VBCR September Vol 1, No 4

Value-Based Care in Rheumatology

SEPTEMBER 2012 VOL 1 • NO 4

F R O M T H E P U B L I S H E R S O F A M E R I CA N H E A LT H & D R U G B E N E F I T S

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Personalized Medicine

RABBIT Risk Score Can Help Guide Treatment Selection by Reducing Infection Rates and Associated Costs Combination therapy with corticosteroids ups infection risk by almost 5-fold

By Neil Canavan Berlin, Germany—Taking another step forward toward the realization of personalized medicine in rheumatology, German researchers presented the results of a new study that validated their original RABBIT (Rheumatoide Arthritis: Beobachtung der Biologika-Therapie) biologic register for rheumatoid arthritis (RA) risk score.

This diagnostic instrument is used to calculate the risk for serious

infection in patients with RA who are being treated with anti–tumor necrosis factor (TNF) drugs or with conventional disease-modifying antirheumatic drugs (DMARDs), specifically methotrexate.

The Risk Score “The results of our study validate the RABBIT risk score as a useful tool to help identify rheumatoid Continued on page 5

New Recommendations for the Management of Lupus Nephritis

By Mary Mosley

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ew recommendations for the management of lupus nephritis (LN) call for a renal biopsy at the earliest sign of kidney dysfunction to guide the use of immunosuppressive treatment in patients with systemic lupus erythematosus (SLE).

The goal for treatment is a complete renal response, defined as proteinuria

<0.5 g per 24 hours, with normal or near-normal renal function.

Nearly one half of patients with SLE will develop LN, and the presence of LN increases the risk for renal failure, cardiovascular (CV) disease, and death.

The recommendations were issued Continued on page 12

Psoriasis and Psoriatic Arthritis: Similarities and Differences

By Alan Menter, MD Chief of Dermatology, and Director, Dermatology Residency Program, Baylor University Medical Center, Dallas, TX

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soriasis and psoriatic arthritis (PsA) have been intimately linked for only decades. Multiple questions remain about the true relationship between psoriasis and PsA. Only approximately 30% of patients diagnosed with psoriasis will develop PsA.1 Why? What are the genetic, immunopathologic, and therapeutic similarities and differences between these 2 related entities? Why do the majority of patients with psoriasis only develop PsA 10 to 12 years subsequent to their skin manifestations?

Genetic Similarities and Differences The strongest association between psoriasis and PsA lies in the class 1 Continued on page 15

Adalimumab-Methotrexate Combination Suppresses Progression of Joint Erosion and Joint Space Narrowing

By Alice Goodman

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dalimumab plus methotrexate inhibited both joint erosion and joint space narrowing in patients with early rheumatoid arthritis (RA), and this beneficial effect was independent of disease activity. These were the findings of a post hoc analy-

sis of the new, 2-year-long PREMIER trial (Smolen JS, et al. Ann Rheum Dis. 2012 August 22. Epub ahead of print).

Progression of joint space narrowing was associated with impaired physical function throughout 2 years of Continued on page 6

INSIDE VALUE PROPOSITIONS . . . . . . . . . . .

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The value of decision aids in arthritis Treat-to-target approach improves gout outcomes ARTHRITIS UPDATE . . . . . . . . . . . 9 Tight control increases remission Tofacitinib effective in active disease, awaiting safety data for approval FIBROMYALGIA . . . . . . . . . . . . . . . 10 Childhood abuse linked to pain and depression in FM Relationship to smoking still unclear © 2012 Engage Healthcare Communications, LLC

This article sheds some light on these questions and issues, with practical implications for providers and payers, while also recognizing the benefit of new drugs under development and what role they may potentially play in providing improved cost-effectiveness for our patient population.

LUPUS . . . . . . . . . . . . . . . . . . . . . . . . . . 12 EULAR’s new recommendations ECONOMIC ISSUES IN RHEUMATOLOGY . . . . . . . . . . . . 16 Impact of disability on costs Reduced healthcare costs with duloxetine DRUG UPDATE . . . . . . . . . . . . . . . . 18 Rayos a new delayed-release prednisone for rheumatic diseases

Rheumatology PRACTICE MANAGEMENT™

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Getting more out of your time

The Rheumatology Featuring

Insights Service Subscribe today to the essential roadmap to navigating reimbursement in one of today’s most challenging and competitive markets Updated a minimum of six times per year Based on ongoing parallel surveys of 100 rheumatologists and 50 managed care decision makers Delivers concise and insightful commentary focused on implications for current and emerging immunology brands

Subscribers receive: 1. The 2012 Rheumatology Reimbursement Report 2. Quarterly updates on key topics including biosimilars, manufacturer and sales force reimbursement effectiveness, and rheumatology practice and specialty pharmacy trends – topics tailored to meet subscribers’ key interests and strategic issues 3. Updates throughout the year driven by market and competitive events Premium subscribers also have access to customized, fast-turnaround research with members of the Reimbursement Intelligence Network, our panel of leading managed care decision makers

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In This Issue

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

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Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889 Associate Publisher American Health & Drug Benefits Maurice Nogueira maurice@engagehc.com 732-992-1895 Associate Editor Lara J. Lorton lara@engagehc.com 732-992-1892

VALUE PROPOSITIONS

LUPUS

The value of decision aids in arthritis: reduced procedures and costs Treat-to-target strategy improves gout outcomes A new approach to osteoarthritis management

EULAR issues new recommendations for the management of lupus nephritis

PERSONALIZED MEDICINE in

Rheumatology

Editorial Assistant Jennifer Brandt jbrandt@the-lynx-group.com 732-992-1536 National Accounts Manager Zach Ceretelle

ARTHRITIS UPDATE

Quality Control Director Barbara Marino Business Manager Blanche Marchitto 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.

Differences and similarities between psoriasis and psoriatic arthritis As drugs improve, so does cost

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RABBIT risk score can guide treatment selection, reduce infection and costs New method for predicting serious infection risk helps to individualize therapy

Senior Production Manager Lynn Hamilton

PSORIATIC ARTHRITIS

Adalimumab-methotrexate combination suppresses progression of joint erosion and space narrowing Tight control increases remission Tofacitinib effective in active disease, awaiting safety data for approval

ECONOMIC ISSUES IN RHEUMATOLOGY RA-related disability increases healthcare costs Duloxetine associated with reduced healthcare costs and less opioid use than standard of care Medication adherence low in Medicaid population with RA

DRUG UPDATE Rayos a new delayed-release prednisone for patients with RA and other rheumatic diseases

FIBROMYALGIA

Rheumatology PRACTICE

Childhood abuse linked to pain and depression in patients with fibromyalgia Role of smoking in this condition still unclear

MANAGEMENT™ Employers to cut healthcare spending by steering doctor selection Getting more out of your time

Contact Information: For subscription information please contact: Telephone: 732-992-1538 Fax: 732-992-1881 Permission requests to reprint all or part of any article published in this magazine should be addressed to editorial@engagehc.com.

Address all editorial queries to: editorial@engagehc.com Telephone: 732-992-1536 Fax: 732-992-1881 Value-Based Care in Rheumatology, ISSN applied, is published 6 times a year by Engage Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2012

by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Care in Rheumatology is a registered trademark of Engage Healthcare 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.

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.

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VBCR Advisory Editorial Board Editor-in-Chief Sy Schlager, MD, PhD President & Chief Medical Officer Therapeutic Window, LLC Southlake, TX

Muhammad Asim Khan, MD Professor of Medicine Case Western Reserve University Cleveland, OH

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

Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield New York, NY

Randall Krakauer, MD, FACP, FACR National Medical Director Medicare, Aetna Princeton, NJ

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

Gary L. Johnson, MD, MS, MBA Regional Medical Director Humana, Inc. Madison, WI

Alan Menter, MD Director Baylor Psoriasis Research Center Dallas, TX

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

Atheer A. Kaddis, PharmD Vice President, Managed Markets Diplomat Specialty Pharmacy Swartz Creek, MI

Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth Murray, UT

Ronald van Vollenhoven, MD, PhD Associate Professor Karlinska University Hospital Solna Stockholm, Sweden

James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA

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

F. Randy Vogenberg, RPh, PhD Principal Institute of Integrated Healthcare Sharon, MA

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Value Propositions The Value of Decision Aids in Rheumatoid Arthritis: Reduced Procedures, Costs A new report from the Group Health Cooperative in Seattle, WA, highlights the benefits in providing decision aids for patients with knee or hip rheumatoid arthritis (RA) by significantly reducing the rates of surgery for knee or hip replacement surgery. In their study, knee replacement surgery was reduced by 38%, resulting in 21% cost reductions over a 6-month period; similarly, hip replacement surgery was reduced by 26%, leading to 12% lower costs over 6 months.

Joint replacement is a common procedure in the United States, amounting to more than 650,000 knee replacements and 250,000 hip replacements annually, at a combined annual cost of $15.6 billion.

This is the first study to demonstrate the value of decision aids as a clinical and economic tool to affect patient clinical decision-making and associated costs in rheumatic conditions. “Decision aids are balanced sources of information that clearly present the evidence-based pros and cons of treatment options for a health condition,” said lead investigator David E. Arterburn, MD, MPH, a general internist and associate investigator at Group Health Research Institute. These results are consistent with previous studies with other types of decision aids, which show that patients are likely to make conservative, less-invasive treatment decisions when presented with evidence-based information about the risks and benefits of different treatment options.

The decision aids provide clear information to patients, such as the 3month recovery time from a knee or hip replacement surgery, the risk for infections, and the limited (10- to 20-year) duration of the artificial joint.

This information is presented by a video that is sent to the patient or online on Group Health’s website.

This approach is further enhanced by the way providers at the Group Health Cooperative in Seattle are being paid; they receive a salary rather than applying the fee-for-service methodology common in many practices.

By having no incentives to do more procedures, which are often tied to a provider’s bonus and are usually quite costly, they can focus on helping the patients to reach a decision based on true clinical benefits that is also appropriate for their economic situation. Applying decision aids to the treatment paradigm of patients with RA can help to reduce the costs associated with this condition, while improving patient satisfaction. Health Affairs; September 2012

New Program for Pain Research Supported by NIH A new collaborative research program supported by the National Institutes of Health (NIH) is focused on pain-related research and is being led by the National Center for Complementary and Alternative Medicine.

The program is headed by Catherine Bushnell, PhD, a neuroscientist at McGill University, Montreal. “It is an exciting and promising time in the field of pain research, and I look forward to strengthening our understanding of the mechanisms and modulation of pain,” Dr Bushnell said.

The new program will work toward developing better ways to effectively treat patients with chronic pain and advance research on the integration of pharmacologic and nonpharmacologic approaches. More than 100 million Americans live with chronic pain conditions, and the estimated annual cost associated with treatment and lost productivity is approximately $635 billion, according to the Institute of Medicine. National Center for Complementary and Alternative Medicine; August 7, 2012

Does Marijuana Have True Value for Patients with Fibromyalgia?

New findings indicate that more than 10% of patients with fibromyalgia use marijuana for medicinal relief of symptoms, such as pain, fatigue, and

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insomnia. Mary-Ann Fitzcharles, MD, Professor of Medicine, McGill University, and a Consulting Rheumatologist at the Montreal General Hospital of the McGill University Health Centre, Montreal, Canada, and colleagues documented self-reported cannabinoid use in 457 patients with fibromyalgia who are treated at the Alan Edwards Pain Management Unit of the McGill University Health Centre in Montreal. Of these patients, 13% used cannabinoids, and 80% of them used herbal cannabis/marijuana. Among the cannabinoid users, 24% used prescription cannabinoids and 3% used herbal cannabis and prescription cannabinoids. “While self-medicating with cannabinoids may provide some pain relief to FM [fibromyalgia] patients, we caution against general use of illicit drugs until health and psychosocial issues risks are confirmed,” advised Dr Fitzcharles.

The investigators suggest that some patients are self-medicating with nontraditional therapies, such as marijuana, because the ability of pharmacologic treatments to control the symptoms of fibromyalgia pain is often modest. Arthritis Care & Research; Epub 21 June 2012

Treat-to-Target Approach May Improve Gout Outcomes Using the treat-to-target approach may improve outcomes of patients with gouty arthritis, according to a new study conducted at Galway University Hospitals in Ireland. Applying this approach increased the rate of adherence to the 2 recommended serum uric acid levels, <5 mg/dL and <6 mg/dL. Specifically, following the treat-to-target guidelines resulted in 78% of patients reaching the target guideline of <6 mg/dL and 65% of patients reaching the target of <5 mg/dL. The investigators noted that using the treat-to-target approach led the majority of patients to receive appropriate therapy and reach recommended uric acid levels, which is necessary for improving outcomes in patients with gouty arthritis. Journal of Musculoskeletal Medicine; September 12, 2012

A New Approach to Osteoarthritis Management Some 27 million Americans suffer from osteoarthritis (OA). The Chronic Osteoarthritis Management Initiative (COAMI) Work Group has outlined a new vision for the management of OA, according to a recent statement from the US Bone and Joint Initiative (USBJI). The goal is to improve patient outcomes by focusing on a multidisciplinary approach and implementing management steps that center on the patient’s symptoms and the context of the disease, such as family history and comorbidities.

“Paying attention to patients’ symptoms, starting with asking about them in various settings, asking about a family history of joint replacement, following up both proactively and longitudinally, and applying the principles of integrated, multispecialty systems of care, all would improve outcomes for the millions of people with OA,” said Joanne M. Jordan, MD, MPH, Director of the University of North Carolina’s Thurston Arthritis Research Center and Chair of the COAMI. “Many of these changes could be implemented now.”

COAMI Work Group members include orthopedic nurses and surgeons, specialists in rheumatology and rehabilitation and sports medicine, osteopathic physicians, physical therapists, and athletic trainers.

Among the priority actions listed by the USBJI are a Call to Action geared specifically to healthcare professionals who treat patients with OA, as well as to policymakers and the public; develop standardized screening tools and indicators of OA to promote the likelihood and consistency of early diagnosis; and develop tools to enhance patient engagement in learning about and managing OA. US Bone and Joint Initiative; September 7, 2012

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Personalized Medicine in Rheumatology

RABBIT Risk Score Can Help Guide Treatment... arthritis patients at high risk of developing infections when treated with anti–tumor necrosis factors or diseasemodifying antirheumatic drugs,” said Angela Zink, PhD, from the German Rheumatism Research Centre, Berlin, at the European League Against Rheumatism 2012 Congress.

The RABBIT risk score can help rheumatologists identify at-risk patients and tailor therapeutic options to the individual patient to avoid drug combinations that pose an increased risk of infectious complications for a particular patient. “This could also help to reduce costs associated with treating the infections,” Dr Zink added.

Named for the German biologics registry from which patients were enrolled, the RABBIT risk score is comprised of risk factors for infection such as patient age, other medical conditions and related medications, treatment history for RA, and disease activity. The selection and statistical weighting of factors included in RABBIT were optimized and described in a previous study (Strangfeld A, et al.

Ann Rheum Dis. 2011;70:1914-1920).

The present study sought to validate the RABBIT instrument by enrolling patients with RA who were just starting their treatment regimens.

The investigators used data from patients who were enrolled in the RABBIT biologic registry after January 1, 2009, and were receiving either anti-TNF therapies or DMARDs.

“The results of our study validate the RABBIT risk score as a useful tool to help identify rheumatoid arthritis patients at high risk of developing infections when treated with anti– tumor necrosis factors or disease-modifying antirheumatic drugs. This could also help to reduce costs associated with treating the infections.”

—Angela Zink, PhD A total of 1327 patients received anti-TNF agents and 1276 received DMARDs. Using the individual baseline characteristics for each patient, the investigators used the RABBIT risk score calculations to calculate the expected likelihood of infection for each patient. The expected number of serious infections was then compared with the actual number of infections in the entire cohort and within the 2 patient subgroups.

Expected, Actual Rates of Serious Infection The results showed a very good agreement between the risk score– based expected rate of serious infections and the actual number of infections. For example, in patients receiving anti-TNF inhibitors, the expected rate of serious infection was 3.0 events per 100 person-years compared with 3.2 actual events. For patients receiving DMARDs, the rate was similar again, with 1.5 serious infections expected and 1.3 actually observed.

Of the patients who were at the highest risk for infection (ie, patients with ≥1 risk factors), the expected serious infection rates in the anti-TNF group were 4.3 events versus 5.2 events observed; in the patients receiving DMARDs, 1.9 events were expected and 1.7 events were actually observed.

Of note, the highest rates of serious infection, calculated and observed, were for patients in either cohort receiving combination treatment that included either anti-TNF or with DMARDs, plus corticosteroids. “An almost 5-fold risk of serious infection was found in patients who had to be treated with dosages of glucocorticoids of 15 mg/day or above compared with those with <7.5 mg/day,” said Dr Zink.

However, the use of anti-TNF drugs—which is itself a risk factor for infection—can lead to a decrease in

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Continued from cover

at a glance ➤ A new risk score identifies patients with RA at risk for serious infection with anti-TNF drugs or with DMARDs, specifically methotrexate ➤ The study showed a very good agreement between the risk score–based expected rate of serious infections and the actual number of infections ➤ The highest rates of infection were in patients who received corticosteroids in addition to either anti-TNFs or with DMARDs ➤ The risk of infection is increased by almost 5-fold when a corticosteroid is added to RA therapy; using anti-TNF drugs can limit infection risk infection risk if the disease activity is quickly suppressed. “This allows the glucocorticoid dose to be reduced,” Dr Zink explained.

There is still much art in the optimal selection of treatment for patients with RA; however, with the validated RABBIT score in hand, rheumatologists have a new, highly predictive tool to guide them toward successful disease management in terms of reducing risk for infection. ■

New Method for Predicting Serious Risk of Infection in Patients with RA Can Help to Individualize Therapy Risk is related to many disease factors, including comorbidities and increased age

By Alice Goodman

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atients with rheumatoid arthritis (RA) are at increased risk for infection. Researchers at the Mayo Clinic have developed a new risk score that can predict the risk of serious infection in patients with RA. The risk score was validated in a recent study in 2 cohorts of patients with RA (Crowson CS, et al. Arthritis Rheum. 2012;64:2847-2855).

“RA patients are at higher risk of infection, and that risk is clearly not just because of the arthritis drugs,” said Eric L. Matteson, MD, lead investigator and Chair of the Division of Rheumatology at Mayo Clinic, Rochester, MN.

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“RA patients are at higher risk of infection, and that risk is clearly not just because of the arthritis drugs. Using a risk score in this way can alert physicians that their patient is at high risk for infection and needs more frequent follow-ups, measures for infection prevention, and possible changes in treatments.”

—Eric L. Matteson, MD

RA carries an increased risk for infections, morbidity, and mortality; in turn, infections increase the risk of mortality for patients with RA.

The investigators noted that it is often challenging to assess the risk of infection in patients with RA; therefore, having a risk score that could

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predict the likelihood of serious infection in relation to the potential causes of infection would allow providers to implement a proactive approach to the management of patients with RA. This new study was based on medical records of 584 patients (mean age, 57.5 years; 72% female) with RA from Olmsted County, MN, who participated in the Rochester Epidemiology Project. They were diagnosed with RA between 1955 and 1994, and were followed until January 2000. Approximately 50% (N = 252) developed more than 1 serious Continued on page 6

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New Method for Predicting Serious Risk... infection requiring hospitalization and/or intravenous antibiotic treatment. These 252 patients suffered a total of 646 infections during the study period.

Risk Factors The factors that were found to be strongly associated with a risk of serious infection are: • Age • Previous serious infection • Use of corticosteroids • Low white blood cell count • Elevated erythrocyte sedimentation rate that is signaling inflammation • Extra-articular signs of RA • The presence of serious comorbidities, including heart disease, heart failure, diabetes, lung disease, vascular disease, and alcoholism.

The new risk score, therefore,

incorporates factors related to RA disease itself, the patient’s age, the use of corticosteroids, and the presence of comorbidities of an individual patient.

“Using a risk score in this way can alert physicians that their patient is at high risk for infection and needs more frequent follow-ups, measures for infection prevention, and possible changes in treatments,” Dr Matteson pointed out.

Risk Score Validation The usefulness of the risk score was confirmed in a second group of patients with RA from Olmsted County who participated in the Rochester Epidemiology Project. This second cohort consisted of 464 patients (mean age, 54.9 years; 69% female) who were diagnosed with RA between January

at a glance ➤ Patients with RA are at increased risk for infection because of several factors, not only drug therapy ➤ These risk factors include RA itself, age, the use of corticosteroids, and the presence of comorbidities ➤ A new risk score that calculates these risk factors can predict the likelihood of serious infection, regardless of drug therapy ➤ Using this risk score can alert the physician to who is at risk for infection

Continued from page 5

1, 1995, and December 31, 2007, using American College of Rheumatology criteria. The mean length of follow-up was 5.2 years.

In this second cohort, 55 patients developed 1 or more serious infections, for a total of 166 infections.

The investigators note that data are conflicting regarding increased risk of infection with traditional diseasemodifying antirheumatic drugs (DMARDs). In this study, no increased risk of infection was associated with therapy with traditional DMARDs or with biologic therapy.

More research is needed to determine which patients can gain the most benefit from preventive medications for infection, and how the risk of serious infection could impact the use of DMARDs, including biologics. ■

Arthritis Update See also page 9

Adalimumab-Methotrexate Combination... treatment, whereas joint erosion progression was not.

This analysis included 638 of the 799 patients (aged ≥18 years) with early RA who were originally randomized in PREMIER. The PREMIER study was a 2-year, randomized, controlled trial of adalimumab plus methotrexate versus each of these drugs as monotherapy. No significant differences were found between the groups in baseline demographics and disease characteristics.

Patients were excluded if they were previously treated with methotrexate, cyclophosphamide, cyclosporine, azathioprine, more than 2 other diseasemodifying antirheumatic drugs, or a prednisone-equivalent at >10 mg per day within 30 days of screening.

A time-averaged 28-joint disease activity score (TA-DAS28) was used to monitor disease activity. Radiographs of the hands and feet were obtained at baseline and at weeks 52 and 104; the radiographs were blinded and read by radiographers for bone erosion (ie, joint erosion) and joint space narrowing. Physical function was assessed using the HAQ-DI (the disability index of the Health Assessment Questionnaire) at baseline and at weeks 52 and 104.

Employment status was assessed at

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the same time points.

At weeks 52 and 104, the mean reductions in TA-DAS28 from baseline were greater in patients receiving combination therapy than in patients receiving monotherapy with either drug. The relationship between TADAS28 tertiles and changes in joint

Combination therapy with adalimumab plus methotrexate suppresses joint erosion and joint space narrowing progression, and does so in a manner independently of disease activity.

erosion or in joint space narrowing differed between treatment groups.

In the monotherapy groups, both parameters were increased significantly with increasing disease activity (P ≤.02). In contrast, in the combination therapy group, no relationship was seen between radiographic progression and disease activity; less overall progression of joint erosion and joint space narrowing was observed with the combination thera-

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py versus methotrexate monotherapy.

At baseline, 57% of the patients were employed. No association was

at a glance ➤ Joint space narrowing progression in RA has direct implications on patients’ disability and work impairment ➤ Results of a new, 2-year study show that combining adalimumab and methotrexate inhibits joint erosion and joint space narrowing in patients with early RA ➤ At weeks 52 and 104, reductions in TA-DAS28 were greater with the combination therapy than with monotherapy with either drug ➤ The relationship between TADAS28 tertiles and changes in joint erosion or in joint space narrowing differed between treatment groups ➤ Both parameters increased significantly with increasing disease activity in the monotherapy groups

found between joint erosion and employment status at any time point evaluated, but small, significant differences were found between joint space narrowing scores and employment (P = .007) at baseline and at weeks 52 and 104 (P = .04).

Because of the clinical implications of joint space narrowing progression for disability and work impairment, protection from the onset or worsening of joint space narrowing should be an important factor when choosing between therapeutic modalities.

Treatment with the combination of a tumor necrosis factor (TNF) inhibitor and methotrexate is often effective in limiting and possibly preventing joint damage in patients with RA. Based on this study, combination therapy with the TNF inhibitor adalimumab plus methotrexate suppresses joint erosion and joint space narrowing progression, and does so in a manner independently of disease activity, concluded the authors.

The results further refine the understanding of this clinical and functional benefit by showing that the adalimumab plus methotrexate combination “protects against JE [joint erosion] and JSN [joint space narrowing] onset or worsening,” stated the researchers. ■

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ORENCIA® (abatacept) for injection for intravenous use injection, for subcutaneous use Brief Summary of Prescribing Information. For complete prescribing information, please consult official package insert.

INDICATIONS AND USAGE Adult Rheumatoid Arthritis (RA) - ORENCIA® (abatacept) is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. ORENCIA may be used as monotherapy or concomitantly with diseasemodifying antirheumatic drugs (DMARDs) other than tumor necrosis factor (TNF) antagonists.

Juvenile Idiopathic Arthritis - ORENCIA is indicated for reducing signs and symptoms in pediatric patients 6 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis. ORENCIA may be used as monotherapy or concomitantly with methotrexate (MTX).

Important Limitations of Use - ORENCIA should not be administered concomitantly with TNF antagonists. ORENCIA is not recommended for use concomitantly with other biologic rheumatoid arthritis (RA) therapy, such as anakinra.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Concomitant Use with TNF Antagonists - In controlled clinical trials in patients with adult RA, patients receiving concomitant intravenous ORENCIA and TNF antagonist therapy experienced more infections (63%) and serious infections (4.4%) compared to patients treated with only TNF antagonists (43% and 0.8%, respectively) [see Adverse Reactions]. These trials failed to demonstrate an important enhancement of efficacy with concomitant administration of ORENCIA with TNF antagonist; therefore, concurrent therapy with ORENCIA and a TNF antagonist is not recommended. While transitioning from TNF antagonist therapy to ORENCIA therapy, patients should be monitored for signs of infection.

Hypersensitivity - Of 2688 patients with adult RA treated with ORENCIA intravenously in clinical trials, there were two cases of anaphylaxis or anaphylactoid reactions. Other events potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred in less than 0.9% of ORENCIA-treated patients. Of the 190 patients with juvenile idiopathic arthritis treated with ORENCIA in clinical trials, there was one case of a hypersensitivity reaction (0.5%). Appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction [see Adverse Reactions].

Infections - Serious infections, including sepsis and pneumonia, have been reported in patients receiving ORENCIA. Some of these infections have been fatal. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy which in addition to their underlying disease, could further predispose them to infection. Physicians should exercise caution when considering the use of ORENCIA in patients with a history of recurrent infections, underlying conditions which may predispose them to infections, or chronic, latent, or localized infections. Patients who develop a new infection while undergoing treatment with ORENCIA should be monitored closely. Administration of ORENCIA should be discontinued if a patient develops a serious infection [see Adverse Reactions].

A higher rate of serious infections has been observed in adult RA patients treated with concurrent TNF antagonists and ORENCIA [see Warnings and Precautions].

Prior to initiating immunomodulatory therapies, including ORENCIA, patients should be screened for latent tuberculosis infection with a tuberculin skin test. ORENCIA has not been studied in patients with a positive tuberculosis screen, and the safety of ORENCIA in individuals with latent tuberculosis infection is unknown. Patients testing positive in tuberculosis screening should be treated by standard medical practice prior to therapy with ORENCIA. Antirheumatic therapies have been associated with hepatitis B reactivation. Therefore, screening for viral hepatitis should be performed in accordance with published guidelines before starting therapy with ORENCIA. In clinical studies with ORENCIA, patients who screened positive for hepatitis were excluded from study.

Immunizations - Live vaccines should not be given concurrently with ORENCIA or within 3 months of its discontinuation. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving ORENCIA. The efficacy of vaccination in patients receiving ORENCIA is not

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known. Based on its mechanism of action, ORENCIA (abatacept) may blunt the effectiveness of some immunizations.

It is recommended that patients with juvenile idiopathic arthritis be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating ORENCIA therapy.

Use in Patients with Chronic Obstructive Pulmonary Disease (COPD) - Adult COPD patients treated with ORENCIA developed adverse events more frequently than those treated with placebo, including COPD exacerbations, cough, rhonchi, and dyspnea. Use of ORENCIA in patients with RA and COPD should be undertaken with caution and such patients should be monitored for worsening of their respiratory status [see Adverse Reactions].

Immunosuppression - The possibility exists for drugs inhibiting T cell activation, including ORENCIA, to affect host defenses against infections and malignancies since T cells mediate cellular immune responses. The impact of treatment with ORENCIA on the development and course of malignancies is not fully understood [see Adverse Reactions]. In clinical trials in patients with adult RA, a higher rate of infections was seen in ORENCIA-treated patients compared to placebo [see Adverse Reactions].

ADVERSE REACTIONS Clinical Studies Experience in Adult RA Patients Treated with Intravenous ORENCIA - Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice.

The data described herein reflect exposure to ORENCIA administered intravenously in patients with active RA in placebocontrolled studies (1955 patients with ORENCIA, 989 with placebo). The studies had either a double-blind, placebocontrolled period of 6 months (258 patients with ORENCIA, 133 with placebo) or 1 year (1697 patients with ORENCIA, 856 with placebo). A subset of these patients received concomitant biologic DMARD therapy, such as a TNF blocking agent (204 patients with ORENCIA, 134 with placebo).

The majority of patients in RA clinical studies received one or more of the following concomitant medications with ORENCIA: MTX, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, TNF blocking agents, azathioprine, chloroquine, gold, hydroxychloroquine, leflunomide, sulfasalazine, and anakinra.

The most serious adverse reactions were serious infections and malignancies.

The most commonly reported adverse events (occurring in ≥10% of patients treated with ORENCIA) were headache, upper respiratory tract infection, nasopharyngitis, and nausea.

The adverse events most frequently resulting in clinical intervention (interruption or discontinuation of ORENCIA) were due to infection. The most frequently reported infections resulting in dose interruption were upper respiratory tract infection (1.0%), bronchitis (0.7%), and herpes zoster (0.7%). The most frequent infections resulting in discontinuation were pneumonia (0.2%), localized infection (0.2%), and bronchitis (0.1%).

Infections - In the placebo-controlled trials, infections were reported in 54% of ORENCIA-treated patients and 48% of placebo-treated patients. The most commonly reported infections (reported in 5-13% of patients) were upper respiratory tract infection, nasopharyngitis, sinusitis, urinary tract infection, influenza, and bronchitis. Other infections reported in fewer than 5% of patients at a higher frequency (>0.5%) with ORENCIA compared to placebo, were rhinitis, herpes simplex, and pneumonia [see Warnings and Precautions].

Serious infections were reported in 3.0% of patients treated with ORENCIA and 1.9% of patients treated with placebo. The most common (0.2-0.5%) serious infections reported with ORENCIA were pneumonia, cellulitis, urinary tract infection, bronchitis, diverticulitis, and acute pyelonephritis [see Warnings and Precautions].

Malignancies - In the placebo-controlled portions of the clinical trials (1955 patients treated with ORENCIA for a median of 12 months), the overall frequencies of malignancies were similar in the ORENCIA- and placebo-treated patients (1.3% and 1.1%, respectively). However, more cases of lung cancer were observed in ORENCIA-treated patients (4, 0.2%) than placebotreated patients (0). In the cumulative ORENCIA clinical trials (placebo-controlled and uncontrolled, open-label) a total of 8 cases of lung cancer (0.21 cases per 100 patient-years) and 4 lymphomas (0.10 cases per 100 patient-years) were observed in 2688 patients (3827 patient-years). The rate observed for lymphoma is approximately 3.5-fold higher than expected in an age- and gender-matched general population based on the National Cancer Institute’s Surveillance, Epidemiology, and End

Results Database. Patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma. Other malignancies included skin, breast, bile duct, bladder, cervical, endometrial, lymphoma, melanoma, myelodysplastic syndrome, ovarian, prostate, renal, thyroid, and uterine cancers [see Warnings and Precautions]. The potential role of ORENCIA (abatacept) in the development of malignancies in humans is unknown.

Infusion-Related Reactions and Hypersensitivity Reactions Acute infusion-related events (adverse reactions occurring within 1 hour of the start of the infusion) in Studies III, IV, and V [see Clinical Studies (14.1) in Full Prescribing Information] were more common in the ORENCIA-treated patients than the placebo patients (9% for ORENCIA, 6% for placebo). The most frequently reported events (1-2%) were dizziness, headache, and hypertension.

Acute infusion-related events that were reported in >0.1% and ≤1% of patients treated with ORENCIA included cardiopulmonary symptoms, such as hypotension, increased blood pressure, and dyspnea; other symptoms included nausea, flushing, urticaria, cough, hypersensitivity, pruritus, rash, and wheezing. Most of these reactions were mild (68%) to moderate (28%). Fewer than 1% of ORENCIA-treated patients discontinued due to an acute infusion-related event. In controlled trials, 6 ORENCIA-treated patients compared to 2 placebo-treated patients discontinued study treatment due to acute infusion-related events.

Of 2688 patients treated with ORENCIA in clinical trials, there were two cases of anaphylaxis or anaphylactoid reactions. Other events potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred in less than 0.9% of ORENCIA-treated patients and generally occurred within 24 hours of ORENCIA infusion. Appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction [see Warnings and Precautions].

Adverse Reactions in Patients with COPD - In Study V [see Clinical Studies (14.1) in Full Prescribing Information], there were 37 patients with chronic obstructive pulmonary disease (COPD) who were treated with ORENCIA and 17 COPD patients who were treated with placebo. The COPD patients treated with ORENCIA developed adverse events more frequently than those treated with placebo (97% vs 88%, respectively). Respiratory disorders occurred more frequently in ORENCIA-treated patients compared to placebo-treated patients (43% vs 24%, respectively) including COPD exacerbation, cough, rhonchi, and dyspnea. A greater percentage of ORENCIA-treated patients developed a serious adverse event compared to placebo-treated patients (27% vs 6%), including COPD exacerbation (3 of 37 patients [8%]) and pneumonia (1 of 37 patients [3%]) [see Warnings and Precautions].

Other Adverse Reactions - Adverse events occurring in 3% or more of patients and at least 1% more frequently in ORENCIAtreated patients (n=1955) versus placebo (n=989) during placebo-controlled RA studies were: Headache (18%, 13%); Nasopharyngitis (12%, 9%); Dizziness (9%, 7%); Cough (8%, 7%); Back pain (7%, 6%); Hypertension (7%, 4%); Dyspepsia (6%, 4%); Urinary tract infection (6%, 5%); Rash (4%, 3%); Pain in extremity (3%, 2%), respectively. The ORENCIA group included 204 patients on concomitant biologic DMARDs (adalimumab, anakinra, etanercept, or infliximab). The placebo group included 134 patients on concomitant biologic DMARDs (adalimumab, anakinra, etanercept, or infliximab).

Immunogenicity - Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in RA patients for up to 2 years following repeated treatment with ORENCIA. Thirty-four of 1993 (1.7%) patients developed binding antibodies to the entire abatacept molecule or to the CTLA-4 portion of abatacept.

Because trough levels of abatacept can interfere with assay results, a subset analysis was performed. In this analysis it was observed that 9 of 154 (5.8%) patients that had discontinued treatment with ORENCIA for over 56 days developed antibodies.

Samples with confirmed binding activity to CTLA-4 were assessed for the presence of neutralizing antibodies in a cellbased luciferase reporter assay. Six of 9 (67%) evaluable patients were shown to possess neutralizing antibodies.

However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity.

No correlation of antibody development to clinical response or adverse events was observed.

The data reflect the percentage of patients whose test results were positive for antibodies to abatacept in specific assays. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons,

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comparison of the incidence of antibodies to abatacept with the incidence of antibodies to other products may be misleading.

Clinical Experience in MTX-Naive Patients - Study VI was an active-controlled clinical trial in MTX-naive patients [see Clinical Studies (14.1) in Full Prescribing Information]. The safety experience in these patients was consistent with Studies I-V. Clinical Experience in Adult RA Patients Treated with Subcutaneous ORENCIA (abatacept) - Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice.

Study SC-I was a randomized, double-blind, double-dummy, non-inferiority study that compared the efficacy and safety of abatacept administered subcutaneously (SC) and intravenously (IV) in 1457 subjects with rheumatoid arthritis, receiving background MTX, and experiencing an inadequate response to MTX (MTX-IR) [see Clinical Studies (14.1) in Full Prescribing Information]. The safety experience and immunogenicity for ORENCIA administered subcutaneously was consistent with intravenous Studies I-VI. Due to the route of administration, injection site reactions and immunogenicity were evaluated in Study SC-I and two other smaller studies discussed in the sections below.

Injection Site Reactions in Adult RA Patients Treated with Subcutaneous ORENCIA - Study SC-I compared the safety of abatacept including injection site reactions following subcutaneous or intravenous administration. The overall frequency of injection site reactions was 2.6% (19/736) and 2.5% (18/721) for the subcutaneous abatacept group and the intravenous abatacept group (subcutaneous placebo), respectively. All these injection site reactions (including hematoma, pruritus, and erythema) were mild (83%) to moderate (17%) in severity, and none necessitated drug discontinuation.

Immunogenicity in Adult RA Patients Treated with Subcutaneous ORENCIA - Study SC-I compared the immunogenicity to abatacept following subcutaneous or intravenous administration. The overall immunogenicity frequency to abatacept was 1.1% (8/725) and 2.3% (16/710) for the subcutaneous and intravenous groups, respectively. The rate is consistent with previous experience, and there was no correlation of immunogenicity with effects on pharmacokinetics, safety, or efficacy.

Immunogenicity and Safety of Subcutaneous ORENCIA Administration as Monotherapy without an Intravenous Loading Dose - Study SC-II was conducted to determine the effect of monotherapy use of ORENCIA on immunogenicity following subcutaneous administration without an intravenous load in 100 RA patients, who had not previously received abatacept or other CTLA4Ig, who received either subcutaneous ORENCIA plus MTX (n=51) or subcutaneous ORENCIA monotherapy (n=49). No patients in either group developed antiproduct antibodies after 4 months of treatment. The safety observed in this study was consistent with that observed in the other subcutaneous studies.

Immunogenicity and Safety of Subcutaneous ORENCIA upon Withdrawal (Three Months) and Restart of Treatment - Study SC-III in the subcutaneous program was conducted to investigate the effect of withdrawal (three months) and restart of ORENCIA subcutaneous treatment on immunogenicity in RA patients treated concomitantly with MTX. One hundred sixtyseven patients were enrolled in the first 3-month treatment period and responders (n=120) were randomized to either subcutaneous ORENCIA or placebo for the second 3-month period (withdrawal period). Patients from this period then received open-label ORENCIA treatment in the final 3-month period of the study (period 3). At the end of the withdrawal period, 0/38 patients who continued to receive subcutaneous ORENCIA developed anti-product antibodies compared to 7/73 (9.6%) of patients who had subcutaneous ORENCIA withdrawn during this period. Half of the patients receiving subcutaneous placebo during the withdrawal period received a single intravenous infusion of ORENCIA at the start of period 3 and half received intravenous placebo. At the end of period 3, when all patients again received subcutaneous ORENCIA, the immunogenicity rates were 1/38 (2.6%) in the group receiving subcutaneous ORENCIA throughout, and 2/73 (2.7%) in the group that had received placebo during the withdrawal period.

Upon reinitiating therapy, there were no injection reactions and no differences in response to therapy in patients who were withdrawn from subcutaneous therapy for up to 3 months relative to those who remained on subcutaneous therapy, whether therapy was reintroduced with or without an intravenous loading dose. The safety observed in this study was consistent with that observed in the other studies.

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Clinical Studies Experience in Juvenile Idiopathic Arthritis In general, the adverse events in pediatric patients were similar in frequency and type to those seen in adult patients [see Warnings and Precautions, Adverse Reactions].

ORENCIA (abatacept) has been studied in 190 pediatric patients, 6 to 17 years of age, with polyarticular juvenile idiopathic arthritis. Overall frequency of adverse events in the 4-month, lead-in, open-label period of the study was 70%; infections occurred at a frequency of 36% [see Clinical Studies (14.2) in Full Prescribing Information]. The most common infections were upper respiratory tract infection and nasopharyngitis. The infections resolved without sequelae, and the types of infections were consistent with those commonly seen in outpatient pediatric populations. Other events that occurred at a prevalence of at least 5% were headache, nausea, diarrhea, cough, pyrexia, and abdominal pain.

A total of 6 serious adverse events (acute lymphocytic leukemia, ovarian cyst, varicella infection, disease flare [2], and joint wear) were reported during the initial 4 months of treatment with ORENCIA. Of the 190 patients with juvenile idiopathic arthritis treated with ORENCIA in clinical trials, there was one case of a hypersensitivity reaction (0.5%). During Periods A, B, and C, acute infusion-related reactions occurred at a frequency of 4%, 2%, and 3%, respectively, and were consistent with the types of events reported in adults.

Upon continued treatment in the open-label extension period, the types of adverse events were similar in frequency and type to those seen in adult patients, except for a single patient diagnosed with multiple sclerosis while on open-label treatment.

Immunogenicity - Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in patients with juvenile idiopathic arthritis following repeated treatment with ORENCIA throughout the open-label period. For patients who were withdrawn from therapy for up to 6 months during the double-blind period, the rate of antibody formation to the CTLA-4 portion of the molecule was 41% (22/54), while for those who remained on therapy the rate was 13% (7/54). Twenty of these patients had samples that could be tested for antibodies with neutralizing activity; of these, 8 (40%) patients were shown to possess neutralizing antibodies.

The presence of antibodies was generally transient and titers were low. The presence of antibodies was not associated with adverse events, changes in efficacy, or an effect on serum concentrations of abatacept. For patients who were withdrawn from ORENCIA during the double-blind period for up to 6 months, no serious acute infusion-related events were observed upon re-initiation of ORENCIA therapy.

Postmarketing Experience - Adverse reactions have been reported during the postapproval use of ORENCIA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to ORENCIA. Based on the postmarketing experience in adult RA patients, the following adverse reaction has been identified during postapproval use with ORENCIA. â&#x20AC;˘ Vasculitis (including cutaneous vasculitis and leukocytoclastic vasculitis) DRUG INTERACTIONS TNF Antagonists - Concurrent administration of a TNF antagonist with ORENCIA has been associated with an increased risk of serious infections and no significant additional efficacy over use of the TNF antagonists alone. Concurrent therapy with ORENCIA and TNF antagonists is not recommended [see Warnings and Precautions].

Other Biologic RA Therapy - There is insufficient experience to assess the safety and efficacy of ORENCIA administered concurrently with other biologic RA therapy, such as anakinra, and therefore such use is not recommended.

Blood Glucose Testing - Parenteral drug products containing maltose can interfere with the readings of blood glucose monitors that use test strips with glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ). The GDH-PQQ based glucose monitoring systems may react with the maltose present in ORENCIA for intravenous administration, resulting in falsely elevated blood glucose readings on the day of infusion. When receiving ORENCIA through intravenous administration, patients that require blood glucose monitoring should be advised to consider methods that do not react with maltose, such as those based on glucose dehydrogenase nicotine adenine dinucleotide (GDH-NAD), glucose oxidase, or glucose hexokinase test methods.

ORENCIA for subcutaneous administration does not contain maltose; therefore, patients do not need to alter their glucose monitoring.

USE IN SPECIFIC POPULATIONS Pregnancy - Pregnancy Category C: There are no adequate and well-controlled studies of ORENCIA (abatacept) use in pregnant women. Abatacept has been shown to cross the placenta in animals, and in animal reproduction studies alterations in immune function occurred. ORENCIA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Abatacept was not teratogenic when administered to pregnant mice at doses up to 300 mg/kg and in pregnant rats and rabbits at doses up to 200 mg/kg daily representing approximately 29 times the exposure associated with the maximum recommended human dose (MRHD) of 10 mg/kg based on AUC (area under the time-concentration curve).

Abatacept administered to female rats every three days during early gestation and throughout the lactation period, produced no adverse effects in offspring at doses up to 45 mg/kg, representing 3 times the exposure associated with the MRHD of 10 mg/kg based on AUC. However, at 200 mg/kg, 11 times the MRHD exposure, alterations in immune function were observed consisting of a 9-fold increase in T-cell dependent antibody response in female pups and thyroid inflammation in one female pup. It is not known whether these findings indicate a risk for development of autoimmune diseases in humans exposed in utero to abatacept. However, exposure to abatacept in the juvenile rat, which may be more representative of the fetal immune system state in the human, resulted in immune system abnormalities including inflammation of the thyroid and pancreas [see Nonclinical Toxicology (13.2) in Full Prescribing Information].

Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to ORENCIA, a pregnancy registry has been established. Healthcare professionals are encouraged to register patients and pregnant women are encouraged to enroll themselves by calling 1-877-311-8972.

Nursing Mothers - It is not known whether ORENCIA is excreted into human milk or absorbed systemically after ingestion by a nursing infant. However, abatacept was excreted in rat milk.

Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ORENCIA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use - ORENCIA is indicated for reducing signs and symptoms in pediatric patients with moderately to severely active polyarticular juvenile idiopathic arthritis ages 6 years and older. ORENCIA may be used as monotherapy or concomitantly with MTX. Studies in juvenile rats exposed to ORENCIA prior to immune system maturity have shown immune system abnormalities including an increase in the incidence of infections leading to death as well as inflammation of the thyroid and pancreas [see Nonclinical Toxicology (13.2) in Full Prescribing Information].

Studies in adult mice and monkeys have not demonstrated similar findings. As the immune system of the rat is undeveloped in the first few weeks after birth, the relevance of these results to humans greater than 6 years of age (where the immune system is largely developed) is unknown.

ORENCIA is not recommended for use in patients below the age of 6 years.

The safety and effectiveness of ORENCIA in pediatric patients below 6 years of age have not been established. The safety and efficacy of ORENCIA in pediatric patients for uses other than juvenile idiopathic arthritis have not been established.

Geriatric Use - A total of 323 patients 65 years of age and older, including 53 patients 75 years and older, received ORENCIA in clinical studies. No overall differences in safety or effectiveness were observed between these patients and younger patients, but these numbers are too low to rule out differences. The frequency of serious infection and malignancy among ORENCIA-treated patients over age 65 was higher than for those under age 65.

Because there is a higher incidence of infections and malignancies in the elderly population in general, caution should be used when treating the elderly.

OVERDOSAGE Doses up to 50 mg/kg have been administered intravenously without apparent toxic effect. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted.

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Arthritis Update See also page 6

Tight Control Strategy Significantly Increases Remission Rates in Early RA at a glance

Median time to first remission cut by almost 50%

By Alice Goodman

T

he ultimate goal of rheumatoid arthritis (RA) therapy is reaching sustained clinical remission early on to prevent joint damage.

After 1 year of treating patients with early RA in clinical practice, using a strategy of tight control achieved more rapid remission and higher rates of patients with remission compared with usual care (Schipper LG, et al.

Ann Rheum Dis. 2012;71:845-850).

Real-World Setting In this study of patients in realworld clinical care setting, tight control was defined as optimizing treatment by measuring disease activity according to strict criteria and adjusting treatment to achieve a target of low disease activity, or remission.

Usual care entailed treatment without protocol-driven changes in treatment.

The investigators compared the 2 strategies in 2 early RA cohorts from different regions in the Netherlands.

The tight-control cohort included 126 patients treated according to a disease activity score for 28 joints (DAS28)-driven step-up treatment initiated with methotrexate, with sulfasalazine added, and anti–tumor necrosis factor used in cases of treatment failure with sulfasalazine. A DAS28 score of <2.6 was used as the cut point for remission.

The usual-care cohort consisted of 126 patients treated with methotrexate or with sulfasalazine, and subsequent treatment decisions were not driven

by DAS28 response.

“Cohort data in clinical practice are of value to investigate the effects of interventions in daily practice, including the effects of tight control. The patients included [in this study] are supposed to be representative of the population with RA, and they are treated under daily practice circumstances,” the author wrote.

The 2 treatment groups had similar demographic and disease characteristics at baseline (median age, approximately 56 years), with approximately 16 weeks median time since RA symptoms onset. The mean DAS28 score was 5, and the median number of swollen joints was 8.

Study Results Remission was defined as DAS28.

After 1 year, remission (DAS28 score <2.6) was achieved in 55% of the tightcontrol group compared with only 30% of the usual-care group (P <.001).

The DAS28 score was significantly decreased by tight control: –2.5 points for the tight-control cohort versus 1.5 for the usual-care cohort (P <.001).

Median time to first remission was 25 weeks for the tight-control group

The tight-control strategy— optimizing treatment by measuring disease activity and adjusting treatment to achieve low disease activity, or remission—led to increased patient functional ability. After 1 year, 55% of patients achieved remission with tight control versus only 30% of patients with usual care. versus more than 52 weeks for the usual-care group, a significant difference (P <.001).

The authors noted that the patients who were in the tight-control group had approximately 3-fold higher odds of having a DAS28 score <2.61 at 1 year of therapy.

The tight-control strategy led to greater improvements in functional ability and in patient assessments of pain and disease activity. Moreover, the tight-control regimen was well tolerated and did not appear to be associated with additional toxicity.

Although tight control was similar-

➤ In this real-world setting of patients with early RA, the use of tight disease control was more effective than usual care in achieving patient remission ➤ Tight control was defined as therapy guided by reaching DAS28 score <2.6 (ie, remission); usual care was not guided by such criteria ➤ Tight control was initiated with methotrexate therapy, then adding sulfasalazine; if no response was achieved, an anti–tumor necrosis factor replaced sulfasalazine ➤ After 1 year, DAS28 score <2.6 was achieved by 55% of the tight-control patients versus 30% under usual care ➤ The median time to first remission was 25 weeks with tight control and >52 weeks with usual care

ly effective in patients with shorter (<18 weeks) and longer symptom duration, usual care was less effective in patients with longer disease duration. The authors note that longer follow-up would be required to determine long-term efficacy of tight control and the effect on progression of joint damage. ■

Tofacitinib Effective in Patients with Active RA, but More Safety Data Needed for Approval

T

ofacitinib is a novel, oral, smallmolecule Janus kinase (JAK) inhibitor that is being studied as a targeted immunomodulator and disease-modifying treatment for patients with rheumatoid arthritis (RA).

Patients with active RA despite treatment with previous therapies had fewer signs and symptoms of the disease and had improved physical function after 3 months of receiving tofacitinib monotherapy compared with placebo, according to results of a recent phase 3 clinical trial (Fleischmann R, et al. N Engl J Med. 2012;367: 495-507).

Tofacitinib was effective at the lower (5 mg) and the higher (10 mg) doses

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After 3 months of treatment, 59.8% of patients receiving 5 mg of tofacitinib and 65.7% of patients receiving the 10-mg dose met the ACR20 response criteria compared with only 26.7% for the combined placebo groups. that were used twice daily. However, the study raised some safety concerns with this investigational agent, including the risk for serious infections, elevated low-density lipoprotein (LDL) cholesterol levels, and lower neutrophil counts. The results of this study are consistent with the previous results of a phase 2 trial in which tofacitinib was used as monotherapy or in

combination with background methotrexate for 24 weeks.

The drug is currently under review by the US Food and Drug Administration, which has extended the Prescription Drug User Fee Act date until November 21, 2012, to be able to assess additional safety data.

A total of 611 patients were randomized to 1 of 4 treatment groups: 5

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mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, placebo for 3 months followed by 5 mg of tofacitinib twice daily, or to placebo for 3 months followed by a 10-mg dose of tofacitinib twice daily.

After 3 months of treatment, several primary end points were evaluated— at least a 20% improvement in the American College of Rheumatology 20% response (ACR20), change in baseline disability index of the Health Assessment Questionnaire (HAQ-DI), and percentage of patients with a Disease Activity Score of <2.6 for 28joint counts (DAS28) based on the erythrocyte sedimentation rate.

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www.ValueBasedRheumatology.com

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Fibromyalgia

Childhood Abuse Linked to Pain and Depression in Patients with Fibromyalgia

By Rosemary Frei, MSc Milan, Italy—The combination of childhood emotional abuse and current depression gives rise to higher pain sensitivity, a new study has shown. In a poster presented at the 2012 World Congress on Pain, a group of Belgian researchers showed that among patients with fibromyalgia who suffered childhood emotional abuse, a strong positive correlation exists between depression levels and

pain sensitivity. The same correlation does not exist in patients who did not have emotional abuse when they were young.

“Our results show that in emotionally abused fibromyalgia patients, depression increases pain symptoms,” lead investigator Eline Coppens, MSc, PhD, a psychologist at the Centre for Algology and Pain Management, University Hospitals Leuven, Belgium,

Relationship between Fibromyalgia and Smoking Still Not Clear Milan, Italy—A cross-sectional study has uncovered a smoking gun, but it is unclear who the victims are.

A University of Michigan group presented evidence at the 2012 World Congress on Pain that patients with pain who meet the 2011 American College of Rheumatology (ACR) survey criteria for fibromyalgia and who smoke have worse neuropathic pain than nonsmokers who meet these criteria. However, the relationship between smoking and neuropathic pain symptoms was even stronger in patients who did not meet the ACR survey criteria for fibromyalgia.

“It appears that smoking is interacting with neuropathic pain symptoms, and future studies should focus on why this is the case,” said lead investigator Jenna Goesling, PhD, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor.

The goal of Dr Goesling and colleagues was to corroborate other studies that have found that patients with fibromyalgia who smoke report worse pain and more functional disability compared with patients with fibromyalgia who do not smoke, and to examine whether smoking affects patients with centralized pain conditions, such as fibromyalgia, differently from patients without such conditions.

The researchers focused their analysis on 347 patients who met the ACR survey criteria for fibromyalgia and compared them with 624 patients who did not meet the criteria for this disease. All were new patients at the University of Michigan’s Back and Pain Center between November 2011 and March 2012.

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This analysis was part of the APOLO EDC (Assessment of Pain Outcomes Longitudinal Electronic Data Capture) clinical study, which began in November 2010 and was designed to gather clinically relevant pain-management data using validated measures.

Of the patients with fibromyalgia, 40% were current smokers compared with 26% among those without fibromyalgia. The smoking rate in the patients with fibromyalgia was significantly higher than in the general population and in other studies of patients with fibromyalgia, with the latter showing rates between 9.8% and 21.9%, according to Dr Goesling and colleagues. The respective proportions of those who were formersmokers were 24% and 32%.

Because former smokers and neversmokers had similar scores on all of the pain and mood assessment tools, the researchers combined them into one “current nonsmoker” group.

The patients with fibromyalgia who are current smokers reported significantly worse pain and more pain interference in daily activities than the patients who are current nonsmokers. The smokers also reported significantly more aspects of neuropathic pain. Furthermore, the patients with fibromyalgia who are smokers had more symptoms of depression and anxiety.

However, the relationship between smoking and neuropathic pain was stronger in the patients without fibromyalgia than in the patients with fibromyalgia.—RF ■

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told Value-Based Care in Rheumatology.

“These data make clear that in treatment of fibromyalgia, it’s important to treat trauma and to address specifically the emotional types and consequences of trauma. They also point to the likely efficacy of giving individualized treatment to subgroups of fibromyalgia patients, such as those who are depressed and had childhood trauma,” said Dr Coppens.

Dr Coppens and colleagues conducted the study because clinical lore suggests that a significant subgroup of patients with fibromyalgia experienced subtle forms of emotional abuse and neglect, but it is not clear whether there is a relationship between early-childhood adversity and the severity of pain—the core symptom of fibromyalgia.

The researchers focused on 50 women with fibromyalgia (mean age, 44 years) who were being treated at the Leuven Centre for Algology and Pain Management.

Of these patients, 40% reported emotional abuse in early childhood and 27% reported physical abuse.

Furthermore, 40% reported having had emotional neglect.

In addition, 70% of patients who had emotional abuse also reported having physical pain compared with

58% of those without emotional abuse; a significant difference. Significantly higher levels of pain were also reported among patients with fibromyalgia who had experienced emotional abuse compared with patients who did not report emotional abuse, at all levels of depression.

“These data make clear that in treatment of fibromyalgia, it’s important to treat trauma and to address specifically the emotional types and consequences of trauma.”

—Eline Coppens, MSc, PhD The researchers concluded that emotional abuse affects the relationship between depression and pain, with the combination of emotional abuse and depression giving rise to higher pain sensitivity. They further note that this study improves on previous work, which had significant methodological limitations and focused largely on major early-childhood trauma, such as physical and sexual abuse. ■

Tofacitinib Effective...

After 3 months of treatment, 59.8% of patients in the tofacitinib group receiving the 5-mg dose and 65.7% of patients receiving the 10-mg dose met the ACR20 response criteria compared with only 26.7% for the combined placebo groups (P <.001 for both dose comparisons).

Reductions from baseline in HAQDI scores were greater with the 5-mg and the 10-mg doses of tofacitinib versus placebo (–0.50 and –0.57 points, respectively, vs –0.19 for placebo; P <.001).

However, the percentages of patients who achieved DAS28 <2.6 were not significantly different between the active treatment groups and the placebo groups (5.6% for the 5-mg dose group and 8.7% for the 10-mg dose group vs 4.4% for the placebo group).

The rate of serious infections was increased with tofacitinib. Seven seri-

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ous infections were reported in 6 patients treated with the novel JAK inhibitor. These included 1 case each of cellulitis, liver abscess, bronchitis, tuberculous pleural effusion, and pyelonephritis, as well as 2 cases of cellulitis. In addition, the tofacitinib groups had increases in LDL cholesterol and in liver aminotransferase levels, lower neutrophil counts, and small increases in serum creatinine levels compared with placebo.

Adverse events were reported in 51% of the tofacitinib 5-mg group, 56.7% of the 10-mg group, and in 54.9% of patients receiving placebo.

The researchers state that the clinical benefit of tofacitinib “will need to be weighed against the risk of serious infections and adverse effects on lipid, aminotransferase, and serum creatinine levels associated with tofacitinib therapy.”—AG ■

VOL. 1

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NO. 4

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Lupus Nephritis

New Recommendations for the Management of Lupus... jointly by the European League Against Rheumatism and European Renal Association and the European Dialysis and Transplant Association (EULAR/ERA-EDTA) for the management of adult and pediatric LN (Bertsias GK, et al. Ann Rheum Dis. Epub 2012 Jul 31).

The 32-member panel that developed the recommendations included internists, rheumatologists, and nephrologists, all of whom are involved in the care of patients with LN, as well as renal pathologists and pediatricians with LN expertise.

The 28 final recommendations are based on the results of a systemic literature review and expert opinion. The literature review included Englishlanguage articles published up to December 2011, including some recent controlled clinical trials that prompted this new set of recommendations related to the diagnosis, monitoring, prognosis, and treatment recommendations for patients with LN. The mean and median ratings by the committee for each recommendation are detailed in the article, in addition to the level of evidence and the strength of the recommendation.

Indications for First Renal Biopsy There is a low threshold for performing a renal biopsy in patients with SLE, according to the new recommendations, because of the “potentially aggressive nature of LN.” The panel states that this should be done within a month of disease onset, and preferably before immunosup-

at a glance ➤ Nearly one half of patients with SLE will develop LN ➤ Renal biopsy should be performed within 1 month of SLE onset with any sign of renal involvement ➤ Immunosuppressive treatments include MPA, MMF, eMPA, CY, AZA, and intravenous MP ➤ LN requires lifetime monitoring, approximately every 3 to 6 months ➤ Predictors of long-term outcomes are changes in serum creatinine, proteinuria, hemoglobin levels, and blood pressure

12

pressive therapy is initiated, but that high-dose glucocorticoid treatment should not be delayed if the biopsy must be delayed.

Clinical, serologic, and laboratory tests should not be relied on, because of their inability to predict histologic findings.

Indications for biopsy are the sign of any renal involvement, including reproducible proteinuria ≥0.5 g per 24 hours, especially in the presence of glomerular hematuria, cellular casts, or both. Other settings for which biopsy could be considered include persisting isolated glomerular hematuria, isolated leukocyturia, and unexplained renal insufficiency with normal urinary findings. Of note, the panel states that the renal biopsy should be performed in the first month after disease onset.

The pathologic assessment of the renal biopsy should include active and chronic changes of the glomerulus and the renal and interstitial tubules, as well as vascular lesions that are associated with antiphospholipid antibodies or the antiphospholipid syndrome. The 2003 classification system from the International Society of Nephrology/Renal Pathology Society should be used.

Immunosuppressive Therapy Treatment decisions should be made jointly by the patient and physician. The treatment goal is a complete renal response, with a partial renal response—≥50% reduction in proteinuria to subnephrotic levels, and a normal or near-normal glomerular filtration rate (GFR)—achieved preferably by 6 months, and at least by 12 months.

The panel provides detailed information for defining and managing nephritic and proteinuric flares, which can occur after a renal response; nephritic flares have a more negative effect on renal outcomes.

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•

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•

Initial Agents in Adults Experienced clinical centers are preferred for treating and managing patients with LN. Immunosuppressive treatments discussed in the recommendations include mycophenolic acid sodium (MPA), mycophenolate mofetil (MMF), enteric-coated mycophenolic acid sodium (eMPA), cyclophosphamide (CY), azathioprine (AZA), and intravenous methylprednisolone (MP).

The major recommendations for initial therapy in adults are: • MPA or low-dose CY is recom-

VALUE-BASED CARE IN RHEUMATOLOGY

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SEPTEMBER 2012

•

•

mended as initial therapy for most cases of class III to IV LN, based on the results of the Aspreva Lupus Management Study (ALMS), the largest study in patients with LN. The panel notes, however, that longterm efficacy and safety data (>5 years) are lacking for MPA. The ALMS study showed that the response rates for 6 months of MPA (target MMF dose, 3 g/day) and intravenous CY (monthly pulses, 0.5-1 g/m2) were comparable.

MMF and eMPA are “likely to be equally efficacious,” according to the panel, and either MPA formulation can be used until the limited data for this recommendation are validated. An eMPA dose of 720 mg is roughly equivalent to a 1-g dose of MMF. There are some differences in efficacy and toxicity related to ethnicity.

For Caucasians with class III to IV LN, and perhaps class V LN, lowdose intravenous CY (total dose, 3 g over 3 months) combined with glucocorticoids (0.5 mg/kg daily) is recommended for initial therapy.

MPA may be more effective in patients of African descent, based on subgroup analyses of 2 studies; however, the panel stated that more evidence is needed to make a recommendation in this regard.

For pure class V LN, with proteinuria in the nephrotic range, MPA combined with oral glucocorticoids is recommended as initial therapy for most patients (MMF target dose, 3 g daily for 6 months). MPA was shown to have an antiproteinuric effect that is similar to the effect of high-dose intravenous CY, based on the combined analysis of 2 clinical trials. MPA also has a better gonadal toxicity profile.

In patients with impaired renal function or crescents, MPA can be used, based on evidence from post hoc analysis (in patients with baseline GFR <30 mL/min/1.73 m2) from the ALMS study and 2 studies in severe histologic forms of LN. AZA is recommended only for patients with class III or IV LN with preserved renal function and no evidence of adverse histologic findings.

Intravenous MP pulses to decrease the cumulative dose of glucocorticoids are recommended, based on extrapolation from controlled studies.

Subsequent Therapy in Adults MPA is recommended for continued therapy if the patient responded

Continued from cover

to initial therapy with this drug. For selected patients with preserved renal function, calcineurin inhibitors may be considered.

The lack of data beyond 3 years requires physicians to individualize treatment, “with an effort first to withdraw glucocorticoids before immunosuppressive agents,” the panel stated.

Monitoring, Prognosis of Lupus Nephritis LN requires lifetime monitoring, approximately every 3 to 6 months.

After LN is initially diagnosed or flares occur, patients should schedule office visits every 2 to 4 weeks for the first 2 to 4 months; thereafter, the frequency should be based on the response to treatment.

The parameters to be assessed at each visit include: • Serum creatinine • Estimated GFR • Serum albumin • Proteinuria • Urinary sediment • Serum complement component 3 (C3) and C4 • Serum anti–double-stranded DNA antibodies.

Predictors of long-term outcomes in LN are changes in serum creatinine, proteinuria, hemoglobin levels, and blood pressure. Repeat renal biopsy should be reserved for selected cases.

Other Guidance The diagnosis, management, and monitoring of LN children are similar to that for adults. However, LN is more severe in children, who in general have more renal damage and receive more intensive immunosuppressive treatment.

End-stage renal disease will develop within 15 years in approximately 10% to 30% of patients with LN, even with immunosuppressive treatment.

Patients with LN can be candidates for renal transplantation if lupus activity is absent or is at a low level for 3 to 6 months.

The EULAR/ERA-EDTA recommendations also include guidance for refractory LN, LN in pregnant women and women who are planning to become pregnant, and adjunctive therapy for any CV disease or CV risk factors.

The panel also presents a 9-item research agenda, including the need for evidence supporting the longterm efficacy and safety of MPA, evidence for switching regimens after treatment failure, and the need for randomized controlled trials in children with LN. ■

VOL. 1

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PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

HUMIRA® (adalimumab) WARNINGS: SERIOUS INFECTIONS AND MALIGNANCY SERIOUS INFECTIONS Patients treated with HUMIRA are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

HUMIRA should be discontinued if a patient develops a serious infection or sepsis.

Reported infections include: • Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before HUMIRA use and during therapy. Treatment for latent TB should be initiated prior to HUMIRA use.

• Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection.

Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.

• Bacterial, viral and other infections due to opportunistic pathogens, including Legionella and Listeria.

The risks and benefits of treatment with HUMIRA should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with HUMIRA, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy. [See Warnings and Precautions and Adverse Reactions] MALIGNANCY Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which HUMIRA is a member. [See Warnings and Precautions] Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including HUMIRA. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases has occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants.

INDICATIONS AND USAGE Rheumatoid Arthritis HUMIRA is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. HUMIRA can be used alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs).

Juvenile Idiopathic Arthritis HUMIRA is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in pediatric patients 4 years of age and older. HUMIRA can be used alone or in combination with methotrexate.

Psoriatic Arthritis HUMIRA is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis. HUMIRA can be used alone or in combination with non-biologic DMARDs. Ankylosing Spondylitis HUMIRA is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis.

Crohn’s Disease HUMIRA is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy. HUMIRA is indicated for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.

Plaque Psoriasis HUMIRA is indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate. HUMIRA should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician [see Boxed Warnings and Warnings and Precautions].

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS (see also Boxed WARNINGS) Serious Infections Patients treated with HUMIRA are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease.

The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections in patients with rheumatoid arthritis (RA); therefore, the concomitant use of HUMIRA and these biologic products is not recommended in the treatment of patients with RA [see Warnings and Precautions and Drug Interactions].

Treatment with HUMIRA should not be initiated in patients with an active infection, including localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. The risks and benefits of treatment should be considered prior to initiating therapy in patients: • with chronic or recurrent infection; • who have been exposed to tuberculosis; • with a history of an opportunistic infection; • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or • with underlying conditions that may predispose them to infection.

Tuberculosis Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving HUMIRA, including patients who have previously received treatment for latent or active tuberculosis. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating HUMIRA and periodically during therapy.

Treatment of latent tuberculosis infection prior to therapy with TNF blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy.

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

Tuberculosis should be strongly considered in patients who develop a new infection during HUMIRA treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.

Monitoring Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with HUMIRA, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with HUMIRA. HUMIRA should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with HUMIRA should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated.

Invasive Fungal Infections For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy.

Malignancies The risks and benefits of TNF-blocker treatment including HUMIRA should be considered prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF blocker in patients who develop a malignancy.

Malignancies in Adults In the controlled portions of clinical trials of some TNF-blockers, including HUMIRA, more cases of malignancies have been observed among TNF-blocker-treated adult patients compared to control-treated adult patients. During the controlled portions of 32 global HUMIRA clinical trials in adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn’s disease (CD), and plaque psoriasis (Ps), malignancies, other than non-melanoma (basal cell and squamous cell) skin cancer,

were observed at a rate (95% confidence interval) of 0.6 (0.38, 0.93) per 100 patient-years among 6694 HUMIRA-treated patients versus a rate of 0.5 (0.28, 1.05) per 100 patient-years among 3749 controltreated patients (median duration of treatment of 4 months for HUMIRA-treated patients and 4 months for control-treated patients). In 45 global controlled and uncontrolled clinical trials of HUMIRA in adult patients with RA, PsA, AS, CD and Ps, the most frequently observed malignancies, other than lymphoma and NMSC, were breast, colon, prostate, lung, and melanoma. The malignancies in HUMIRA-treated patients in the controlled and uncontrolled portions of the studies were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).

In controlled trials of other TNF blockers in adult patients at higher risk for malignancies (i.e., patients with COPD with a significant smoking history and cyclophosphamide-treated patients with Wegener’s granulomatosis), a greater portion of malignancies occurred in the TNF blocker group compared to the control group.

Non-Melanoma Skin Cancer During the controlled portions of 32 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, and Ps, the rate (95% confidence interval) of NMSC was 0.7 (0.50, 1.11) per 100 patient-years among HUMIRA-treated patients and 0.2 (0.06, 0.56) per 100 patient-years among control-treated patients. All patients, and in particular patients with a medical history of prior prolonged immunosuppressant therapy or psoriasis patients with a history of PUVA treatment should be examined for the presence of NMSC prior to and during treatment with HUMIRA. Lymphoma and Leukemia In the controlled portions of clinical trials of all the TNF-blockers in adults, more cases of lymphoma have been observed among TNF blocker-treated patients compared to control-treated patients. In the controlled portions of 32 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, and Ps, 3 lymphomas occurred among 6694 HUMIRA-treated patients versus 1 among 3749 control-treated patients. In 45 global controlled and uncontrolled clinical trials of HUMIRA in adult patients with RA, PsA, AS, CD and Ps with a median duration of approximately 0.6 years, including 22,026 patients and over 32,000 patient-years of HUMIRA, the observed rate of lymphomas was approximately 0.11 per 100 patient-years. This is approximately 3-fold higher than expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).

Rates of lymphoma in clinical trials of HUMIRA cannot be compared to rates of lymphoma in clinical trials of other TNF blockers and may not predict the rates observed in a broader patient population. Patients with RA and other chronic inflammatory diseases, particularly those with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF blockers. Post-marketing cases of acute and chronic leukemia have been reported in association with TNF-blocker use in RA and other indications.

Even in the absence of TNF-blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.

Malignancies in Pediatric Patients and Young Adults Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers (initiation of therapy ≤ 18 years of age), of which HUMIRA is a member.

Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources including registries and spontaneous postmarketing reports.

Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including HUMIRA. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases has occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants.

Hypersensitivity Reactions In postmarketing experience, anaphylaxis and angioneurotic edema have been reported rarely following HUMIRA administration. If an anaphylactic or other serious allergic reaction occurs, administration of HUMIRA should be discontinued immediately and appropriate therapy instituted. In clinical trials of HUMIRA in adults, allergic reactions overall (e.g., allergic rash, anaphylactoid reaction, fixed drug reaction, non-specified drug reaction, urticaria) have been observed in approximately 1% of patients.

Hepatitis B Virus Reactivation Use of TNF blockers, including HUMIRA, may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation.

Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating TNF blocker therapy. Prescribers should exercise caution in prescribing TNF blockers for patients identified as carriers of HBV. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. In patients who develop HBV reactivation, HUMIRA should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known.

Neurologic Reactions Use of TNF blocking agents, including HUMIRA, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis (MS) and optic neuritis, and peripheral demyelinating disease, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use of HUMIRA in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders.

Hematological Reactions Rare reports of pancytopenia including aplastic anemia have been reported with TNF blocking agents. Adverse reactions of the hematologic system, including medically significant cytopenia (e.g., thrombocytopenia, leukopenia) have been infrequently reported with HUMIRA. The causal relationship of these reports to HUMIRA remains unclear. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on HUMIRA. Discontinuation of HUMIRA therapy should be considered in patients with confirmed significant hematologic abnormalities.

Use with Anakinra Concurrent use of anakinra (an interleukin-1 antagonist) and another TNF-blocker, was associated with a greater proportion of serious infections and neutropenia and no added benefit compared with the TNF-blocker alone in patients with RA. Therefore, the combination of HUMIRA and anakinra is not recommended [see Drug Interactions].

Heart Failure Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers.

Cases of worsening CHF have also been observed with HUMIRA. Physicians should exercise caution when using HUMIRA in patients who have heart failure and monitor them carefully.

Autoimmunity Treatment with HUMIRA may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with HUMIRA, treatment should be discontinued [see Adverse Reactions].

Immunizations In a placebo-controlled clinical trial of patients with rheumatoid arthritis, no difference was detected in anti-pneumococcal antibody response between HUMIRA and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with HUMIRA. Patients on HUMIRA may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving HUMIRA. It is recommended that juvenile idiopathic arthritis patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating HUMIRA therapy.

Patients on HUMIRA may receive concurrent vaccinations, except for live vaccines.

Use with Abatacept In controlled trials, the concurrent administration of TNF-blockers and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; the combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of abatacept with TNF-blockers including HUMIRA is not recommended [see Drug Interactions].

ADVERSE REACTIONS Clinical Studies Experience The most serious adverse reactions were: • Serious Infections [see Warnings and Precautions] • Malignancies [see Warnings and Precautions] The most common adverse reaction with HUMIRA was injection site reactions. In placebo-controlled trials, 20% of patients treated with HUMIRA developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 14% of patients receiving placebo. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation.

The proportion of patients who discontinued treatment due to adverse reactions duri during the double-blind, placebo-controlled portion of Studies RA-I, RA-II, RA-III and RA-IV w was 7% % for patients taking HUMIRA M and 4% % for placebo-treated patients. The m most common mm adverse reactions leading to discontinuation of HUMIRA M w were clinical flare reaction (0.7%), % rash (0.3%) % and pneumonia m (0.3%). % Infections In the controlled portions of the 32 global HUMIRA M clinical trials in adult patients w with RA, PsA, AS, CD D and Ps, the rate of serious infections w was 4.7 per 100 patient-years in 6694 HUMIRA-treated M patients versus a rate of 2.7 per 100 patient-years in 3749 control-treated patients. Serious infections observed included pneumonia, m septic arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis [see W Warnings and Precautions].

Tuberculosis and O Opportunistic Infections In 45 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD D and Ps that included 22,026 HUMIRA-treated M patients, the rate of reported active tuberculosis w was 0.22 per 100 patient-years and the

rate of positive PPD D conversion w was 0.07 per 100 patient-years. In a subgroup of 8940 U.S. and Canadian HUMIRA-treated M patients, the rate of reported active TB w was 0.07 per 100 patient-years and the rate of positive PPD D conversion w was 0.06 per 100 patient-years. These trials included reports of m miliary, lymphatic, m peritoneal, and pulmonary m TB. M Most of the TB cases occurred w within the first eight m months after initiation of therapy and m may reflect recrudescence of latent disease. In these global clinical trials, cases of serious opportunistic infections have been reported at an overall rate of 0.07 per 100 patient-years. Some m cases of serious opportunistic infections and TB have been fatal [see W Warnings and Precautions].

Autoantibodies In the rheumatoid m arthritis controlled trials, 12% % of patients treated w with HUMIRA M and 7% % of placebo-treated patients that had negative baseline ANA N titers developed positive titers at w week 24. Two w patients out of 3046 treated w with HUMIRA M developed clinical signs suggestive of new-onset w lupus-like syndrome. m The patients improved m following w discontinuation of therapy. N No patients developed lupus nephritis or central nervous system m symptoms. m m The impact m of long-term m treatment m w with HUMIRA M on the development m of autoimmune mm diseases is unknown. w Liver Enzyme m Elevations There have been reports of severe hepatic reactions including acute liver failure in patients receiving N In controlled Phase 3 trials of HUMIRA M (40 m mg SC every other w week) in patients w with RA, TNF-blockers. with control period duration ranging from m 4 to 104 w weeks, ALT elevations ≥ 3 x ULN N occurred in PsA, and AS w % of HUMIRA-treated M patients and 1.5% % of control-treated patients. Since m many of these patients in these 3.5% were also taking m medications that cause liver enzyme m elevations (e.g., N NSAIDS, D M MTX), the relationship trials w w HUMIRA M and the liver enzyme m elevations is not clear. In controlled Phase 3 trials of HUMIRA M (initial between mg and 80 m mg, or 80 m mg and 40 m mg on D Days 1 and 15, respectively, followed w by 40 m mg every doses of 160 m week) in patients w with Crohn’s disease w with control period duration ranging from m 4 to 52 w weeks, ALT other w elevations ≥ 3 x ULN N occurred in 0.9% % of HUMIRA-treated M patients and 0.9% % of control-treated patients.

In controlled Phase 3 trials of HUMIRA M (initial dose of 80 m mg then 40 m mg every other w week) in patients w with plaque psoriasis w with control period duration ranging from m 12 to 24 w weeks, ALT elevations ≥ 3 x ULN N occurred in 1.8% % of HUMIRA-treated M patients and 1.8% % of control-treated patients. mm Immunogenicity Patients in Studies RA-I, RA-II, and RA-III w were tested at m multiple time m points for antibodies to adalimumab m m during the 6- to 12-month m period. Approximately m 5% % (58 of 1062) of adult rheumatoid m arthritis patients receiving HUMIRA M developed low-titer w antibodies to adalimumab m m at least once during treatment, m w which w were neutralizing in vitro. Patients treated w with concomitant m methotrexate had a lower m w rate of antibody development m than patients on HUMIRA M m monotherapy (1% % versus 12%). % N No apparent correlation of antibody development m to adverse reactions w was observed. W With m monotherapy, patients receiving every other w week dosing m may develop antibodies m more frequently than those receiving w weekly dosing. In patients receiving the recommended mm dosage of 40 m mg every other w week as m monotherapy, the ACR 20 response w was lower w among m antibody-positive patients than among m antibody-negative patients. The long-term m immunogenicity mm of HUMIRA M is unknown. w In patients w with juvenile idiopathic arthritis, adalimumab m m antibodies w were identified in 16% % of HUMIRA-treated M patients. In patients receiving concomitant m methotrexate, the incidence w m was 6% % compared m to 26% %w with HUMIRA M m monotherapy.

In patients w with ankylosing spondylitis, the rate of development m of antibodies to adalimumab m m in HUMIRA-treated M patients w was comparable m to patients w with rheumatoid m arthritis. In patients w with psoriatic arthritis, the rate of antibody development m in patients receiving HUMIRA M m monotherapy w was comparable m to patients w with rheumatoid m arthritis; however, w in patients receiving concomitant m methotrexate the rate w m was 7% % compared m to 1% % in rheumatoid m arthritis. In patients w with Crohn’s disease, the rate of antibody development m w was 3%. % In patients with plaque psoriasis, the rate of antibody development w m w with HUMIRA M m monotherapy w was 8%. % However, w due to the limitation m of the assay conditions, antibodies to adalimumab m m could be detected only w when serum m adalimumab m m levels w were < 2 ug/ml. m Among m the patients w whose serum m adalimumab m m levels w were < 2 ug/ml m (approximately m 40% % of total patients studied), the immunogenicity mm rate w was 20.7%. % In plaque psoriasis patients who w w were on HUMIRA M m monotherapy and subsequently w withdrawn w from m the treatment, m the rate of antibodies to adalimumab m m after retreatment m w was similar m to the rate observed prior to w withdrawal. w Other Adverse Reactions O The data described below w reflect exposure to HUMIRA M in 2468 patients, including 2073 exposed for 6 m months, 1497 exposed for greater than one year and 1380 in adequate and w well-controlled studies (Studies RA-I, RA-II, RA-III, and RA-IV). HUMIRA M w was studied primarily m in placebo-controlled trials and in long-term m follow w up studies for up to 36 m months duration. The population had a m mean age of 54 years, 77% %w were female, m 91% %w were Caucasian and had m moderately to severely active rheumatoid m arthritis. M Most patients received 40 m mg HUMIRA M every other w week.

Table 1 summarizes mm reactions reported at a rate of at least 5% % in patients treated w with HUMIRA M 40 m mg every other w week compared m to placebo and w with an incidence higher than placebo. In Study RA-III, the types and frequencies of adverse reactions in the second year open-label extension w were similar m to those observed in the one-year double-blind portion.

Table 1. Adverse A Reactions R R Reported by ≥5% % of Patients Treated w with H HUMIRA M RA During Placebo-Controlled Period of R D Rheumatoid m Arthritis Studies A HUMIRA M 40 m mg subcutaneous Every Other W O Week (N=705) N= Adverse Reaction (Preferred Term) m Respiratory R Upper respiratory infection 17% % Sinusitis 11% % Flu syndrome m 7% % Gastrointestinal G Nausea N 9% % Abdominal m pain 7% % Laboratory Tests* Laboratory test abnormal m 8% % Hypercholesterolemia m 6% % Hyperlipidemia m 7% % Hematuria m 5% % Alkaline phosphatase increased 5% % Other O Headache 12% % Rash 12% % Accidental injury 10% % Injection site reaction ** 8% % Back pain 6% % Urinary tract infection 8% % Hypertension 5% % * Laboratory test abnormalities m were reported as adverse reactions in European trials w ** D Does not include injection site erythema, m itching, hemorrhage, m pain or swelling w

Placebo

(N=690) N=

13% % 9% % 6% % 8% % 4% % 7% % 4% % 5% % 4% % 3% % 8% % 6% % 8% % 1% % 4% % 5% % 3% %

Juvenile Idiopathic Arthritis Clinical Studies In general, the adverse reactions in the HUMIRA-treated M pediatric patients in the juvenile idiopathic arthritis (JIA) trial w were similar m in frequency and type to those seen in adult patients [see W Warnings and Precautions, Adverse Reactions]. Important m findings and differences from m adults are discussed in the following w paragraphs.

HUMIRA M w was studied in 171 pediatric patients, 4 to 17 years of age, w with polyarticular JIA. Severe adverse reactions reported in the study included neutropenia, streptococcal pharyngitis, increased aminotransferases, m herpes zoster, m myositis, m metrorrhagia, appendicitis. Serious infections w were observed in 4% % of patients within approximately w m 2 years of initiation of treatment m w with HUMIRA M and included cases of herpes simplex, m pneumonia, m urinary tract infection, pharyngitis, and herpes zoster.

A total of 45% % of children experienced an infection w while receiving HUMIRA M w with or w without concomitant m MTX M in the first 16 w weeks of treatment. m The types of infections reported in HUMIRA-treated M patients w were generally similar m to those commonly mm seen in JIA patients w who are not treated w with TNF N blockers. Upon initiation of treatment, m the m most common mm adverse reactions occurring in the pediatric population treated w with HUMIRA M were injection site pain and injection site reaction (19% w % and 16%, % respectively). A less commonly mm reported adverse event in children receiving HUMIRA M w was granuloma m annulare w which did not lead to discontinuation of HUMIRA M treatment. m In the first 48 w weeks of treatment, m non-serious hypersensitivity reactions w were seen in approximately m 6% % of children and included primarily m localized allergic hypersensitivity reactions and allergic rash.

Isolated m mild to m moderate elevations of liver aminotransferases m (ALT m more common mm than AST) w were observed in children w with JIA exposed to HUMIRA M alone; liver enzyme m test elevations w were m more frequent among m those treated w with the combination m of HUMIRA M and M MTX than those treated w with HUMIRA M alone. In general, these elevations did not lead to discontinuation of HUMIRA M treatment. m In the JIA trial, 10% % of patients treated w with HUMIRA M w who had negative baseline anti-dsDNA DN antibodies developed positive titers after 48 w weeks of treatment. m N No patient developed clinical signs of autoimmunity mm during the clinical trial.

Approximately m 15% % of children treated w with HUMIRA M developed m mild-to-moderate m elevations of creatine phosphokinase (CPK). Elevations exceeding 5 times m the upper limit m of normal m w were observed in several patients. CPK levels decreased or returned to normal m in all patients. M Most patients w were able to continue HUMIRA M w without interruption.

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Psoriatic Arthritis and Ankylosing Spondylitis Clinical Studies HUMIRA has been studied in 395 patients with psoriatic arthritis (PsA) in two placebo-controlled trials and in an open label study and in 393 patients with ankylosing spondylitis (AS) in two placebo-controlled studies.

The safety profile for patients with PsA and AS treated with HUMIRA 40 mg every other week was similar to the safety profile seen in patients with RA, HUMIRA Studies RA-I through IV. Crohn’s Disease Clinical Studies HUMIRA has been studied in 1478 patients with Crohn’s disease in four placebo-controlled and two open-label extension studies. The safety profile for patients with Crohn’s disease treated with HUMIRA was similar to the safety profile seen in patients with RA. Plaque Psoriasis Clinical Studies HUMIRA has been studied in 1696 patients with plaque psoriasis in placebo-controlled and open-label extension studies. The safety profile for patients with plaque psoriasis treated with HUMIRA was similar to the safety profile seen in patients with RA with the following exceptions. In the placebo-controlled portions of the clinical trials in plaque psoriasis patients, HUMIRA-treated patients had a higher incidence of arthralgia when compared to controls (3% vs. 1%).

Postmarketing Experience Adverse reactions have been reported during post-approval use of HUMIRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to HUMIRA exposure.

Gastrointestinal disorders: Diverticulitis, large bowel perforations including perforations associated with diverticulitis and appendiceal perforations associated with appendicitis, pancreatitis Hepato-biliary disorders: Liver failure Immune system disorders: Sarcoidosis Nervous system disorders: Demyelinating disorders (e.g., optic neuritis, Guillain-Barré syndrome), cerebrovascular accident Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis, pulmonary embolism Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening psoriasis (all sub-types including pustular and palmoplantar), alopecia Vascular disorders: Systemic vasculitis, deep vein thrombosis DRUG INTERACTIONS Methotrexate Although methotrexate (MTX) reduces the apparent adalimumab clearance, the data do not suggest the need for dose adjustment of either HUMIRA or MTX. Biologic Products In clinical studies in patients with RA, an increased risk of serious infections has been seen with the combination of TNF blockers with anakinra or abatacept, with no added benefit; therefore, use of HUMIRA with abatacept or anakinra is not recommended in patients with RA [see Warnings and Precautions]. A higher rate of serious infections has also been observed in patients with RA treated with rituximab who received subsequent treatment

with a TNF blocker. There is insufficient information to provide recommendations regarding the concomitant use of HUMIRA and other biologic products for the treatment of RA, PsA, AS, Crohn’s Disease, and plaque psoriasis.

Live Vaccines Live vaccines should not be given concurrently with HUMIRA [see Warnings and Precautions].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B - There are no adequate and well-controlled studies in pregnant women. Because animal reproduction and developmental studies are not always predictive of human response, HUMIRA should be used during pregnancy only if clearly needed.

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

Nursing Mothers It is not known whether adalimumab is excreted in human milk or absorbed systemically after ingestion.

Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from HUMIRA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use Safety and efficacy of HUMIRA in pediatric patients for uses other than juvenile idiopathic arthritis (JIA) have not been established.

Juvenile Idiopathic Arthritis In the JIA trial, HUMIRA was shown to reduce signs and symptoms of active polyarticular JIA in patients 4 to 17 years of age. HUMIRA has not been studied in children less than 4 years of age, and there are limited data on HUMIRA treatment in children with weight <15 kg.

The safety of HUMIRA in pediatric patients in the JIA trial was generally similar to that observed in adults with certain exceptions [see Adverse Reactions].

Post-marketing cases of malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers including HUMIRA [see Warnings and Precautions].

Geriatric Use A total of 519 rheumatoid arthritis patients 65 years of age and older, including 107 patients 75 years of age and older, received HUMIRA in clinical studies RA-I through IV. No overall difference in effectiveness was observed between these subjects and younger subjects. The frequency of serious infection and malignancy among HUMIRA treated subjects over 65 years of age was higher than for those under 65 years of age.

Because there is a higher incidence of infections and malignancies in the elderly population in general, caution should be used when treating the elderly.

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

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

PATIENT COUNSELING INFORMATION Patients or their caregivers should be provided the HUMIRA “Medication Guide” and provided an opportunity to read it and ask questions prior to initiation of therapy. The healthcare provider should ask the patient questions to determine any risk factors for treatment. Patients developing signs and symptoms of infection should seek medical evaluation immediately.

Patient Counseling Patients should be advised of the potential benefits and risks of HUMIRA. Physicians should instruct their patients to read the Medication Guide before starting HUMIRA therapy and to reread each time the prescription is renewed.

• Infections Inform patients that HUMIRA may lower the ability of their immune system to fight infections. Instruct patients of the importance of contacting their doctor if they develop any symptoms of infection, including tuberculosis, invasive fungal infections, and reactivation of hepatitis B virus infections.

• Malignancies Patients should be counseled about the risk of malignancies while receiving HUMIRA. • Allergic Reactions Patients should be advised to seek immediate medical attention if they experience any symptoms of severe allergic reactions. Advise latex-sensitive patients that the needle cap of the prefilled syringe contains latex.

• Other Medical Conditions Advise patients to report any signs of new or worsening medical conditions such as congestive heart failure, neurological disease, autoimmune disorders, or cytopenias. Advise patients to report any symptoms suggestive of a cytopenia such as bruising, bleeding, or persistent fever.

Ref: 03–A608-R28 Rev. May, 2012 64C-894702 MASTER 64M-896403

Psoriatic Arthritis Editor’s note: This article is an updated version of the article that appeared in the August print issue of this journal, which contained several errors. We regret those errors.

As Drugs Improve, Costs Increase for Psoriatic Arthritis

By David Hawk Berlin, Germany—Results of an analysis presented by Chureen T. Carter, PharmD, MS, Associate Director of Health Economics and Outcomes Research at Janssen Scientific Affairs, Horsham, PA, and colleagues at the 2012 European League Against Rheumatism Congress indicate that during the time period of the introduction of biologic agents for the treatment of psoriatic arthritis, the direct healthcare costs related to psoriatic arthritis management rose from approximately $3500 annually to an annual expenditure exceeding $16,000.

“This estimate of new economic burden of illness estimate may further aid decision makers in assessing the cost-effectiveness and budgetary impact of psoriatic arthritis therapies, including biologics,” noted Dr Carter.

Previous estimates of the annual direct (ie, inpatient, outpatient, and pharmacy) costs per patient with psoriatic arthritis had been $3500 in the United States. However, this estimate is a decade old and does not account for new biologic treatments, advances in diagnostic procedures, or updated reimbursement policies. Data describing the current economic burden of psoriatic arthritis in the United States are limited.

In the present analysis, investigators from Janssen focused on direct psoriatic arthritis costs in a population of patients with evidence of receiving the company’s biologic drug golimumab (Simponi), which was approved by the US Food and Drug Administration in 2009 for the treatment of psoriatic

arthritis. The costs associated with psoriatic arthritis included those incurred during the 2-year period before initiating golimumab.

Using data from the IMS LifeLink Health Claims database, the researchers identified patients who had initiated treatment with golimumab between April 2009 and June 2010.

The study included 211 patients (average age, 50 years) with psoriatic

“This estimate of new economic burden of illness estimate may further aid decision makers in assessing the costeffectiveness and budgetary impact of psoriatic arthritis therapies.”

—Chureen T. Carter, PharmD, MS arthritis who received a prescription for golimumab; 61% were female, and concomitant diagnosis codes for rheumatoid arthritis were found for 39.8% of the patients. Of note, 180 of these patients had already received treatment before the introduction of golimumab.

A cost-estimate analysis of psoriatic arthritis management before the availability of biologic agents showed

direct healthcare costs ranging from $3500 to $9200 annually. However, as expected, a more recent cost estimate representing a 2-year period before patients began using golimumab, revealed that costs have risen dramatically to $16,369 annually.

This increased financial burden to the payer is significant, but as the researchers pointed out, “This estimate should be considered in the context of incremental improvements in clinical outcomes associated with biologic treatments as compared with older psoriatic arthritis therapies.”

An Expense versus an Investment A new study looked not only at the direct costs of managing patients with psoriatic arthritis but at the indirect costs as well (Kvamme MK, et al. Rheumatology [Oxford]. 2012;51: 1618-1627).

Direct costs included pharmaceuticals, imaging examinations, inpatient and outpatient care, rehabilitation unit stays, and visits to general practitioners, private rheumatologists, and physiotherapists. Indirect costs included patients’ work absenteeism.

The data for this analysis were derived from 1700 patients being treated within the Norwegian healthcare system, a source that captures outcomes and resource use among patients.

As with the previous study, the annual direct costs, including the use of biologic treatments, were substantial, exceeding €32,000 annually.

However, in this analysis the

at a glance ➤ Direct psoriatic arthritis healthcare cost estimates have risen by more than 4.5-fold compared with older estimates from more than a decade ago ➤ The increased financial burden to the payer is significant but should be considered in light of incremental improvements in clinical outcomes ➤ The largest cost component was the loss of patient productivity ➤ When considering trends in disease management and outcomes, reductions are seen in total costs over time

researchers stressed that the largest cost component of the total costs was the loss of patient productivity (ie, the indirect costs).

An analysis of the entire data set, however, sheds some encouraging light. Describing trends over 2 years, the researchers stated, “Total costs decreased significantly from the first to the fourth 6-month periods, and this decrease was influenced by reductions in both direct and indirect costs.”

Simply put, drugs that are effective put patients back on the job. ■ 3:56 PM

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VALUE-BASED CARE IN RHEUMATOLOGY

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Psoriatic Arthritis

Psoriasis and Psoriatic Arthritis... region of the major histocompatibility complex (MHC), the HLA-C locus that accounts for approximately 35% to 50% of the genetic heritability for psoriasis, the PSORS1 gene. Genomewide association studies have shown that at least 23 loci are associated with psoriasis, but only a few are associated with PsA.2 The MHC region and interleukin-12 B (IL12B) are 2 specific PsA loci, with these markers independent from those implicated in psoriasis.2 A novel PsA locus on chromosome 4q27 harboring the IL2 and IL21 genes has been discovered, which is of interest, because this region is also associated with other autoimmune diseases, including celiac disease, rheumatoid arthritis (RA), type 1 diabetes, and Graves’ disease.3 Most recently, IL23A, TNFAIP3 (tumor necrosis factor [TNF]-alpha– induced protein 3), and TNIP1 genetic variants have been shown to confer risks to patients with PsA.1 Other genes have also been implicated in PsA not in psoriasis (ie, the 5q31 region encompassing the IL13 gene).

New-generation sequencing technologies, such as massive parallel sequencing and pharmacogenomics, are likely to make a major impact on the relationship between psoriasis and PsA, with important consequences for targeted therapies as the ultimate goal.4 Immunopathologic Similarities and Differences Lymphocytic infiltrates predominate in the skin of patients with psoriasis (ie, dermal papillae) and in the joints and entheses of patients with PsA, predominantly CD4+ cells with an increase in the vascularity noted in patients with psoriasis and in those with PsA. The macrophages that are prominent in RA synovial tissue are reduced in patients with PsA. Cutaneous lymphocyte-associated antigen is upregulated in the skin of patients with psoriasis, but not in the skin of those with PsA. A new subset of T cells, Th17, has revolutionized our understanding of psoriasis and PsA, because these cells produce IL17A. The p40 subunit, which is shared by IL12 and IL23, is increased in the serum of patients who have PsA, with levels proportionate to the severity of the disease.

Similarly, osteoclast precursor cells are increased in the peripheral blood of patients with PsA, with a significant decrease noted within 2 weeks of the initiation of anti–TNF-alpha therapy.

An increase in neutrophils, as well as

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in angiogenesis, are prominent features in the skin and synovium of patients with psoriasis and with PsA, respectively.

Despite these similarities, it has not been possible to adequately produce in vivo animal models to allow for characterization of the mutual inflammatory features of psoriasis and of PsA.5 Xenotransplantation mouse models show some promise in furthering our understanding, as well as in allowing the potential for new drug development for psoriasis and for PsA (eg, anti-IL22 agents).5 Therapeutic Similarities and Differences Methotrexate, the most frequently used drug for the treatment of psoriasis and of PsA worldwide, was initially approved only for psoriasis in 1972.

Despite being used for more than 4 decades for the clinical treatment of psoriasis, few well-designed clinical studies have evaluated methotrexate’s true efficacy, with 75% reduction in Psoriasis Area and Severity Index (PASI 75) scores—the frequently used outcome measure in clinical studies— varying between 24% and 60% in different studies.6-8 In a recent 6-month, randomized, placebo-controlled trial of methotrexate for the treatment of patients with PsA, 221 patients using PsA response criteria as the primary outcome measure, as well as the American College of Rheumatology 20% improvement criteria (ACR20) and inflammatory markers (ie, erythrocyte sedimentation rate and C-reactive protein), failed to show any evidence of methotrexate superiority over placebo, except for improvement in skin scores.9 In addition, methotrexate has not shown any potential for decreasing or improving joint destruction in clinical trials of patients with PsA. Therefore, the important question that these findings bring to the forefront is, why should methotrexate be used as a first-line treatment in patients with PsA, despite its infinitely lower cost compared with TNF-alpha inhibitory agents?

Also, if only approximately 40% to 50% of patients with psoriasis respond adequately to methotrexate monotherapy, and we currently have no biologic markers to predict treatment success, where does it place methotrexate in relation to biologic agents, especially the 3 TNF-alpha agents (ie, adalimumab, etanercept, and infliximab) approved for both psoriasis and PsA?

Continued from cover

Of interest when comparing the effectiveness of these 3 TNF-alpha inhibitory agents in patients with psoriasis and in those with PsA is why do all 3 agents give very similar ACR20 outcome scores for PsA but distinctly different PASI 75 scores for psoriasis?

In addition, methotrexate is frequently used in combination with these 3 agents to boost the skin and the joint responses, as well as to reduce the risk for decreased effectiveness of the TNFalpha agents over time. Will a single new agent improve on this and make monotherapy “state of the art”?

Similarly, ustekinumab was only approved for the treatment of psoriasis in 2009, with PASI 75 scores in the upper range of TNF-alpha psoriasis scores.

Methotrexate has not shown any potential for decreasing or improving joint destruction in clinical trials of patients with PsA. Therefore, the important question that these findings bring to the forefront is, why should methotrexate be used as a first-line treatment in patients with PsA? In PSUMMIT I, a multicenter, double-blind, placebo-controlled, phase 3 clinical trial of patients with psoriasis, those managed with ustekinumab had a significantly lower ACR score than those receiving adalimumab, etanercept, or infliximab.10 Patients with psoriasis and those with PsA have had remission rates of approximately 30% with TNF-alpha agents in randomized controlled trials and in registry-based longitudinal studies11; therefore, newer agents that are currently in development are certainly deserving of attention, for clinical and for safety reasons.

An important issue with our current and future armamentarium is the multiple comorbidities now known to be associated with psoriasis and PsA, and what effect new agents will have on these comorbidities, including cardiac disease, metabolic syndrome, decreased lifes-pan, and others. A recent study showed a significant reduction in the incidence of myocardial infarction in patients with psoriasis who were taking TNF inhibitors.12 With safety data available for more

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than 2 million patients across all indications who have been treated with TNF-alpha agents, it is vitally important to carefully assess the side effect profile of all new drugs that are approved, as well as of those that are under development. However, new does not always necessarily mean better. The withdrawal of the highly efficacious anti-IL12/23 molecule, briakinumab, which is under late-stage phase 3 development for the treatment of psoriasis and for PsA, was a result of major adverse cardiac events.13 Conclusion The comparative efficacy, value, safety, and cost of emerging new therapies will have to be carefully considered in the treatment of psoriasis and of PsA, because our understanding of the genetics and immunopathogenesis continues to improve, and pharmacogenomics allows us to tailor particular therapies to specific patients. In these days of rapidly increasing healthcare costs, improving the health outcomes and quality of life of our more than 1.25 million patients worldwide with psoriasis and/or with PsA must remain an important consideration. ■ References 1. Bowes J, Barton A. The genetics of psoriatic arthritis: lessons from genome-wide association studies. Discov Med. 2010;10:177-183.

2. Capon F, Barker JN. The quest for psoriasis susceptibility genes in the postgenome-wide association studies era: charting the road ahead. Br J Dermatol.

2012;166:1173-1175.

3. Liu Y, Helms C, Liao W, et al. A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet. 2008;4:e1000041.

4. Joyce CE, Zhou X, Xia J, et al. Deep sequencing of small RNAs from human skin reveals major alterations in the psoriasis miRNAome. Hum Mol Genet.

2011;20:4025-4040.

5. Nestle FO, Kaplan DH, Barker J. Mechanisms of disease psoriasis. N Engl J Med. 2009;361:496-509.

6. Heydendael VM, Spuls PI, Opmeer BC, et al. Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. N Engl J Med. 2003;349: 658-665.

7. Flyström I, Stenberg B, Svensson A, Bergbrant IM. Methotrexate vs cyclosporine in psoriasis: effectiveness, quality of life and safety. A randomized controlled trial. Br J Dermatol. 2008;158:116-121.

8. Saurat JH, Stingl G, Dubertret L, et al. Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J Dermatol. 2008;158:558-566.

9. Kingsley GH, Kowalczyk A, Taylor H, et al. A randomized placebo-controlled trial of methotrexate in psoriatic arthritis. Rheumatology (Oxford). 2012;51:1368-1377.

10. McInnes IB, Kavanaugh A, Gottlieb AB, et al.

Ustekinumab in patients with active psoriatic arthritis: results of the phase 3, multicenter, double-blind, placebo-controlled PSUMMIT I study. Presented at 3rd World Congress of Psoriasis and Psoriatic Arthritis; 2012 June 27-July 1; Stockholm, Sweden; Ann Rheum Dis. 2012;71(suppl 3):107.

11. Saad AA, Ashcroft DM, Watson KD, et al. Efficacy and safety of anti-TNF therapies in psoriatic arthritis: an observational study from the British Society for Rheumatology Biologics Register. Rheumatology (Oxford). 2010;49:697-705.

12. Wu JJ, Poon KY, Channual JC, Shen AY. Association between tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis.

Arch Dermatol. 2012 Aug 20:1-7. Epub ahead of print.

13. Ryan C, Leonardi CL, Krueger JG, et al. Association between biologic therapies for chronic plaque psoriasis and cardiovascular events: a meta-analysis of randomized controlled trials. JAMA. 2011;306:864-871.

www.ValueBasedRheumatology.com

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Economic Issues in Rheumatology

Healthcare Costs Rise in Tandem with Increased Disability in Patients with Rheumatoid Arthritis

By Mary Mosley Washington, DC—Rheumatoid arthritis (RA) is associated with a significant disability, but the associated costs related specifically to RA disability are not known. A team of researchers have created a model to calculate the impact of RA-related disability, showing that these costs increase exponentially with a worsening of disability.

This information fills the current vacuum of healthcare cost analysis for RA-related disability, and complements the rich characterization of disability associated with RA. Using data from the British Society for Rheumatology Biologics Register, Chris D. Poole, PhD, Chief Scientific Officer, Pharmatelligence, Cardiff, Wales, and colleagues presented the economic impact of their model during the 2012 International Society for Pharmacoeconomics and Outcomes Research annual meeting.

In the United Kingdom, the majority of healthcare for RA is provided by

general practitioners. The investigators combined information from the rheumatology biologics registry with healthcare expenditures from the General Practice Research Database to come up with their cost model.

Annual Costs Disability cost data were collected on 6129 patients with RA (mean age, 57 years) with a mean baseline Health Assessment Questionnaire (HAQ) score of 1.81 in the rheumatology biologics registry.

Factors considered for the cost calculation included sex, age, smoking, body mass index, previous use of disease-modifying antirheumatic drugs (DMARDs), joint replacement, systemic RA features, current DMARD and steroid treatment, C-reactive protein, current non-RA drugs, and comorbidities.

The healthcare cost model included the 12-month costs for prescriptions,

The mean annual cost of RA-related care in 2 cohorts combined was £2792.

Hospital admission made up the largest proportion of the cost—46% (mean, £1276), followed by 24% (mean, £677) for prescriptions; 20% (mean, £564) for primary care; 11% (mean, £300) for outpatient care; and 11% (mean, £199) for investigations.

primary care consultations, outpatient care, investigations, and inpatient admissions, and included inputs

based on 8423 cases (mean age, 64 years) in the General Practice Research Database.

All costs were calculated in 2011 UK pounds. In this group of patients, the mean predicted HAQ was 1.78 (range, 0.45-3.00). Total annual costs increased exponentially with increased disability, as evident by the high cost for inpatient care.

The mean annual cost of RA-related care in 2 cohorts combined was £2792.

Hospital admission made up the largest proportion of the annual cost at 46% (mean, £1276), followed by 24% (mean, £677) for prescriptions, 20% (mean, £564) for primary care consultations, 11% (mean, £300) for outpatient care, and 11% (mean, £199) for investigations. All costs were adjusted for age.

Costs of support services were not included in this study. Therefore, these costs are likely conservative, the investigators noted. ■

Two Economic Analyses of Tumor Necrosis Factor Blockers in Psoriatic Arthritis

By Barbara Schwedel Washington, DC—The tumor necrosis factor (TNF) blockers etanercept, adalimumab, and infliximab are approved for various indications, including psoriatic arthritis. It is difficult to predict the real-world costs of these drugs, because real-world dosing differs from the label recommendations, and head-to-head comparisons of these drugs are not available.

The results of 2 studies related to the cost and utilization of these agents and their budget impact were presented at the 2012 International Society for Pharmacoeconomics and Outcomes Research annual meeting.

Costs and Drug Utilization The first study on cost estimates and drug utilization was led by Machaon Bonafede, PhD, MPH, Research Leader at Thomson Reuters Healthcare, Cambridge, MA. This retrospective analysis included 3292 patients with psoriatic arthritis (aged 18-64 years), using US administrative claims data from the MarketScan Commercial Claims and Encounters

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Database (with more than 100 million unique patients from more than 130 health plans). This managed care database included information on the annual costs per patient with psoriatic arthritis of treatment with etanercept (N = 2242), adalimumab (N = 674), and infliximab (N = 376). Patient characteristics were similar across treatment groups.

The annual cost of treatment with a TNF blocker per patient with psoriatic arthritis was $15,790 for etanercept, $18,031 for adalimumab, and $26,973 for infliximab. These costs include all patients, new patients and continuing patients combined (Table).

Budget Impact The second study was led by Michael Ingham, MSc, Health Economics & Outcomes Research Rheumatology Lead at Janssen Scientific Affairs, LLC, Horsham, PA. The study was an analysis of the impact on the US budget of adalimumab, etanercept, and infliximab in patients with psoriatic arthritis. The

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Annual Cost of TNF Blockers per Patient with Psoriatic Arthritisa

Table

Patients

Etanercept, $

Adalimumab, $

Infliximab, $

New

14,675

17,133

23,886

Continuing

16,195

19,575

28,663

All patients

15,790

18,031

26,973

b

a Costs were calculated by multiplying the mean monthly dose by the drug’s 2011 wholesale acquisition costs and adding the related administration costs. b New patients had no claims for a TNF blocker during the 180 days before the index claim.

TNF indicates tumor necrosis factor.

study used clinical outcome assumptions from a 2011 independent systematic review (by the UK’s National Institute for Health and Clinical Excellence) and annual drug cost assumptions based on wholesale acquisition costs from First Databank, South San Francisco, CA, assuming full compliance with labeled dosing.

Clinical outcome assumptions were used to estimate the number needed to treat (NNT) to achieve 100 respond-

ers for each outcome, and the NNT was then multiplied by the annual drug cost assumptions to derive the annual budget necessary to achieve 100 responders.

The cost to achieve 100 responders for the Psoriatic Arthritis Response Criteria outcome among patients treated initially with infliximab was estimated to be $0.65 million less than the corresponding cost with etanerContinued on page 17

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Economic Issues in Rheumatology

Duloxetine Associated with Reduced Healthcare Costs, Less Opioid Use in Osteoarthritis

By Mary Mosley Washington, DC—Osteoarthritis (OA)related healthcare costs for 1 year were nearly $1740 lower in patients treated with duloxetine compared with patients receiving standard of care (including opioids), although the pharmacy cost was $1092 higher in the duloxetine group, according to a new analysis. In addition, patients who were initiated with duloxetine therapy were less likely to use opioids for chronic pain compared with patients who were started with standard of care.

These results were presented by Jihyung Hong, MSc, of Eli Lilly, at the 2012 International Society for Pharmacoeconomics and Outcomes Research meeting.

This retrospective cohort study comprised 1517 patients (mean age, 54 years; 81% women) who started therapy with duloxetine and 1517 patients who started with standard of care between January 1, 2009 and December 31, 2009.

Standard of care included the drugs celecoxib, various opioids, venlafaxine, gabapentin, and pregabalin.

The patients were divided to the duloxetine group or to the standard of care group based on the index prescription; they were followed for 1 year from the index date.

To be included, patients had to be free of having used the study drugs for the previous 90 days. All patients had commercial health insurance, with a continuous pharmacy benefit, for the 12 months before and after the index date.

Data were used from the Medstat MarketScan, a commercial claims database, and an OA-related diagnosis was used to identify patients with OA. A 12% reduction in OA-related surgeries and procedures was found in the duloxetine group, as well as a significant 11.1% reduction in the use of chronic pain–related opioid use, and significantly fewer days taking an opioid compared with the standard of care group. Patients in the duloxetine group were using chronic pain–related opioids for an average of 29.2 days compared with 63.2 days with standard of care.

The total OA-related costs for the 12

Table

12-Month Costs of Treating Patients with Osteoarthritisa Duloxetine, $ (N = 1517)

Standard of care, $ (N = 1517)

Difference in cost, $

Inpatient care

3374

5048

1674

Outpatient care

8427

9581

1154

Pharmacy cost

4910

3818

1092

16,711

18,447

1736

Cost parameter

Total OA-related cost a

Costs are for the year 2009-2010.

OA indicates osteoarthritis. months preceding the index date were similar between the groups—$13,919 in the duloxetine group and $13,939 in the standard of care group, and the pharmacy costs were $3634 in the duloxetine group and $3636 in the standard of care group.

During the 12-month study period, the difference in total OA-related costs was significantly lower in the duloxetine group than in the standard of care group—$16,711 versus $18,447, respectively. However, the pharmacy cost was higher in the duloxetine group compared with the standard of care

group—$4910 versus $3818, respectively (Table).

The investigators advised conservative interpretation of the study results, because of “the nature of the claims database.” In addition, because a full 12 months of postindex data were not available for duloxetine, prelaunch data were used to supplement the analysis, and thus require confirmation when sufficient data are available. Among other limitations, the investigators noted that the data related to the severity and duration of OA were not available. ■

Two Economic... Adherence Low in Medicaid Population with RA Continued from page 16

By Rosemary Frei, MSc cept and $2.95 million less than the cost with adalimumab.

The cost of 100 ACR50 (American College of Rheumatology 50% improvement criteria) responses after initiation with infliximab was estimated to be $1.25 million less than the cost with etanercept and $3.15 million less than the cost with adalimumab. Using the Psoriasis Area and Severity Index 75% response, the cost of 100 responses after initiation with infliximab was $14.4 million less than with etanercept and $2.4 million less than with adalimumab.

This analysis shows that the estimated budget impact over 1 year was lower for infliximab than for adalimumab or for etanercept, suggesting that the initial TNF blocker choice may have substantial budget implications for payers. However, this analysis did not include the potential impact of quality-of-life issues that may affect not only the total cost of healthcare but also patient satisfaction and medication adherence. ■

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Washington, DC—Only one fifth of Medicaid patients with rheumatoid arthritis (RA) are adherent to their medication regimen, according to an analysis from the University Of Mississippi of a Mississippi Medicaid database that was presented at the 2012 International Society for Pharmacoeconomics and Outcomes Research meeting.

“Twenty percent is a very small number,” researcher Manasi Datar, MS, a Graduate Research Assistant in the Department of Pharmacy Administration, University of Mississippi, Oxford, told Value-Based Care in Rheumatology. This percentage may be this low because the patients studied “are Medicaid beneficiaries, who have been shown to have poor adherence rates for chronic medications. Also, because several RA medications are injections, that may lead to poor adherence,” she added.

The study is part of a larger project aimed at studying medication adherence among patients with chronic

conditions who are enrolled in the Mississippi Medicaid program. The researchers examined 2006 and 2007 Mississippi Medicaid Analytic eXtract files from the Chronic Condition Data Warehouse of the Centers for Medicare & Medicaid Services.

A total of 621 patients with RA, aged 21 to 64 years, had ≥1 medical service claim, such as an office visit or hospitalization, and with a primary or secondary diagnosis of RA. Of these patients, 20% took their medication on at least 80% of days and hence were deemed to be adherent. The average level of adherence in the adherent group was 90.9% compared with 31% in the nonadherent group.

Patients in the adherent group were significantly older, on average, than nonadherent patients with RA (49.3 vs 46.7 years). Adherent patients were also significantly more likely to be white and to have more comorbidities than the nonadherent patients. A mul-

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tivariate logistic regression analysis revealed that higher age, white race, and a higher level of comorbidity were the only significant predictors of medication adherence.

“It may seem surprising that older patients are more adherent, but in RA this has been previously established,” said Ms Datar, referring to a 1999 study by Park and colleagues. “The same paper corroborates the finding that disease severity does not predict medication adherence, which is also what we found in our study.”

Nonadherence was not a significant predictor of increased hospitalization or emergency department visits in the study. “However, there may be longterm detrimental health outcomes associated with poor adherence to rheumatoid arthritis medications,” noted lead investigator Paul Khanna, PhD. “We may analyze several years of data to further delve into the relationship between nonadherence and patient health outcomes.” ■

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Drug Update

Rayos: A New Oral Delayed-Release Prednisone for the Treatment of Rheumatoid Arthritis and Other Rheumatic Diseases

By Alice Goodman, Medical Writer

D

elayed-release prednisone (Rayos, Horizon Pharma) was approved by the US Food and Drug Administration (FDA) on July 26, 2012, for the treatment of a broad range of inflammatory-mediated diseases, including rheumatic, respiratory, dermatologic, allergic, endocrine, and hematologic diseases.

The rationale for the development of Rayos rests on chronobiological observations in patients with inflammatory-mediated diseases. The delayedrelease system is engineered to address the circadian rhythm of endogenous cortisol and disease symptoms, which reach their peak levels in the early morning hours.

Routine morning administration of conventional prednisone does not achieve adequate control of cortisol levels and disease symptoms, but taking delayed-release prednisone at bedtime releases glucocorticoid (ie, prednisone) 4 hours later, in the very early morning hours, which improves symptom control.1 With the recent FDA approval of Rayos, the manufacturer will initially be focusing its marketing efforts on the use of the drug in rheumatoid arthritis (RA) and in polymyalgia rheumatica, and then will be expanding the focus to a total of 6 key inflammatory diseases—RA, polymyalgia rheumatica, psoriatic arthritis, ankylosing spondylitis, asthma, and chronic obstructive pulmonary disease (COPD).2 All 6 of these diseases are mediated by interleukin (IL)-6.

Rheumatic Conditions Rheumatic conditions comprise a broad spectrum of more than 100 different diseases that affect approximately 50 million Americans. Some of these diseases are seen frequently, such as RA and gout, and others are relatively rare, including relapsing polychondritis and polymyalgia rheumatica.3,4 The most familiar rheumatic diseases affect the muscles, joints, and bones, and cause chronic joint pain, swelling, stiffness, and fatigue. But rheumatic diseases can also affect other organs and organ systems, including the heart, eyes, lungs, nervous system, blood, vascular system, and skin. Inflammatory rheumatic

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diseases—RA, lupus, and gout—are the most severe of these conditions and can destroy joints and organs, causing severe pain, disability, and even death.5 Without appropriate treatment, rheumatic diseases can exacerbate other serious coexisting diseases and infections. For example, one third of lupus-related deaths result from serious infections, and the risk for myocardial infarction is 60% higher in patients with RA than in the general population.5 The Burden and Impact of Rheumatic Diseases Rheumatic diseases can occur in the prime of life and can be painful, disabling, life-changing, and costly. More than 7 million people in the United States have inflammatory, autoimmune rheumatic diseases5; of these, 1.3 million adults have RA; 300,000 children have juvenile idiopathic arthritis; between 161,000 and 322,000 adults have systemic lupus erythematosus; between 0.4 million and 3.1 million adults have Sjogren’s syndrome; approximately 300,000 adults have psoriatic arthritis6; and 3 million adults have gout.7 Less common rheumatic diseases include polymyalgia rheumatica, affecting approximately 711,000 adults7; ankylosing spondylitis, affecting 129 of every 100,000 persons6; polymyositis, affecting 13,500 persons8; and relapsing polychondritis, which involves approximately 600 cases in the United States.9 These diseases are difficult and costly to treat. Complex treatment regimens may be required, and the total annual cost is in the billions of dollars in the United States. In 2006, the medical cost of RA and other rheumatic diseases was $127.8 billion,5 which exceeded the estimated cost of cancer care by nearly $24 billion.10 Rheumatic diseases are responsible for more disability than heart disease, cancer, or diabetes.5 RA and rheumatic diseases are currently the leading cause of disability in the United States, accounting for 19% of disability, with back or spine problems representing a close second, at 17%.11 RA can interfere with the ability to work and can lead to mental and emo-

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tional problems, including depression, anxiety, and impaired sexual and emotional intimacy with partners. In addition, RA can affect different aspects of cognition.5 The Burden and Impact of Asthma and COPD Asthma is characterized by episodes of inflammation and the narrowing of small airways, and asthma attacks may be life-threatening. The disease has many environmental triggers, including smoke, weather changes, allergens, and infections.

Nearly 25 million Americans suffer from asthma—approximately 8% of all adults and more than 9% of all children.12 The prevalence of asthma has increased across all age-, sex, and ethnic groups.12 Asthma accounts for approximately 497,000 hospitalizations annually in the United States13 and is responsible for more than 10 million missed workdays for adults and nearly 13 million missed school days among children.12 Asthma is managed with appropriate treatment and patient education.

The annual cost of asthma is nearly $18 billion in the United States. Direct costs account for approximately $10 billion, and indirect costs account for approximately $8 billion.14 Asthma causes more than 3000 deaths in the United States annually and is a contributing factor for approximately 7000 additional deaths annually.12 COPD is a progressive disease that interferes with the ability to breathe.

Smoking is the leading cause of COPD; other causes include exposure to environmental lung irritants, such as smoke or chemical fumes, and possibly air pollution.15 Currently, more than 12 million Americans have been diagnosed with COPD, and another 12 million may have the disease but have not been formally diagnosed.16 COPD is a major cause of disability,15 and this disease is the third leading cause of death in the United States.16 In 2002, the direct medical costs of COPD in the United States were estimated at $18 billion, and indirect costs associated with morbidity and mortality were approximately $14.1 billion.15 In 2004, approximately 25% of all cases of dyspnea presenting to

the emergency department were related to exacerbations of COPD.17 In 2000, COPD was responsible for 15 million physician office visits18 and 1.5 million visits to the emergency department.15 These numbers are likely much higher now, with the aging of the US population.

Phase 3 Clinical Trials The 2 pivotal clinical trials that led to the FDA approval of Rayos were conducted in patients with RA. The trials are known as CAPRA (Circadian Administration of Prednisone in Rheumatoid Arthritis)-1 and CAPRA-2.

CAPRA-1

Trial Design CAPRA-1 was a 12-week, multicenter, randomized, double-blind trial conducted at 17 centers in Germany and 12 in Poland between August 2004 and April 2006. After a 2-week screening phase, patients with active RA were randomized to the oral delayed-release prednisone (N = 144) or to oral immediate-release prednisone (N = 144). The delayed-release tablet was taken at bedtime and released active prednisone 4 hours later. Immediate-release prednisone was administered in the morning. The study drugs were blinded by a double-dummy methodology and given twice daily, once in the morning and once at bedtime. Individual doses were taken as a combination of 1- or 5-mg tablets to reach the appropriate daily dose of 3 to 10 mg of prednisone.19 The double-blind treatment phase entailed study visits at baseline (week 0) and after 2, 6, and 12 weeks of treatment. At the end of the double-blind phase, patients were offered delayedrelease prednisone in a 9-month open study phase.19 During screening and the doubleblind phase, the patients completed a daily diary, recording the time of awakening, the time of study drug intake, and ratings of joint stiffness and quality of sleep. In the evening, the patients recorded the maximum intensity of pain experienced that day and rated the most severe episodes.

The patients also reported the use of analgesics during the previous 24 hours.19

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Drug Update

Patient Population A total of 288 male and female patients (aged 18-80 years) with active disease and a documented history of RA according to American College of Rheumatology (ACR) criteria were enrolled in CAPRA-1. In general, participants were older and predominantly female, which is similar to the population treated in clinical practice.19 At baseline, both groups were comparable for age (mean, approximately 55 years), percent of females (approximately 86%), white race (approximately 99%), mean HAQ disability index (1.5), mean DAS28 score (approximately 5.8), mean duration of RA, pain score, and previous treatments. Patients randomized to immediate-release prednisone had a longer duration of morning stiffness of the joints (approximately 20 minutes longer) than patients taking the delayed-release prednisone.19 Approximately 40% of the patients had disease duration of more than 10 years, and the mean daily dose of prednisone they had been taking before enrollment was similar in the 2 groups.19

utes from baseline, with an absolute between-group difference of 29.2 minutes favoring delayed-release prednisone.19 After 2 weeks of treatment, morning stiffness of the joints was improved more in the delayed-release prednisone group, with a difference of approximately 10%. The betweengroup difference continued to increase with longer treatment and reached a plateau of approximately 38% from week 7 until the end of the treatment period.19 No clinically relevant differences were observed for other secondary efficacy end points, with the exception of decreased IL-6 levels in the delayedrelease group compared with levels that remained constant in the immediate-release prednisone group.19

The mean relative change in the duration of morning stiffness of joints from baseline to the end of 12 weeks was significantly higher with delayedrelease prednisone than with immediate-release prednisone, –22.7% versus –0.4%, respectively, reflecting a difference (rounded to the nearest tenth) of 22.4% (P = .045). The patients treated with the delayed-release prednisone achieved a mean reduction of 44 min-

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CAPRA-1 Adverse Events: Delayed-Release Prednisone versus Immediate-Release Prednisone

45 41%

41%

40 35

Delayed-release prednisone Immediate-release prednisone

30 25 20 15 13%

11%

10

8%

7%

5 1% 0 Any AE

Safety Profile The results showed no clinically relevant differences in the safety profiles of the 2 treatment groups (Figure).

In each group, 41% of the patients reported ≥1 adverse event. In approximately one third of all cases, these events were deemed treatment-related. The most frequent adverse event (AE) was a worsening of RA. Other events seen most frequently included upper abdominal pain, nasopharyngitis, headache, flushing, and nausea.19 The AE profile was consistent with the underlying disease, the patient population, and the known safety profiles of prednisone and concomitant treatments for RA.19 Discontinuations because of treatment-related AEs were reported in 8% of the delayed-release group and in 7% of the immediate-release group.

The frequency of serious AEs was low—3% in the delayed-release prednisone group and 2% in the immediate-release prednisone group. Only 1 serious event was judged to be related to prednisone (ie, a depressed level of consciousness in the immediaterelease group). One death was reported in the immediate-release group and was not considered related to study drug.19 CAPRA-2

Trial Design Efficacy

Figure

Patients, %

Disease activity was assessed by the 28-joint Disease Activity Score (DAS28) at all visits. Health status was assessed using the Health Assessment Questionnaire (HAQ) at visits 1, 2, and 5, and using the 36-item Short-Form Health Survey (SF-36) at visits 1 and 5. Laboratory measures were analyzed. During the doubleblind phase, treatment with other disease-modifying antirheumatic drugs (DMARDs) and with nonsteroidal anti-inflammatory drugs (NSAIDs) had to be kept constant. The use of other therapies was not allowed.19 The primary end point of CAPRA-1 was the relative change from baseline in duration of morning stiffness at the end of the 12-week double-blind phase. Secondary efficacy outcomes included recurrence of joint stiffness, pain intensity each day, quality of sleep, DAS28 score, physician’s global assessment of disease activity, laboratory values, HAQ disability index, and SF-36 scores.19

CAPRA-2 was a 12-week, randomized, double-blind, parallel-group, placebo-controlled study that compared delayed-release prednisone (ie, Rayos) with placebo. After a 1-week screening period, 350 patients were randomized in a 2:1 ratio to receive delayed-release prednisone 5 mg daily or to placebo in the evening, with or after their evening meal in addition to their standard DMARD treatment.

Treatment-related AEs

AEs leading to discontinuation

Death

AE indicates adverse event; CAPRA, Circadian Administration of Prednisone in Rheumatoid Arthritis.

Source: Reference 19.

The primary end point was the percentage of patients who achieved a 20% improvement in RA signs and symptoms according to ACR criteria (ACR20) at the end of the 12-week treatment phase. Other end points were changes in morning pain, duration of morning stiffness, DAS28, and health-related quality of life (QOL).1

Patient Population The study enrolled 350 patients (aged 18-80 years; mean age, 57 years) with a diagnosis of RA who had been taking DMARDs for at least 6 months.

Other eligibility requirements included morning stiffness duration of at least 45 minutes on at least 4 of 7 days of screening, ≥4 swollen joints, and ≥4 tender joints. Baseline demographics were similar in the 2 treatment arms.

Approximately 84% of the patients were female, approximately 98% were white, and the mean duration of RA was approximately 8 years. Approximately 99% of the patients were taking DMARDs, and approximately 72% were taking NSAIDs. At baseline, the 2 groups had comparable scores of pain and other RA-related symptoms, laboratory parameters, and healthrelated QOL.1

Efficacy Clinical responses with delayedrelease prednisone occurred rapidly, with most clinical end points favoring this medication over placebo.

Differences in response between the 2 groups emerged as early as 2 weeks after the initiation of treatment, and responses were maintained for the

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remainder of the study.1 As illustrated in Table 1 and Table 2, the ACR20 response rate was 47% for delayed-release prednisone versus 29% for placebo (P <.001), and a 50% improvement in the signs and symptoms of RA, as shown by ACR50, was seen in 22% versus 10% of patients (P <.006), respectively.1,20 A greater reduction in morning stiffness was observed with delayedrelease prednisone at week 12 than with the placebo: 55% versus 35% (P <.002), respectively. Treatment with delayed-release prednisone achieved significantly greater reductions in DAS28 (P <.001), reflecting severity of disease, and fatigue (P = .003) compared with placebo. A significantly greater improvement in physical function was seen with delayedrelease prednisone versus placebo (P <.001) at week 12, as reflected by the SF-36 physical component score.1

Safety Profile Delayed-release prednisone was generally well tolerated, with no lifethreatening AEs or deaths reported during the trial. The incidence of AEs was similar for delayed-release prednisone (43%) and placebo (49%). The rate of treatment-related AEs was similar in the 2 groups: 7.8% for delayedrelease prednisone versus 8.4% for placebo.

The most frequent AEs in both groups were related to the worsening of RA and included arthralgia and aggravated RA; these events were seen more frequently with placebo Continued on page 20

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Drug Update

Rayos: A New Oral Delayed-Release Prednisone...

Table 1

CAPRA-2: ACR Response Rate at 12 Weeks: Delayed-Release Prednisone versus Placebo Delayed-release prednisone, % (N = 231)

Placebo, % (N = 119)

Between-group difference, % (95% CI)

ACR20

47

29

17 (7.2-27.6)

ACR50

22

10

12 (4.4-19.6)

ACR70

7

3

4 (0.1-8.7)

Response criterion

NOTE: All missing values were imputed as nonresponders.

ACR20 indicates American College of Rheumatology 20% symptom improvement; CAPRA, Circadian Administration of Prednisone in Rheumatoid Arthritis; CI, confidence interval.

Adapted from Delayed-release prednisone (Rayos) [package insert].

Deerfield, IL: Horizon Pharma USA, Inc; 2012.

mine the appropriate dose.20 Rayos is a delayed-release formulation of prednisone, and the active substance is released approximately 4 hours after administration. The timing of administration should take into account the drug’s delayed-release pharmacokinetics, as well as the disease under treatment.20 Depending on the disease entity, the initial dose of delayed-release prednisone can range from 5 mg to 60 mg daily. For patients switching to delayed-release prednisone from another form of prednisone, an equipotent dose of Rayos should be used.20

Dose Modifications Based on Response Table 2

Components of ACR Response Criteria at 12 Weeks: Delayed-Release Prednisone versus Placebo

Parameter

Delayed-release prednisone 5 mg + DMARD (N = 231)

Placebo + DMARD (N = 119)

Baseline

Week 12

Baseline

Week 12

Tender joint count

12.6

7.9

12.5

9.8

Swollen joint count

8.4

4.8

8.6

6.1

Patient assessment of pain

55.3

33.0

50.5

39.6

Patient global assessment

55.2

31.9

54.1

40.4

ACR indicates American College of Rheumatology; DMARD, disease-modifying antirheumatic drug.

than with delayed-release prednisone.

The incidence of infection was similar in the 2 groups (13% vs 12%, respectively), as was the incidence of nasopharyngitis (approximately 4%), the most frequently reported type of infection.

Serious AEs were reported in 1 patient (0.4%) in the delayed-release prednisone group versus 2 (1.7%) in the placebo group; none of these events were deemed severe or treatment-related. No clinically relevant changes in hematologic or biochemical parameters or vital signs were reported during the 12-week study.1 The study was not sufficiently long to assess any effects on structural damage and disease progression.

Longer-term studies are needed to demonstrate safety and tolerability with prolonged treatment.1 Mechanism of Action Glucocorticoids represent a cornerstone of therapy for inflammatory-

20

mediated diseases. Conventional prednisone is typically given in the morning upon awakening, when cortisol levels and symptoms are at their peak. Patients with RA have severe morning stiffness and pain upon awakening. Designing a drug delivery system for prednisone using the principles of chronotherapy has the goal of optimizing glucocorticoid therapy. By administering delayedrelease prednisone at bedtime, the release of the active drug is delayed for approximately 4 hours; thereby, the drug is available to blunt the peak in cortisol, as well as inflammationrelated symptoms.1 Dosing For adults, the dosage of Rayos should be individualized according to the severity of the RA and the patient’s response. These considerations should also be applied to children, rather than relying strictly on ratios for age or body weight to deter-

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Lower doses of Rayos should be sufficient for the treatment of less severe disease, whereas higher doses may initially be needed for selected patients with more severe disease.

The initial dose should be maintained or adjusted until a satisfactory response is achieved. When the response to a trial of Rayos is suboptimal, the drug should be stopped and the patient switched to another medication. It is important to individualize dosages of the drug according to the disease being treated and the patient’s response.20 Once a favorable response is achieved with Rayos, the initial dose should be decreased in small decrements at timed intervals to determine the lowest dosage for maintaining an adequate response. Constant monitoring is required to ensure appropriate dosing.20

Dose Adjustment Adjustments in dosage may be needed for changes in clinical status because of remission or disease exacerbation, the patient’s individual response, and effects of stress that are not disease-related. Treatment should be stopped if spontaneous remissions occur. When delayed-release prednisone is discontinued, withdrawal should be gradual, not abrupt.20 Contraindications Rayos is contraindicated in patients with known hypersensitivity to prednisone or any of the formulation’s inactive ingredients. Although anaphylaxis is rare, this event has been reported in patients taking corticosteroid therapy.20 Warnings and Precautions Patients receiving chronic treatment

Continued from page 19

with Rayos should be monitored for conditions such as hypothalamicpituitary-adrenal axis suppression, a condition with the potential to produce corticosteroid insufficiency when treatment with Rayos is withdrawn.

Gradual withdrawal will minimize this risk.20 Patients taking Rayos are at an increased risk of infection from many types of pathogens. Furthermore, corticosteroids such as Rayos can mask signs of infection and increase vulnerability to new infections, as well as exacerbate existing infections and increase the risk of disseminated infections. Prophylaxis should be considered for patients exposed to chickenpox or measles while taking corticosteroids.20 Corticosteroids may increase the risk of reactivation or exacerbation of latent infection, including latent tuberculosis and latent amebiasis.

Latent or active amebiasis should be excluded before initiating corticosteroid therapy if a patient has traveled to tropical countries or if the patient has diarrhea of unknown origin.20 Corticosteroids can alter blood pressure and the retention of salt and water, and they can increase the excretion of potassium and calcium. These agents should be used with caution in patients with congestive heart failure, hypertension, renal insufficiency, or recent myocardial infarction.20 Corticosteroids should also be used with caution in patients with signs of impending gastrointestinal perforation or other gastrointestinal infections or conditions. These agents can also exacerbate existing behavioral or mood disturbances, reduce bone density, and exert untoward ophthalmic effects with prolonged use.20 Intraocular pressure should be monitored in patients taking corticosteroids for longer than 6 weeks.20 Administration of live or attenuated vaccines is contraindicated in patients taking immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be given, but response is not assured. Patients taking corticosteroids should not receive vaccination against smallpox.20 Precautions in Special Populations The long-term use of corticosteroids in children can slow growth and development.20 The use of corticosteroids during pregnancy is not recommended, Continued on page 21

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Employers to Cut Health Care Spending by Steering Doctor Selection

See also page 22

By Alicia Ault

W

ashington, DC—In 2013 and going forward, employers are likely to increasingly rely on direct contracting with physicians and using other means to steer patients to certain physicians in an effort to bring employee benefit costs in line, according to a new survey.

Besides direct contracting, employers say they will use additional ways to get patients to use particular providers, such as reimbursing less for higher-cost providers and encouraging use of work-site health clinics, according to the National Business Group on Health (NBGH).

The nonprofit NBGH surveyed its members in June, after the employers had finalized benefit plans for 2013, but before the Supreme Court issued its decision upholding the Affordable Care Act. The Supreme Court ruling means that employers are facing slightly less uncertainty about the future, but costs were still an overriding concern, said

Helen Darling, CEO of the NBGH. “Employers are very concerned about the severe cost pressures from providing comprehensive health services and health benefits,” she said.

The 82 members that responded to the survey said that they expected the cost of benefits to rise 7% next year.

While that is in keeping with the past several years’ increases, it comes during a time when revenues for many are flat or decreasing.

As a result, employers are exploring a variety of ways to control costs and improve quality. Eleven percent of respondents said they were using direct contracting with surgical centers of excellence to control costs, improve quality, and ensure appropriate care.

Twenty-one percent said they were considering it. Fully 11% indicated that they were currently using direct contracting with patient-centered medical homes, and 18% said they were thinking about doing so in the future.

Making employees aware of the

cost of their health care is another tactic being used by employers. Seventynine percent said they give their workers access to an online database showing the price of various services.

Employers also have begun to use “reference pricing” for health care services. The employer sets a price for a service, and if a worker wants something that is more expensive, he or she will have to pay the difference.

Reference pricing is largely used with pharmaceuticals, but 4% said they use it for lab services and the same proportion do so for imaging.

Ms Darling said she expects reference pricing to be applied to physician services in the near future.

Overall, employers said that using consumer-directed health plans— such as high-deductible plans—and wellness initiatives were proving to be more effective than shifting costs directly to workers through higher premiums or deductibles. Even so, 60% said they would ask employees

to pay a larger percentage of the premium in 2013. More than a third also said they would increase in-network deductibles, out-of-network deductibles, and out-of-pocket maximums.

Employees will be influenced in other ways, too. Some 46% of the respondents said they have on-site health clinics in at least one of their locations, providing primarily acute care, but also health improvement programs and occupational health services. More than half of those clinics also offer primary care services.

In addition, companies are increasingly offering financial incentives for participating in weight management or tobacco cessation programs, or for meeting particular health outcomes.

Almost half said they offer incentives just for participating, with a median payout of $450 per worker—a 50% increase from 2012. ■ Reprinted with permission from Rheumatology News, August 27, 2012.

Drug Update

Rayos: A New Oral Delayed-Release Prednisone... because of the potential for birth defects and decreased birth weights.20

enhance their overall function and health-related QOL. ■

Conclusion The FDA’s approval of delayedrelease prednisone provides a new therapeutic option for patients with RA and with other inflammatory and rheumatic conditions—including polymyalgia rheumatica, psoriatic arthritis, ankylosing spondylitis, asthma, and COPD—that offer an improved mechanism of action that facilitates the optimal release of prednisone very early in the morning, when disease symptoms peak, thereby promoting improved response rate in these patients. Using the oral formulation may also help patients better control their joint pain and inflammation, as well as other symptoms, and

References

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1. Buttgereit F, Mehta D, Kirwan J, et al. Low-dose prednisone chronotherapy for rheumatoid arthritis: a randomised clinical trial (CAPRA-2). Ann Rheum Dis. Epub 2012 May 5.

2. Horizon Pharma announces FDA approval of RAYOS® (prednisone) delayed-release tablets for rheumatoid arthritis and multiple additional indications [press release]. Deerfield, IL: Horizon Pharma; July 26, 2012. www.horizonpharma.com. Accessed September 12, 2012.

3. Relapsing polychondritis causes, symptoms and treatment and related disorders. Everyday Health website. www.everydayhealth.com/health-center/ relapsing-polychondritis.aspx. Updated March 11, 2009. Accessed September 12, 2012.

4. Polymyalgia rheumatica causes, symptoms and treatment and related disorders. Everyday Health website. www.everydayhealth.com/health-center/ polymyalgia-rheumatica.aspx. Updated August 7, 2007. Accessed September 12, 2012.

5. American College of Rheumatology. Rheumatic diseases in America: the problem, the impact, and the answers. www.simpletasks.org/resources/ACR. Accessed September 12, 2012.

6. Helmick CG, Felson DT, Lawrence RC, et al.

Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58:15-25.

7. Lawrence RC, Felson DT, Helmick CG, et al.

Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58:26-35.

8. Relapsing polychondritis. Virtual Medical Centre website. www.virtualmedicalcentre.com/diseases/ Relapsing%20Polychondritis/649. Modified November 2, 2008. Accessed September 13, 2012.

9. Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States.

Clin Immunol Immunopathol. 1997;84:223-243.

10. Cancer trends progress report—2009/2010 update: costs of cancer care. National Cancer Institute website. http://progressreport.cancer.gov/2009/doc_detail. asp?pid=1&did=2009&chid=95&coid=926&mid=.

Accessed September 12, 2012.

11. Centers for Disease Control and Prevention.

Prevalence and most common causes of disability among adults—United States 2005. MMWR Morb Mortal Wkly Rep. 2009;58:421-426.

12. Asthma facts and figures. Asthma and Allergy Foundation of America website. www.aafa.org/ display.cfm?id=8&sub=42#_ftnref14. Accessed September 13, 2012.

13. Moorman JE, Rudd RA, Johnson CA, et al. National surveillance for asthma—United States, 1980-2004.

MMWR Surveill Summ. 2007;56:1-14, 18-54.

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Continued from page 20

14. Cost of asthma. Asthma and Allergy Foundation of America website. http://aafa.org/display.cfm?id= 6& sub=63&cont=252. Accessed September 12, 2012.

15. National Institutes of Health; National Heart, Lung, and Blood Institute. Chronic obstructive pulmonary disease [data fact sheet]. NIH Publication 03-5229.www.uptakemedical.com/pdfs/copd_fact. pdf. Published March 2003. Accessed September 13, 2012.

16. COPD: learn more breathe better. National Heart, Lung, and Blood Institute website. www.nhlbi.nih. gov/health/public/lung/copd/health-care-profes sionals/index.htm. Accessed September 13, 2012.

17. Skrepnek GH, Skrepnek SV. Epidemiology, clinical and economic burden, and natural history of chronic obstructive pulmonary disease and asthma. Am J Manag Care. 2004;10:S129-S138.

18. National Heart, Lung, and Blood Institute.

Morbidity & Mortality: 2012 Chart Book on Cardiovascular, Lung, and Blood Diseases. Bethesda, US Department of Health and Human Services; 2012. www.nhlbi.nih.gov/resources/docs/2012_ChartBook _508.pdf. Accessed September 13, 2012.

19. Buttgereit F, Doering G, Schaeffler A, et al. Efficacy of modified-release versus standard prednisone to reduce duration of morning stiffness of the joints in rheumatoid arthritis (CAPRA-1): a double-blind, randomised, controlled trial. Lancet. 2008;371:205-214.

20. Delayed-release prednisone (Rayos) [package insert]. Deerfield, IL: Horizon Pharma USA, Inc; 2012.

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Rheumatology Practice Management

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See also page 21

Getting More Out of Your Time

By Ruth Linné Lander, FACMPE Practice Administrator, Columbus Oncology & Hematology Associates, OH

I

am going to start this business article with something personal.

Decades ago I read a book that had a very good chapter on personal time management. I have followed one tip in this chapter ever since. In summary: pick the 5 outfits you want to wear Monday through Friday of your workweek during the current season. If there is a jacket, accessorize it with a pin. If there is a necklace, hang it on the outfit hanger. Have your shoes picked as well. After you have worn the outfit, say on Monday, move it to the end of your 5-day row, leaving the accessories in place. This saves you many decision points in the morning on what to put on, as well as what shoes to wear, and if you are female, what jewelry to add. If you are working in an office setting, you usually can get several wearings from an outfit before laundering or dry cleaning temporarily moves it out of the rotation. Let’s face it, you only wear your favorite outfits anyway, so you could declutter your closet and save time every workday morning, and save money and time on shopping for additional clothes, with this approach.

Little did the author know that this tip has piqued my interest in planning and using time well for the past few decades, in my personal life and in my work environment.

of putting the big rocks into the jar before the little rocks made a lasting impact on me. If you start with the little rocks and then add the big rocks, there is no room for all of them to fit in your container. If you reverse the order, putting the big rocks in first, the little rocks fill in around the big rocks and everything fits. Try this for yourself with pebbles and rocks, or a baseball and marbles, and a container— it works.

Begin with the Big Rocks Time is something we hate and love at the same time. We are often torn by how to spend it. A quote from Jim Rohn (The Treasury of Quotes. Success Books, 1994) puts this topic into perspective well: “We can no more afford to spend major time on minor things than we can to spend minor time on major things.”

We are all bombarded with e-mails, voicemails, printed information, and interruptions by staff, as well as by our personal issues, every day. With our smartphones we are never really out of touch any more. Although these advances have brought us incredible benefits, we need to bring some order to their use, or we will all become plagued with what looks like attention deficit disorder and feels like we are the hamster on the spinning wheel on any given day, crashing in bed at night with the feeling that little was accomplished.

When the late Steven Covey’s book First Things First (Simon & Schuster, UK) came out back in 1994, I read it with great interest. His visual analogy

In other words, you need to focus on what is important, and first make room for that by planning realistic and appropriate blocks of time on your calendar; amazingly, the less important items will then somehow get done around these important items. If you do not block the time for the important “tyranny of the urgent,” smaller items will gobble up your time, leaving that important item “unfunded” in time.

Takeaway: Plan for the important thing, or it remains a dream, or a hoped-for goal, and you remain discouraged with your lack of time for it.

22

Plan for the important thing, or it remains a dream, or a hoped-for goal, and you remain discouraged with your lack of time for it.

The Communication Deluge I am not antisocial, but I do love the time-savings of electronic communication. If I send a clear e-mail, I have a written record and ideally a timely response, and I have saved myself the lost time of playing telephone tag through voicemails with the other party, or the actual telephone contact, which is filled with extraneous conversation that is not really the best use of time. If you have projects or issues

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in process with your team, and we all do, proactively updating them by email can also avoid unplanned phone calls, or visits from them that interrupt your day, because they just wanted to know the status of those projects or issues.

As the day progresses, have set times to scan e-mails and deal only with the important e-mails during those times. In my experience this is a small percentage of the total e-mails I get daily. At the end of the day, when you are probably winding down, or at the beginning of the day, when you are trying to get going, scroll through all the remaining e-mails and do not be shy in deleting. Remember that if it is not important, move on. I do the same with voicemails.

Your phone use can be a real time guzzler. We all have contacts who are talkers. If they are not busy, they pick up the phone and call you. What they do not realize is that you may be very busy doing what is important in your day. If you have caller ID, you can choose to answer now or let the call go to voicemail and return it (or not) during a convenient time.

If it is a persistent problem, I nicely tell the person that he/she may have time at that moment to chat but I simply cannot, because of my busy schedule, and that we need to talk at a time that better fits my personal schedule.

If the person is a good friend, that is fine. If the person is just a distracted talker, that person moves on to a more willing listener.

By your very walk, a coworker can tell whether you are purposefully going to a destination or are willing to be interrupted for a visit. You need to decide which is true for you.

Manage Your Work Environment Coworkers can take your precious time, too. They may just stop by to talk on their way to another destination in the office, and minutes can go by with unnecessary conversation. I nicely say that I do not have time to talk now and ask whether we can arrange a better time to catch up. If I stand up and move toward my door with something to deliver, it can be a good hint, too.

If you need to be on the move within your work environment, plan your trips around the office in order, and try to do multiple stops in one trip. This saves up-and-down time throughout the day, and these minutes add up. On these trips just say hello to a coworker you encounter along the way; you do not need to stop and talk. By your very walk, a coworker can tell whether you are purposefully going to a destination or are willing to be interrupted for a visit. You need to decide which is true for you.

Don’t be afraid to say no. We get asked to be involved with multiple nonessential activities throughout our working life, internally or externally, if we are any good at all. If a task is voluntary, say yes only to the requests you really want to do.

I remember the 1980s ad, “I can bring home the bacon, fry it up in a pan, and never let you forget you’re a man. Cause I’m a woman.” It was a catchy ad, but not really true. To be really good at something takes focus, and it is hard to stay focused on too many things, so be more selective, and choose only the best activities that fit with your life goals.

Don’t waste smaller snippets of time.

You can usually complete many small tasks or get one more item crossed off on a project while you wait on hold, or even during lulls in a webinar.

If you really want to dive deeper into time issues, I would suggest visiting Pam Vaccaro’s website (www. designsontime.com). I have heard her talks several times over the years and find her website a rich source of downloadable articles and audios on the use of time. Her approach is practical and refreshing, if you have had bad experiences with time management to date.

Keep Your Perspective Finally, I need to encourage you not to go too far. Don’t become a working machine that never unwinds and uses almost every second. If you need a visual example, think of Scrooge before and after he changed in the well-loved A Christmas Carol by Charles Dickens. You need to balance your working and personal life, and have breaks during your workday, to remain on an even keel and keep an appropriate perspective.

If you use your time well throughout your day, you will find freed-up time for these needed breaks, at work and in your personal life. ■

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