VBCR October 2013

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www.ValueBasedRheumatology.com

Burden of Musculoskeletal Disorders in the United States Greatest number of years lived with disability

By Eileen Koutnik-Fotopoulos

VBCR Perspective

The Many Rewards of Participating in Clinical Research for Physicians and for Patients

By Jeffrey S. Peller, MD Dr Peller is Practicing Rheumatologist at Harbin Clinic/Rheumatology in Rome, GA

I Copyright © MedicalRF/Science Source

had my first experience with clinical research during my fellowship 30 years ago. The new drug isotretinoin (Accutane) was being used to treat acne, and the concern was that it triggered spondyloarthritis. Rheumatologists were therefore asked to evaluate young patients who were being treated with that drug, and I was one of those rheumatologists.

This first experience had lasting

Although life expectancy in the United States increased during the period of 1990 to 2010, and the United States

spends more per person on health than any other country, Americans

Continued on page 11

Durable Improvement Achieved with Ustekinumab in Psoriatic Arthritis

Stelara a new treatment option for this patient population

By Phoebe Starr Madrid, Spain—One-year open-label follow-up of the phase 3 PSUMMIT 2 trial showed that the early improvement that was achieved by week 24

with ustekinumab (Stelara), an interleukin (IL)-2 and IL-23 antagonist, was sustained at week 52 in patients Continued on page 8

Continued on page 10

New Recommendations Issued for the Treatment of Patients with Systemic Juvenile Idiopathic Arthritis Canakinumab, rilonacept, and tocilizumab considered for the first time

By Rosemary Frei, MSc New recommendations from the American College of Rheumatology for the treatment of patients with systemic juvenile idiopathic arthritis

(JIA) have been published simultaneously in the October 2013 issues of Arthritis Care & Research (Hoboken) (Ringold S, et al. 2013;65:1551-1563)

Continued on page 9

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

Value-based care will change medicine FDA UPDATE. . . . . . . . . . . . . . . . . . . . . .

Stelara for psoriatic arthritis GOUT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

New study highlights gout characteristics

4 4 8

VBCR PERSPECTIVES. . . . . . . . . . . 10 Systemic lupus erythematosus: value and the art of medicine HEALTH ECONOMICS. . . . . . . . . . 11 Rituximab infusions given in private clinics can reduce costs © 2013 Engage Healthcare Communications, LLC

benefits for me as a rheumatologist. It made concrete the need to specifically define patient populations, study entry criteria, exclusion criteria, primary outcomes, secondary outcomes, statistical requirements for study validity, and the importance of reporting of adverse events and serious adverse events.

As a practicing rheumatologist, these have been essential measures for

RHEUMATOID ARTHRITIS. . . . 19 Patients with early RA rate quality of life as worse than death Personalized Medicine in Rheumatology™ . . . . . . . . . . . . . . . . . .

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Genetic variants and environmental factors predict RA risk LUPUS . . . . . . . . . . . . . . . . . . . . . . . . . . . .

BTK inhibitors promising in lupus

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OSTEOARTHRITIS. . . . . . . . . . . . . . 23 Patients with lower-limb arthritis should keep exercising DRUG UPDATE. . . . . . . . . . . . . . . . . . 24 Simponi Aria approved for moderate-­ to-severe RA

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.

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

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In This Issue

Publishing Staff Senior Vice President/Group Publisher Nicholas Englezos nick@engagehc.com Director, Client Services Zach Ceretelle Editorial Director Dalia Buffery dalia@engagehc.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 Travean Digital Programmer Michael Amundsen Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Engage Healthcare Communications, LLC 1249 South River Road, Ste 202A Cranbury, NJ 08512 Telephone: 732-992-1882 Fax: 732-992-1881

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.

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.

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VALUE PROPOSITIONS

RHEUMATOID ARTHRITIS

New proteins are potential targets for anti-­ inflammatory therapies More…

Golimumab plus methotrexate reduce the symptoms of rheumatoid arthritis More…

FDA UPDATE

Personalized Medicine in Rheumatology™

Stelara approved for active psoriatic arthritis

Gout New study highlights poor quality of life and increased disability in gout

Genetic variants and environmental factors predict rheumatoid arthritis risk

LUPUS BTK inhibitors show promise in lupus

VBCR PERSPECTIVES Systemic lupus erythematosus: value and the art of medicines More…

OSTEOARTHRITIS

HEALTH ECONOMICS

DRUG UPDATE

Rituximab given in private clinics can reduce costs More…

Simponi Aria approved for moderate-to-severe rheumatoid arthritis

Tell your patients with lower-limb arthritis to keep exercising

VBCR Editorial Advisory Board Howard B. Blumstein, MD

James T. Kenney, Jr, RPh, MBA

Scott Breidbart, MD

Muhammad Asim Khan, MD

Rheumatology Associates of Long Island Smithtown, NY Chief Medical Officer Empire BlueCross BlueShield New York, NY Gary R. Feldman, MD, FACR

Private Practice Pacific Rheumatology Los Angeles, CA

Gary L. Johnson, MD, MS, MBA

Regional Medical Director Humana, Inc. Madison, WI

Atheer A. Kaddis, PharmD

Vice President, Managed Markets Diplomat Specialty Pharmacy Swartz Creek, MI Shelly P. Kafka, MD, FACR

Rheumatologist, Mountain State Rheumatology Medical Director, Mountain State Clinical Research Clarksburg, WV Clinical Assistant Professor West Virginia University School of Medicine Morgantown, WV

Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA

Lynn Nishida, RPh

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

Professor of Medicine Case Western Reserve University Cleveland, OH

Gary M. Owens, MD

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

Kim A. Papp, MD, PhD

Randall Krakauer, MD, FACP, FACR

National Medical Director Medicare, Aetna Princeton, NJ

President, Gary Owens Associates Philadelphia, PA 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

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

Manager, Pharmacy Services SelectHealth Murray, UT

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.

october 2013

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Value Propositions Value-Based Care Will Change the Face of Medicine

In a recent guest blog on the Harvard Business Review website, Toby Cosgrove, MD, President and CEO of the Cleveland Clinic in Ohio, suggested that value-based care represents a life-saving “breakthrough” by focusing on lowering costs and improving quality of care and outcomes as its main goals. According to Dr Cosgrove, value-based care “is being slowed by criticism, misunderstanding, and a reluctance to do things differently,” but it is inevitable, and it will change the way medicine is being practiced in this country.

Value-based care “will eventually affect every patient across the United States. Not everyone, however, is on board yet, because part of the value-based equation is that hospitals will be paid less to deliver better care.

That’s quite a challenge, but one that [the] Cleveland Clinic is embracing as an opportunity to do better. Others must, too,” says Dr Cosgrove.

Value-based care, Dr Cosgrove notes, is moving away from a fee-forservice reimbursement model to a system that rewards quality and patient outcomes. “No longer will healthcare be about how many patients you can see, how many tests and procedures you can order, or how much you can charge for these things. Instead, it will be about costs and patient outcomes: quicker recoveries, fewer readmissions,… and fewer medical errors….In other words, it will be about value. And that is good.”

He predicts that as medicine is increasingly becoming a data-driven science, there will be further consolidation from community hospitals to large hospitals that are driven by physicians “based on what is best for the patient.” Reducing waste and unnecessary procedures or tests are keys to lowering costs without compromising quality.

“A key part of the cost solution is to educate all caregivers, including doctors, about what items cost,” Dr Cosgrove says. Harvard Business Review Blog Network; September 24, 2013

New Proteins Are Potential New Targets for Anti-Inflammatory Therapies

An inflammatory signaling pathway has been identified that involves key signaling proteins in the inflammatory process that are responsible for many inflammatory diseases, including rheumatoid arthritis (RA) and psoriasis. The proteins were identified by researchers from The Scripps Research Institute (TSRI), and may suggest potential new treatments for these inflammatory diseases.

“We hope our approach will lead to the development of drugs that augment current anti-inflammatory strategies,” said TSRI Assistant Pro-

fessor Young Jun Kang, principal investigator for this new study (Ma J, et al. Sci Signal. 2013;6:ra87).

The inflammatory pathway is triggered by Toll-like receptors (TLRs) on white blood cells, which recognize the molecular patterns that are associated with common microbes. When detecting such inflammatory or bacterial intruders, the TLRs produce within the host cells a variety of inflammatory and antimicrobial compounds, including the inflammatory protein tumor necrosis factor-alpha, which are involved in RA. This discovery further adds to previous research showing that this type of inflammation typically has an early acute phase and a late sustained phase—2 phases that are driven by clusters of signaling molecules, and which could help to develop new therapies to suppress the late phase, while leaving the early phase intact to fight infections and inflammation. Medical News Today; October 14, 2013

A Panel of 6 Biomarkers Can Predict Atherosclerosis in Patients with SLE

In a new study, PREDICTS, which was supported by the Lupus Research Institute, the Alliance for Lupus Research, the American College of Rheumatology Research and Education Foundation, the National Institutes of Health, the Arthritis Foundation, the Iris Cantor Women’s Health Foundation, the Arthritis National Research Foundation, and a Kirkland Award, a panel of 6 biomarkers was shown able to predict which female patients with systemic lupus erythematosus (SLE) are at increased risk for cardiovascular events as confirmed by carotid artery ultrasound examinations.

Female patients with SLE with a high-risk score on the PREDICTS scale had a 28-fold increased risk for having or acquiring carotid plaque on serial ultrasounds during a 2-year period versus patients with SLE whose scores were lower on the PREDICTS scale, and who were at much higher risk (odds ratio, 15.5) of showing plaque progression, according to Maureen McMahon, MD, Rheumatology Division at the University of California, Los Angeles, and colleagues.

The score was more accurate at predicting the incidence or progression of carotid plaque than were any individual biomarkers or any other panel of traditional cardiovascular risk factors in patients with SLE. These 6 biomarkers were combined into the PREDICTS score, which resulted in the best predictive profile of any of the variables tested alone and in combination. Dr McMahon and colleagues noted, “Our study was not exhaustive. It is likely that other, additional biomarkers have been or will be identified as promising candidates” to include in the PREDICTS scale, they added. McMahon M, et al. Arthritis Rheum; 2013 Sep 24.

Epub ahead of print

FDA Update FDA Approves Stelara for Active Psoriatic Arthritis

The US Food and Drug Administration (FDA) approved the first anti– interleukin (IL)-12 and anti–IL-23, ustekinumab (Stelara; Janssen Biotech), alone or in combination with methotrexate, for the treatment of adult patients aged ≥18 years with active psoriatic arthritis.

“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,” said investigator Alice B. Gottlieb, MD, PhD, Chief and Dermatologist-in-Chief,

4

Department of Dermatology, Tufts Medical Center, who is also certified in rheumatology. “Therapy that targets the cytokines interleukin-12 (IL-12) and interleukin-23 (IL-23), 2 naturally occurring proteins believed to play a role in the development of this debilitating immune-mediated inflammatory disease, could improve patient care,” Dr Gottlieb said.

The FDA approval of Stelara is based on safety and efficacy results from 2 pivotal phase 3, multicenter, randomized, double-blind, placebo-controlled trials of ustekinumab, a fully human anti–IL-12 and IL-23p40 monoclonal antibody—PSUMMIT I and PSUMMIT II. In these trials, ustekinumab

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was administered subcutaneously in doses of 45 mg or 90 mg at weeks 0 and 4, and then every 12 weeks. A total of 927 patients with active psoriatic arthritis who had at least 5 tender and 5 swollen joints and C-reactive protein levels of ≥0.3 mg/dL despite previous treatment with conventional therapy, were included in these 2 trials. PSUMMIT II also included 180 patients who were previously exposed to 1 of 5 tumor necrosis factor inhibitors.

In PSUMMIT I, at week 24, 42% of patients receiving ustekinumab 45 mg and 50% of patients receiving 90 mg achieved at least a 20% improvement in the American College of Rheumatology criteria (ACR20), the primary end

point for the 2 trials. In PSUMMIT II, 44% of patients receiving ustekinumab 45 mg and 44% of patients receiving 90 mg achieved ACR20 by week 24. In addition, ustekinumab improved soft-tissue components of the disease, including dactylitis, enthesitis, and skin component as measured by Psoriasis Area and Severity Index 75.

Ustekinumab was approved in 2009 by the FDA for the treatment of patients with moderate-to-severe plaque psoriasis. When used for the treatment of patients with psoriatic arthritis, ustekinumab is administered as a 45-mg subcutaneous injection at weeks 0 and 4, and then every 12 weeks thereafter. (September 23, 2013) VOL. 2

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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 % % 15 12 Nausea Diarrhea 12 9 8 Pyrexia 10 Nasopharyngitis 9 7 Bronchitis 9 5 Insomnia 7 5 Pain in extremity 6 4 Depression 5 4 5 4 Migraine Pharyngitis 5 3 3 Cystitis 4 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

Psoriatic Arthritis

Durable Improvement Achieved with Ustekinumab... with psoriatic arthritis who had previously received as well as those who had not previously received an anti– tumor necrosis factor (TNF) inhibitor, said lead investigator Christopher T. Ritchlin, MD, MPH, Chief, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, NY, at the 2013 European League Against Rheumatism annual meeting.

In September 2013, the US Food and Drug Administration (FDA) approved ustekinumab (Stelara), alone or in combination with methotrexate, for the treatment of adult patients with active psoriatic arthritis (see page 4). Ustekinumab was previously approved by the FDA for adult patients with moderate-to-severe psoriasis.

Ustekinumab is a good treatment option for patients who fail to respond to anti-TNF therapy. Heretofore no good options were available for such patients, who represent a substantial population, Dr Ritchlin

said. “Now an alternative drug has demonstrated improvements not just in anti-TNF–naïve patients, but also in those who have been treated with one or more anti-TNF agent,” he said.

“Now an alternative drug has demonstrated improvements not just in anti-TNF–naïve patients, but also in those who have been treated with one or more anti-TNF agent.”

—Christopher T. Ritchlin, MD, MPH Study Results The study included 312 patients randomized to 1 of 3 arms—placebo, ustekinumab 45 mg daily, and ustekinumab 90 mg daily. Patients received ustekinumab at week 0, week 4, and week 16, followed by every 12 weeks up to week 40, or placebo at week 0,

week 4, and week 16, followed by a crossover to ustekinumab 45 mg for week 24, week 28, and week 40. Of the 312 patients, 180 were previously exposed to between 1 and 5 anti-TNF agents.

In the 24-week results of PSUMMIT2, ustekinumab led to a significantly better American College of Rheumatology 20% criteria for improvement (ACR20) response compared with placebo (P <.001).

ACR20 response was sustained from week 24 in an open-label trial in which all patients received ustekin­ umab 45 mg or 90 mg. ACR20 responses with ustekinumab at week 52 were 46.8% in the lower-dose arm and 48.4% in the higher-dose arm.

Although responses were observed in all patients, the rate was higher in the anti–TNF-naïve patients versus in previously anti-TNF inhibitor–treated patients. ACR20 was achieved by 59% to 73% of the patients in the treatment-naïve group versus by 37% to

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41% of patients in the treatment-experienced group.

Ustekinumab treatment also improved physical function according to the Health Assessment Questionnaire-Disability Index. Skin involvement with psoriatic plaque was improved by at least 75% on the Psoriasis Area and Severity Index (PASI 75), and the drug improved dactylitis and enthesitis. No new ustekinumab-related safety concerns emerged in this trial.

Overall ACR50 response at week 52 was 29% for the placebo group assigned to 45 mg of ustekinumab, 28% for ustekinumab 45 mg, and 26% for ustekinumab 90 mg. ACR70 response rates were 16%, 12%, and 18%, respectively. PASI 75 was seen in 56%, 57%, and 84% of patients, respectively.

Ustekinumab was well tolerated, with no deaths, tuberculosis, or opportunistic infections being reported through 60 weeks of the study. No new safety signals were reported related to ustekinumab. n

Gout

Poor Quality of Life and Increased Disability in Gout Highlighted in a New Study

By Rosemary Frei, MSc

A

new multicenter study confirms that there is an independent association between gout and gout-related characteristics on the one hand and functional impairment and quality of life on the other. For example, polyarticular joint involvement is significantly associated with increased disability and with poorer overall quality of life for this patient population (Scirè CA, et al. Arthritis Res Ther. 2013;15:R101).

Investigators from the Italian Society for Rheumatology’s Kick-off of the Italian Network for Gout (KING) recruited patients with gout who were se­ lected by random sampling from rheumatology centers across Italy for this national, multicenter, cohort study.

A total of 446 patients with gout from 30 rheumatology centers between June 2011 and January 2012 were included in the study. Overall, 99% of the patients were Caucasian, 90.4% were male, and their average age was 63.9 years. Most were overweight or obese, and 90% had at least 1 comorbidity.

Furthermore, more than 92% of the patients fulfilled the preliminary

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American College of Rheumatology criteria for gout. The median disease duration at baseline was 3.8 years.

Approximately 30% of the patients had an attack of gout in the month before the baseline clinical evaluation.

Of the patients, 410 had their serum urate levels assessed at baseline, and 214 (52.2%) of these patients had levels of >6 mg/dL, despite the majority receiving urate-lowering therapy.

Health Assessment Questionnaire– Disability Index (HAQ-DI) scores were assessed for 444 of the patients.

Of these, 72 (16.2%) patients had scores corresponding to moderate functional ability, and 22 (4.95%) had scores indicative of severe disability.

The median HAQ-DI score was 0.25.

As expected, the patients’ Short Form-36 Physical Component Summary (SF-36 PCS) scores were lower than for individuals in the age- and sex-matched general population.

The results also revealed that female sex and lower education significantly influenced functional disability and SF-36 PCS scores. Furthermore, having comorbidities and being over-

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weight or obese were significantly associated with higher HAQ-DI scores and with lower SF-36 PCS scores in age- and sex-adjusted models.

“Given that excess disability is seen in patients whose disease has evolved to a chronic arthropathy, we concluded that…preventing the transition from acute to chronic arthropathy by appropriate therapeutic strategies is the mainstay of the management of gout, in order to limit both shortand long-term consequences of the disease.”

—Carlo A. Scirè, MD, PhD

In addition, indications of chronic disease, such as longer disease dura-

tion and the presence of tophi, as well as the presence of uncontrolled joint inflammation, were significantly associated with higher HAQ-DI scores and lower SF-36 PCS scores. For example, polyarticular involvement was associated with an odds ratio of 3.82 for a higher HAQ-DI score. Gout duration of more than 5 years was associated with an odds ratio of 2.03, and the presence of tophi was associated with an odds ratio of 1.92.

“In this context, given that excess disability is seen in patients whose disease has evolved to a chronic arthropathy, we concluded that—independently of the obvious need to control general risk factors, such as hypertension, diabetes, obesity—preventing the transition from acute to chronic arthropathy by appropriate therapeutic strategies is the mainstay of the management of gout, in order to limit both short- and long-term consequences of the disease,” said principal investigator Carlo A. Scirè, MD, PhD, Coordinator of the Epidemiology Unit, Italian Society for Rheumatology, Milan. n VOL. 2

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Systemic JIA

New Recommendations Issued for the Treatment of Patients with Systemic Juvenile Idiopathic...

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and Arthritis & Rheumatism (Ringold S, et al. 2013;65:2499-2512).

This is the first time rheumatology recommendations or guidelines have been published in these 2 journals simultaneously, signaling the importance of proper management of this condition, which affects between 4% and 15% of children with JIA. One highlight of the new recommendations is that they include considerations for the recently approved drug canakinumab (Ilaris), as well as the more established drugs rilonacept (Arcalyst) and tocilizumab (Actemra), none of which were included in the original 2011 ACR recommendations (Beukelman T, et al. Arthritis Care Res [Hoboken]. 2011;63:465-482), because these treatments were not available in earlier years; they target the cytokines interleukin (IL)-1 and IL-6—cytokines that are central to the development of systemic JIA. The new recommendations are also applicable to 3 different phenotypes of systemic JIA compared with 1 phenotype in the 2011 version. In addition, the new guidelines address repeat tuberculosis screening for all patients with JIA who are receiving biologic agents.

at a glance ➤ The ACR has issued new recommendations for the treatment of systemic JIA ➤ The recommendations highlight the use of canakinumab, rilonacept, and tocilizumab, which were not included in the 2011 recommendations ➤ They also address repeat tuberculosis screening for all patients with JIA who are receiving biologics ➤ The 3 phenotypes of systemic JIA being discussed include patients with active systemic features and varying degrees of synovitis, patients without active systemic features, and systemic JIA with features related to macrophage activation syndrome ➤ Combination therapy with a biologic agent, as well as costs, were not considered in the new guidelines

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Combination therapy with a biologic agent was not considered, nor was cost. The latter is because, as Sarah Ringold, MD, MS, Codirector, Clinical Research, Seattle Children’s Hospital, WA, told Value-Based Care in Rheumatology, “By definition, the

“Few data are available regarding the costeffectiveness of medications for JIA, in part due to lack of validated metrics for this outcome, and generating such data was beyond the scope of the project.”

—Sarah Ringold, MD, MS

RAND/UCLA Appropriateness Methodology, used for both the current recommendations and the 2011 recommendations, excludes cost. [Also,] few data are available regarding the cost-effectiveness of medications for JIA, in part due to lack of validated metrics for this outcome, and generating such data was beyond the scope of the project.”

Dr Ringold is a joint first investigator of the recommendations, along with Pamela F. Weiss, MD, MSCE, Associate Professor of Pediatrics, Children’s Hospital of Philadelphia, PA. An 11-member core expert panel and a 12-member task force panel worked together on creating the new recommendations, which were based on a systematic literature review and a series of clinical scenarios. Most of the recommendations were based on levels C and D evidence, which are uncontrolled studies and expert opinion, respectively.

Clinical Scenarios I: Patients with Active Systemic JIA Features For the clinical scenario of patients with active systemic features of the disease and varying degrees of synovitis, the main recommendations for drug therapies, with recommended agents being listed in alphabetical order, are: • First-line therapy with anakinra (Kineret), oral or intravenous sys-

temic glucocorticoid monotherapy, or nonsteroidal anti-inflammatory drugs (NSAIDs), depending on the patient’s active joint count (AJC) and physician global assessment (MD-global) • If disease activity persists in patients initially treated with anakinra for a month, they should be given canakinumab, tocilizumab, methotrexate (Trexall), or leflunomide (Arava), or a tumor necrosis factor (TNF)-alpha inhibitor, depending on their AJC • If disease activity persists in patients initially treated with glucocorticoid monotherapy for 2 weeks, they can be given a trial of either anakinra, canakinumab, tocilizu­ mab, methotrexate, or leflunomide, depending on their MD-global scores • Patients whose disease activity persists despite 1 month of NSAID treatment can be given anakinra, glucocorticoid monotherapy, cana­ kinumab, or tocilizumab, depending on their AJC and MD-global scores • Patients who still have disease activity after 1 month of anakinra as the second drug therapy can be given the next round of continued therapy with canakinumab, tociliz­ umab, methotrexate, or leflunomide, or a TNF-alpha inhibitor, depending on their AJC • Children with symptoms that persist after 1 month of glucocorticoids as second drug therapy can be given anakinra, canakinumab, methotrexate, or leflunomide, or tocilizumab, depending on their AJC and MD-global scores • All patients can be given adjunct intra-articular glucocorticoid injections or systemic glucocorticoids, as needed at any point in their therapy.

Clinical Scenarios II: Patients without Active Systemic Features The main recommendations for patients without active systemic features are: • Patients with an AJC of >4 should be given initial therapy of either methotrexate or leflunomide, or NSAID monotherapy • Patients with an AJC of >0 but ≤4 should be given initial NSAID monotherapy or an intra-articular glucocorticoid injection • Patients who still have symptoms after 3 months of methotrexate or october 2013

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leflunomide treatment and an AJC of >0 should receive continued therapy with abatacept (Orencia), anakinra, a TNF-alpha inhibitor, or tocilizumab • Patients with disease activity after 1 month of NSAID therapy should be given anakinra, methotrexate, or leflunomide, depending on their AJC • Those with disease activity after an initial glucocorticoid injection should receive continued therapy with either anakinra, or methotrexate or leflunomide, depending on their AJC • If patients still have symptoms after 1 month of anakinra as a second drug therapy and their AJC is >0, they can be given the next round of continued therapy with abatacept, methotrexate, leflunomide, a TNF-alpha inhibitor, or tocilizumab

Most of the recommendations were based on levels C and D evidence, which are uncontrolled studies and expert opinion, respectively.

• Patients with persisting symptoms after 3 months of methotrexate or leflunomide as second drug therapy and an AJC of >0 can be given the next round of continued therapy with abatacept, anakinra, a TNF-alpha inhibitor, or tocilizumab.

Clinical Scenario III: Systemic JIA plus Macrophage Activation Syndrome The third clinical scenario is systemic JIA with features concerning for macrophage activation syndrome.

The initial options are anakinra, a calcineurin inhibitor, or systemic oral or intravenous glucocorticoid monotherapy.

The experts also recommended that patients who test negative for tuberculosis before starting a biologic agent have another test if their tuberculosis risk changes to moderate or high as determined by infectious disease guidelines in their area. n

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VBCR Perspectives

The Many Rewards of Participating in Clinical Research for Physicians and for...

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me to understand and consider, as new treatments have become available.

In my private practice, I was excited to discover that opportunities for clinical research existed “in the community,” that is, outside of a university hospital setting. My first study in private practice was for misoprostol (Cytotec). At that time, it was a novel idea that we might prevent nonsteroidal anti-inflammatory drug–induced ulcers. I conducted this study with my office staff, but over the years, clinical research has grown to be a more significant part of my practice. I have been a principal investigator for dozens of studies, and the level of required reporting and record-keeping would be very difficult without having a registered nurse who is certified in clinical research.

As I evaluate my experience with clinical research, I have considered the many benefits it has offered. First and

Many of the patients who participate in clinical studies Jeffrey S. Peller, MD receive direct benefits, such as those who received a biologic treatment for rheumatoid arthritis before it became available by prescription, and got it for no cost. foremost, I know that every treatment available for my patients is in part the

results of someone, somewhere, who participated in a clinical study. When my patients participate in a clinical trial, they often tell me they feel that they are providing a service that goes beyond their self-­interest. Sure, they hope that a new treatment would help them, but I have often heard them express the hope that it would help their children and grandchildren.

Many of the patients do receive direct benefits, such as those who received a biologic treatment for rheumatoid arthritis before such treatment became available by prescription, and got it for no cost. In the current medical environment, getting free office visits, medications, laboratory testing, and imaging has much value, and may be the only way some patients can get these treatments. So, from the patient perspective, there are tangible and intangible benefits.

The same can be said for the benefits

I have experienced as a clinician— some are tangible and some are intangible. With proper selection of studies and negotiation of payment, clinical research can offer revenue to your practice. Since 2000, clinical research has added, on average, 11% annually to my practice revenue. In addition, patients often perceive my participation in research as a sign of excellence and my staying on top of the newest treatments. For example, doing research offered me years of experience with anti-TNF (tumor necrosis factor) agents years before I was able to prescribe them to my patients. It also gave me access to extensive information about treatments in a setting removed from pharmaceutical marketing.

In my experience, clinical research has been a worthwhile endeavor. It offers value to the pharmaceutical company, to my patients, to future patients, to society, and to me as a clinician. n

Systemic Lupus Erythematosus: Adding Value to Our Patients with the Art of Medicine

T

By John Kolstoe, MD Dr Kolstoe is in private practice at Kolstoe Rheumatology: Musculoskeletal Medicine, East Lansing, MI, and an editorial board member of Value-Based Care in Rheumatology

he August 2013 issue of Value-­ Based Care in Rheumatology devoted 3 articles to systemic lupus erythematosus (SLE). Two of the articles pertained to refining the clinical “state” of SLE through newer laboratory criteria (“New Biomarkers and Biomarker Panels Show Promise for Diagnosing and Monitoring Patients with Lupus”)1 or through available clinical criteria (“New Diagnostic Algorithm for SLE Can Facilitate Early Treatment, Improve Outcomes”)2; the third article reviewed the effect of treatment with vitamin D (“Increasing Vitamin D Intake in Patients with Lupus Provides Modest Benefit”).3 All 3 articles will assist the clinician’s decision on how and when to treat the individual patient with SLE. The science of medicine yields models to explain the nature of disease. Science helps us to ask pertinent questions of the individual patient. The answers to these questions guide a diagnosis to determine the risks versus benefits related to symptoms versus treatments for the individual patient.

The “art of medicine” is the application of the “science of medicine” onto

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the unique individual patient. The art of medicine (or the “cycle of clinical care”) consists of translating an individual’s symptoms into a diagnosis, which, in turn, leads to treating the patient, and then repeating the process as needed or as tolerated. The art of medicine provides value-based care to the patient, guided by models derived from the science of medicine.

SLE has long been noted for its pleomorphism, making it difficult to conform to an exclusive diagnostic and treatment regimen. The American Rheumatism Association in the 1960s recognized this complexity and sponsored a committee to develop criteria for the classification of SLE to form a more uniform patient population to study. The articles discussing new biomarkers and a new algorithm for SLE continue these efforts to fine-tune the science of medicine.1,2 Science has confirmed the polygenetic background allowing for multiple autoimmune disorders “overlapping” in a patient with SLE and/or in the patient’s family members. Genome-wide studies have identified more than 30 loci seen with a high enough frequency to be tied to autoimmunity. Few of

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these loci confer enough risk to explain the full manifestation of autoimmunity, but the more loci (approximately 4+), the greater the risk.

We do not treat groups of patients, we treat individuals.

From a probabilistic point of view, the number of ways 4 items can be chosen from 30 different items is 27,405 (ie, 30 × 29 × 28 × 27 ÷ 4 × 3 × 2 = 27,405). This would be the number of possible genetic combinations that could underlie a clinical presentation of SLE. This explains the uniqueness of the individual patient, and why no 2 individual patients are likely to be “identical” in their disease manifestation, let alone in their response to a therapy.

Even the immune systems of socalled identical twins evolve somatic mutations (genetic and epigenetic) to respond to new environmental exposures.4,5 This explains the lack of uniform disease manifestations in identi-

cal twin pairs. Individuals are unique, therefore rarely “fulfilling criteria.”

Using the cycle of clinical care, our “diagnosis” is close enough to the model disorder (ie, SLE) to warrant either treatment or further observation.

We do not treat groups of patients, we treat individuals. Two of the articles mentioned above address constellations of laboratory values or clinical features—criteria that could refine “treatment thresholds” for the individual patient. The vitamin D study used a group of patients who fulfill SLE criteria to see if that group derives benefit from such treatment. Devising these criteria to help determine “how sick” a patient is can help to define the value of a therapeutic medicine needed in value-based care. n References

1. Frei R. New biomarkers and biomarker panels show promise for diagnosing and monitoring patients with lupus. Value-Based Care in Rheumatology. August 2013;2(4):1.

2. Frei R. New diagnostic algorithm for SLE can facilitate early treatment, improve outcomes. Value-Based Care in Rheumatology. August 2013;2(4):15.

3. In The Literature. Increasing vitamin D intake in patients with lupus provides modest benefit. ValueBased Care in Rheumatology. August 2013;2(4):14.

4. Taylor KE, Chung SA, Graham RR, et al. Risk alleles for systemic lupus erythematosus in a large case-­control collection and associations with clinical subphenotypes. PLoS Genet. 2011;7:e1001311.

5. Anaya JM, Gómez L, Castiblanco J. Is there a common genetic basis for autoimmune diseases? Clin Dev Immunol. 2006;13:185-195.

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Health Economics

Burden of Musculoskeletal Disorders in the United States...

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are not necessarily healthy. And even though life expectancy has risen over the years in the United States, the increase is lower than that in other developed countries. Morbidity and chronic disability now account for nearly 50% of the US health burden.

Of all chronic diseases, musculoskeletal disorders are one of the key contributors to the increases in chronic disability in the United States, accounting for the conditions with the

“The diseases with the largest number of YLDs in 2010 were low back pain, major depressive disorder, other musculoskeletal disorders, neck pain, and anxiety disorders. As the population aged, YLDs have comprised a larger share of the disability-adjusted lifeyears than have YLLs.” —US Burden of Disease Collaborators

greatest number of years lived with disability (YLDs), based on a new report from the US Burden of Disease Collaborators, titled “The state of US health, 1990-2010: burden of diseases, injuries, and risk factors” (JAMA. 2013;310:591-608).

According to this new report, the leading risk factors contributing to the rising disease burden include poor diet, smoking, high body mass index, and high blood pressure.

However, musculoskeletal conditions lead the way in terms of the number of YLDs in the United States.

“The diseases with the largest number of YLDs in 2010 were low back pain, major depressive disorder, other musculoskeletal disorders, neck pain, and anxiety disorders. As the population aged, YLDs have comprised a larger share of the disability-adjusted life-years than have YLLs [years of life lost due to premature mortality],” the team of collaborators states.

The research team, which consisted of 488 scientists from 50 countries led by the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, Seattle, used the same VOL. 2

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methodology as that used in the Global Burden of Disease (GBD) Study 2010 for this analysis. The investigators reviewed data from population health surveys to quantify health loss on 291 diseases and injuries and 67 risk factors from 1990 to 2010 across 34 countries. Primary outcome measures included YLLs; YLDs; disability-adjusted life-years; and healthy life expectancy, which looks at overall population health and factors in mortality and disability.

Overall, life expectancy in the United States increased from 75.2 years in 1990 to 78.2 years in 2010; during the same period, healthy life expectancy increased from 65.8 years to 68.1 years. However, the gap between life expectancy and healthy life expectancy increased from 9.4 years to 10.1 years, indicating that longevity does not necessarily translate to good health. Although the United States has made significant health improvements over the past 2 decades, other countries are improving at a faster rate. Furthermore, “in some US counties, life expectancy has decreased in the past 2 decades, particularly for women,” the research team reports.

As a result, among its economic peer countries, the United States fell in the rankings between 1990 and 2010 on nearly every major health issue. The US rank for the age-standardized death

with the largest number of YLLs were ischemic heart disease, lung cancer, stroke, chronic obstructive pulmonary disease, and road injury.

Since 1990, there has been a steady

“In the past we either made no separate estimates (ie, other musculoskeletal disorders, neck pain) or underestimated the true extent of the prevalence (ie, low back pain). In addition, the extensive survey work on disability weights… showed that the general public gave relatively more severe weights to conditions involving pain.”

—Theo Vos, MD, MSc, PhD

rate fell from 18th to 27th. Life expectancy at birth dropped from 20th to 27th, and healthy life expectancy fell from 14th to 26th. Diseases and injuries

anking of 30 Leading US Diseases Contributing to YLDs, by 2010 Table R Descending Order 2010 ranking 1990 ranking YLDs Condition of YLDs of YLDs in 2010 Low back pain 1 1 24.9 Major depressive disorder

2

2

42.7

Other musculoskeletal disorders

3

3

28.5

Neck pain

4

4

29.1

Anxiety disorders

5

5

21.3

COPD

6

6

34.1

Drug use disorders

7

7

20.1

Diabetes

8

8

56.2

Osteoarthritis

9

12

56.1

Asthma

10

9

21.2

Falls

11

15

54.1

Alzheimer disease

12

a

17

56.0

Ischemic heart disease

16

b

16

25.4

Rheumatoid arthritis

23

c

24

28.3

Epilepsy

30

30

25.0

13-15: alcohol use, migraine, schizophrenia.

17-22: stroke, bipolar disorder, other hearing loss, dysthymia, sickle-cell disorder, chronic kidney disease. c 24-29: benign prostatic hyperplasia, eczema, road injuries, other vision loss, edentulism, diarrheal diseases.

COPD indicates chronic obstructive pulmonary disease; YLDs, years lived with disability.

Source: US Burden of Disease Collaborators. JAMA. 2013;310:591-608. a

b

shift from conditions that shorten life to chronic disability from musculoskeletal conditions, mental and behavioral disorders, and neurological conditions. The investigators note that research and drug development has had more success in finding solutions for the prevention of heart disease and some cancers and their associated risk factors than for the leading causes of disability in the United States, including low back pain, neck pain, osteoarthritis, and rheumatoid arthritis (Table).

Although heart disease still leads the way as a cause for disease-related mortality, its disability burden is lower than that of many musculoskeletal disorders, as shown in the Table. “Cardiovascular diseases, cancer, and chronic respiratory diseases are all related to YLDs, but the largest contributors are the mental and behavioral disorders and the musculoskeletal disorders,” the researchers emphasize.

As shown in the Table, in 2010 alone, low back pain, other musculoskeletal disorders, and neck pain were among the 4 conditions topping the disability list in the United States.

The ranking for these conditions was not changed from 1990 to 2010. Osteoarthritis ranks number 9 in terms of YLDs and rheumatoid arthritis number 23 in 2010, up from number 24 in 1990, despite growing and improved therapies for rheumatic disease conditions.

Continued on page 12

october 2013

I

www.ValueBasedRheumatology.com

11

Health Economics

Pilot Program Shows Rituximab Infusion Can Be Switched to Private Clinics, Reduce Costs

By Rosemary Frei, MSc

A

Canadian pilot program that required patients with rheumatoid arthritis (RA) to use their private and/or public insurance to cover the costs of rituximab (Rituxan) for RA and switch its site of administration from in-hospital to a private clinic may provide a good example for the United States on moving infusion out of the hospital and saving costs in the management of patients with RA. This move from administering rituximab in the hospital to private clinics for patients with RA reduced the overall hospital’s rituximab-associated costs by a total of $323,825 over the 3-month span of the pilot program.

This new approach also required a great deal of preparation for the project team, and physicians now have to spend significantly more time doing administration and paperwork. Yet, the project team constantly improved the process throughout the pilot program, and as a result, approximately 70% of staff and other stakeholders responding to a survey said that they felt positive about the pilot program and agreed that this approach could be emulated in other clinics.

“We heard from a rheumatologist who said, ‘from my own perspective, things have been running very smoothly with this program, and I commend you and your team for tweaking the

process’,” explained project lead Bernadette Chevalier, BSc Pharm, Drug Utilization Pharmacist and Pharmacist Education Coordinator, Pharmacy Services, Capital District Health Authority, Halifax, Nova Scotia, Canada (Chevalier B, et al. Healthc Q. 2013;16:42-47).

well, they then received the rest of their doses in private infusion clinics.

The Pilot Program It took 5 months of planning and preparation to launch this pilot program. One of the major moves during this phase was the hiring of a rheumatology medication resource specialist (MRS). Other steps included in-servicing for nurses, physicians, and pharmacy of the medical day unit and the rheumatology clinic, and establishing contacts with a private infusion clinic and with a company hired by Roche, the drug manufacturer, to administer the company’s Patient Assistance Program. The Patient Assistance Program covers the administration costs of rituximab infusions in the private clinic and up to 30% to 100% of patients’ insurance copayments and deductibles. The hospital acted as payer of last resort for any leftover costs; patients were not expected to pay anything for their rituximab treatment.

The program was launched in June 2012. The MRS worked with patients and rheumatology clinic staff to ensure that patients had private or public drug insurance in place, to enroll them in the Patient Assistance Program, and to help them transition to the private infusion clinic.

Despite ongoing improvements in

“We heard from a rheumatologist who said, ‘from my own perspective, things have been running very smoothly with this program, and I commend you and your team for tweaking the process.’”

—Bernadette Chevalier, BSc Pharm

The goal of the program was to reduce the rituximab drug costs, which have increased considerably over the past 5 years, and to make the best use of resources at the hospital, which is part of the Canadian Capital District Health Authority. The plan was to have rituximab-naïve patients with RA receive their first dose of rituximab at a medical day unit in the hospital. If they tolerated that first dose

the reimbursement processes by Ms Chevalier and the team, patients experienced a significantly longer median time between the writing of the prescription and the first infusion than before the program.

Streamlining continued after the pilot program, resulting in considerably shorter delays. One aspect of the streamlining entailed the MRS and the rheumatologists coordinating and anticipating upcoming patient infusions so the paperwork could be done in advance.

During the 3-month program, the hospital avoided $304,700 in drug costs, and an additional $19,125 for the 51 infusions that were given in private clinics and paid for by the manufacturer’s Patient Assistance Program.

This also meant that other patients at the hospital were able to receive infusions with less delay.

Of the 20 patients who completed an online satisfaction survey, most indicated that they were satisfied with the new approach. In addition, 21 of the 42 hospital staff and external stakeholders involved in the program completed the survey; approximately 70% of them said they felt positive about the pilot and that they thought it could be successfully implemented in other clinics besides rheumatology.

In addition, 62% said they had an increased workload with the switch. n

Burden of Musculoskeletal Disorders in the United States... Continued from page 11

at a glance

➤ Although life expectancy in the United States has risen over the years, the increase is lower than that in other developed countries ➤ Morbidity and chronic disability now account for nearly 50% of the US health burden ➤ Musculoskeletal disorders are key contributors to the increases in chronic disability and are the cause of the greatest number of years lived with disability

12

change over the 10-year period. “In the past we either made no separate estimates (ie, other musculoskeletal disorders, neck pain) or underestimated the true extent of the prevalence (ie, low back pain). In addition, the extensive survey work on disabil-

➤ In 2010 alone, low back pain, other musculoskeletal disorders, and neck pain were among the 4 conditions topping the disability list in the United States ➤ Osteoarthritis ranks number 9 in terms of years lived with disability and rheumatoid arthritis number 23 in 2010, despite growing and improved therapies for these conditions

value-based CARE in Rheumatology

I

October 2013

ity weights, which reflect the relative severity of the range of conditions/ health states for which we estimate disability, carried out in this GBD

Copyright © MedicalRF/Science Source

Theo Vos, MD, MSc, PhD, Professor of Global Health at IHME and a participant in this study as one of the US Burden of Disease Collaborators, offered insight on why the ranking for low back pain, other musculoskeletal disorders, and neck pain did not

skeletal disability varies a lot between the types of conditions,” Dr Vos continued. “We’ve quantified the size of the problem and clearly

“The ability to deal with musculoskeletal disability varies a lot between the types of conditions.

We’ve quantified the size of the problem and clearly show that these problems are highly prevalent, and that there is very significant health loss associated with these conditions.”

—Theo Vos, MD, MSc, PhD study showed that the general public gave relatively more severe weights to conditions involving pain.”

“The ability to deal with musculo-

show that these problems are highly prevalent, and that there is very significant health loss associated with these conditions.” 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.

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.

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.

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.

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

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

Rheumatoid Arthritis

Patients with Early Rheumatoid Arthritis Rate Quality of Life as Worse than Death

By Neil Canavan

A

significant number of patients with early rheumatoid arthritis (RA) rate the impact of pain and discomfort on their lives as causing a health condition worse than death, according to results of a new study known as ESPOIR (Gaujoux-Viala C, et al. Rheumatology. 2013;52: 832-838).

The ESPOIR study, conducted by Cécile Gaujoux-Viala, MD, PhD, Associate Professor of Rheumatology, Nîmes University Hospital, France, and colleagues, determined that at least 11% of patients with early RA consider their quality of health condition at the time of diagnosis as being worse than death, as determined by the health outcomes EuroQol (quality of life) EQ-5D test. Furthermore, at least 3% of patients with early RA held the same negative outlook a full 2 years after being diagnosed.

According to lead investigator Dr Gaujoux-Viala and her colleagues, these results clearly underscore the need to identify, as soon as possible, patients with early RA who are experiencing the greatest pain and discomfort. “EA [early arthritis] patients with a negative EQ-5D score should be a priority for health care: they have specific needs necessitating better management of pain and psychological state.”

The quality-of-life instrument used in this study, the EQ-5D, is an indirect preference-based health-related quality-of-life instrument increasingly used for economic evaluations of clinical interventions and health programs.

The EQ-5D evaluation consists of 5 domains—pain/discomfort, anxiety/depression, mobility, self-care, and usual activity. Each domain is rated on a scale of 1 to 3, with 1

meaning no problem; 2, some problem; and 3, severe problem. A score of 33333 is the worst possible outcome and 11111, the best.

“EA [early arthritis] patients with a negative EQ-5D score should be a priority for health care: they have specific needs necessitating better management of pain and psychological state.”

—Cécile Gaujoux-Viala, MD, PhD, and colleagues

As used in the ESPOIR study, the final interpretation of the EQ-5D results allowed for scores that theoretically corresponded to health states worse than death.

The goal of the study was to describe patients with an EQ-5D score of <0—a health state worse than death— to determine those aspects of early arthritis associated with such a dire condition, as well as to identify patient characteristics that are associated with elevated risk for such an outcome.

Results of ESPOIR Between December

2002

and

March 2005, 813 patients with early RA from 14 French regional centers were included in the study; 78% of patients in this cohort fulfilled the 2010 American College of Rheumatology criteria for RA. All patients completed the EQ-5D, as well as the Health Assessment Questionnaire (HAQ) and the Short Form 36-Item questionnaire (SF-36).

At the time of the initial evaluation, 90 patients had EQ-5D scores of <0; nearly all patients with subzero scores reported extreme pain or discomfort, and 36 (40%) patients were experiencing extreme anxiety or depression.

After 2 years of follow-up, 24 patients still had an EQ-5D of <0, despite having been diagnosed with early RA. Greater risk for an EQ-5D of <0 score was associated with lower educational level, greater disease activity, a higher HAQ score, a lower SF-36 score, and higher levels of the inflammatory biomarker C-reactive protein (all P <.001).

Link to Fibromyalgia Not Explored “The ESPOIR study did not document if patients with poor QoL had fibromyalgia,” wrote Janet Pope, MD, Professor and Chair, Division of Rheumatology, Western University, London, Ontario, Canada, commenting on the ESPOIR results in an editorial in the same issue of Rheumatology.

In previous studies, wrote Dr Pope, patients with fibromyalgia had lower quality of life than patients with RA. For example, in the Canadian Early Arthritis (CATCH) cohort with RA, “the development of fibromyalgia was related to pain and poor mental health, both of which would have a negative effect on QoL. Perhaps pain

at a glance ➤ At least 11% of patients with early arthritis rate the associated pain and discomfort as being worse than death ➤ At least 3% of patients in this study held the same negative outlook a full 2 years after being diagnosed ➤ The ESPOIR trial highlights the great need to identify patients with early arthritis who are experiencing the greatest pain and discomfort ➤ Greater risk was associated with a lower educational level, greater disease activity, and higher levels of C-reactive protein ➤ A higher Health Assessment Questionnaire score and a lower SF-36 score were also predictors of worse EuroQol EQ-5D scores ➤ The development of an instrument specific to early RA may help, thereby providing a clearer picture of the patients who require more aggressive treatment interventions

and fibromyalgia contribute strongly to worse-than-death QoL and not inflammatory arthritis in the ESPOIR cohort.”

That said, Dr Pope described the ESPOIR effort as “valuable” and suggested that the development of an instrument specific to patients with early RA would be more appropriate, thereby providing a clearer picture of those patients requiring more aggressive interventions. n

GO-FURTHER: Golimumab plus Methotrexate Combination Reduces Symptoms of RA Out to 1 Year

By Rosemary Frei, MSc

P

atients with rheumatoid arthritis (RA) whose symptoms continue despite treatment with methotrexate benefit from the addition of golimumab (Simponi Aria). In July 2013, the US Food and Drug Administration approved golimumab for

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this indication (see article, page 24).

The 1-year results from the Golimu­ mab, an Anti-TNF-alpha Monoclonal Antibody, Administered Intravenously, in Subjects with Active Rheumatoid Arthritis Despite Methotrexate Therapy (GO-FURTHER) trial show

that compared with placebo plus methotrexate, the combination of go­ limumab and methotrexate is associated with significantly less structural damage and with sustained clinical improvement (Weinblatt ME, et al; for the GO-FURTHER Investigators. Ann october 2013

I

Rheum Dis. Epub 2013 Sep 3).

The trial included 592 patients with moderately to severely active RA who had at least 6 tender and 6 swollen joints at screening and at baseline, had elevated C-reactive protein levels at screening, and had been receiving Continued on page 20

www.ValueBasedRheumatology.com

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Rheumatoid Arthritis

Researchers Probe Details of Autoimmunity in Rheumatoid Arthritis

By Rosemary Frei, MSc

R

esearchers from across the United States are collaborating to elucidate the details of the complex molecular mechanism that leads to autoimmunity in patients with rheumatoid arthritis (RA), as was outlined in a recent study (Khandpur R, et al.

Sci Transl Med. 2013;5:178ra40).

An earlier study was published 4 years ago, which was the first article to describe neutrophil extracellular traps (NETs) in autoimmune disease (Kessenbrock K, et al. Nat Med. 2009;15:623625). These NETs are composed of a chromatin lattice strewn with particles from neutrophils and other antigens, and they present an attractive target for an autoimmune response.

Lead investigator of the study published in 2013, Mariana Kaplan, MD, Associate Professor of Rheumatology at the University of Michigan, Ann Arbor, explained that NETs are formed when neutrophils are exposed to bacteria, inflammatory cytokines, or autoantibodies. During NET formation, neutrophils extrude the con-

tents of the cells’ nuclei, including the chromatin, as well as their own granular material.

“Through this NET formation things inside the cell get externalized, and some of those molecules may be important triggers of autoimmune response in RA; specifically, proteins that are modified in a way in which the immune system may recognize as abnormal.”

—Mariana Kaplan, MD

“Through this NET formation things inside the cell get externalized, and some of those molecules may be important triggers of autoimmune re-

sponse in RA; specifically, proteins that are modified in a way in which the immune system may recognize as abnormal,” Dr Kaplan said.

Dr Kaplan and coinvestigators from the University of Michigan, Scripps Florida, and the University of California, Los Angeles, analyzed the peripheral blood and synovial fluid of patients with and without RA. The key antibodies in patients with RA include autoantibodies to citrullinated protein antigens (ACPAs); they are present years before RA is clinically diagnosed. Dr Kaplan’s team found that during NET formation, neutrophils pull citrullinated autoantigens outside of the cells. Once these citrullinated autoantigens are exposed to the immune system outside of the cell, ACPAs may in turn induce a great deal more NETosis, the process by which most NETs are formed. The result is that “enhanced and accelerated NET formation occurs in RA neutrophils,” the investigators noted.

They performed other experiments

which confirmed that autoantibodies in patients with RA mediate NETosis, and also that those patients’ neutrophils create autoantibodies against NETs, thereby contributing to the drastic acceleration of NETosis in patients with full-blown RA. In addition, the researchers were able to demonstrate that NETs are strong stimulators of fibroblast-like synoviocytes, which play a key role in causing joint damage in patients with RA. This is “a phenomenon that may amplify deleterious inflammatory responses in the RA synovium,” the team explained.

Their studies also provide a clue as to why some patients with RA develop the disease or experience a flare after an infection.

“NETs form during exposure to a microbe, and this may be a preceding event that in the predisposed individual would lead to a vicious cycle of autoantigen externalization and more NET synthesis by the RA milieu,” Dr Kaplan said. n

GO-FURTHER: Golimumab plus Methotrexate Combination Reduces Symptoms...

Continued from page 19

background methotrexate for ≥3 months. The baseline median duration of disease was 4.7 years. In all, 570 (96.3%) patients completed 24 weeks of the study and 550 (92.9%) patients completed all 52 weeks. Between weeks 24 and 52, 7 patients quit because of adverse events (AEs) and 5 withdrew their consent.

Between September 2009 and November 2011, 395 patients were administered 2-mg/kg infusions of golimumab at week 0 and at week 4, followed by injections every 8 weeks.

The 197 control patients received placebo, and all patients received methotrexate. Patients receiving placebo crossed over to golimumab at week 16 if they had a <10% improvement in tender and swollen joints, and at week 24 in the remainder of the patients.

The 24-week results showed that adding golimumab to methotrexate

20

In all, 570 (96.3%) patients completed 24 weeks of the study and 550 (92.9%) patients completed all 52 weeks….Similar rates of ACR response maintenance from weeks 24 to 52 were seen in patients who switched from placebo to golimumab or who received golimumab from baseline.

significantly improved the signs and symptoms of RA. The mean changes from baseline in van der Heijde-Sharp

value-based CARE in Rheumatology

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October 2013

(vdH-S) radiographic scores were lower for golimumab versus placebo (0.03 vs 1.09, respectively, to 24 weeks [P <.001], and 0.13 vs 1.22, respectively, to 52 weeks [P = .001]). Golimu­ mab resulted in more reduction in erosion compared with placebo to 24 weeks (–0.12 vs 0.53, respectively; P = .002) and lower joint space narrowing scores to 24 weeks (P = .002).

Similar rates of American College of Rheumatology (ACR) response were seen at week 52 in patients who switched from placebo to golimumab and in patients receiving golimumab from baseline—61.4% and 65.8%, respectively, reached ACR20, and 14.7% and 18.2%, respectively, achieved ACR70. Similar rates of ACR response maintenance from weeks 24 to 52 were seen in patients who switched from placebo to golimumab or who received golimumab from baseline—ACR20, 84.1% and

82.0%, respectively; ACR70, 62.5% and 60.9%, respectively.

The rates of AEs in patients receiving golimumab from baseline were 52.9% to week 24 and 64.6% to week 52. The respective rates of serious AEs were 4.1% and 8.6%, with serious infections being the most frequent.

Also, 1 patient receiving placebo died from a presumed stroke, and 1 patient receiving golimumab died from a presumed heart attack secondary to community-acquired pneumonia.

The 3 serious cardiovascular events (ie, unstable angina, atrial fibrillation, and myocardial infarction) occurred between weeks 24 and 52, when all patients were taking golimumab.

Lead investigator of GO-FURTHER, Michael E. Weinblatt, MD, told Value-Based Care in Rheumatology that there is “no evidence to date of a cardiac signal with all of the studies with this molecule.” n VOL. 2

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Personalized Medicine in Rheumatology

™

Genetic Variants and Environmental Factors Can Predict Rheumatoid Arthritis Risk Assessing genetic risk can improve outcomes

By Charles Bankhead

T

he ability to predict who is at risk for developing rheumatoid arthritis (RA) improved significantly with a new model based on a combination of genetic risk scores, environmental factors, and gene–­ environment interactions (GEIs), according to an analysis of 2 large cohort studies.

A primary model that combined these 3 types of factors led to area under the receiver operating characteristic curve (AUC) values of 0.716 to 0.756. Expanding the model to include more factors in each category improved the AUC values by 0.08 to 0.22 across the 2 studies and in separate analyses of women and men.

These results suggest that a multifactorial approach that incorporates

at a glance ➤ A multifactorial approach adding genetic risk factors and environmental factors to rheumatoid arthritis (RA) risk prediction can improve the diagnostic assessment of asymptomatic patients ➤ Predicting the risk for developing RA improved significantly with a new model that combines genetic risk scores, environmental factors, and gene–environment interactions (GEIs) ➤ Data derived from studies offer the potential to develop more accurate methods to predict the risk for RA in asymptomatic patients ➤ A necessary first step toward developing accurate riskprediction models is identifying optimal variables to include in a model of RA ➤ In the EIRA study, models that included genetic factors or genetics and GEIs improved reclassification versus using only environmental factors ➤ Further work on the development of highly specific prediction models using prospective cohorts to assess weights is still needed for primary prevention trials

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genetic risk factors and environmental factors to RA risk prediction can improve the diagnostic assessment of asymptomatic individuals, as reported by a team of Swedish and American investigators (Karlson EW, et al.

Arthritis Care Res [Hoboken]. 2013;65: 1147-1156).

“We demonstrate that inclusion of information on genetic variants and GEI models significantly improves the predictive power of epidemiologic models.”

—Elizabeth W. Karlson, MD, and colleagues

“Leveraging an extensive body of epidemiologic and genetic research on the risk of developing RA among asymptomatic cohorts along with modern statistical techniques, we developed and validated comprehensive risk models for RA,” concluded Elizabeth W. Karlson, MD, Harvard Medical School and Brigham and Women’s Hospital, Boston, and colleagues. “We demonstrate that inclusion of information on genetic variants and GEI models significantly improves the predictive power of epidemiologic models,” the authors wrote.

“The variance explained by the expanded E [environmental factors], G [genetic factors], and GEI models... suggested that there are more risk factors yet to be discovered,” they added.

Current theories on the etiology of RA focus on the exposure of genetically susceptible individuals to environmental factors that include smoking, residential history, air pollution, occupational exposures, alcohol, female reproductive factors, and socioeconomic status. Genome-wide association studies and meta-analyses have identified allelic risks for RA, and the discovery of GEIs has provided additional insight into the origin of RA, the researchers noted. Data derived from these studies offer the potential to develop more accurate methods to predict the risk for RA in asymptomatic patients.

In cardiovascular medicine, the Framingham Risk Score has demonstrated the feasibility and utility of developing risk-prediction strategies to aid the clinical decision-making.

“This successful paradigm of individualized risk factor assessment and stratification has led to a reduction of cardiovascular morbidity and mortality worldwide,” Dr Karlson and colleagues stated. “Efforts are now under way to develop similar predictive models for the early identification of individuals at high risk of developing RA among asymptomatic populations who could be enrolled in primary prevention trials.”

The identification of optimal variables to include in a model of RA is a necessary first step toward the development of accurate risk-prediction models. In this study, investigators in the United States and Sweden combined data from 2 large prospective cohorts—the Nurses’ Health Studies (NHS) and the Swedish Epidemiologic Investigation of Rheumatoid Arthritis (EIRA) to develop a personalized RA risk-prediction model.

The NHS included 121,700 female nurses (aged 30-55 years), 27% of whom provided blood samples and 27% of whom provided buccal cell samples. The NHSII included 116,900 female nurses (aged 25-42 years), 25% of whom provided blood samples.

The NHS cohorts included 585 women with documented RA who had provided blood samples. Previous genetic association studies had focused on individuals with seropositive RA. For consistency, Dr Karlson and colleagues limited their analysis of NHS participants to 317 women who had seropositive RA, who were matched with 551 healthy controls.

The EIRA study is a population-based case-control study that involved Swedish patients (aged 18-70 years) who were newly diagnosed with RA between May 1996 and December 2009. For their analysis, inves­ tigators included 987 patients with anticitrullinated protein antibody (ACPA)-positive RA (702 women, 285 men) and a matched control group of 958 participants (715 women, 243 men).

The base model for the study included sex, age, smoking, alcohol consumption, parity, a weighted genetic risk score (based on 31 non–human leukocyte antigen [HLA] alleles and 8 october 2013

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HLA-DRB1 alleles), and HLA–smoking interaction. Expanded models included reproductive, geographic, and occupational factors, as well as additional GEIs. Primary analyses resulted in AUC values of 0.716 for NHS participants and for women in the EIRA and 0.756 for men in the EIRA. The expanded models increased the AUC value to 0.738 for NHS participants, to 0.724 for women in the EIRA, and to 0.769 for men in the EIRA. Models that included genetic factors or genetics and GEIs improved reclassification over the use of environmental factors alone. A model that incorporated environmental factors, genetic factors, and GEI provided the optimal predictive ability by integrated discrimination improvement.

“Efforts are now under way to develop similar predictive models for the early identification of individuals at high risk of developing RA among asymptomatic populations who could be enrolled in primary prevention trials.”

—Elizabeth W. Karlson, MD, and colleagues

“These results demonstrate the challenges of creating a simple risk prediction model for primary prevention trials of RA,” the investigators stated. “Therefore, further work on development of highly specific prediction models using prospective cohorts to assess weights is still needed for primary prevention trials.”

“Our data suggest that addition of cumulative RA genetic variants as a GRS [genetic risk score] and, in some cases, GEI to an RA prediction model with E, significantly improves the predictive ability of the model for this complex human autoimmune disease,” they concluded. “However, the inclusion of highly specific biomarkers such as ACPA in risk models is likely to improve risk stratification of asymptomatic individuals.” n

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21

Lupus

BTK Inhibitors Show Promise in Lupus

By Neil Canavan

T

he new class of drugs called Bruton’s tyrosine kinase (BTK) inhibitors may hold the key to more effective treatment for systemic lupus erythematosus (SLE), according to the results of a study just published in the peer-reviewed journal Arthritis & Rheumatism (Mina-Osorio P, et al.

2013;65:2380-2391).

In an early-phase trial, a new BTK inhibitor, RN486, was able to completely stop the disease progression of SLE for 8 weeks, as determined by histologic and functional analyses of glomerulonephritis.

“Our data suggest that BTK inhibitors may simultaneously target autoantibody-producing and effector cells in SLE, thus constituting a promising therapeutic alternative for this disease,” wrote the study investigators.

Although the sequelae of SLE are remarkably heterogeneous, lupus nephritis is present in more than 50% of the patient population and is a cause of significant reductions in survival rates. Improvements in this condition are often used as a clinical end point in the investigation of novel lupus treatments.

Previous investigations of BTK inhibitors suggest that these agents are able to affect autoimmune diseases, such as SLE, by blocking the signaling pathway of antigen receptors on B-cells,

thereby preventing the maturation of B-cells that drive disease progression.

There are drugs already on the market that work on the same general principle; however, as the investigators here suggest, “The fact that BTK blockade impacts numerous cell types (eg, B-cells, plasmablasts, plasma cells, and monocytes) simultaneously might represent an advantage over other B-cell–depleting therapies for the treatment of lupus nephritis.”

These data suggest “that BTK inhibitors may simultaneously target autoantibody-producing and effector cells in SLE, thus constituting a promising therapeutic alternative for this disease.”

Many of the drugs now in development for SLE target B-cells, and recent recommendations published by the American College of Rheumatology, as well as the European League

Against Rheumatism, strongly encourage this line of investigation.

To date, however, all clinical trials using BTK inhibitors are of patients with B-cell malignancies. Investigations for the use of BTK blockade in autoimmune disorders, such as SLE and rheumatoid arthritis, are only now maturing to the point that human trials are being considered.

In previous BTK/SLE animal studies, the efficacy for RN486 was observed in the Murphy Roths Large mouse model, a mutated mouse strain that is bred to develop a lupus-like disease. In the present study, the so-called NZB/NZW mouse strain was used.

This disease model also spontaneously develops a lupus-like syndrome similar to human SLE, but also has intrinsic B-cell defects that allow researchers to more clearly understand how RN486 is actually working.

Results of the present study showed that treating NZB/NZW mice with RN486 for 8 weeks completely arrested SLE disease progression. Furthermore, on a molecular level, the drug was able to markedly reduce the production of a host of disease-causing antibodies and associated signaling factors.

“This is consistent with recent reports on the cross-species similarities in transcriptional networks between this animal model of lupus and the

at a glance ➤ Bruton’s tyrosine kinase (BTK) inhibitors may hold the key to more effective treatment for systemic lupus erythematosus (SLE) ➤ In an early-phase trial, RN486, a new BTK inhibitor was able to completely stop the disease progression of SLE for 8 weeks ➤ The data suggest that BTK inhibitors may simultaneously target autoantibody-producing and effector cells in SLE ➤ BTK blockade impacts numerous cell types simultaneously, which may show an advantage over other B-cell–depleting therapies for lupus nephritis ➤ Many of the drugs now in development for SLE target B-cells, and recent recommendations strongly encourage this line of investigation

human disease and enhances the potential translational significance of our findings,” the article stated.

Clinical trials in humans have not yet begun. n

In the Literature Real-World Analysis Shows Efficacy of Adalimumab in Established Active RA

Rheumatoid arthritis (RA) leads to joint inflammation and damage, disability, diminished quality of life, and shorter life expectancy compared with the general population. Treating-to-target approaches in patients with early RA have been shown to be more effective at managing the disease progression than routine care. A new study sought to determine if the treat-to-target strategy also has better outcomes than routine care in patients with established active RA (Pope JE, et al. Arthritis Care Res [Hoboken]. 2013;65:1401-1409).

The study was an 18-month, real-­ world, multicenter, parallel-group, single-blind, cluster-randomized trial in patients with established active RA who were starting treatment with the tumor necrosis factor (TNF) inhibitor

adalimumab (Humira) as part of their usual care. Patients were randomized to routine care, treating to the 28-joint Disease Activity Score (DAS28) of <2.6 (DAS group), or treating to a swollen joint count of 0 of 28 (0-SJC group).

The study included 308 patients with active RA who were randomized to routine care, to the DAS group, or to the 0-SJC group. The primary end point was the change in DAS28 between baseline and 12 months.

When adjusting for baseline DAS28, a comparable but significant (P <.001) improvement in DAS28 mean score was seen in all 3 groups at 12 months (routine care, 3.1; DAS group, 3.4; and 0-SJC group, 3.2, respectively). No significant between-group differences were seen in the improvement of clinical parameters and patient-reported outcomes, except for the mean change in patient satisfaction over time (P =

.020), which was highest in the DAS group. The time to achieving a good or moderate European League Against Rheumatism (EULAR) response was significantly shorter in the DAS group (hazard ratio [HR], 2.99; 95% confidence interval [CI], 1.715.24; P <.001) and the 0-SJC group (HR, 1.86; 95% CI, 1.09-3.13; P = .023) than in the routine care group. Significantly more patients dropped out of the study from the routine care group versus from the DAS group and the 0-SJC group (52.3% vs 27.0% and 22.2%, respectively).

Overall, patients in all 3 groups experienced significant improvements in all outcomes during 18 months of adalimumab treatment without any differences in DAS28. Treating to target in patients with established active RA was beneficial in all groups in patients who continued therapy. How-

ever, it took significantly less time to achieve good or moderate EULAR response in the groups that received the TNF inhibitor and significantly fewer of these patients dropped out of the study, than in the routine care group.

The researchers suggest adopting a treat-to-target approach when initiating a biologic agent in established RA to improve duration of therapy to good outcomes and to facilitate a higher retention rate of patients on treatment.

Creatine Supplementation a Novel Dietary Intervention in Fibromyalgia, Improves Muscle Function

A new randomized controlled trial is the first to investigate the efficacy and safety of creatine supplementation in patients with fibromyalgia (Alves CR, et al. Arthritis Care Res [Hoboken].

Continued on page 26

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Osteoarthritis

Tell Your Patients with Lower-Limb Osteoarthritis to Keep on Exercising

By Rosemary Frei, MSc Québec, Canada—The evidence is strong that exercise is beneficial for patients with lower-limb osteoarthritis (OA), particularly knee OA, according to a new analysis that was presented at the 2013 Cochrane Colloquium. Rheumatologists and primary care physicians should continue to advise patients with OA to stay active and to exercise, the investigators say.

“It’s important that exercises aim to improve muscle strength, but our research shows the best results may be achieved with a combined exercise program that includes exercises to improve flexibility and endurance,” coinvestigator Danielle A. van der Windt, PhD, Professor in Primary Care Epidemiology, Keele University, Staffordshire, United Kingdom, told Value-Based Care in Rheumatology.

“The evidence is presently strongest for land-based exercises, but aquatic programs also appear to show promising results.”

Dr van der Windt and her coinvestigators, led by Olalekan A. Uthman,

“It’s important that exercises aim to improve muscle strength, but our research shows the best results may be achieved with a combined exercise program that includes exercises to improve flexibility and endurance. The evidence is presently strongest for landbased exercises, but aquatic programs also appear to show promising results.”

—Danielle A. van der Windt, PhD

MBBS, MPH, PhD, University of Warwick, Coventry, United Kingdom, searched 9 literature databases for randomized controlled trials pub-

lished up to March 2012 on exercise interventions for adults with knee or hip OA. A total of 60 studies met the inclusion criteria, including 44 on knee OA, 2 on hip OA, and 14 on both. The risk for bias varied between the studies; therefore, the team will analyze the influence of bias in more detail in a separate study.

The trials investigated 12 different types of exercise interventions. Of the 60 trials, 54 included a no-exercise control group. The team determined that 5 types of exercise intervention were significantly more effective than no exercise in reducing pain—landbased strengthening, land-based strengthening plus flexibility, landbased strengthening plus flexibility and aerobics, aquatic strengthening, and aquatic strengthening plus flex­ ibility. One of these—land-based strengthening plus flexibility and aero­ bics—also was more effective in improving function.

The combination of strengthening, flexibility, and aerobic exercise re-

duced pain by an average of 1.74 points on a scale of 0 to 10 relative to no exercise. It also resulted in a 1.32point improvement in average score on the Western Ontario and McMaster Universities function scale ranging from 0 to 10. Patients’ mean scores at baseline of approximately 6 points translate into a reduction in pain intensity of approximately 28% and an improvement of approximately 22% in physical function, explained Dr van der Windt.

“The results for aquatic exercise appeared statistically to be somewhat stronger than for land-based exercise, but there is more uncertainty around these estimates—with fewer and smaller studies contributing to them— and the results were not statistically significant for outcomes of function,” she said.

Dr van der Windt concluded that the current evidence for the benefits of exercise over no exercise is so strong that further trials are unlikely to overturn this result. n

Lupus Conference Reports from ACR OCTOBER 26-30, 2013

an e-newsletter brought to you by the publishers of

TOPICS INCLUDE:

Information for payers and healthcare providers treating patients with lupus On-site coverage from ACR/ARHP 2013 Annual Meeting • Review of currently approved and future therapies for lupus • •

www.ValueBasedRheumatology.com VBCR_ACR81313

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Drug Update

Simponi Aria: A New Intravenous TNF Inhibitor for the Treatment of Patients with Moderate-to-Severe Rheumatoid Arthritis

By Loretta Fala, Medical Writer

R

heumatoid arthritis (RA), a chronic inflammatory autoimmune disorder that affects the lining, or synovium, of the joints, affects 1.3 million people in the United States.1,2 In addition to causing painful swelling that may eventually lead to bone erosion and joint deformity, RA can also affect other organs of the body, including the skin, eyes, lungs, and blood vessels.1,2 Although RA can occur in people in their 20s and 30s, it usually begins after age 40, affecting more than twice as many women as men.1,2 The average age of patients with RA is 66.8 years.2 In its early stage, RA may first affect smaller joints (ie, those that attach the fingers and toes), and as the disease progresses, it spreads to the knees, ankles, elbows, hips, and shoulders.1 An estimated 22% of all deaths from arthritis and other rheumatic conditions are attributed to RA.3 Aside from being associated with a high risk of disability and mortality, people with RA are twice as likely to die as persons of the same age without RA.3 Approximately 40% of all deaths associated with RA are attributed to cardiovascular causes, including ischemic heart disease and stroke.3

RA also has a substantial impact on a patient’s functional status and quality of life. One study showed that people with RA were 40% more likely to report fair or poor general health and twice as likely to have a health-related physical activity limitation.3,4 RA is also associated with substantial costs. According to one study, RA accounted for $19.3 billion (2005 dollars) in societal costs excluding intangible costs, and $39.2 billion including intangible costs (ie, consequences of RA).5 The management of patients with RA is aimed at reducing joint pain and swelling, alleviating stiffness, and preventing joint damage.2 According to the 2012 American College of Rheumatology (ACR) recommendations for the use of disease-modifying antirheumatic drugs (DMARDs) and biologic agents, including tumor necrosis factor (TNF) blockers, in the treatment of RA.6 “The goal for each RA patient should be low disease activity or remission. In ideal circumstances, RA remission should be the target of therapy, but in others, low disease activity may be an acceptable target,” the authors of the updated guidelines state.6 The ACR recommendations also state that decisions about treating to target are left to the clinician who is

Table 1 P roportion of Patients with an ACR Response: Golimumab IV plus Methotrexate versus Placebo plus Methotrexate in the GO-FURTHER Trial Active RA, despite methotrexate treatment Placebo + Golimumab IV + 95% confidence methotrexate, % methotrexate, % (N = 197)a (N = 395)a intervalb ACR20 Week 14

25

59

25.9-41.4

Week 24

32

63

23.3-39.4

Week 14

9

30

15.3-27.2

Week 24

13

35

15.1-28.4

Week 14

3

12

5.3-13.4

Week 24

4

18

8.8-18.1

ACR50

ACR70

N reflects randomized patients. b For difference in proportions.

ACR indicates American College of Rheumatology; ACR20, ACR 20% improvement response criteria; ACR50, ACR 50% improvement response criteria; ACR70, ACR 70% improvement response criteria; IV, intravenous; RA, rheumatoid arthritis.

Source: Simponi Aria (golimumab) injection [prescribing information]. Horsham, PA: Janssen Biotech, Inc; 2013 a

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October 2013

caring for the individual patient, based on the patient’s preferences, comorbid conditions, and other relevant factors. Moreover, treatment plans involve patient-tailored risk-­ benefit analysis based on the clinician’s assessment and collaboration with the patient.6 The nonpharmacologic treatment of RA generally includes a combination of joint protection, the use of heat or cold to reduce pain, and physical or occupational therapy.2 Other self-management approaches include maintaining a healthy body weight and performing physical activity as appropriate, depending on the patient’s level of physical mobility.2 Because joint damage caused by RA occurs early, generally within the first 2 years of disease onset, it is vital that RA be diagnosed and treated early.1,2 The ACR panel recommended more aggressive treatment in early RA in the 2012 update than in the previous 2008 recommendations, most likely based on the potential for better outcomes, prevention of irreversible joint damage, preservation of physical function and health-related quality of life, and reduced work-related disability.6 Simponi Aria: A New Intravenous Option for RA In July 2013, the US Food and Drug Administration (FDA) approved Simponi Aria (golimumab intravenous [IV]), a TNF inhibitor, for the treatment of moderate-to-severe RA in combination with methotrexate.7 Golimumab (Simponi) injection for subcutaneous use was previously approved by the FDA in 2009 for moderately to severely active RA in combination with methotrexate.7,8 In May 2013, golimumab for subcutaneous use received a new indication from the FDA for the treatment of ulcerative colitis that is resistant to previous treatment or requires continuous steroid therapy.9 According to John Hardin, MD, Director of Osteoarthritis at the Arthritis Foundation in Atlanta, and Professor of Medicine at Albert Einstein College of Medicine in the Bronx, NY, the availability of golimumab IV allows for its administration at an infusion center, which ensures that the patient is receiving the appropriate dose, because patient self-injection techniques

may vary.7 Dr Hardin commented, “Logistically, it’s easier in some cases with IV infusions.”7 Mechanism of Action Golimumab, a TNF blocker, is a human monoclonal antibody that binds to the soluble and the transmembrane bioactive forms of human TNF-alpha to its receptors. This interac­ tion prevents the binding of TNF-alpha to its receptors, thereby inhibiting the biological activity of TNF-alpha (a cytokine protein).10 Elevated TNF-alpha levels in the blood, synovia, and joints have been implicated in the pathophysiology of RA. TNF-alpha is an important mediator of the articular inflammation that is characteristic of RA.10 Dosing The recommended dose of golimumab IV for patients with moderate-to-severe RA is 2 mg/kg as an IV infusion over 30 minutes at weeks 0 and 4, and then every 8 weeks. The dilution of supplied golimumab IV solution with 0.9% weight/volume sodium chloride is required before administration. Golimumab IV should be given in combination with methotrexate. Other nonbiologic DMARDs, corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or analgesics may be continued during treatment with golimumab IV.10 Phase 3 Clinical Trial: GO-FURTHER The FDA approval of the new indication for golimumab IV was based on the randomized, double-blind, phase 3, placebo-controlled trial known as GO-FURTHER, which included 592 patients (aged ≥18 years) with moderately to severely active RA despite concurrent treatment with methotrexate who had not previously received a biologic TNF blocker. Patients were randomized to either go­ limumab IV 2 mg/kg (N = 395) or to placebo (N = 197) over a 30-minute IV infusion at weeks 0, 4, and every 8 weeks thereafter in addition to their weekly maintenance dose of methotrexate (15-25 mg/kg).10,11 All patients who were initially receiving placebo plus methotrexate in the trial received golimumab IV plus methotrexate after week 24; however, the trial remained blinded until all paVOL. 2

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Drug Update tients had completed 52 weeks of treatment. Efficacy data were collected and analyzed through week 52.

Patients were allowed to continue receiving stable doses of concomitant low-dose corticosteroids (equal to ≤10 mg of prednisone daily) and/or NSAIDs, and patients might have received oral methotrexate during the trial. The use of other DMARDs, including cytotoxic agents or other biologics, was prohibited.10 The primary end point in this trial was the percentage of patients who achieved an American College of Rheumatology (ACR)20 response at week 14.9 ACR20 is defined by the ACR as a 20% improvement in tender and swollen joint counts and a 20% improvement in at least 3 of the 5 remaining ACR core set measures— patient global assessment, physician global assessment, pain, disability, and an acute-phase reactant.12 ACR50 represents a 50% improvement in these measures, and ACR70 represents a 70% improvement.12 A total of 58.5% of the patients in the golimumab IV plus methotrexate group achieved a 20% improvement in their ACR 20 score at week 14 compared with 24.9% (49:197) of the patients in the placebo plus methotrexate group (P <.001).7,11 Moreover, a larger proportion of patients treated with golimumab IV plus methotrexate had a disease activity score (DAS) of a good or moderate (European League Against Rheumatism) response (81% vs 40%, respectively), and a greater median improvement in health assessment questionnaire scores (0.5 vs 0.125, respectively) versus placebo plus methotrexate (P <.001).

Table 1 shows that a greater percentage of patients in the active arm achieved ACR20 at week 14 and ACR50 at week 24 than patients in the placebo arm.10 In all components of the ACR response criteria, improvement was either equal among the 2 groups or was greater in the golimumab IV plus methotrexate group than in the placebo plus methotrexate group (Table 2).

In addition, at week 14, a greater proportion of patients who received golimu­mab IV plus methotrexate (15%) achieved a low level of disease activity, as measured by a DAS28 using C-reactive protein (DAS28-CRP) score of <2.6 compared with patients treated with placebo plus methotrexate (5%; 95% confidence interval, 6.3%-15.5% for the difference).10 The DAS28-CRP is an index of disease activity for the 28 joints that are frequently affected by RA based on CRP levels.13 Adverse Events The most common adverse reacVOL. 2

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tions (incidence >3%) are upper respiratory tract infection, viral infection, bronchitis, hypertension, and rash.10 Golimumab contains a boxed warning about serious infections and malignancy. Serious infections that can lead to hospitalization or to death, including tuberculosis, bacterial sepsis, and invasive fungal (ie, histoplasmosis) and other opportunistic infections have occurred in patients receiving golimumab. Therapy with golimu­ mab should not be started during an active infection. If an infection develops, the patient should be monitored carefully and golimumab treatment should be stopped if the infection becomes serious.

Patients should be tested for latent tuberculosis before the initiation of golimumab therapy. If the tuberculosis test is positive, treatment should be started for tuberculosis before initiating golimumab. Patients should be monitored for active tuberculosis during treatment, even if the initial latent tuberculosis test is negative.

Lymphoma and other malignancies, some fatal, have been reported in

children and in adolescent patients who were treated with TNF blockers, of which golimumab is a member.10 Warnings and Precautions Invasive fungal infections. For patients who develop a systemic illness while taking golimumab IV, empiric antifungal therapy should be considered for those who live in or travel to regions where mycoses are endemic.10 Hepatitis B reactivation. Hepatitis B virus carriers should be monitored during and several months after therapy. If reactivation occurs, golimu­ mab should be discontinued and antiviral therapy should be initiated.10 Malignancies. More cases of lymphoma have been observed among patients receiving TNF blockers compared with patients in the control groups. Cases of other malignancies have been observed among patients receiving TNF blockers.10 Heart failure. The worsening or new onset of heart failure may occur with golimumab. If worsening symptoms occur, the use of golimumab should be stopped.10

omponents of ACR Response at Week 14: Golimumab IV plus Table 2 C Methotrexate versus Placebo plus Methotrexate in the GO-FURTHER Trial Active RA, despite methotrexate treatment Placebo + methotrexate (N = 197)a

Golimumab IV + methotrexate (N = 395)a

Baseline

15

15

Week 14

11

6

Baseline

26

26

Week 14

20

13

Baseline

6.5

6.5

Week 14

5.6

3.9

Swollen joints, N (0-66)

Tender joints, N (0-68)

Patient’s assessment of pain (0-10)

Patient’s global assessment of disease activity (0-10) Baseline

6.5

6.5

Week 14

5.5

4.0

Physician’s global assessment of disease activity (0-10) Baseline

6.3

6.2

Week 14

4.9

3.1

Baseline

1.6

1.6

Week 14

1.4

1.1

Baseline

2.2

2.8

Week 14

1.8

0.9

HAQ score (0-3)

CRP, mg/dL (0-1)

N reflects randomized patients; actual number of patients evaluable for each end point may vary.

NOTE: All values are means.

ACR indicates American College of Rheumatology; CRP, C-reactive protein; HAQ, health assessment questionnaire; IV, intravenous; RA, rheumatoid arthritis.

Source: Simponi Aria (golimumab) injection [prescribing information]. Horsham, PA: Janssen Biotech, Inc; 2013.

a

Demyelinating diseases. The exacerbation or new onset of demyelin­ ating diseases may occur with golimumab.10 Hypersensitivity reactions. Serious systemic hypersensitivity reactions, including anaphylaxis, may occur with golimumab.10 Switching between DMARDs. Care should be taken when switching from one biologic agent to another biologic agent, because overlapping biologic activity may further increase the risk of infection.10 Hematologic cytopenias. In postmarketing reports, pancytopenia, leukopenia, neutropenia, aplastic anemia, and thrombocytopenia have occurred in patients receiving TNF blockers. In clinical studies, cases of pancytopenia, leukopenia, neutropenia, and thrombocytopenia have occurred in patients treated with golimu­ mab IV. Caution should be exercised when using TNF blockers, including golimumab IV, in patients who have or have had significant cytopenias.10 Drug Interactions Abatacept. In controlled trials, the concurrent administration of another TNF blocker and abatacept, a selective T-cell costimulation modulator, was associated with a greater proportion of serious infections than the use of a TNF blocker alone. The combination therapy, compared with the use of a TNF blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. The combination of TNF blockers, including golimu­ mab IV, and abatacept is therefore not recommended.10 Anakinra. The concurrent administration of anakinra, an interleukin-1 antagonist, and another TNF blocker, was associated with a greater portion of serious infections and neutropenia but with no additional benefit compared with the TNF blocker alone.

The combination of anakinra with TNF blockers, including golimumab IV, is therefore not recommended.10 Live vaccines. Live vaccines should not be given concurrently with golimumab.10 Use in Specific Populations Pregnancy. There are no adequate and well-controlled trials of golimu­ mab in pregnant women. Golimumab should be used during pregnancy only if clearly needed.10 Nursing mothers. It is unknown whether golimumab is excreted in human milk or is absorbed systemically after ingestion. Because many drugs are excreted in human milk and there is a potential for adverse reactions in nursing infants from golimumab, consideration should be given Continued on page 26

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Drug Update

Simponi Aria: A New Intravenous TNF Inhibitor... as to whether to discontinue nursing or to discontinue golimumab, taking into account the importance of the drug to the mother.10 Pediatric use. The safety and effectiveness of golimumab in pediatric patients aged <18 years have not been established.10 Geriatric use. With respect to RA, there were no overall differences in serious adverse events, serious infections, and adverse events in golimumab-treated patients aged ≥65 years (N = 155) compared with younger golimumab-treated patients. Because there is usually a higher incidence of infections in the geriatric population in general, caution should be used in treating geriatric patients with golimumab.10 Conclusion The approval of Simponi Aria (go­ limumab IV) by the FDA in July 2013

for the treatment of moderate-to-­ severe RA in combination with methotrexate adds a new TNF inhibitor to the treatment options of patients with this chronic and debilitating disease.

An earlier, subcutaneous version of Simponi (golimumab subcutaneous) injection had been approved by the FDA in 2009 for moderately to severely active RA in combination with methotrexate. The IV route means in-office administration of the medication, which can be an advantage in cases where patient adherence is problematic, which can greatly affect outcomes.

The safety and efficacy of golimu­ mab IV were assessed in the GO-FURTHER randomized, double-blind, placebo-controlled trial in adults with moderate-to-severe RA with moderately to severely active RA despite concurrent methotrexate therapy. The improvements associated with golimu­

mab IV plus methotrexate, compared with placebo plus methotrexate, were observed by week 2.

The most common adverse reactions occurring in >3% of patients using golimumab IV are upper respiratory tract infection, viral infection, bronchitis, hypertension, and rash. n

Continued from page 25

1. Mayo Clinic. Rheumatoid arthritis. July 27, 2013. www.mayoclinic.com/health/rheumatoid-arthritis/ DS00020. Accessed July 31, 2013.

2. Arthritis Foundation. Rheumatoid arthritis fact sheet.

2008. www.arthritis.org/files/images/newsroom/ media-kits/Rheumatoid_Arthritis_Fact_Sheet.pdf.

Accessed July 31, 2013.

3. Centers for Disease Control and Prevention. Rheumatoid arthritis. Updated November 19, 2012. www. cdc.gov/arthritis/basics/rheumatoid.htm. Accessed July 31, 2013.

4. Dominick KL, Ahern FM, Gold CH, Heller DA. Health-related quality of life among older adults with arthritis. Health Qual Life Outcomes. 2004;2:5.

5. Birnbaum H, Pike C, Kaufman R, et al. Societal cost of rheumatoid arthritis patients in the US. Curr Med Res Opin. 2010;26:77-90.

6. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology rec-

ommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken).

2012;64:625-639.

7. Brown T; Medscape News. FDA approves intravenous golimumab (Simponi Aria) for rheumatoid arthritis. Press release. July 18, 2013. www.medscape. com/viewarticle/807965. Accessed July 31, 2013.

8. Simponi (golimumab) injection [package insert].

Horsham, PA: Janssen Biotech, Inc; 2013.

9. US Food and Drug Administration. FDA approves Simponi to treat ulcerative colitis. Press release. May 15, 2013. Updated May 17, 2013. www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ ucm352383.htm. Accessed August 6, 2013.

10. Simponi Aria (golimumab) injection [prescribing information]. Horsham, PA: Janssen Biotech, Inc; 2013.

11. Weinblatt ME, Bingham CO 3rd, Mendelsohn AM, et al. Intravenous golimumab is effective in patients with active rheumatoid arthritis despite methotrexate therapy with responses as early as week 2: results of the phase 3, randomised, multicentre, double-blind, placebo-controlled GO-FURTHER trial. Ann Rheum Dis. 2013;72:381-389.

12. Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum.

1995;38:727-735.

13. Wells G, Becker JC, Teng J, et al. Validation of the 28-joint Disease Activity Score (DAS28) and European League Against Rheumatism response criteria based on C-reactive protein against disease progression in patients with rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate. Ann Rheum Dis. 2009;68:954-960.

replacement surgery for osteoarthritis (OA), the treatment options are limited. Better knowledge of the underlying pathogenesis of OA is crucial for the development of disease-modifying drugs. Chondrocytes are the single cell type that is responsible for maintaining the extracellular matrix of articular cartilage and repair of any damage. Whereas articular cartilage has evolved to facilitate joint mobilization, severe loading can induce cell death, which is associated with OA progression. To avoid apoptosis, chondrocytes synthesize heat-shock proteins (HSPs). A new study investigated the roles of Hsp70 and Hsp90, 2 of the major classes of HSPs involved in the regulation of cell stress, in biochemically induced OA, and the potential for Hsp90 inhibition in OA management (Siebelt M, et al. Arthritis Rheum. 2013;65:2102-2112).

The study included 38 male rats in which OA was biomechanically induced by strenuous running. The researchers formed 5 groups: a baseline group; 2 control OA groups, a group that was followed up for 6 weeks, and a group that was followed up for 12 weeks; and 2 treatment groups, 1 group that was followed up for 6 weeks, and 1 group that was followed up for 12 weeks. The researchers compared disease progression between the groups treated with an

Hsp90 inhibitor and a control group.

After a 6-week regimen of running, Hsp90 protein levels were increased 2.1-fold in the untreated control groups with OA compared with the untreated baseline group that did not run. After 6 weeks of subsequent rest, Hsp90 levels remained higher in the untreated control rats with OA than in those in the baseline group (an approximate 1.7-fold increase); however, neither of the effects were significant.

Compared with baseline values, Hsp70 levels did not change at 6 or 12 weeks in untreated rats with OA. However, chondrocytes from rats treated with an Hsp90 inhibitor did exhibit a significant difference in response to biomechanical stress exposure through running. Rats treated with an Hsp90 inhibitor produced significantly higher amounts of Hsp90 at the end of the running protocol compared with the control rats with OA (an approximate 1.9-fold increase; P = .02). Hsp90 remained elevated after the subsequent 6 weeks of rest (an approximate 2.2-fold increase; P = .001).

The findings suggest that Hsp90 has a major role in protecting or improving cartilage health. Therapeutic interventions that block Hsp90 may be a new approach to prevent the development of OA in humans. n

References

In the Literature Creatine Supplementation a Novel Dietary Intervention in Fibromyalgia, Improves...

Continued from page 22 2013;65:1449-1459). Creatine has a significant role in the rapid provision of energy during muscle contraction.

Creatine supplementation recently has been recognized as a potential adjunct treatment in a broad spectrum of diseases, including those associated with muscle wasting and dysfunction, low bone mass, joint syndromes, and central nervous system disorders. Fibromyalgia is a chronic syndrome that is characterized by generalized pain, muscle dysfunction, fatigue, disability, and sleep and mood disturbances.

This 16-week, randomized, double-blind, placebo-controlled, parallel-group study included 28 women who were diagnosed with primary fibromyalgia according to the revised American College of Rheumatology preliminary criteria. The creatine group (N = 15) received 20 g of creatine monohydrate for 5 days that was divided into 4 equal doses, followed by 5 g daily as a single dose throughout the trial. The group receiving placebo (N = 13) was given the same dose of dextrose. The patients were evaluated at baseline and after 16 weeks.

Drug therapy remained stable throughout the study. Muscle func-

26

tion, aerobic conditioning, cognitive function, quality of sleep, quality of life, kidney function, and adverse events were assessed. Phosphorous magnetic resonance spectroscopy measured muscle phos­phorylcreatine.

After 16 weeks, the creatine group displayed significantly increased muscle phosphorylcreatine content compared with the patients receiving placebo (+80.3% vs −2.7%, respectively; P = .04). Patients taking creatine also presented greater muscle strength than the group receiving placebo in leg-press exercises (+9.8% vs −0.5%, respectively; P = .02), chest-press exercises (+1.2% vs −7.2%, respectively; P = .002), and isometric strength (+6.4% vs −3.2%, respectively; P = .007). No general changes were seen in aerobic conditioning, pain, cognitive function, quality of sleep, or quality of life. The patients’ food intake remained the same, and there were no self-reported side effects throughout the study.

These results demonstrate that creatine supplementation is a useful dietary intervention in patients with fibromyalgia for improving lowerand upper-body muscle function.

Hsp90 Inhibition Plays a Crucial Role in Biomechanically Induced Osteoarthritis

Besides expensive and invasive joint

value-based CARE in Rheumatology

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Don’t Face the Maze of Changes in Rheumatology Alone

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NORM’s mission is to provide rheumatology managers, administrators and managing physicians countless opportunities to network with colleagues through our listserv and annual conference.

At NORM, our goals involve addressing, educating, distributing, and functioning as a conduit for rheumatologic practice management needs and expertise.

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