months of exposure, and comparisons between XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily were based on the first 12 months of exposure.

The long-term safety population includes all patients who participated in a double-blind, controlled trial (including earlier development phase studies) and then participated in one of two long-term safety studies. The design of the long-term safety studies allowed for modification of XELJANZ doses according to clinical judgment. This limits the interpretation of the long-term safety data with respect to dose.

Clinical Trial Experience The most common serious adverse reactions were serious infections.

The proportion of patients who discontinued treatment due to any adverse reaction during the 0 to 3 months exposure in the double-blind, placebo-controlled trials was 4% for patients taking XELJANZ and 3% for placebo-treated patients.

Overall Infections In the seven controlled trials, during the 0 to 3 months exposure, the overall frequency of infections was 20% and 22% in the 5 mg twice daily and 10 mg twice daily groups, respectively, and 18% in the placebo group.

The most commonly reported infections with XELJANZ were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively).

Serious Infections In the seven controlled trials, during the 0 to 3 months exposure, serious infections were reported in 1 patient (0.5 events per 100 patient-years) who received placebo and 11 patients (1.7 events per 100 patient-years) who received XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 1.1 (-0.4, 2.5) events per 100 patient-years for the combined 5 mg twice daily and 10 mg twice daily XELJANZ group minus placebo.

In the seven controlled trials, during the 0 to 12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 33 patients (2.7 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 -0.1 (-1.3, 1.2) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection.

Tuberculosis In the seven controlled trials, during the 0 to 3 months exposure, tuberculosis was 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, tuberculosis was reported in 0 patients who received 5 mg twice daily of XELJANZ and 6 patients (0.5 events per 100 patient-years) who received 10 mg twice daily

of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% conďŹ dence 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).

cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the ďŹ rst 3 months of exposure in the controlled clinical trials are summarized below: s -EAN ,$, CHOLESTEROL INCREASED BY IN THE 8%,*!.: 5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm.

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.

s -EAN ($, CHOLESTEROL INCREASED BY IN THE 8%,*!.: 5 mg twice daily arm and 12% in the XELJANZ 10 mg twice daily arm.

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% conďŹ dence interval) was 0 (-0.5, 0.5) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ.

In a controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy.

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% conďŹ dence 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% conďŹ dence 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, conďŹ rmed 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 ďŹ rst 3 months of exposure.

ConďŹ rmed lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections.

Neutrophils In the controlled clinical trials, conďŹ rmed 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 ďŹ rst 3 months of exposure.

There were no conďŹ rmed 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 conďŹ rmed decreases in ANC remained consistent with what was seen in the controlled clinical trials.

Liver Enzyme Tests ConďŹ rmed 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, modiďŹ cation 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

s -EAN ,$, ($, RATIOS WERE ESSENTIALLY UNCHANGED IN XELJANZ-treated patients.

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-speciďŹ ed discontinuation criterion of an increase in creatinine by more than 50% of baseline. The clinical signiďŹ cance 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

XELJANZ XELJANZ 5 mg 10 mg Twice Daily Twice Daily N = 1336 N = 1349 Preferred Term (%) (%) Diarrhea 4.0 2.9 Nasopharyngitis 3.8 2.8 Upper respiratory tract 4.5 3.8 infection

Placebo N = 809 (%) 2.3 2.8 3.3

Headache

4.3

3.4

2.1

Hypertension

1.6

2.3

1.1

N reďŹ&#x201A;ects randomized and treated patients from the seven clinical trials Other adverse reactions occurring in controlled and open-label extension studies included: Blood and lymphatic system disorders: Anemia Metabolism and nutrition disorders: Dehydration Psychiatric disorders: Insomnia Nervous system disorders: Paresthesia Respiratory, thoracic and mediastinal disorders: Dyspnea, cough, sinus congestion Gastrointestinal disorders: Abdominal pain, dyspepsia, vomiting, gastritis, nausea Hepatobiliary disorders: Hepatic steatosis Skin and subcutaneous tissue disorders: Rash, erythema, pruritus Musculoskeletal, connective tissue and bone disorders: Musculoskeletal pain, arthralgia, tendonitis, joint swelling General disorders and administration site conditions: Pyrexia, fatigue, peripheral edema DRUG 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., ďŹ&#x201A;uconazole).

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

TRA476916-01

should be used during pregnancy only if the potential beneďŹ t justiďŹ es 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, ďŹ bula, 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 efďŹ cacy 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 speciďŹ c 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 XELJANZÂŽ (tofacitinib) Prescribing Information LAB-0445-1.0 Issued: November 2012

Š 2012 PďŹ zer Inc.

All rights reserved.

November 2012

Psoriatic Arthritis

“Treat to Target” Superior to Standard Care... first study to evaluate a treat-to-target strategy in this patient population,” stated lead investigator Laura C. Coates, MD, PhD, National Institute for Health Research Clinical Lecturer in Rheumatology, University of Leeds, United Kingdom. Dr Coates presented the results of the study at the 2013 American College of Rheumatology (ACR) annual meeting.

The multicenter, open-label, randomized TICOPA trial included 206 patients with newly diagnosed psoriatic arthritis from 8 centers in the United Kingdom. Patients had not previously received conventional or biologic disease-modifying antirheumatic drugs (DMARDs). The patients were randomized in a 1:1 ratio to a tight control (ie, treat-to-target) strategy or to standard care.

Tight control was based on a strict protocol in which patients were seen monthly and therapy was started with

“Treating to a specific objective target [tight control] has as its goal excellent disease control.

Aiming for this high bar improved outcomes for patients with psoriatic arthritis in TICOPA, the first study to evaluate a treatto-target strategy in this patient population.”

—Laura C. Coates, MD, PhD

methotrexate and a rapid escalation to 25 mg after 6 weeks; after 12 weeks, if the target of minimal disease activity (MDA) was not met, the patients received combination DMARD therapy.

After a further 12 weeks, if the target of MDA was not met, therapy was further escalated to anti–tumor necrosis factor if the patient had ≥3 tender and swollen joints, or to an alternative DMARD in combination with methotrexate if the patient did not achieve MDA and had <3 active joints. By contrast, patients in the standard care arm saw the rheumatologist every 3 months, with no set target or escalation plan.

By week 48, 61.8% of the patients in the tight control arm achieved at least a 20% reduction in the signs and symptoms of psoriatic arthritis according to ACR20 criteria versus 44.6% of patients assigned to standard treatment (P = .039). By week 48, the rates of ACR50 and ACR70 (reflecting at least a 50%

Continued from page 1 improvement and a 70% improvement, respectively) in the tight control arm were 51.8% and 38.4%, respectively, versus 25% and 17%, respectively, in the standard care arm.

Tight control was also superior to standard therapy in controlling the skin manifestations of psoriasis: 75% reduction in the Psoriasis Area and Severity Index score was achieved in 58.7% of patients in the tight control arm versus in 33.3% of those receiving standard care.

Dr Coates noted that more patients in the tight control arm received biologic therapies.

In general, tight control was well tolerated. Adverse events were reported in 97% of the tight control group and in 80% of the patients assigned to standard care. The most common adverse events were nausea, liver function abnormalities, and respiratory tract infections. n

Recently Approved for Active Psoriatic Arthritis, Ustekinumab Slows Joint Destruction Integrated analysis confirms benefits of 45-mg and 90-mg dosing

By Wayne Kuznar San Diego, CA— Ustekinumab (Stelara), a human monoclonal antibody against interleukin (IL)-12 and IL-23, was approved by the US Food and Drug Administration in September 2013, alone or in combination with methotrexate, for the treatment of adults with active psoriatic arthritis. A new integrated analysis of 2 phase 3 clinical trials was presented at the 2013 meeting of the American College of Rheumatology, showing that ustekinumab reduces radiographic progression of joint disease in patients with active psoriatic arthritis.

Impeding joint damage is an impor­ tant part of the long-term management of psoriatic arthritis, said the study’s lead investigator Iain B. McInnes, FRCP, PhD, Professor of Medicine, University of Glasgow, Scotland.

The IL-23/IL-17 axis mediates pathways that have the potential to drive inflammation and matrix destruction, said Dr McInnes.

The integrated analysis incorporated patients enrolled in the Phase 3 Multicenter, Randomised, Doubleblind, Placebo-controlled Trials of Ustekinumab, a Fully Human AntiIL-12/23 p40 Monoclonal Antibody, VOL. 2

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Administered Subcutaneously, in Subjects with Active Psoriatic Arthritis (PSUMMIT) I and PSUMMIT II. In PSUMMIT I, the 615 participants had inadequate response to methotrexate and no exposure to tumor necrosis factor (TNF)-alpha inhibitors. Previous anti–TNF-alpha therapy was permitted in PSUMMIT II, in which 312 patients were enrolled. The integrated analysis included 927 patients with active disease despite previous treatment.

In both trials, patients were randomized to ustekinumab 45 mg or 90 mg or to placebo at weeks 0 and 4 and then every 12 weeks. Patients with no response to placebo (defined as <5% improvement in the tender and swollen joint count from baseline) at week 16 were crossed over to ustekinumab 45 mg. All remaining patients who were randomized to placebo crossed over at week 24 to ustekinumab 45 mg. The patients randomized to ustekinumab 45 mg who had no response had their dose of ustekinumab increased to 90 mg starting at week 16.

Radiographic progression was a secondary end point of the analysis. It

was assessed in the hands and the feet by the change from baseline to 24 weeks in modified Sharp/van der Heijde (SHS) scores.

“The overall x-ray data are supportive of inhibition of progression of structural damage in patients with psoriatic arthritis at both the 45-mg and the 90-mg dose of ustekinumab.”

—Iain B. McInnes, FRCP, PhD

At 24 weeks, patients randomized to ustekinumab 45 mg and 90 mg had mean changes from baseline in total SHS scores of 0.40 and 0.39, respectively, compared with a mean change of 0.97 for patients receiving placebo december 2013

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(P = .017 and P <.001, respectively).

The favorable effect of ustekinumab on radiographic progression continued to week 52.

The treatment effect on radiographic progression of disease was expected to be similar for the 2 studies. Although results from PSUMMIT I showed significant inhibition of structural damage at week 24 for both ustekinumab doses, the effect of ustekinumab on inhibiting the progression of structural damage could not be ascertained in the smaller PSUMMIT II study. There was a higher proportion of dropouts in the placebo group in PSUMMIT II, which required that missing x-ray data be imputed as no progression of disease.

This rule may have obscured any true difference between the groups in radiographic progression in PSUMMIT II, said Dr McInnes.

Nevertheless, “the combined x-ray analysis met the prespecified major radiographic end point,” he said. “The overall x-ray data are supportive of inhibition of progression of structural damage in patients with psoriatic arthritis at both the 45-mg and the 90-mg dose of ustekinumab.” n

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Personalized Medicine in Rheumatology

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Osteoarthritis Biomarker Field Fraught with Challenges

By Wayne Kuznar San Diego, CA—Biomarkers for osteoarthritis (OA) hold great promise, but they need further refinement before they can be effectively used in clinical research and daily practice, said Erwin W.E. van Spil, MD, PhD, of the Rheumatology and Immunology Clinic, University Medical Center Utrecht, the Netherlands, at the 2013 American College of Rheumatology meeting.

OA is the most prevalent rheumatic disease, affecting an estimated 27 million Americans in 2005, but treatments have been lagging.

Biomarkers for managing OA have the potential to assist in the early diagnosis of OA, which could allow for the treatment of OA before structural changes can occur.

“Ultimately, they [biomarkers] can help identify therapeutic targets for disease-modifying OA drugs,” said Dr van Spil. “Altogether, effective biomarkers would aid in identifying preclinical or early-stage OA, and create an opportunity for disease-modifying treatment at this stage.”

The Search for OA Biomarkers Selected biomarkers should have sufficient molecular validity, and the markers must relate to the process of interest, “so they should be able to discriminate between healthy and OA

See also Osteoarthritis subjects or between different OA categories,” Dr van Spil noted.

"Effective biomarkers would aid in identifying preclinical or early-stage OA, and create an opportunity for diseasemodifying treatment at this stage….We’re all waiting for a more sensitive marker showing efficacy of intervention, so that trials can be shortened and cheaper.”

—Erwin W.E. van Spil, MD, PhD

The C-terminal telopeptide of type II collagen (CTX-II) is a collagen type II cartilage degradation product that is currently considered the most successful OA biomarker. It may be a reflection of bone metabolism, however, because CTX-II has been shown to cluster with bone markers rather than with other cartilage markers in patients with OA, Dr van Spil pointed out.

Synovial levels of potential OA biomarkers do not always correlate with serum or urine levels, and in the case of collagenase-generated cleavage neoepitope of type II collagen, an inverse association exists, calling into question the validity of these potential biomarkers.

“We cannot be sure that things we are measuring in serum or urine represent local joint conditions in synovial fluid, which makes things quite complicated,” said Dr van Spil. “In line with this point, we need to relate systemic levels to 1 or a few joints of interest.”

A recent study (Kraus VB, et al. PLoS One. 2010;5:e9739) showed that as the number of radiographically affected OA joints increases, the levels of hyaluronic acid and CTX-II also increase, but the levels of cartilage oligomeric matrix protein (COMP), a cartilage degradation marker, decrease. The interpretation of biomarker levels may be complicated by various molecular mechanisms, as well as by the complex biology represented by the biomarker, Kraus and colleagues concluded.

Between-subject variability and the natural diurnal rhythm of biomarker levels also need to be considered. The use of COMP as a marker in knee OA may be limited in individual patients, said Dr van Spil. A recent meta-analy-

sis showed that the overall effect of COMP levels was only moderate in patients with radiographically diagnosed knee OA (Hoch JM, et al. Osteoarthritis Cartilage. 2011;19:1396-1404).

Although high levels of CTX-II and urinary glucosyl-galactosyl-pyridinoline are associated with the progression of joint erosion in OA, substantial overlap is seen in the levels of these markers in patients with varying OA severity as assessed radiographically, limiting their clinical utility. The same is true of COMP, Dr van Spil said.

CTX-II performs better when combined with type IIA procollagen amino terminal propeptide, a collagen synthesis marker. “Especially when levels of cartilage degradation are high and levels of cartilage synthesis are low, the chances of showing knee progression in the future increase,” Dr van Spil pointed out, which suggests that combining biomarkers may be more efficient than individual markers.

“We’re all waiting for a more sensitive marker showing efficacy of intervention, so that trials can be shortened and cheaper,” he said.

CTX-II has shown mixed results, with some clinical trials showing decreases in CTX-II levels after intra­ articular injections of hyaluronic acid in patients with knee OA, and other trials showing increases in CTX-II. n

Potential Biomarkers for Preeclampsia in Pregnant Women with Lupus

See also Lupus

By Phoebe Starr San Diego, CA—The dysregulation of angiogenic factors early in pregnancy may pave the way for a test to predict poor pregnancy outcomes in women with systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS), according to a study presented at the 2013 American College of Rheumatology meeting.

Researchers found that the presence of the following 3 factors could predict the development of preeclampsia and other poor outcomes as early as 16 weeks gestation: 1. Absolute levels of the angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt1) 2. The ratio of sFlt1/placental growth factor (PlGF) 3. The rate of change of angiogenic factors.

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“Our findings reveal novel targets for treatment. Low sFlt1/PlGF ratios, as well as low sFlt1 levels or high PlGF levels, can reassure physicians and patients that preterm preeclampsia is unlikely, and the ratio can be used at 16 to 19 weeks to stratify risk in future trials of SLE and/or APL [antiphospholipid] pregnant patients,” said lead investigator Jane E. Salmon, MD, Director, SLE APS Center of Excellence, Hospital for Special Surgery, New York.

If such a test or diagnostic profile were available to follow patients with SLE/APS during pregnancy and can predict which patients are likely to have poor outcomes, it would represent a major advance, because there is currently no way to identify which of these patients may be at increased risk.

The maternal response to pre-

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eclampsia is mediated by angiogenic factors in the placenta, and the imbalance of these factors has been shown to damage the endothelium in animal models, Dr Salmon said.

Observations in animal models led the researchers to find the angiogenic biomarkers that would predict poor pregnancy outcomes in patients with SLE and/or APS. They studied patients enrolled in the Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus (PROMISSE) trial, which included 503 pregnant women with SLE, and 204 healthy pregnant controls.

The composite end point for poor outcomes was defined as fetal death; neonatal death; preterm delivery at <36 weeks as a result of hypertension,

preeclampsia, or placental insufficiency; and an infant small for his or her gestational age.

Poor outcomes occurred in 85 patients with SLE and/or APS; of these patients, 42 outcomes happened in women who had preeclampsia at any time during pregnancy, and 33 in women who developed preeclampsia at <34 weeks gestation. No poor outcomes were reported in 336 patients with SLE/APS or in 168 of the healthy controls.

Elevated sFlt1 preceded poor outcome, and an elevated sFlt1/PlGF ratio was associated with poor outcome. When the sFlt1/PlGF ratio was used as a screening test with a cutoff of >3.45 at 16 to 19 weeks, the positive predictive value was 41%, and the negative predictive value was 97%. n VOL. 2

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Osteoarthritis

Regular Physical Activity in Patients with Osteoarthritis Can Improve Health, Save Money

See also Personalized Medicine

By Phoebe Starr San Diego, CA—Regular physical activity has the potential to improve physical health and to reduce healthcare costs for patients with osteoarthritis (OA), based on a study presented at the 2013 American College of Rheumatology meeting.

Interventions to increase the level of physical activity to a moderate or vigorous level were estimated to cost $1450 per quality-adjusted life-year (QALY), which is cost-effective and falls considerably below the current ceiling of $50,000 per QALY that is deemed cost-effective for other common medical interventions.

“We wanted to see if meeting the US Department of Health and Human Services [HHS] guidelines for regular physical activity translated into better QALYs for adults with OA or those at risk for OA. We also wanted to postulate whether interventions that increase physical activity were cost-e­f­ fec­ tive,” ex­ plained lead investigator Kai Sun, MD, Medical Resident and Re­ search Trainee, Northwestern Univer­sity Feinberg School of Medicine, Chicago, IL. The HHS guidelines define regular physical activity as 150 minutes of

moderate-to-vigorous activity weekly in bouts of ≥10 minutes.

“The costs associated with treatment of inactivityrelated diseases and injuries, lost productivity, and diminished quality of life pose an economic burden.”

—Kai Sun, MD

Study Parameters The investigators used results from the Osteoarthritis Initiative (OAI), a National Institutes of Health–sponsored study that included questionnaires, laboratory tests, and imaging test results for more than 4700 adults who have or who are at risk for knee OA. Participants were divided into 3 groups based on their level of physical activity and were measured for 1 week with accelerometers (N = 2127): those who met the HHS physical activity guidelines, those who were insufficiently physically active (ie, <150

minutes weekly of physical activity), and those who were inactive (no bouts of physical activity lasting >10 minutes weekly).

Levels of physical activity were monitored at the beginning of the study (the 4-month visit for those participating in the OAI), and then again 2 years later (the OAI 72-month follow-up visit). At both visits, health-related utility scores were used to calculate QALYs; 1794 patients completed baseline and 2-year visits.

Increased Activity Improves Quality of Life in OA Results showed a graded relationship between higher levels of physical activity and QALYs. In an analysis adjusted for socioeconomic and health factors, over the 2-year study, participants who met the HHS guidelines for physical activity had QALYs that were 0.11 higher than the inactive group, which was statistically significant (P <.001). Even some physical activity seems to pay off, Dr Sun emphasized, because the group with insufficient physical activity had QALYs that were 0.058 higher than the inactive group.

The inactive group tended to be

older, female, nonwhite, have lower education levels, lower income, and to live alone.

“These QALYs represent about 10 to 20 additional days of perfect health over 1 year. Interventions to encourage adults to increase their physical activity could potentially translate to better quality of life, adding years of healthy life, and thereby lower overall healthcare costs,” Dr Sun said.

She noted that although it is clear that regular physical activity improves health, reduces mortality in the general population, and has arthritis-specific health benefits and improvement in symptoms, functioning, and psychosocial well-being, as well as reduced disability, the majority of adults in the United States do not attain the recommended levels of physical activity.

“The costs associated with treatment of inactivity-related diseases and injuries, lost productivity, and diminished quality of life pose an economic burden. Promoting physical activity is an important component of promoting overall health, addressing the epidemic of obesity, chronic illnesses like OA, and reducing healthcare costs over the long-term,” Dr Sun stated. n

In the Literature ACR Survey Addresses Ethical Issues among Rheumatologists

Ethical dilemmas in providing healthcare are well documented, with more than 99% of primary care physicians reporting ethical problems arising in their medical practices. However, ethical challenges in rheumatology literature are negligible. To better understand the scope of ethical problems occurring in rheumatology, the American College of Rheumatology (ACR) initiated an electronic survey of 5500 of its members (Mackenzie CR, et al. Arthritis Rheum. 2013;65:2524-2532). In the survey, rheumatologists reported ways in which they see themselves as bending ethical standards and presented justifications for their actions.

The survey included 12 close-ended questions addressing 5 core areas and 2 open-ended questions asking respondents to list the 3 ethical issues that are most relevant to rheumatology. Of the 5550 surveyed, 771 responses were received, for a response rate of 14%.

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Overall, the respondents believe that ethical issues in rheumatology arise most frequently in clinical practice (44%) and in basic research (26%).

The most common practice-related ethical issues cited were the high cost of medications for patients (51%) and for society (48%), and profits from infusions (nearly 40%).

Other practice-related issues cited by rheumatologists were accepting gifts from pharmaceutical companies (>25%) and profiting from imaging (>25%). Three ethical issues that garnered similar responses (>20% for each) were (1) profiting from enrolling patients in clinical trials, (2) embellishing of symptoms for reimbursement, and (3) profiting from diagnostic laboratories. Less than 20% of rheumatologists said they embellish symptoms for disability. Overall, 47% of rheumatologists noted they did not have adequate resources to help them resolve ethical issues.

In a series of questions on process-related circumstances, the top

concerns for the respondent rheumatologists were the practice of defensive medicine (45%), not spending enough time with patients (approximately 30%), caring for the uninsured or for patients with limited insurance (>20%), and practice productivity obligations (>20%). Racial and cultural disparities, responding to medical errors, confidentiality and Health Insurance Portability and Accountability Act compliance, and obtaining consent for clinical trials were each cited by less than 20% of the respondents.

Based on this survey, more than 50% of rheumatologists perceive multiple ethical issues regarding relationships with the pharmaceutical industry. The most prevalent concerns are serving on a board of directors (76%), participating on a speakers’ bureau (66%), and consulting (61%). Two ethical issues cited by more than 40% of rheumatologists were serving as an investigator for a company trial and attending company dinners or continuing medical education functions. december 2013

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Industry-related activities considered to have the fewest ethical implications were meeting with company sales representatives (39%) and meeting with medical liaisons (30%).

These findings show that many rheumatologists face moral dilemmas when trying to do what is best for their patients, and ethical problems in rheumatology are of concern to the ACR membership. The findings also underscore the need for the ACR to develop educational programs targeted at helping ACR members address such ethical challenges related to their practice of rheumatology.

Long-Term Golimumab Therapy Beneficial for Rheumatoid Arthritis

Data from the ongoing Golimumab Before Employing Methotrexate as the First-Line Option in the Treatment of Rheumatoid Arthritis of Early Onset (GO-BEFORE) trial have shown that the tumor necrosis factor blocker golimumab (Simponi) reduced the

Continued on page 24

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In the Literature Long-Term Golimumab Therapy Beneficial for Rheumatoid...

Continued from page 23

signs and symptoms of rheumatoid arthritis (RA). GO-BEFORE is a 5-year, phase 3, multicenter, randomized, placebo-controlled clinical trial of 637 patients with active RA who had never taken methotrexate.

In a new interim analysis, researchers assessed the trialâ&#x20AC;&#x2122;s major secondary end pointsâ&#x20AC;&#x201D;improvement in the Health Assessment Questionnaire Disability Index (HAQ-DI) score from baseline to week 52, and change in the Sharp/van der Heijde score (SHS)

from baseline to week 52 among patients with a baseline C-reactive protein (CRP) level >1.0 mg/dL, as well as week 104 findings (Emery P, et al.

Arthritis Care Res. 2013;65:1732-1742).

The GO-BEFORE trial randomized participants in a 1:1:1:1 ratio to receive placebo plus methotrexate (group 1), golimumab 100 mg plus placebo (group 2), golimumab 50 mg plus methotrexate (group 3), or golimumab 100 mg plus methotrexate (group 4) every 4 weeks. Nonresponders based on week 28 swollen or tender joint counts switched treatment. Patients in group 1 switched from placebo to golimumab 50 mg, group 2 switched from placebo

to methotrexate, group 3 increased golimumab to 100 mg, and group 4 continued with the original treatment.

At week 52, a considerably higher proportion of patients in groups 3 and 4 compared with group 1 achieved 20% improvement in American College of Rheumatology criteria (ACR20) response (63.2% vs 51.9%, respectively) and ACR50 response (45.3% vs 35.6%, respectively). Patients showed clinically meaningful improvement in the mean HAQ-DI in groups 3 and 4 compared with group 1 at week 52 (0.70 vs 0.58, respectively). For the same comparison, the mean changes in SHS were 0.41 versus 1.37, respec-

tively, among all patients and 0.74 versus 2.16, respectively, in all patients with a CRP level >1 mg/dL. These improvements were sustained through week 104. Patients treated with golimumab plus methotrexate for 2 years yielded statistically less radiographic progression than patients who began treatment with methotrexate or golimumab 100 mg monotherapy.

The 2-year findings of the study show that long-term treatment with golimumab in combination with methotrexate reduces the signs and symptoms of active RA and improves physical function and radiographic progression. n

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Drug Update

Stelara Receives New FDA Indication for the Treatment of Patients with Active Psoriatic Arthritis

By Loretta Fala, Medical Writer

P

soriatic arthritis (PsA), a chronic, inflammatory disease that causes pain, stiffness, and swelling in and around the joints, generally develops between the ages of 30 and 50 years, but it can affect people of all ages, including children.1 In the United States, the overall prevalence of PsA is estimated to range from 101 to 250 cases per 100,000 people; however, the prevalence of PsA has historically been challenging to determine, because of its misdiagnosis and the lack of widely accepted diagnostic criteria.2 PsA is sometimes misdiagnosed as rheumatoid arthritis, gout, or osteoarthritis.3 Both PsA and psoriasis are chronic autoimmune diseases.3 Of the estimated 7.5 million patients (approximately 2.2% of the US population) who have psoriasis, 10% to 30% will also develop PsA.3,4 Although the exact cause of PsA is unknown, research suggests that it develops from a combination of genetic (ie, heredity) and environmental factors.1 In addition, immune system conditions, infection, and physical trauma may play a role in the development of PsA.5 PsA may also be triggered by a streptococcal throat infection.3 PsA also has a substantial impact on the patient’s psychological and psychosocial functioning and daily living activities.2 The visible nature of skin involvement may also lead to embarrassment, self-consciousness, and, in some cases, depression. Moreover, PsA may be associated with an increased risk for osteoporosis and cardiovascular disease, as well as an increased risk for other inflammatory conditions, including uveitis and iritis.2 Patients with PsA have a slightly increased risk for high blood pressure, high cholesterol, obesity, or diabetes.3 Anemia and fatigue are also common in patients with PsA.3 Based on a 2010 review of 49 studies, PsA accounts for nearly $1.9 billion in direct annual healthcare costs.2 Hospitalizations are the key driver of the direct costs, accounting for approximately 60% of the total direct costs. Indirect costs, including disability and lost productivity, account for 52% to 72% of the total costs.2 Furthermore, worsening physical function and disease activity are associated with increases in both direct and indirect costs.2 The early diagnosis and treatment of PsA are essential to relieving pain

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and inflammation and to helping prevent progressive joint involvement and damage.5 The therapeutic goals for patients with PsA are to alleviate symptoms, including pain and skin symptoms; to protect the joints; and to maintain mobility.3,5 Treatment decisions are based on disease severity, the number of joints involved, and associated skin symptoms.5 Treatments for PsA may include a combination of nonpharmacologic and pharmacologic options. Nonpharmacologic approaches include exercise, heat and cold therapy, water therapy, the use of splints, joint protection and energy conservation, and surgery (when severely damaged joints need replacement).3,5 Pharmacologic treatments include nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs).5 Corticosteroid injections may be useful in patients with PsA and swollen joints.3 DMARDs are generally used in patients with erosive disease or in patients who fail to respond to NSAIDs.5 DMARDs that are effective in treating PsA include methotrexate, sulfasalazine (Azulfidine), cyclosporine, and leflunomide (Arava).3 In addition to reducing the signs and symptoms of PsA, the biologic DMARDs also slow the progression of joint damage. The biologic DMARDs include the following tu­ mor necrosis factor (TNF)-α inhibitors: adalimumab (Humira), etanercept (Enbrel), golimumab (Simponi), and infliximab (Remicade).3 Recently, ustekin­ umab—a new biologic DMARD that targets the interleukin (IL)-12 and IL-23 cytokines—became available for the treatment of patients with PsA.6 Stelara Injection: A New Biologic Option for Patients with PsA In September 2013, the US Food and Drug Administration (FDA) approved a new indication for Stelara (ustekinumab) injection, alone or in combination with methotrexate, for the treatment of adult patients (aged ≥18 years) with active PsA.6 Ustekinumab, a human immunoglobulin (Ig)G1κ monoclonal antibody that targets the shared p40 protein subunit of the IL-12 and IL-23 cytokines,7 is the first and only anti– IL-12/23 therapy approved by the FDA for adults with PsA.8 According to study investigator Alice B. Gottlieb, MD, Chief and Der-

matologist-in-Chief in the Department of Dermatology at Tufts Medical Center, “It is critical for dermatologists and rheumatologists to be able to offer new and novel treatment options to our adult patients living with psoriatic arthritis, a disease where additional biologic options are very much needed.”8 She further commented, “Therapy that targets the cytokines interleukin-12 (IL-12) and interleukin-23 (IL-23), two naturally occurring proteins believed to play a role in the development of this debilitating immune-mediated inflammatory disease, could improve patient care.”8 Mechanism of Action Ustekinumab is a human IgG1κ monoclonal antibody that binds with specificity to the shared p40 protein subunit used by the IL-12 and IL-23 cytokines. These naturally occurring cytokines are involved in inflammatory and immune responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation.7 Levels of IL-12, IL-23, and p40 are elevated in the skin and blood of patients with psoriasis, and in the blood of patients with PsA, implicating IL-12 and IL-23 in the pathophysiology of psoriatic inflammatory diseases. In in vitro models, ustekinumab was shown to disrupt IL-12– and IL-23– mediated signaling and cytokine cascades by upsetting the interaction of these cytokines with a shared cell-surface receptor chain, IL-12Rβ1.7 Dosing Ustekinumab is administered by subcutaneous injection. For the treatment of PsA, the initial recommended dose is 45 mg followed 4 weeks later by 45 mg every 12 weeks. For patients with coexistent moderate-to-severe plaque psoriasis weighing >100 kg (220 lb), the recommended dose is 90 mg initially and, 4 weeks later, followed by 90 mg every 12 weeks.7 Ustekinumab injection is available in several dosage forms and strengths: 45 mg/0.5 mL in a single-use prefilled syringe, 45 mg/0.5 mL in a single-use vial, and 90 mg/mL in a single-use prefilled syringe.

Ustekinumab is intended for use under the guidance and supervision of a physician. It should only be administered to patients who will be closely monitored and who will have regular follow-up visits with a physician. december 2013

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After proper training in subcutaneous injection technique, a patient may self-inject with ustekinumab if a physician determines that it is appropriate.7 Clinical Studies The safety and efficacy of ustekin­ umab were evaluated in 927 patients in 2 randomized, double-blind, placebo-controlled studies of patients aged ≥18 years with active PsA (≥5 swollen joints and ≥5 tender joints), despite therapy with NSAIDs or DMARDs. The patients enrolled in these studies had a diagnosis of PsA for a minimum of 6 months. The patients had the following subtypes of PsA: polyarticular arthritis with the absence of rheumatoid nodules (39%), spondy­ litis with peripheral arthritis (28%), asymmetric peripheral arthritis (21%), distal interphalangeal involvement (12%), and arthritis mutilans (0.5%).

More than 70% of the patients had enthesitis (ie, inflammation of the sites where tendons, ligaments, and joint capsules of the fascia attach to the bone) at baseline, and more than 40% had dactylitis (ie, inflammation of a finger or toe) at baseline.7 The patients in study 1 (N = 615) and study 2 (N = 312) were randomized to receive treatment with ustekin­ umab 45 mg or 90 mg or with placebo subcutaneously at weeks 0 and 4, followed by dosing every 12 weeks. Approximately 50% of the patients continued to receive stable doses of methotrexate (≤25 mg weekly).7 In study 1, 80% of the patients had previously received DMARDs; previous treatment with an anti–TNF-α agent was not allowed. In study 2, 86% of the patients had previously received DMARDs, and 58% had previously received an anti–TNF-α agent, of whom more than 70% had discontinued their anti–TNF-α treatment for lack of efficacy or intolerance at any time.7 The primary end point in study 1 and study 2 was the percentage of patients achieving an ACR20 response at week 24.7 ACR20 is defined by the American College of Rheumatology (ACR) as a 20% improvement in tender and swollen joint counts and a 20% improvement in at least 3 of the 5 following ACR core set measures: patient and physician global assessments, patient-assessed pain, patient self-assessed disability, and an acutephase reactant.9 Other responses measured included the presence of lesions

Continued on page 26

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Drug Update

Stelara Receives New FDA Indication... over the body surface area (0%-3% = mild; 3%-10% = moderate; and >10% = severe)10; and the Psoriasis Area and Severity Index (PASI), which measures 3 features of psoriatic plaque— redness, scaling, and thickness— where each is assigned a rating of 0 to 4, with 4 being the worst.11 The extent of involvement of each region of the body is given a rating of 0 to 6; the subsequent total score can range from 0 to 72.11 The clinical response results for studies 1 and 2 are shown in Table 1.

In both studies, at week 24 a greater proportion of patients achieved ACR20, ACR50, and PASI 75 response in the ustekinumab 45-mg and 90-mg groups compared with those receiving placebo. ACR70 responses were also higher in the ustekinumab 45-mg and 90-mg cohorts, although the difference was not statistically significant in study 2. The responses were similar in patients regardless of previous TNF-α exposure.7 The results of the components of the ACR response criteria from study 1 are shown in Table 2. In the 2 groups receiving ustekinumab (45 mg and 90 mg), improvements in enthesitis and dactylitis scores were observed at week 24 compared with placebo. The patients receiving ustekinumab also showed improvement in physical function compared with patients receiving placebo, as assessed by the Health Assessment Questionnaire– Disability Index at week 24.7

Safety

The safety of ustekinumab was assessed in 927 patients in 2 randomized, double-blind, placebo-controlled studies in adult patients with active PsA. The overall safety profile of ustekinumab in patients with PsA was consistent with the safety profile seen in clinical trials of patients with psoriasis. In the placebo-controlled groups of the PsA clinical trials, a higher incidence in several adverse events was seen in patients receiving ustekinumab compared with patients receiving placebo, including arthralgia (3% vs 1%, respectively), nausea (3% vs 1%, respectively), and dental infections (1% vs 0.6%, respectively).7 The most common adverse events (incidence ≥3% and more than with placebo) were nasopharyngitis, upper respiratory tract infection, headache, and fatigue.7

Drug Interactions

Drug interaction studies have not been conducted with ustekinumab.7 Live vaccines. Live vaccines should

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Table 1 Ustekinumab in 2 PsA Clinical Studies: ACR20, ACR50, ACR70, and PASI 75 Responses at Week 24 PsA study 1 PsA study 2 Ustekinumab Ustekinumab Placebo 45 mg 90 mg Placebo 45 mg 90 mg Measurement (N = 206) (N = 205) (N = 204) (N = 104) (N = 103) (N = 105) ACR20 response, N (%)

47 (23)

87 (42)

101 (50)

21 (20)

45 (44)

46 (44)

ACR50 response, N (%)

18 (9)

51 (25)

57 (28)

7 (7)

18 (17)

24 (23)

5 (2)

25 (12)

29 (14)

3 (3)

7 (7)

9 (9)

146

145

149

80

80

81

16 (11)

83 (57)

93 (62)

4 (5)

41 (51)

45 (56)

ACR70 response, N (%) Patients with ≥3% body surface area, N a

PASI 75 response, N (%)

Number of patients with ≥3% body surface area psoriasis skin involvement at baseline.

ACR indicates American College of Rheumatology; ACR20, 20% improvement in tender and swollen joint counts and 20% improvement in at least 3 of 5 ACR core set measures (ACR50 and ACR70 indicate 50% or 70% improvement); PASI 75, 75% reduction in Psoriasis Area and Severity Index (PASI) score; PsA, psoriatic arthritis.

Source: Stelara (ustekinumab) injection [prescribing information]. September 2013.

a

not be given concurrently with ustekinumab.

Concomitant therapies. In PsA studies, concomitant methotrexate use did not influence the safety or efficacy of ustekinumab.

CYP450 substrates. The formation of cytochrome (CY) P450 enzymes can be altered by increased levels of certain cytokines (eg, IL-1, IL-6, IL-10, TNF-α, interferon) during chronic inflammation. Thus, ustekinumab, an antagonist of IL-12 and IL-23, could normalize the formation of CYP450 enzymes. On initiation of ustekinumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, monitoring for therapeutic effect (eg, of warfarin) or drug concentration (eg, of cyclospor­ ine) should be considered, and the individual dose of the drug should be adjusted as needed.

Allergen immunotherapy. Ustekin­ umab has not been evaluated in patients who have undergone allergy immunotherapy. Ustekinumab may decrease the protective effect of allergen immunotherapy, which may increase the risk for an allergic reaction to a dose of allergen immunotherapy.

Therefore, caution should be exercised in patients receiving or those who have received allergen immunotherapy, particularly for anaphylaxis.7

Warnings and Precautions

Contraindications. Ustekinumab is contraindicated in patients with clinically significant hypersensitivity to ustekinumab or to any of the excipients.7 Infections. Ustekinumab may increase the risk of infections and the reactivation of latent infections. Serious bacterial, fungal, and viral infections were observed in patients receiving ustekinumab. In the PsA clinical studies, serious infections in-

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December 2013

stekinumab in PsA Study 1: Mean Change from Baseline in ACR Table 2 U Response Criteria, at Week 24 Ustekinumab Placebo 45 mg 90 mg Measurement (N = 206) (N = 205) (N = 204) Number of swollen joints (0-66 counted) Baseline, N

15

12

13

Mean change at week 24, N

–3

–5

–6

25

22

23

–4

–8

–9

6.1

6.2

6.6

–0.5

–2.0

–2.6

6.1

6.3

6.4

–0.5

–2.0

–2.5

5.8

5.7

6.1

–1.4

–2.6

–3.1

Number of tender joints (0-68 counted) Baseline, N Mean change at week 24, N Patient’s assessment of pain

a

Baseline, N Mean change at week 24, N Patient global assessment

a

Baseline, N Mean change at week 24, N Physician global assessment

a

Baseline, N Mean change at week 24, N HAQ-DI

b

Baseline, N

1.2

1.2

1.2

–0.1

–0.3

–0.4

Baseline, mg/dL

1.6

1.7

1.8

Mean change at week 24, mg/dL

0.01

–0.5

–0.8

Mean change at week 24, N CRPc

VAS score: 0 = best, 10 = worst.

HAQ-DI: 0 = best, 3 = worst; measures the patient’s ability to perform daily activities. c CRP normal range, 0-1 mg/dL. ACR indicates American College of Rheumatology; CRP, C-reactive protein; HAQ-DI, Health Assessment Questionnaire–Disability Index; PsA, psoriatic arthritis; VAS, visual analog scale.

Source: Stelara (ustekinumab) injection [prescribing information]. September 2013. a

b

cluded cholecystitis. Ustekinumab should not be started during any clinically important active infection. If a serious infection develops, ustekin­ umab should be stopped until the infection resolves.

Serious infections from mycobacteria, Salmonella, and Bacillus Calmette–

Guérin vaccinations have been reported in patients who are genetically deficient in IL-12 or IL-23. Diagnostic tests for these infections should be considered as dictated by the clinical circumstances.

Tuberculosis. Patients should be evaluated for tuberculosis infection before VOL. 2

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Drug Update initiating treatment with ustekinumab, which should not be administered to patients with active tuberculosis. Patients receiving ustekinumab should be monitored closely for signs and symptoms of active tuberculosis. Treatment of latent tuberculosis should be initiated before administering ustekinumab.

Malignancies. Ustekinumab is an immunosuppressant, and it may increase the risk for malignancy. The safety of ustekinumab has not been evaluated in patients who have a history of or a known malignancy.

Hypersensitivity reactions. Anaphylaxis and angioedema have been reported postmarketing. If an anaphylactic or other clinically significant hyper­sensitivity reaction occurs, the appropriate therapy should be given and ustekinumab should be discontinued.

Reversible posterior leukoencephalopathy syndrome (RPLS). One case of RPLS was observed during the psoriasis clinical development program; no additional cases of RPLS were ob-

served in the PsA clinical development program. If RPLS is suspected, appropriate treatment should be administered and ustekinumab should be discontinued.7 Pregnancy. There are no adequate and well-controlled studies of ustekin­ umab in pregnant women. Ustekin­ umab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.7 Nursing mothers. Caution should be used when ustekinumab is administered to a nursing woman.7 Pediatric/geriatric use. The safety and effectiveness of ustekinumab in pediatric patients have not been established. And although no differences in safety or efficacy were observed between older and younger subjects in clinical trials, the number of adults aged ≥65 years was not sufficient to determine whether they respond differently from younger patients.7

available for patients with PsA with the FDA approval of a new indication for ustekinumab, the first and only anti–IL-12/23 therapy approved by the FDA for this complex and potentially debilitating condition. Previously approved by the FDA in 2009 for the treatment of adults with moderate-to-severe plaque psoriasis, ustekin­­ umab is now also indicated for the treatment of patients with active PsA. Evidence from phase 3 randomized, double-blind, placebo-controlled studies shows the benefits of ustekinumab for adults with PsA. Patients who received ustekinumab showed improvement in physical function compared with patients who received placebo at week 24. The most common adverse reactions (incidence ≥3% and higher than placebo) were nasopharyngitis, upper respiratory tract infection, headache, and fatigue. n

Conclusion A novel biologic option became

1. National Psoriasis Foundation. Facts about psoriatic arthritis. www.psoriasis.org/document.doc?id=1493.

Accessed November 21, 2013.

References

2. Lee S, Mendelsohn A, Sarnes E. The burden of psoriatic arthritis: a literature review from a global health systems perspective. P T. 2010;35:680-689.

3. Emery P, Ash Z; for the American College of Rheumatology. Psoriatic arthritis. Fact sheet. Updated September 2012. www.rheumatology.org/Practice/ Clinical/Patients/Diseases_And_Conditions/Psoriatic_ Arthritis/. Accessed November 26, 2013.

4. National Psoriasis Foundation. Statistics. www.psori asis.org/learn_statistics. Accessed November 20, 2013.

5. The Cleveland Clinic Foundation. Psoriatic arthritis. http://my.clevelandclinic.org/orthopaedics-rheu matology/diseases-conditions/hic-psoriatic-arthritis. aspx. Accessed November 22, 2013.

6. Walsh N. FDA OKs Stelara for psoriatic arthritis.

MedPage Today. September 24, 2013. www.medpage today.com/Rheumatology/Arthritis/41808. Accessed November 19, 2013.

7. Stelara (ustekinumab) injection [prescribing in­ formation]. Horsham, PA: Janssen Biotech, Inc; September 2013.

8. Johnson & Johnson. Stelara (ustekinumab) receives FDA approval to treat active psoriatic arthritis: first and only anti-IL-12/23 treatment approved for adult patients living with psoriatic arthritis. Press release.

September 23, 2013. www.investor.jnj.com/release detail.cfm?ReleaseID=792461. Accessed November 20, 2013.

9. Felson DT, Anderson JJ, Boers M, et al; for the American College of Rheumatology. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum.

1995;38:727-735.

10. Van Voorhees A, Feldman SR, Koo JY, et al; for the National Psoriasis Foundation. The psoriasis and psoriatic arthritis pocket guide: treatment algorithms and management options. 2009. www.psoriasis.org/ document.doc?id=354. Accessed November 25, 2013.

11. Goodless D. What is a PASI score? Updated May 21, 2008. http://psoriasis.about.com/od/psoriasisfaqs/ f/pasi.htm. Accessed November 21, 2013.

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