VBCR April Vol 2, No 2

Value-Based Care in Rheumatology

April 2013 VOL 2 • NO 2

F r o m t h e p u b l i s h e r s of A m e r i c a n H e a l t h & d r u g b e n e f i t s

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Rheumatologists Warned to Watch for Serious Infections in Older Patients with RA Respiratory infections most common events

© Eraxion/bigstock.com

By Rosemary Frei, MSc

H

ospitalizations or emergen­ cy department visits for seri­ ous infections are relatively common in older adults with rheu­

matoid arthritis (RA), according to a recent analysis (Widdifield J, et al.

Arthritis Care Res. 2013;65:353-361).

The investigators documented Continued on page 12

Apremilast Improves Outcomes in Refractory Psoriatic Arthritis

By Phoebe Starr

A

premilast, an oral investi­ gational drug, significant­ ly improved the signs and symptoms of psoriatic arthritis (PsA) in patients whose disease failed to respond to previous disease-modify­

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

“This large, first phase 3 study of apremilast in PsA showed that the drug Continued on page 13

New Classification Criteria for Systemic Sclerosis Proposed

By Wayne Kuznar

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

“There’s a need, because the old

Continued on page 15

Relationship between Chronic Kidney Disease and Gout Uncovered for the First Time

By Rosemary Frei, MSc

B

y analyzing information from the National Health and Nu­ trition Examination Survey (NHANES) from 1988-1994 and 20072010, researchers have uncovered a 30% rate of gout prevalence among Americans with severe chronic kid­ ney disease (CKD). They also found significantly higher rates of gout among individuals with lower aver­ age estimated glomerular filtration rates (eGFRs) or higher levels of albu­

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

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

Continued on page 5

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

Unprecedented growth predicted for monoclonal antibodies GOUT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Prophylaxis with colchicine often used inappropriately

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

© 2013 Engage Healthcare Communications, LLC

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

The 1980 major criteria still work well in classifying sclerodactyly that

PSORIATIC ARTHRITIS. . . . . . . .

Apremilast shows promise in refractory PsA Ustekinumab safe, effective in PsA

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HEALTH ECONOMICS. . . . . . . . . .

Impact of specialty drugs on cost in the management of RA Economic burden of osteoarthritis

Rheumatology PRACTICE

Management™. . . . . . . . . . . . . . . . . . .

Breach notification requirements

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ANKYLOSING SPONDYLITIS. . 18 Early use of TNF inhibitors is beneficial IN THE LITERATURE . . . . . . . . . . 18 Obesity a risk factor for developing 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

Value-Based Carein Rheumatology FROM THE PUBLISHERS OF AMERICAN HEALTH & DRUG BENEFITS

Publishing Staff Senior Vice President/Group Publisher Nicholas Englezos nick@engagehc.com Manager, Client Services Zach Ceretelle Editorial Director Dalia Buffery dalia@engagehc.com Managing Editor Lisa Neuman 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 Rattanonont Ferris Vice President of Finance Andrea Kelly Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino 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 Business Manager Blanche Marchitto 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

Health Economics

Unprecedented growth predicted for monoclonal antibodies to treat RA HHS announces agenda to lower costs and improve quality with health IT More…

Transitioning from conventional to biologic DMARDs a consistent trend in RA

VASCULITIS Rituximab the newest treatment for ANCA vasculitis, but cyclophosphamide still a viable option

GOUT Relationship between chronic kidney disease and gout uncovered for the first time Prophylaxis with colchicine often used inappropriately in patients with gout More…

Rheumatology PRACTICE

ARTHRITIS Update

Early use of TNF inhibitors is beneficial in ankylosing spondylitis

MANAGEMENT™

Breach notification requirements

ANKYLOSING SPONDYLITIS

Study shines new light on deleterious dance between B- and T-cells in RA More…

IN THE LITERATURE Obesity a risk factor for developing rheumatoid arthritis Adalimumab safe for patients with rheumatoid arthritis and renal insufficiency

PSORIATIC ARTHRITIS Apremilast improves outcomes in refractory psoriatic arthritis Ustekinumab shows promise

VBCR Editorial Advisory Board Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield New York, NY 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 James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA Muhammad Asim Khan, MD Professor of Medicine Case Western Reserve University Cleveland, OH

Randall Krakauer, MD, FACP, FACR National Medical Director Medicare, Aetna Princeton, NJ Alan Menter, MD Director Baylor Psoriasis Research Center Dallas, TX Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth Murray, UT Lynn Nishida, RPh Director, Clinical Services Catamaran Center of Excellence Northwest Region Portland, OR

Kim A. Papp, MD, PhD Founder and President Probity Medical Research Waterloo, Ontario, Canada Edmund J. Pezalla, MD, MPH 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

Gary M. Owens, MD President Gary Owens Associates Philadelphia, PA

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.

APRIL 2013

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Value Propositions Unprecedented Growth Predicted for Monoclonal Antibodies to Treat Rheumatoid Arthritis

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

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

For this reason, the growth of the global market is expected to continue in spite of the impending patent expiry of 3 of the 4 top-selling RA mAbs in the US.” Mr Trewartha, citing the expense and approval difficulty associated with bringing new biosimilars to market, also predicts that none of the drugs currently poised to enter the market appear to offer significant improvements or advantages over the existing class of mAbs, which will leave Remicade, Humira, and Enbrel able to maintain their top-selling status in the United States, Japan, Germany, France, United Kingdom, Italy, and Spain, growing from a combined $11.5 billion in sales in 2011 to $15.7 billion in 2018. www.gbiresearch.com; January 2013

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

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

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

HHS has stated that this year it will: • Set the goal of 50% of physician offices using electronic health records (EHRs) and 80% of eligible hospitals receiving meaningful use incen­ tive payments by the end of 2013 • Increase its emphasis on ensuring electronic exchange across provid­ ers by issuing a request for information seeking public input about a variety of policies that will strengthen the business case for electronic exchange across providers to ensure patients’ health information will follow them seamlessly and securely wherever they access care • Enhance the use of EHRs through initiatives such as the Blue Button initiative, in which Medicare beneficiaries can access their full Medi­ care records online. HHS is working with the Veterans Administration and 450 other organizations to make healthcare information available to patients and health plan members • Implement Meaningful Use Stage 2 by implementing rules that define

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what data must be able to be exchanged between health IT systems, including how the data will be structured and coded so that providers will have a uniform way to format and send data securely • Take new steps to ensure that the integrity of the program is sound.

HHS is currently conducting extensive medical reviews and issuing comparative billing reports to identify providers.

According to HHS, EHR adoption has tripled since 2010, increasing 44% in 2012 alone. www.HHS.gov; March 6, 2013

Optimizing 3 Tesla MRI of the Spine in Spondyloarthropathy

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

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

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

Reminder Forms about Pneumococcal Vaccination Important for Immunosuppressed Patients

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

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

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

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

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Gout

Relationship between Chronic Kidney Disease and Gout... in their write-up of the study. “More­ over, practitioners treating patients with gout should be wary of CKD as an underlying factor contributing to both hyperuricemia and gout risk, be­ cause many urate-lowering medica­ tions require renal dosing or have as­ sociated nephrotoxicity.”

at a glance ➤ The NHANES from 1988-1994 and 2007-2010 uncovered a 30% rate of gout prevalence among Americans with severe chronic kidney disease ➤ There was an inverse relationship between the proportion of patients with a reduced eGFR and gout or hyperuricemia, and a direct relationship between increased albuminuria and gout or hyperuricemia

Dr Gelber and his colleagues looked at the signals produced by lev­ els of albuminuria, serum uric acid, hyperuricemia, and eGFR among 15,132 adults in the 1988-1994 NHANES and 10,814 adults in the 2007-2010 NHANES. The overall prevalence of gout among Americans was 2.7% in the 1988-1994 time frame and 3.7% during 2007-2010. In both periods, there was an inverse relationship between the proportion of patients with a reduced eGFR and gout or hyperuricemia, and a direct relationship between in­ creased albuminuria and gout or hy­ peruricemia. The mean eGFR for pa­ tients with gout was 76 mL/min/1.73 m2 to 82 mL/min/1.73 m2, whereas for people without gout it was 97 mL/ min/1.73 m2 to 102 mL/min/1.73 m2.

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

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

See also page 11 Continued from cover

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

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

—Allan C. Gelber, MD, PhD

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

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

Prophylaxis with Colchicine Often Used Inappropriately in Patients with Gout

By Wayne Kuznar

C

olchicine is an effective prophy­ laxis against gout only when it is taken consistently over 14 days by patients who are prone to gout attacks, according to study results by researchers from Boston University.

A second study from the University of Pennsylvania and the Philadelphia VA Medical Center shows that pro­ phylactic colchicine is used inappro­ priately—without concurrent uratelowering therapy—approximately 75% of the time, contributing to unnec­ essary expense.

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

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steroidal anti-inflammatory drug (NSAID) used for prophylaxis was ibuprofen.

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

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

—Michael George, MD

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

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

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

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

Patients who were appropriate­ly prescribed colchicine (compared with inappropriate prescribing) were APRIL 2013

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at a glance ➤ Colchicine is an effective prophylaxis against gout when taken consistently over 14 days ➤ Prophylactic colchicine is used inappropriately in approximately 75% of patients ➤ Patients who were appropri­ ately prescribed colchicine were younger, taking the drug for a shorter time, and were more likely to be seen by a rheumatologist

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

By instituting appropriate-use crite­ ria, the Philadelphia VA Pharmacy es­ timated cost avoidance of $227,656 for colchicine in fiscal year 2013, said Dr George. n

www.ValueBasedRheumatology.com

5

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

Introducing XELJANZ Powerful efficacy. First in a new class.

2

Choose XELJANZ for robust efficacy as monotherapy or in combination with MTX 1-3 • XELJANZ monotherapy ACR20/50/70 response rates (month 3)1-3: - XELJANZ 5 mg twice daily: 59%†, 31%†, and 15%* - Placebo: 26%, 12%, and 6% Results of a 6-month, randomized, double-blind, controlled, multicenter monotherapy study in which 610 patients with moderate to severe active RA who had an inadequate response to a biologic or nonbiologic DMARD due to lack of efficacy or toxicity received XELJANZ 5 mg twice daily (N=241) or placebo (N=120).

At the month 3 visit, all placebo patients were advanced blindly to a second predetermined treatment of XELJANZ.

• XELJANZ in combination with DMARDs ACR20/50/70 response rates (month 6)1,2: - XELJANZ 5 mg twice daily + DMARDs: 53%†, 34%†, and 13%† - Placebo + DMARDs: 31%, 13%, and 3% Results of a 12-month, randomized, double-blind, controlled, multicenter study in which 792 patients with moderate to severe active RA who had an inadequate response to a biologic or nonbiologic DMARD due to intolerance, toxicity, or inadequate response received XELJANZ 5 mg twice daily (N=311) or placebo (N=157) added to background nonbiologic DMARD treatment. At 3 months, nonresponding placebo patients were advanced blindly to a second predetermined treatment of XELJANZ. At 6 months, all placebo patients were advanced in the same fashion.

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

INDICATION

• XELJANZ (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs).

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

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

Consider a change to the way you treat moderate to severe RA. 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 benefi ts 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 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: • 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.

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

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.

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© 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/March 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% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. Cases of disseminated tuberculosis were also reported. The median XELJANZ exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days).

cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the first 3 months of exposure in the controlled clinical trials are summarized below: • Mean LDL cholesterol increased by 15% in the XELJANZ 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.

• Mean HDL cholesterol increased by 10% in the XELJANZ 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% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ.

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% confidence interval) was 0.3 (-0.1, 0.7) events per 100 patient-years for the combined 5 mg and 10 mg twice daily XELJANZ group minus placebo.

In the seven controlled trials, during the 0 to 12 months exposure, malignancies excluding NMSC were reported in 5 patients (0.4 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 7 patients (0.6 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.2 (-0.4, 0.7) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. One of these malignancies was a case of lymphoma that occurred during the 0 to 12 month period in a patient treated with XELJANZ 10 mg twice daily.

The most common types of malignancy, including malignancies observed during the long-term extension, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma, and malignant melanoma.

Laboratory Tests Lymphocytes In the controlled clinical trials, confirmed decreases in lymphocyte counts below 500 cells/mm3 occurred in 0.04% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 months of exposure.

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

Neutrophils In the controlled clinical trials, confirmed decreases in ANC below 1000 cells/mm3 occurred in 0.07% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 months of exposure.

There were no confirmed decreases in ANC below 500 cells/mm3 observed in any treatment group.

There was no clear relationship between neutropenia and the occurrence of serious infections.

In the long-term safety population, the pattern and incidence of confirmed decreases in ANC remained consistent with what was seen in the controlled clinical trials.

Liver Enzyme Tests Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3x ULN) were observed in patients treated with XELJANZ. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of XELJANZ, or reduction in XELJANZ dose, resulted in decrease or normalization of liver enzymes.

In the controlled monotherapy trials (0-3 months), no differences in the incidence of ALT or AST elevations were observed between the placebo, and XELJANZ 5 mg, and 10 mg twice daily groups.

In the controlled background DMARD trials (0-3 months), ALT elevations greater than 3x ULN were observed in 1.0%, 1.3% and 1.2% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3x ULN were observed in 0.6%, 0.5% and 0.4% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively.

One case of drug-induced liver injury was reported in a patient treated with XELJANZ 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3x ULN and bilirubin elevations greater than 2x ULN, which required hospitalizations and a liver biopsy.

Lipids In the controlled clinical trials, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL

• Mean LDL/HDL 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-specified discontinuation criterion of an increase in creatinine by more than 50% of baseline. The clinical significance of the observed serum creatinine elevations is unknown.

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

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

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 reflects 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., fluconazole).

Potent CYP3A4 Inducers Tofacitinib exposure is decreased when XELJANZ is coadministered with potent CYP3A4 inducers (e.g., rifampin).

Immunosuppressive Drugs There is a risk of added immunosuppression when XELJANZ is coadministered with potent immunosuppressive drugs (e.g., azathioprine, tacrolimus, cyclosporine). Combined use of multiple-dose XELJANZ with potent immunosuppressives has not been studied in rheumatoid arthritis.

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic effects: Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. XELJANZ

TRA476916-01

should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Tofacitinib has been shown to be fetocidal and teratogenic in rats and rabbits when given at exposures 146 times and 13 times, respectively, the maximum recommended human dose (MRHD).

In a rat embryofetal developmental study, tofacitinib was teratogenic at exposure levels approximately 146 times the MRHD (on an AUC basis at oral doses of 100 mg/kg/day).

Teratogenic effects consisted of external and soft tissue malformations of anasarca, and membranous ventricular septal defects, respectively, and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day). In the rabbit embryofetal development study, tofacitinib was teratogenic at exposure levels approximately 13 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects.

In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day).

Nonteratogenic effects: In a peri- and postnatal rat study, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the MRHD (on an AUC basis at oral doses of 50 mg/kg/day). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day).

Pregnancy Registry: To monitor the outcomes of pregnant women exposed to XELJANZ, a pregnancy registry has been established. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.

Nursing Mothers Tofacitinib was secreted in milk of lactating rats. It is not known whether tofacitinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from tofacitinib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug for the mother.

Pediatric Use The safety and effectiveness of XELJANZ in pediatric patients have not been established.

Geriatric Use Of the 3315 patients who enrolled in Studies I to V, a total of 505 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older. The frequency of serious infection among XELJANZ-treated subjects 65 years of age and older was higher than among those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.

Hepatic Impairment No dose adjustment is required in patients with mild hepatic impairment. XELJANZ dose should be reduced to 5 mg once daily in patients with moderate hepatic impairment. The safety and efficacy of XELJANZ have not been studied in patients with severe hepatic impairment or in patients with positive hepatitis B virus or hepatitis C virus serology.

Renal Impairment No dose adjustment is required in patients with mild renal impairment. XELJANZ dose should be reduced to 5 mg once daily in patients with moderate and severe renal impairment. In clinical trials, XELJANZ was not evaluated in rheumatoid arthritis patients with baseline creatinine clearance values (estimated by the Cockroft-Gault equation) less than 40 mL/min.

OVERDOSAGE Signs, Symptoms, and Laboratory Findings of Acute Overdosage in Humans There is no experience with overdose of XELJANZ. Treatment or Management of Overdose Pharmacokinetic data up to and including a single dose of 100 mg in healthy volunteers indicate that more than 95% of the administered dose is expected to be eliminated within 24 hours.

There is no specific antidote for overdose with XELJANZ. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions.

Patients who develop adverse reactions should receive appropriate treatment.

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

© 2012 Pfizer Inc.

All rights reserved.

November 2012

Biologic Drug Therapy

Quick Questionnaire Can Elicit Information on Adverse Events Associated with Biologic Therapy

By Rosemary Frei, MSc Ottawa, Ontario—A simple question­ naire can help clinicians track adverse events (AEs) and plan medication ad­ justments in patients receiving biolog­ ic drug therapy, according to research­ ers at The Hospital for Sick Children in Toronto, Ontario, who presented at the recent Canadian Rheumatology Association annual meeting.

In the Safety in Patients Receiving Biologic Therapies (SPOT) study, the researchers analyzed the responses from children with rheumatic diseas­ es or their parents to a standardized, self-administered questionnaire be­ tween June and August 2012.

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

Dr Tse and her team asked 22 fe­

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

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

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

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

In total, 43 children and parents completed the questionnaire, with 88% completing the questionnaires without missing data. Only 3 patients needed help answering the questions.

All of the responders said the ques­ tions were clear and easy to answer, and that enough space was provided for their responses.

The results showed that 33 patients

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

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

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

Gout

Educational Materials for Patients with Gout Have Room for Improvement

A

careful analysis of education­ al resources for patients with gout indicates that there is significant room for improvement in conveying the right messages to pa­ tients in the right ways (Robinson PC, Schumacher JR Jr. Clin Rheumatol. 2013 Jan 16 [Epub ahead of print]).

Researchers looked at 10 patient ed­ ucation guides, including the Ameri­ can College of Rheumatology’s Gout Patient Fact Sheet, the Mayo Clinic’s Gout Information Page, the United Kingdom Gout Society’s booklet “All About Gout: A Patient Guide to Man­ aging Gout,” the Australian Rheuma­ tology Association’s Arthritis/Gout Information Sheet, and the medical database UpToDate’s Patient Infor­ mation: Gout (The Basics) and Gout (Beyond the Basics).

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

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

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

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

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

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

—Philip Robinson, MD

the materials also did not include the fact that chronic renal failure is associ­ ated with gout, nor did they name the APRIL 2013

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See also page 5

authors or their qualifications.

Six sets of educational materials avoided jargon, whereas another had only a few instances of jargon use. All 10 explained the terms that were used, 7 used pictures and/or dia­ grams, and 6 had clear instructions.

However, only 4 stated the intended audience, only 2 had key messages at the beginning, and 7 had less than 2500 words.

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

www.ValueBasedRheumatology.com

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Arthritis Update

Study Shines New Light on Deleterious Dance between B-Cells and T-Cells in Rheumatoid Arthritis

By Rosemary Frei, MSc

R

esearchers are finding tantaliz­ ing clues about how the im­ mune system is thrown off bal­ ance in diseases such as rheumatoid arthritis (RA).

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

“People with active rheumatoid ar­ thritis have lower levels of regulatory B-cells in their peripheral blood, and their regulatory B-cells also are less able to prevent the development of autoreactive responses and inflamma­ tion—tipping the balance of the im­ mune system toward the presence and action of pathogenic cells,” lead investigator Claudia Mauri, PhD, Pro­ fessor of Immunology at University

College London, told Value-Based Care in Rheumatology.

Dr Mauri said that her team had al­ ready shown in previous studies that regulatory B-cells are very important for “restraining” RA and other auto­

B-cells in 97 healthy individuals ver­ sus 103 patients with active RA and 76 persons with inactive RA. In a series of in vitro experiments, the researchers found that healthy people’s regulatory B-cells “maintain

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

—Claudia Mauri, PhD

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

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

toimmune diseases to develop. How­ ever, regulatory B-cells from patients with active RA failed to maintain this balance. In addition, the team found a lower titer of regulatory B-cells in the peripheral blood of people with active RA. This helps to elucidate not only what is happening in RA, but it also uncovers more of the details of the regulatory functions within the im­ mune system.

“The idea was to deepen our under­ standing of how regulatory B-cells work; eventually we hope to help de­ velop a therapy that can restore their number and functioning to levels sim­ ilar to those in healthy individuals,” said Dr Mauri.

“We have moved on to genetic work in our research, because we now have a good understanding of how regula­ tory B-cells work and how they inter­ act with other cells in the immune system, and we have to take other steps to bring our work to the clinic.” n

Rheumatologists Warned to Watch for Serious Infections...

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

at a glance ➤ Serious respiratory infections occurred at a rate of >2 cases per 100 patients with RA who were followed for 1 year ➤ The greatest increases in infection risk were associated with medications ➤ Predictors of serious infection in older patients with RA include living in rural areas, having past infections, other serious conditions, or extraarticular features of RA ➤ Having a past infection con­ ferred a 51% increased risk of developing a serious infection in senior patients with RA

12

Predictors of serious infection in this population included: • Living in a rural area • Having a past infection • Having other serious conditions (such as renal disease or chronic lung disease) • Having extraarticular features of RA. Medications—including diseasemodi­ fying antirheumatic drugs (DMARDs), anti–tumor necrosis fac­ tor (TNF) agents, methotrexate, and glucocorticoids—also increased the rate of serious infections.

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

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

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matched patients with RA without such infections.

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

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

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

Continued from cover

was quite surprising, according to Dr Bernatsky.

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

The greatest increases in infection risk were associated with medications.

For example, there was a >7.5-fold higher risk with a very high predni­ sone-equivalent dose. Overall infec­ tion risk was more than doubled with the use of methotrexate azathioprine, cyclophosphamide, or other DMARDs. An approximately 60% increased risk of infection was associated with cur­ rent anti-TNF drug use.

“Our data, being unselected and population-based, likely represent a somewhat different patient profile from that seen in clinical registries,” noted Dr Bernatsky. “[But] popula­ tion-based administrative data can generate precise, reasonably generaliz­ able estimates for the risk of important events such as serious infections, in­ cluding relatively uncommon ones, like significant fungal infections.” n VOL. 2

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Psoriatic Arthritis

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

Apremilast was effective in combi­ nation with other DMARDs, but was even more effective as a monother­ apy and in biologic-naïve patients.

No unexpected safety concerns were reported. Apremilast inhibits phos­ phodiesterase 4 and acts by decreas­ ing proinflammatory mediators while increasing anti-inflammatory media­ tors, Dr Kavanaugh noted. Approxi­ mately 3000 patients have been treated with the drug to date.

The multicenter, double-blind, pla­ cebo-controlled, parallel-group PAL­ ACE-1 trial randomized 168 patients (median age, 60 years) with moder­ ate-to-severe PsA to receive apremi­ last 30 mg twice daily, apremilast 20 mg twice daily, or placebo. The study enrolled patients with active PsA (defined as at least 3 tender and 3 swol­ len joints) who had failed 1 to 3 pre­ vious DMARDs or biologics. During the trial, 66% of the patients received

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

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

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

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

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

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

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

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

PALACE-1 is 1 of 3 pivotal phase

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at a glance ➤ Apremilast decreases proinflammatory mediators while increasing antiinflammatory mediators ➤ The primary end point of reaching ACR20 by week 16 was significant for the apremilast 30-mg and 20-mg doses versus placebo 3 clinical studies in the apremilast development program. Results of the PALACE-2 and PALACE-3 trials were reported in September 2012. Represen­ tatives of the drug manufacturer said that the company will submit a New Drug Application to the US Food and Drug Administration in the first half of 2013.

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

Ustekinumab Safe and Effective in PsA

P

hase 3 data for the PSUMMIT I and PSUMMIT II clinical trials show that ustekinumab (Stelara) is safe and effective in patients with psoriatic arthritis (PsA), and that the improvement persists over 1 year of treatment.

Ustekinumab is the first new bio­ logic agent in phase 3 clinical trials for the treatment of PsA. The drug is an interleukin (IL)-12 and IL-23 inhibitor, a mechanism that is thought to be spe­ cific to PsA and not to other autoim­ mune arthritic diseases. Ustekinumab is approved by the US Food and Drug Administration for the treatment of psoriasis, and is investigational for PsA. Approximately 20% of patients with psoriasis will develop PsA. The only drugs currently approved by the FDA for the treatment of PsA are tumor necrosis factor (TNF) inhib­ itors. “TNF inhibitors are not univer­ sally effective, and there is a need for new treatments. The PSUMMIT II

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data are promising,” said lead investi­ gator Arthur F. Kavanaugh, MD, Pro­ fessor of Clinical Medicine and Direc­ tor of the Center for Innovative Therapy at the University of Califor­ nia, San Diego.

Week 24 Data from PSUMMIT II The phase 2, multicenter, ran­ domized, double-blind, placebo-con­ trolled PSUMMIT II trial evaluated 2 doses of ustekinumab given subcuta­ neously to patients with active PsA who were uncontrolled by 1 to 5 dis­ ease-modifying antirheumatic drugs (DMARDs), nonsteroidal anti-inflam­ matory drugs (NSAIDs), and/or TNF inhibitors.

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

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

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

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

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

Significant improvements from APRIL 2013

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

Christopher Ritchlin, MD, Professor of Medicine and Director of the Rheu­ matology Fellowship Program and the Clinical Immunology Research Center at the University of Rochester Medical Center, NY, was the lead investigator of PSUMMIT II. Week 52 Data from PSUMMIT I Ustekinumab was superior to place­ bo in patients with active PsA despite treatment with DMARDs and NSAIDs (but not a TNF inhibitor) at 24 weeks, according to results from the PSUM­ MIT I trial. New 52-week data from PSUMMIT I showed that this improve­ ment persisted from 24 to 52 weeks in patients who were treated with usteki­ numab versus placebo.—PS n

www.ValueBasedRheumatology.com

13

Health Economics

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

By Dalia Buffery San Diego, CA—Rheumatoid arthri­ tis (RA) is associated with significant economic and clinical burden on the US healthcare system as a result of its growing prevalence, the frequent dis­ ability and reduced work productiv­ ity associated with this chronic dis­ ease, and the overall impact on a patient’s quality of life. This clinical impact is directly linked to the in­ creasing costs of managing patients with RA. In 2008, the average annual overall medical cost for a patient with RA was approximately $13,000.

The treatment of RA has evolved with the introduction of so-called tra­ ditional disease-modifying antirheu­ matic drugs (DMARDs) in the past few decades and, more recently, bio­ logic DMARDs. Lisa Mostovoy, PharmD, Clinical Advisor at CVS Caremark, and colleagues have inves­ tigated the impact of the growing availability of biologic DMARDs on the cost and utilization of RA thera­ pies between January 1, 2006, and December 31, 2011; they presented their findings in a poster session at

the 2013 Academy of Managed Care Pharmacy annual meeting.

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

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

In 2006, the difference between the use of conventional DMARDs and the use of biologic agents was more than 50%, favoring the conventional agents.

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

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

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

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

Dr Mostovoy and colleagues sug­ gest that, based on these results, as well as on the 2012 ACR recommen­ dations and on the emerging treat­ ments for RA, the growing use of bio­ logic therapies for RA can be expected to continue, despite the greater costs associated with these agents. n

The Economic Burden of Chronic Pain on the US Healthcare System Osteoarthritis the greatest pain-related cost driver among Medicare patients San Diego, CA—A recent report by the Institute of Medicine estimates that the treatment of noncancerous chronic pain costs the US healthcare system $635 billion annually. Using a commercial database from Humana, a national health insurance plan, Mar­ garet K. Pasquale, PhD, Principal Re­ searcher at Comprehensive Health Insights, and colleagues analyzed the economic burden of chronic versus acute pain in the general US popula­ tion and in Medicare beneficiaries.

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

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

14

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

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

followed by back pain.

The highest drivers for healthcare utilization in patients with chronic pain included outpatient visits and prescriptions for pain medications. In

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

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

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

condition than men, but men had more acute pain.

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

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

This study highlights the significant economic impact of chronic pain on the US healthcare system and the need to manage chronic pain properly to minimize preventable healthcare utili­ zation and its associated costs.—DB n VOL. 2

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Systemic Sclerosis

New Classification Criteria... is continuous and proximal to the metacarpophalangeal joints, accord­

at a glance ➤ The major criteria developed in 1980 still work well in classifying sclerodactyly that is continuous and proximal to the metacarpophalangeal joints ➤ However, they fail to classify a significant proportion of patients with early systemic scleroderma or with the limited subtype of the disease ➤ In the current validation cohort, a score of ≥9 showed a sensitivity of 91% and a specificity of 92% ➤ The 1980 criteria had a sensitivity of 75% and a specificity of 72% in this cohort

Continued from cover

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

The ACR and the European League Against Rheumatism established a committee to develop new criteria.

The committee used an 8-step pro­ cess, first testing the validity of 23 items selected in existing databases of systemic sclerosis cases and controls.

Then, 20 cases that represented the spectrum of systemic sclerosis (low probability to high probability) were selected and ranked by experts and conjoint analysis to assign weights of importance to 17 preliminary items.

A provisional threshold was estab­ lished to classify definite systemic

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

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

—Janet E. Pope, MD, MPH, FRCPC

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

The threshold was refined in a sub­

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

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

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

Health Economics

Impact of Specialty Drugs on the Cost of Rheumatoid Arthritis Management

By Dalia Buffery San Diego, CA—Specialty drugs have been gradually becoming the stan­ dard of care for many chronic diseas­ es, including rheumatoid arthritis (RA), and their costs continue to rise faster than the cost of traditional, non­ specialty drugs, according to Patrick P. Gleason, PharmD, Director of Clin­ ical Outcomes Assessment at Prime Therapeutics, and colleagues. In 2012, drugs used for the treatment of RA had an average cost of $2251 per pre­ scription, a 12.1% cost increase from 2011. Dr Gleason and colleagues dis­ cussed the results of their study on specialty drugs as a cost driver in the management of RA at a poster presen­ tation at the 2013 Academy of Man­ aged Care Pharmacy annual meeting.

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

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ty drugs for RA increased by 0.8%.

The total cost of care per person per year (PPPY) increased from $19,830 in 2008 to $23,128 in 2010 (in­ cluding those using or not using spe­ cialty drugs).

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

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

Many patients will require help toward paying for the ever-growing costs of specialty drugs, whether from payers, from the drug manufacturer, or via other support systems, and it is not too soon to plan for these types of resource allocation mechanisms. bers indicate a gradual increase in the spending on specialty drugs compared with the spending on all other medical services for patients with RA. Between 2008 and 2010, the cost of specialty drugs for RA was growing at a rate of 6.9% annually, while the costs for other drugs remained stable. Fur­ thermore, the wholesale acquisition APRIL 2013

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

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

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

www.ValueBasedRheumatology.com

15

Rheumatology Practice Management

™

Breach Notification Requirements New enforcement provisions go into effect this year

By Jennifer Kirschenbaum, Esq

I

t should be no surprise that medi­ cal practices have an obligation to maintain protected health infor­ mation in certain ways, and to only use and disclose such protected health information as authorized by the patient or otherwise by law. Such requirements are set forth under the Privacy Rule.

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

However, the Final Rule promul­ gated on January 25, 2013, not only modifies the Breach Notification Rule, it incorporates significant en­ forcement provisions should a breach occur and not be dealt with appropri­ ately by the practice. Effective Sep­ tember 23, 2013, every medical prac­ tice is required to notify an individual of an acquisition, access, use, or dis­ closure of protected health informa­ tion in a manner not permitted under the Privacy Rule, otherwise known as a breach. Pursuant to the statute, a breach excludes: 1. Any unintentional acquisition, ac­ cess, or use of protected health in­ formation by a workforce member or person acting under the authori­ ty of the practice or a business asso­ ciate, if such acquisition, access, or use was made in good faith and within the scope of authority and does not result in further use or dis­ closure in a manner not permitted under the practice’s privacy policy.

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

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

16

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

4. Where the practice has demon­ strated that there is a low probabil­ ity that the protected health infor­ mation has been compromised based on a risk assessment of at least the following factors: A. The nature and extent of the protected health information involved, including the types of identifiers and the likelihood of re-identification B. The unauthorized person who used the protected health infor­ mation or to whom the disclo­ sure was made C. Whether the protected health information was actually ac­ quired or viewed D. The extent to which the risk to the protected health informa­ tion has been mitigated (45 CFR 164.402).

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

To the Individual Notification to the individual is re­ quired where, after a risk assessment, it has been determined that protected health information has been—or is reasonably believed by the practice to have been—accessed, acquired, used, or disclosed as a result of a breach. A breach shall be treated as being dis­ covered by the practice on the first day that the breach is actually known to the practice or, by exercising rea­ sonable diligence, would have been known to the practice, meaning that, if such breach is known—or by exer­ cising reasonable diligence would have been known—to any person who is a workforce member or agent of the covered entity other than the person committing the breach. Notifi­ cation to the individual is required no later than 60 calendar days after the discovery of a breach, and in the noti­ fication the practice is required to pro­ vide, to the extent possible, the follow­ ing information: • A brief description of what hap­ pened, including the date of the breach and the date of the discovery of the breach, if the date is known • A description of the types of unse­

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cured protected health informa­ tion that were involved in the breach (such as whether the indi­ vidual’s full name, social security number, date of birth, home ad­ dress, account number, diagnosis, disability code, or other types of information were involved) • Any steps that the individual should take to protect himself or herself from potential harm result­ ing from the breach • A brief description of what the covered entity involved is doing to investigate the breach, to mitigate harm to the individual, and to pro­ tect against any further breaches • Contact procedures for the indi­ vidual to ask questions or learn additional information, which shall include a toll-free telephone number, an e-mail address, web­ site, and/or postal address.

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

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

To the Media When more than 500 residents of a state or jurisdiction are involved in a

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

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

Additional Concerns In addition to the foregoing, busi­ ness associates are required to report the discovery of a breach to the prac­ tice within 60 calendar days (45 CFR 164.410).

Failure to abide by the Breach No­ tification Rule may open up the prac­ tice to substantial liability. The recent modifications to HIPAA allow for the imposition of civil monetary penal­ ties for any entity or individual in violation of any HIPAA requirement, including the Breach Notification Rule, which is why it is imperative to understand and implement the re­ quirements of the rule. Implementa­ tion requires that the policies, proce­ dures, and contracts of the practice reflect the requirements of the Breach Notification Rule.

To discuss your practice’s compli­ ance needs to prepare for September 23, 2013, check out available HIPAA policies at www.healthcarepractice compliance.com, or contact Jennifer at 516-747-6700 x302 or Jennifer@ kirschenbaumesq.com. Prior to Sep­ tember 2013, all practices will be re­ quired to adopt new Notice of Priva­ cy Practices, as well as accompanying documents, such as a Breach Notifi­ cation Policy.

Jennifer Kirschenbaum, Esq, manages Kirschenbaum & Kirschenbaum’s health­ care department, which specializes in representing healthcare practitioners in regulatory compliance, audit defense, licensure, and transactional matters. She may be reached at 516-747-6700 x302 or by e-mail at Jennifer@kirschenbaumesq. com. n VOL. 2

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NO. 2

Vasculitis

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

By Wayne Kuznar

R

ituximab (Rituxan) is the most recent and the only treatment approved by the US Food and Drug Administration (FDA) for antineu­trophil cytoplasmic autoanti­ body (ANCA)-associated vasculitis, but there is still a role for cyclophos­ phamide in these diseases, especially in patients with more severe forms, according to several researchers.

Traditional immunosuppressive drugs have improved treatment out­ comes for patients with ANCA-asso­ ciated vasculitis, but the development of biologic agents and a better under­ standing of the pathogenesis of the disease have contributed to the dis­ covery of rituximab as an effective alternative to the immunosuppres­ sive drug cyclophosphamide.

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

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

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

The primary end point was the per­ centage of patients who achieved clinical remission, defined as a Bir­ mingham Vasculitis Activity Score for Wegener’s granulomatosis of 0 and complete tapering of the predni­ sone dose at 6 months. In the ritux­ imab group, 64% of the patients VOL. 2

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

“This is an exciting period in which we now have 2 options for remission induction for severe GPA and MPA.” —Carol Langford, MD, MHS, FACP

“RAVE demonstrated that ritux­ imab is a proven alternative to cyclo­ phosphamide for induction of remis­ sion in patients with severe ANCAassociated vasculitis, which is of particular importance for patients who have a severe disease flare that requires treatment, and for pa­ tients who want to preserve their fertility,” because infertility is a po­ tential side effect of cyclophospha­ mide, Dr Specks said.

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

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

Remission maintenance was again shown to be similar between the

2 strategies in an analysis of the 18-month follow-up of RAVE partici­pants.

Cyclophosphamide Still an Option in Some Cases Cyclophosphamide is a much bet­ ter-understood agent now than it was nearly 40 years ago. It continues to have a role in inducing remission in patients with GPA and MPA, particu­ larly in patients who have severe forms of these diseases, Dr Langford explained.

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

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

—Ulrich Specks, MD

Toxicity Profile The toxicity profile of these agents involves not only acute toxicities, such as infection, bone marrow sup­ pression, and cystitis, “but also longterm complications, including infer­ tility for both men and women, myelodysplasia that can lead to lym­ phoma and leukemia, and the poten­ tial for bladder cancer,” Dr Langford pointed out.

The risk of bladder cancer with cy­ clophosphamide use is related to the total dose and the duration of the ex­ APRIL 2013

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at a glance

➤ Rituximab is the only treatment approved by the FDA for ANCA-associated vasculitis ➤ There is still, however, a substantial role for cyclophosphamide in patients with severe forms of this disease ➤ In the RAVE study, 64% of the patients in the rituximab group achieved clinical remission compared with 53% of those receiving cyclophosphamide ➤ In the RITUXVAS trial, a 12-month single course of rituximab achieved the same sustained remission levels as a 6-month course of cyclophosphamide posure, with a 5% risk at 10 years from the first cyclophosphamide dose, to a 15% risk at 16 years from the first dose.

Improved Treatment Better use of cyclophosphamide has evolved, Dr Langford said. Strategies by the treatment of ANCA-associated vasculitis is now considered in 2 phases—the induction of remission, followed by maintenance. Azathio­ prine maintenance after 3 to 6 months of cyclophosphamide therapy main­ tains remission without increasing the relapse rate. Methotrexate mainte­ nance is similarly as effective as aza­ thioprine in maintaining remission.

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

Careful Monitoring Recommended The time to remission is equivalent between intermittent IV dosing and daily oral cyclophosphamide at a median of 3 months; however, inter­ mittent therapy is associated with a higher rate of relapse.

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

www.ValueBasedRheumatology.com

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Ankylosing Spondylitis

Early Use of TNF Inhibitors Is Beneficial in Ankylosing Spondylitis

By Rosemary Frei, MSc Ottawa, Ontario—Patients with an­ kylosing spondylitis who take tumor necrosis factor (TNF) inhibitors are 70% less likely to experience radio­ graphic disease progression, accord­ ing to a cohort study presented at the Canadian Rheumatology Associa­ tion’s 2013 annual meeting.

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

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

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

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

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

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

Patients with ankylosing spondyli­ tis who had used TNF inhibitors were 70% less likely to progress than pa­ tients who had never taken this type of medication. In addition, the pa­ tients who started taking TNF inhibi­ tors within 10 years of disease onset had a 3-fold lower probability of dis­ ease progression than those who started taking these types of medica­ tions later.

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

with RA, renal insufficiency is caused by agents such as nonsteroidal antiinflammatory drugs, disease-modify­ ing antirheumatic drugs, and metho­ trexate. Some of these drugs may even have toxic side effects when used in patients with only mild renal insuffi­ ciency. Methotrexate, an anchor drug for the treatment of RA, can cause se­ vere con­­sequences at very low doses (ie, 2.5 mg once weekly), and in some cases, can even be fatal.

A recent study showed that adalim­ umab did not worsen renal function or have other serious adverse events in patients with RA and renal insuffi­ ciency, including patients with endstage renal disease who were under­ going hemodialysis (Sumida K, et al.

Arthritis Care Res [Hoboken]. 2013;65: 471-475).

In the study, 65 patients with RA (in­cluding 2 patients who were under­ going hemodialysis) were treated with adalimumab 40 mg subcutane­ ously every other week in the Ne­ phrology Center of Toranomon Hos­ pital in Toyko, Japan, from December

2008 to June 2011.

The 2 patients who were undergo­ ing hemodialysis received adalimum­ ab on nonhemodialysis days. The pa­ tients’ renal function was evaluated using the estimated glomerular filtra­ tion rate (eGFR). Changes in eGFR were compared between patients with renal insufficiency (N = 39) and pa­ tients without renal insufficiency (N = 26). Renal insufficiency was defined as an eGFR of <60 mL/minute/1.73 m2.

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

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

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

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

—Nigil Haroon, MD, PhD, DM, FACR

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

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

In the Literature Obesity a Risk Factor for Developing Rheumatoid Arthritis

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

A recent study investigated the in­ fluence of obesity on the development of RA to determine whether obesity is a possible risk factor that could help to explain the annual increase in the inci­ dence of RA in the United States since 1995, after a 4-decade de­cline (Crow­ son CS, et al. Arthritis Care Res [Hobo­ ken]. 2013;65:71-77).

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

18

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

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

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

Adalimumab Safe for Patients with RA and Renal Insufficiency

A common comorbidity in patients

value-based CARE in Rheumatology

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APRIL 2013

VOL. 2

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NO. 2

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t eu ifican ty radig n ed g life e ly ts co fro ME poli As is g appr itis ato righ d medic . te m fo m lo Obje therapeu VOLUME Valu s and describ erived definitio e are on benefi stMARCH/APRIL 2012 AN in hr lan s. r 2 id a nom tic c ng treatm5,coNUMBER c co base arthritis TS/PL with p winner report toid art 81% is ic b RA. Ho rthritis he td een ateg efit her of RA tive: To ent, s ory. ben e has b benefi lying th rapy, t sing t ing the iden mos urden o wever, th (RA), pa biolo toid ATIEN ligned imate rovider rheuma at least sive a e f ti p s t rticu fy p e o h ra g lu e ass a h r t p ic ealth n the h p ctice s in P r va units ts. A ult larly e. ten of fp inc decre is a oc e of a plan the c rovider a Meth s. ectiv al ice are the 84% o quests foprovals ore in a more s no althcare iated co biologic nd p urren the s of cos e value her by , or by m ract ersp u o w po s s s ayer t ma colle d: In No of p individ e- p embers , with % of re rting ap need e it in sition ystem. 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How RA the rs, a ment o an not dings s to align for RA b t of R landsca le care Beginning in oth irable, AlthNew ee ra n h t io e Gre paye au ty ed in el, M ctor, p A Ms fits fits rs and he trea mon t . The fi lication m Tze al Dire Milw comin about ad conomic ver, the h pies allow term logics. Th is not lik e. heaDavid B. Nash, d t a r t e m e s in e p s ig ded MD, g to is su ely patie conc of pe h co e lb e Ben provid ics for e in co ug clas nt im ers. edic MBA lu A r m v rv n a e a s o rc a M ts e rn t lu v rket. y eptio o l g e of m a s in ns o furthat f biolo ch mor this dr import memb ctice tient new . Payer s f biologic creasing iona Stak f curo a Nat thera th o ehold use ave mu within everal nts/plan n pra the pa owpies tisfaction erapies ptions fo er Pe ll s a h a will c w r rspe BUSINESS tis, t value have d patie ers c eeds of is by fo reatreate ith curre nd the n effective cti h e a n t u id n e h nt th mato dised fo page ve, challe ing survey ayers, a Prov g the n do t itiate and e id r ra 91 a n A lif utoim pies ges , m He artArthritis: elong Trends in Biologic Therapies for Rheumatoid Results from a h a ri fo a this iders, p ERS: dressin hey ca they in drugs hen lt m n ti h r d Drug new 2012 unce d T ic D popu of inflam une disord s (RA) is B Survey of Payers and Providers ;5 m e rprov ROVI ly in a thritis. nes as eumat rapies w n (2 edica efits. lation er an mato a ch www.A ):83-92 h li e ti P mous id ar ir e R o h t , d ry ns ronic t ecen ™ the mo HDBo art Rhonda Greenapple, MSPH guid g an gic no ato nline.c RA in t epidem st ofttienued hritis. 1 R most com systemic auto rheum e-based odifyin ly biolo om Disclos iologMHSA, adult A on wom MD, t m ures ar Stakeholder Perspective byaffAlbert ic of RA s age 1 affects mon form en h C data FACPE with evidenc isease- ore cos ects Tzeel, e at en 1% o 9d 40 adds d of te rema many in as risen in indic th f a ing t with d ss to m e the a sig xt ir fam l te that to 70 ins a divid th ts n n e e fi r if e il p y th m e ic g ti ies, b ears. 2 ualsen ast 10 m on, ajor c Liver ant e inc pro Impact of the RemovalMof the Monthly Test wh id y Requirement auru g B Function and reduced q ut also to cost not only sG D se of dis o are o ears. 3 Bec ence of subst only uality socie f wo for Ambrisentan abilit ause LLC, reenappelealth & a m to n rk ty u R ti o y, st in p f A al he a th e a MaadnisH is Presi g age JD; be althc life, loss s a whole 1,4tients an cono Harner, Louise A. Durst, RN; John Carlsen, MPH;e Lauren on, NMegan denKuchinski, Be conside eric MHA; t, Rei are mic b and o d . In mbL. urden withincause com red in RA utilizati f work p l AmJ. Harris, RN,J.BSN; Glenna addiDaniel Neves, BA; Stephanie ursTraiger, emen RN, MSN, CNS-BC ro om t Inte treatm months plication managem on are fa ductivity, ne.c Vol li ll ig n s ence, ctors Stakeholder Perspective 5by T. Kenney, Jr, RPh, MBA , NJames imme ent is co of disea of RA m ent. 4,5 DBo o2 th H at se on a l Marc w.A tion, diate sym nsidered set, y begin ww h/Ap c p e to de b ril 20 term ut also to toms of linically arly and velop 12 p n disab CLINICAL ility. 1,6,7slow disea ain associa ecessary aggressiv e to m ted w Histo se prog ana it re ricall 012 Benefits of Novel Oral Anticoagulant Agents for Thromboprophylaxis www y, est ssion to p h inflamm ge ril 2 .AHD imate re /Ap after Total Hip or Knee Arthroplasty Bon s of w vent lon aarch line.c M g o rk om disab 2 l Richard J. 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