VBCR August Vol 1, No 3

Value-Based Care in Rheumatology

AUGUST 2012 VOL 1 • NO 3

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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Tailoring Therapy for the Optimal Sequence of Biologic Needs of the Individual Patient Agents in RA Identified For moderate-to-severe disease, abatacept preferred as second agent with RA Is Cost-Effective

By Rosemary Frei, MSc Improved biologic agents’ efficacy enhances QALYs

By Neil Canavan

Berlin, Germany—Data presented at the 2012 European League Against Rheumatism (EULAR) Congress showed that combating rheumatoid arthritis (RA) with an approach that tailors the administration of biologic agents according to the specific needs of the individual patient with RA can reduce the costs dramatically, saving

€2,595,557 per 272 patients over a 3year period, and at the same time increasing treatment efficacy by an average of 3.67 quality-adjusted lifeyears (QALYs).

“Governments and health authorities around the world are looking to save money by cutting costs and providing reduced access to more expensive treatments,” stated lead investigator Charlotte L.M. Krieckaert, MD, from the Jan van Breemen Research Institute, Reade, the Netherlands.

“This study demonstrates that with careful monitoring and testing of disease activity at 6 months, costs for rheumatoid arthritis treatment can be reduced, and treatment effectiveness can actually increase.”

To evaluate the cost-effectiveness of Continued on page 17

Early, Successful Treatment with Biologics Extends Life in Rheumatic Diseases

By Neil Canavan Berlin, Germany—Data from 2 separate studies presented at the 2012 European League Against Rheumatism Congress led researchers to the same conclusion: successful treatment

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esults of a new study indicate that the most efficacious and cost-effective sequential treatment strategy of biologic agents, when one agent is insufficient, for people with moderate-to-severe rheumatoid arthritis (RA) includes abatacept (ABA) rather than rituximab (RTX) as the second agent in the sequence (Puolakka K, et al. Open Rheumatol J. 2012;6:38-43).

By David Hawk Berlin, Germany—A small study presented during a press conference at the 2012 European League Against Rheumatism Congress sparked a great deal of interest among rheumatology researchers when it was reported that use of the cancer drug bortezomib showed a dramatic reduction in symptom scores in patients with systemic lupus erythematosus (SLE) who are refractory to the current standard of care.

Should these results be supported by future, large-scale investigations, it would represent a major contribution in a disease treatment setting with large unmet needs, according to lead investigator Reinhard E. Voll, MD, Professor, Nikolaus Fiebiger Center of Molecular Medicine, University Medical Center Freiburg, Germany, who presented the study results at the meeting.

Continued on page 15

INSIDE RHEUMATIC DISEASES

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First recommendations for mediumto-high-dose glucocorticoid therapy Early treatment with biologics extends life in rheumatic diseases ECONOMIC ISSUES IN RA . . . . . . . .

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Comparing cost-effectiveness of TNF-alpha inhibitors Two cost analyses show benefits of early therapy IN THE LITERATURE

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Biologic agents enhance work status Nurse-led gout care improves outcomes © 2012 Engage Healthcare Communications, LLC

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Cancer Drug Shows Promise in Treating Lupus

of patients with rheumatic diseases with anti–tumor necrosis factor (TNF) drugs and/or nonbiologic diseasemodifying antirheumatic drugs Continued on page 6

Ariel Beresniak, MD, MPH, PhD, Chief Executive Officer of Data Mining International SA, Geneva, Switzerland, and colleagues used various treatment sequences with 1 of the anti–tumor necrosis factor (TNF) agents adalimumab (ADA), etanercept (ETA), or infliximab (INF) used as the first agent, followed by ABA or RTX as the second agent, followed by

PSORIATIC ARTHRITIS . . . . . . . . .

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Obesity a marker for poor treatment outcomes PERSONALIZED MEDICINE in

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Research on pain medicines seeks a genetic-trait link

Rheumatology PRACTICE MANAGEMENT™

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Medicare Part D: considerations for rheumatology practices GOUT

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Gout studies presented at ISPOR

The Rheumatology Featuring

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

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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VALUE PROPOSITIONS

ANKYLOSING SPONDYLITIS

Biomarkers Consortium launches osteoarthritis biomarkers project New biomarker to measure RA progression More….

New biomarkers predict disease progression in ankylosing spondylitis

RHEUMATIC DISEASES UPDATE Early, successful treatment with biologics extends life of patients with rheumatic diseases EULAR issues first recommendations for management of medium-to-high-dose glucocorticoid therapy More….

PERSONALIZED MEDICINE in

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Tailoring therapy for the needs of the individual patient with RA is cost-effective More….

COMPARATIVE EFFECTIVENESS RESEARCH A head-to-head comparison of 2 biologic agents for the treatment of rheumatoid arthritis

FDA UPDATE

Rheumatology PRACTICE

Rayos approved for several rheumatologic conditions More….

MANAGEMENT™ Medicare Part D: considerations for rheumatology practices

ECONOMIC ISSUES IN RA

GOUT

Comparing cost-effectiveness of TNF-alpha inhibitors in rheumatoid arthritis More….

Gout studies presented at ISPOR

PSORIATIC ARTHRITIS

A new approach to estimating healthcare costs in rheumatology More….

Obesity a marker for poor treatment outcomes in psoriatic arthritis Psoriasis drug safe and effective for treating psoriatic arthritis More….

ISPOR ANNUAL MEETING

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 FNIH Biomarkers Consortium Launches Osteoarthritis Biomarkers Project, Targeting Patients’ Quality of Life Established by the US Congress and the National Institutes of Health (NIH), the Foundation for the NIH (FNIH) is a major driver in advancing complex health issues. Earlier in the year, the FNIH announced the launch of a new study to investigate potential new biomarkers in patients with osteoarthritis (OA) of the knee or those at risk for the disease. The 2.5-year study is being led by an international team of OA experts under the auspices of the FNIH Biomarkers Consortium, a biomedical research partnership managed by the FNIH. The most common form of arthritis, OA involves cartilage loss and bone restructuring leading to joint abnormalities, loss of function, and pain. Knee OA is the leading source of disability in adults. Early medical intervention is suboptimal because of lack of appropriate biomarkers that can help to evaluate disease onset and progress. The discovery of new biomarkers in OA will provide new ways of measuring the disease progress and the efficacy of current and/or new treatments to improve patients’ quality of life.

“NIH is pleased to see the use of this research resource in a biomarker project funded by the FNIH Biomarkers Consortium, and led by a team of international experts. Results from these investigations hold promise for the development of new therapies for this debilitating disease,” said Gayle Lester, PhD, National Institute of Arthritis and Musculoskeletal and Skin Diseases Program Officer for the Osteoarthritis Initiative. www.fnih.org; February 14, 2012.

With an Eye on Inflammatory Conditions, DRX Will Expand Specialty Drugs Coverage DRX DrugCompare provides the most comprehensive dose-specific price comparisons used by health plans, pharmacy benefit managers, drug store chains, and other vendors of pharmaceuticals. This repository of Lower-Cost Alternatives data offered by DrugCompare is the most widely used technology to compare prescription drug prices in the United States in some categories. The company is increasing its focus on specialty drugs as a major factor in drug spending and is continuing to expand its coverage of specialty drugs.

“In 2013, we will focus on enhancing our alternatives database for the number 1 specialty condition, inflammatory conditions, which includes psoriasis and rheumatoid arthritis,” said Toby Rogers, Chief Operating Officer of DRX. The spending on specialty drugs currently represents approximately 20% of the total US drug spending; by 2014 it is expected to rise to 25%. Business Wire; July 30, 2012.

Lupus a Target of New Drug Development Collaboration, Reinforcing Value of Personalized Medicine in Rheumatology Wishing to expand the development of novel treatment compounds and diagnostics for autoimmune diseases, Pfizer and Nodality have launched a collaborative effort to allow Pfizer the use of single-cell network profiling (SCNP) technology toward the development of new pharmaceutical compounds for autoimmune diseases, with an initial focus on lupus. The special tools offered by SCNP technology will allow Pfizer to enhance its focus on personalized medicine toward the development of new treatments in association with companion diagnostics similar to several cases that are already available in cancer therapeutics.

“Our partnership with Nodality exemplifies Pfizer’s commitment to precision medicine by providing us with earlier insight into a compound’s

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potential clinical profile, which can reduce the attrition rates, accelerate development, and improve patient targeting. There is a tremendous patient need for new medicines that can impact the pathophysiology of autoimmune diseases,” said Jose-Carlos Gutiérrez-Ramos, PhD, Senior Vice President of Research and Development at BioTherapeutics, Pfizer. (“Precision medicine” is the evolving term for what is better known as “personalized medicine.”) Business Wire; August 9, 2012.

Multidisciplinary Treatment of Fibromyalgia Effective for Patients with Low Education Levels New data confirm that multidisciplinary treatment of fibromyalgia is beneficial for patients with low education levels in improving patient outcomes by reducing the key symptoms of fibromyalgia, including sleep disturbances and psychological distress. Based on this study, the benefits gained from this approach were maintained at 12 months of follow-up after completing the multidisciplinary treatment. Castel A, et al. Arthritis Care Res (Hoboken). 2012 Aug 12. Epub ahead of print.

New Biomarker to Measure Disease Progression in RA A simple blood test can help to measure the progression of rheumatoid arthritis (RA), according to researchers at the University of Alabama at Birmingham (Curtis J, et al. Arthritis Care Res (Hoboken). 2012 June 26. Epub ahead of print). This new tool is a blood test measuring 12 biomarkers for RA that can help in managing the disease.

“Previously, the disease activity of RA was assessed through clinical observation by a physician, noting the number of tender and swollen joints and assessing pain and functional abilities,” said Jeffrey Curtis, MD, Associate Professor, Division of Clinical Immunology and Rheumatology and lead investigator of the test. “This blood test measures the underlying amount of RA activity within the joints using sophisticated biochemical means intended to reflect the underlying pathophysiology of the disease. A highly reproducible, easily standardized blood test that measures multiple biologic pathways to augment a physician’s and patient’s clinical assessment has not been previously available to physicians.” The test may also help to assess treatment response in patients within a few weeks instead of the current period of 3 to 4 months.

Called Vectra DA, the blood test is a multibiomarker disease activity (MBDA) test developed by Crescendo Bioscience, South San Francisco. The test is a measure of inflammation, looking for the presence of 12 cytokines (or biomarkers) that can indicate the presence of disease.

“The MBDA score is a complementary tool that could provide physicians with an objective, consistent, and biologically rich measure of RA disease activity,” said Dr Curtis. Its value is in predicting disease flare-ups and future joint damage, but these applications have yet to be validated.

University of Alabama at Birmingham Press Release; June 26, 2012.

Value of Adalimumab for Achieving Sustained Remission in Early Psoriatic Arthritis Results of a new study indicate that achieving clinical and sustained remission is possible in a high percentage of patients with early psoriatic arthritis when reducing the dose of adalimumab by 50% in patients with psoriatic arthritis after receiving 40-mg adalimumab therapy every other week for a mean time of 5.1 ± 1.2 months. On reaching remission, the dose was reduced to 40 mg every 4 weeks. Cantini F, et al. Biologics.

2012;6:201-206.

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Rheumatic Diseases Update Rheumatology Meetings SEPTEMBER Clinical Orthopaedic Society Annual Meeting Chicago, IL 9/13-9/15 Contact: www.cosociety.org

Hip Society Scientific Meeting Rochester, MN 9/13-9/15 Contact: www.hipsoc.org

2012 National Caucus on Arthritis and Musculoskeletal Health Disparities Washington, DC 9/18-9/19 Contact: www.movementislifecaucus.com

National Organization of Rheumatology Managers 8th Annual Conference Fort Worth, TX 9/21-9/22 Contact: www.normgroup.org

OCTOBER American Society for Bone and Mineral Research 2012 Annual Meeting Minneapolis, MN 10/12-10/16 Contact: asbmr@asbmr.org www.asbmr.org/Meetings/Future AnnualMeetings.aspx

XIIth Congress of the International Society of Bone Morphometry Minneapolis, MN 10/16-10/18 Contact: wronskit@vetmed.ufl.edu www.bonemorphometry.org

NOVEMBER Association of American Medical Colleges Annual Meeting San Francisco, CA 11/2-11/7 Contact: www.aamc.org

American College of Rheumatology/Association of Rheumatology Health Professionals Annual Scientific Meeting 2012 Washington, DC 11/10-11/14 Contact: www.rheumatology.org

Rheumatology, Chronic Pain & Palliative Care Fort Lauderdale, FL 11/17-12/1 Contact: www.seacourses.com

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First Recommendations for Management of Medium-to-High-Dose Glucocorticoid Therapy Issued by EULAR Task Force

See also page 6

By David Hawk Berlin, Germany—A multidisciplinary task force formed under the aegis of the European League Against Rheumatism (EULAR) has for the first time developed recommendations for the management of medium-to-high-dose systemic glucocorticoid therapy in rheumatic diseases. Task force participant Nurten Duru, PhD, Rheumatologist in Training, Rheumatology and Clinical Immunology, University Medical Center Utrecht, the Netherlands, presented the recommendations in detail in an open session at the EULAR 2012 Congress.

Data for Adverse Events Are Sparse “High doses of systemic glucocorticoids are very important, since they work rapidly and are highly effective,” said Dr Duru. However, she noted, very little is known about adverse event rates with systemic glucocorticoid therapy. Studies of medium-to-high-dose glucocorticoids are available, but adverse events are not systematically assessed; the primary focus of these reports is treatment efficacy.

“We expect to see adverse events at high doses, but the question is how to handle these, and how to take the comorbidities into consideration,” said Dr Duru, emphasizing the lack of knowledge regarding adverse events associated with medium-tohigh-dose glucocorticoids. “This is difficult without data; the best we have is expert opinion.”

The multidisciplinary EULAR task force was comprised of 8 rheumatologists, 1 endocrinologist, 1 rheumatologist-epidemiologist, 4 patients, and 2 research fellows from 7 European countries.

Each participant contributed 10 propositions describing the key clinical points for the safe use of mediumto-high-dose glucocorticoids. After this, an online literature search of PubMed, Embase, and Cochrane Library resources was performed to identify the best available research evidence in support of each of the propositions.

Many of the recommendations

were only indirectly supported by evidence from the published literature, because such evidence is limited. Overall, the evidence level was

“High doses of systemic glucocorticoids are very important, since they work rapidly and are highly effective. We expect to see adverse events at high doses, but the question is how to handle these, and how to take the comorbidities into consideration.”

—Nurten Duru, PhD

low, although this differed by recommendation. The strength of the evidence is provided for each of the recommendations.

The Key Recommendations The final recommendations focused on specific clinical areas, including patient and provider education, preventive measures for osteoporosis, optimal starting doses, risk-benefit ratio of glucocorticoid treatment, screening for comorbidities, and monitoring for adverse events.

The highlights of the final recommendations include: Education and prevention • Explain to patients (and their families and/or caregivers, including general practitioners) the aim of medium- or high-dose glucocorticoid treatment and the potential associated risks • Discuss measures to mitigate such risks, including diet, regular exercise, and awareness of wounds • Dispense appropriate preventive or therapeutic interventions to patients with or at risk of glucocorticoid-induced osteoporosis • Present appropriate, practical advice to patients and the patients’ treatment teams on how to manage glucocorticoid-induced hypothalamicpituitary-adrenal axis suppression

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Dosing and risk-benefit ratio • Consider comorbidities that may predispose patients to adverse effects before starting them on medium- or high-dose glucocorticoid treatment; these comorbidities include diabetes, cardiovascular disease, peptic ulcer disease, chronic infections, glaucoma, and osteoporosis. Patients with these comorbidities require especially tight dosing control to manage the risk-benefit ratio • Select the appropriate starting dose as the (expected) minimum required dose to achieve therapeutic response Monitoring • Keep the requirement for continuing on glucocorticoid treatment under constant review • Regularly monitor all patients for any frequent, clinically significant adverse effects. The minimum set of items to monitor includes diabetes, hypertension, dyslipidemia, weight gain, edema, osteoporosis, infections, osteonecrosis, myopathy, eye problems, skin problems, and neuropsychological adverse effects.

Explain to patients (and their families and/or caregiviers) the aim of medium- or highdose glucocorticoid treatment and the potential associated risks.

The task force rejected the recommendation to actively consider glucocorticoid-sparing therapy if long-term medium- or high-dose glucocorticoid therapy is anticipated to be necessary.

Dr Duru said that the next step in the recommendation process is the development of a patient-friendly version of the recommendations in different languages, as well as a website where physicians can search for more information about glucocorticoids. ■

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Rheumatic Diseases Update

Early, Successful Treatment with Biologics Extends Life...

Continued from cover

(DMARDs) lowers the risk for early mortality compared with patients who do not respond well to treatment.

Anti-TNF Agents Enhance Survival in Patients with RA The first study consisted of 8908 patients with rheumatoid arthritis (RA). Joachim Listing, PhD, Epidemiology Department, German Rheumatism Research Centre, Berlin, explained the rationale for the study, “It is well-known that patients with rheumatoid arthritis have lower life expectancies than the general population. We wanted to demonstrate the positive impact that biologic treatment can have on patients’ life expectancy.”

Dr Listing and colleagues analyzed data from the 8908 patients with RA who were enrolled in the German biologics registry RABBIT (Rheumatoid Arthritis Observation of Biologic Therapy). The mean disease duration in this cohort was 10.3 years; the mean follow-up time was 3.4 years.

Disease activity (measured by the Disease Activity Score in 28 joints [DAS28] score), functional capacity, and treatment regimens for these patients were assessed at fixed time points, and Cox proportional hazard regressions were applied to investigate the influence of remission on mortality risk. The mortality risk rates were adjusted for age, sex, comorbid health conditions, and smoking.

Results showed that compared with the general population, the age- and sex-standardized mortality ratio in the

study population of patients with RA was 1.6, corresponding to a shortening of life expectancy by 3.5 years.

“It is well-known that patients with rheumatoid arthritis have lower life expectancies than the general population. We wanted to demonstrate the positive impact that biologic treatment can have on patients’ life expectancy.”

—Joachim Listing, PhD Life expectancy significantly correlated with disease activity: patients with a mean DAS28 of <4.0 over time had a normal life expectancy; patients with a mean DAS28 score of >4.0 at follow-up died an average of 6.8 years earlier than age- and sexmatched persons from the general population.

The results showed that patients with RA whose disease was success-

fully controlled with the highly efficacious anti-TNF drugs had a significantly lower mortality risk compared with patients whose disease was not well controlled with conventional DMARDs. A similar result favoring biologic agents was seen with the anti-CD20 antibody rituximab.

Benefits of Early Treatment in Inflammatory Polyarthritis The second study consisted of patients with inflammatory polyarthritis, showing that regardless of the method of treatment, achieving early and sustained remission in patients with inflammatory polyarthritis is associated with a decrease in all-cause mortality.

For this study regarding inflammatory polyarthritis and longevity, a British group analyzed a cohort of 2769 patients from a primary care database, which was cross-referenced with the national UK death register.

Patients with at least 3 years of follow-up were included, and the variables of ever-remission, the number of assessments in remission, and the time of first remission within the first 3 years of treatment were evaluated.

Remission was defined as the absence of clinically detectable joint inflammation.

The main end point was all-cause mortality; the relationship between remission and mortality was analyzed using the Cox proportional hazard regression model. Results showed that achieving remission at least once within the first 3 years of follow-up was associated with signif-

at a glance ➤ Compared with the general population, patients with RA have a shorter life expectancy by 3.5 years ➤ In patients with RA, successful disease control with anti-TNF drugs significantly lowers mortality risk compared with patients whose disease is not well controlled with DMARDs ➤ In patients with inflammatory polyarthritis, early and sustained remission increases survival ➤ Achieving remission at least once within the first 3 years of follow-up significantly improves survival ➤ Greater number of times of being in remission significantly decreases all-cause mortality risk

icantly better survival. The number of times in remission was also associated with a significantly decreased risk of all-cause mortality.

Looking at the effect of a time lag until the first remission, patients who were in remission 1 year after the first assessment had the greatest reduction in mortality risk compared with patients who never achieved remission within the first 3 years, whereas no significant association was found for patients who achieved remission at a later time point. ■

TNF Blockers Increase the Risk for Herpes Zoster Infection in Patients with Inflammatory Rheumatic Disease

By Neil Canavan Berlin, Germany—Results of a new meta-analysis concerning patients with inflammatory rheumatic disease suggest that treatment with anti–tumor necrosis factor (TNF) medications compared with traditional disease-modifying antirheumatic drugs (DMARDs), that is, methotrexate, increases the risk for herpes zoster infection by as much as 75%, said lead researcher Helene Che, Lapeyronie Hospital, France, at

the 2012 European League Against Rheumatism Congress.

Traditional DMARDs versus Biologics “Anti–tumor necrosis factors, such as infliximab, adalimumab, and etanercept, have become the treatment of choice for patients with inflammatory rheumatic diseases who are uncontrolled on traditional disease-

“Anti–tumor necrosis factors, such as infliximab, adalimumab, and etanercept, have become the treatment of choice for patients with inflammatory rheumatic diseases who are uncontrolled on traditional disease-modifying antirheumatic drugs. Careful monitoring of patients treated with anti–tumor necrosis factors is required for early signs and symptoms of herpes zoster.”

—Helene Che Continued on page 7

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FDA Update Rayos Approved for Several Key Rheumatologic Indications In July, the US Food and Drug Administration (FDA) approved Rayos (prednisone; Horizon Pharma) delayedrelease tablets in 3 doses—1 mg, 2 mg, and 5 mg—for the treatment of a broad range of diseases, including rheumatoid arthritis (RA), polymyalgia rheumatica, psoriatic arthritis, ankylosing spondylitis, asthma, and chronic obstructive pulmonary disease (COPD).

The FDA approval was based on data bridging the pharmacokinetics of Rayos with immediate-release prednisone and data from the Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA)-1 and CAPRA-2 clinical trials. CAPRA-1 supported the overall safety profile of Rayos, and CAPRA-2 demonstrated that patients with moderate-to-severe RA who received this medication had significant improvement in American College of Rheumatology (ACR) 20 response criteria compared with those receiving placebo.

CAPRA-2 was a double-blind,

placebo-controlled, randomized, 12week trial that included 350 patients (aged 27-80 years) with an active RA diagnosis. Patients were not being treated with corticosteroids but had received nonbiologic disease-modifying antirheumatic drug (DMARD) therapy for at least 6 months before receiving the study medication. All of the patients have shown incomplete response to DMARD therapy alone.

Patients receiving Rayos showed significant improvement in ACR20 response criteria compared with the group receiving placebo (47% vs 29%, respectively; P = .001).

In addition, significant improvement was seen in ACR50 response in patients receiving Rayos compared with those receiving placebo (22% vs 10%; P = .007), as well as an improvement in the more stringent ACR70 response criteria.

“Prednisone is a common therapy for patients with various inflammatory diseases, including RA, and the delayed-release enhancement offered with Rayos is an important treatment advance,” said Michael Schiff, MD,

Clinical Professor of Medicine, University of Colorado School of Medicine, Rheumatology Division, in response to the approval. “Rayos is engineered to benefit the underlying patterns of inflammatory diseases.

Rayos, as studied in its clinical trials… reduces the overnight rise of inflammatory mediators, which results in less pain and stiffness for patients as they begin their day.”

Timothy P. Walbert, Chairman, President, and Chief Executive Officer of Horizon Pharma, said, “Our initial focus will be on the launch of Rayos in rheumatologic diseases, such as rheumatoid arthritis and polymyalgia rheumatica in the fourth quarter of this year. Based on the extent of the approved indications, we will be developing a broader commercial strategy to expand the opportunity for Rayos in key IL-6–mediated diseases, including asthma and COPD.” The safety of Rayos was established based on the evaluation of 375 patients with RA who were enrolled in CAPRA-1 and CAPRA-2. The safety profile of the medication was simi-

lar to the safety profile already established for immediate-release prednisone. (July 26, 2012)

FDA Requesting More Data for Tofacitinib Tofacitinib (tasocitinib; Pfizer), a novel Janus kinase (JAK) 3 inhibitor for the treatment of RA, had an anticipated FDA PDUFA (Prescription Drug User Fee Act) date for August 21, 2012. However, on that day, the FDA announced that it was extending the review period for tofacitinib by 3 months. Pfizer provided additional safety data to the FDA earlier in August, potentially causing the delay in the approval process.

The safety profile rather than the efficacy profile of tofacitinib was a concern during the May 2012 FDA advisory panel meeting. The oral JAK3 therapy is also in phase 3 clinical trials for several additional indications, including psoriasis (oral formulation) and ulcerative colitis, and in phase 2 trials for psoriatic arthritis, ankylosing spondylitis, psoriasis (topical formulation), and Crohn’s disease. (August 21, 2012) ■

Rheumatic Diseases Update

TNF Blockers Increase the Risk for Herpes... modifying antirheumatic drugs,” said Ms Che. It is no secret that the benefit of DMARDs carries with it an increased risk of bacterial infection, but what was not previously known is the magnitude of the risk for reactivation of viral infections, such as herpes zoster, she added.

Che and colleagues performed a systematic literature search of clinical trials regarding inflammatory rheumatic diseases that were reported in medical journals and/or at medical meetings between 2006 and 2010.

Studies were included in this metaanalysis if they reported the respective incidences of herpes infections in patients treated with anti-TNF agents and in patients receiving conventional DMARDs. Of the 655 articles and 134 congress abstracts identified, 22 articles and 28 abstracts met the inclusion criteria.

The data in this study represent outcomes for 74,198 patient-years for antiTNF medications and 50,768 patient-

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years for conventional DMARDs. The rates for herpes zoster outbreaks and associated inflammatory rheumatic disease treatments for the German and US patient population were 4.9% for DMARDs versus 20.9% for anti-TNF medications. In a separate British registry, the rates were 6% for DMARDs versus 0.02% for biologic treatments (ie, anti-TNFs).

Based on pooled results, the overall risk of a herpes zoster infection outbreak with the use of anti-TNF agents was 1.75, or a 75% increased risk with anti-TNF medications versus with DMARDs. “This systematic review and metaanalysis demonstrates that careful monitoring of patients treated with anti-TNFs is required for early signs and symptoms of herpes zoster,” said Ms Che, and this raises the issue as to when vaccination against the virus should occur to avoid this painful complication of treatment of inflammatory rheumatic disease.

ACR Recommendations The American College of Rheumatology (ACR) recently updated its

at a glance ➤ Treatment with anti-TNFs versus traditional DMARDs increases the risk for herpes zoster infection by as much as 75% ➤ Careful monitoring of patients treated with anti-TNFs is required for early identification of herpes zoster infection ➤ Updated ACR recommendations for patients with inflammatory rheumatic disease include vaccinating before starting a DMARD or a biologic and after starting a DMARD, but not for those who are already taking a biologic agent

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Continued from page 6

recommendations regarding vaccinations for patients with inflammatory rheumatic disease, and the guidance for herpes zoster infection is mixed: • The panel recommends that live attenuated (herpes zoster) vaccinations should be undertaken before starting a DMARD or a biologic agent • The panel recommends vaccination with the herpes zoster vaccine in patients with RA who are already taking a DMARD • Vaccination with herpes zoster in patients currently undergoing treatment with biologics is not recommended.

Of note, the level of evidence for these recommendations is “C,” meaning that it is derived from the consensus opinion of experts, case studies, or standards of care. Of the 3 levels of evidence, “C” is the least stringent, and it invites future validation of opinion with evidence from randomized, controlled clinical trials. ■

www.ValueBasedRheumatology.com

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Economic Issues in RA

Optimal Sequence of Biologic Agents Identified... another anti-TNF agent. Based on data from randomized, controlled trials, they created a model to calculate the total direct medical costs of managing RA in Finland.

The costs for patients taking the ADA-ABA-ETA sequence totaled €829 ($597 in 2011 US$) daily for those achieving remission, which was averaged over a 2-year period. This was significantly lower than the daily cost of ADA-RTX-ETA, ETA-RTX-ADA, or

INF-RTX-ETA (Table).

Treatment sequences using ABA as a second-line biologic after an insufficient response to a first anti-TNF agent was more cost-effective than those using RTX as the second biologic option. This is largely because ABA is associated with higher rates of remission and lower disease activity than other anti-RA biologic agents.

“The information we obtained is not country-specific, at least in broad

Table Mean Daily Cost of Sequential Biologic Treatment for RA Daily cost for patients in remission, Biologic drug sequence € (2011 US$)

Daily cost for patients with LDAS, € (2011 US$)

ADA-ABA-ETA

829 (597)

428 (308)

ADA-RTX-ETA

1292 (930)

516 (371)

ETA-ABA-ADA

829 (597)

429 (309)

ETA-RTX-ADA

1292 (930)

517 (372)

INF-ABA-ETA

840 (605)

434 (312)

INF-RTX-ETA

1309 (942)

523 (376)

ABA indicates abatacept; ADA, adalimumab; ETA, etanercept; INF, infliximab; LDAS, low disease activity state; RA, rheumatoid arthritis; RTX, rituximab.

“The information we obtained is not countryspecific, at least in broad terms—while the costs are country-specific, the methodology is relevant to any country, and effectiveness of sequential strategies is not country-specific.”

—Ariel Beresniak, MD, MPH, PhD

terms—while the costs are countryspecific, the methodology is relevant to any country, and effectiveness of sequential strategies is not country-

Continued from cover

specific,” noted lead investigator Dr Beresniak. “Similar and consistent results have been generated in a number of other countries in Europe and in Canada,” he said.

The results indicated that direct medical costs, excluding the costs of the biologic agents, are lower for patients who achieved remission or low disease activity state (LDAS).

The daily costs—including costs of the biologic therapies, doctors’ fees, imaging, blood tests, and physiologist and hospital charges—for patients in remission or in LDAS for the 6 sequences that were used in the models are shown in the Table.

The ADA-ABA-ETA sequence was significantly more cost-effective than the sequences of biologic agents that contained RTX. The investigators noted that the limitations of their models include the assumption that the efficacy of RTX is sustained over time, without any “flares,” and that a potential remission or LDAS is sustained over a 6-month treatment interval. ■

Comparing Cost-Effectiveness of Tumor Necrosis Factor–Alpha Inhibitors for Rheumatoid Arthritis

By Rosemary Frei, MSc

A

study based on a real-world cost utility of 5 tumor necrosis factor (TNF)-alpha inhibitors used for the treatment of moderate-tosevere rheumatoid arthritis (RA) suggests that etanercept (Enbrel) plus methotrexate (MTX) is the most costeffective approach for this patient population from a health plan perspective, based on a payer willingness-to-pay threshold of $139,143 (ie, 3 times the average US gross domestic product per capita) per quality-adjusted life-year (QALY) gained from a treatment (Nguyen CM, et al. Pharmacoeconomics. 2012;30:575-593).

“Our results can influence decisionmaking, but I do not think this study should be the only reference,” commented principal investigator Mark Bounthavong, PharmD, Pharmacoeconomics Clinical Specialist, Veterans Affairs San Diego Healthcare System. “What is required for a decision maker to make the best decision is to look at all the evidence and weigh that with their priorities regarding which treatment to pay for,” Dr Bounthavong said.

8

Cost-Effectiveness Analysis Because of the lack of cost-effectiveness analyses of RA therapies, Dr Bounthavong and colleagues applied a Markov model, using Bayesian methods, to analyze data in previously published studies. A Markov model allows researchers to analyze a sequence of events and determine the general tendency of one event to be

“What is required for a decision maker to make the best decision is to look at all the evidence and weigh that with their priorities regarding which treatment to pay for.”

—Mark Bounthavong, PharmD

followed by another. Bayesian methods provide probabilities to go with those tendencies.

This is the best available approach

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in the absence of published head-tohead trials of US Food and Drug Administration–approved TNF-alpha inhibitors, noted Dr Bounthavong.

Hence, he and his colleagues used this method to perform a cost-utility analysis from the US healthcare payers’ perspective of treatment of patients with moderate-to-severe RA (aged 50 years) who were moderate responders or nonresponders to MTX monotherapy as well as treatment naive to TNF-alpha inhibitors.

Data from 12 clinical trials were used to compare the various TNFalpha inhibitors and MTX. The probabilities of achieving the American College of Rheumatology (ACR) 50 criteria for each TNF-alpha inhibitor combination were calculated. In the model’s “base-case” scenario, patients who achieved the ACR50 criteria for medication effectiveness continued with their combination therapy, and those who did not switch to tocilizumab (Actemra).

The results revealed that in the base-case scenario, etanercept + MTX had the lowest average total direct

cost of $157,413. This was followed by certolizumab (Cimzia ) + MTX, infliximab (Remicade) + MTX, adalimumab (Humira) + MTX, and golimumab (Simponi) + MTX. Furthermore, switching from etanercept + MTX to certolizumab + MTX would cost an additional $546,449 per each additional QALY gained.

Payers’ Willingness to Pay Etanercept + MTX had the highest probability of being the most costeffective strategy between a payer willingness-to-pay threshold of $0/ additional QALY gained and $750,000/ additional QALY gained.

“However, it is unlikely that payers would be willing to increase their budget by $750,000 for each additional QALY gained,” the researchers predicted.

When the base-case criteria were changed to ACR20 criteria, certolizumab + MTX was the most costeffective RA treatment; when the criteria were changed to ACR70, etanercept + MTX was the most costeffective approach. ■

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Economic Issues in RA

Two Cost Analyses Demonstrate Benefits of Early Intervention in RA in Curtailing Productivity Loss

By Neil Canavan Berlin, Germany—A pair of economic studies presented at the 2012 European League Against Rheumatism Congress have analyzed work productivity losses among patients with rheumatoid arthritis (RA), as well as costs associated with sick leave and disability compensation in patients with RA. The results suggest that although the current RA treatment paradigms are able to arrest disease progression, the diminished levels of work productivity experienced before effective disease management only stabilize, rather than recover, after treatment. Therefore, the researchers suggest, RA intervention is necessary at the earliest possible opportunity to lessen the ongoing financial burden of RA on the patient and on society.

In the first study, investigators from the Karolinska Institutet, Stockholm, Sweden, investigated the productivity losses (calculated in euros) among Swedish patients with RA during the few years before and after a definitive diagnosis of RA (Neovius M, et al. Ann Rheum Dis. 2011;70:1010-1015).

at a glance ➤ Although current RA treatments can arrest disease progression, the diminished work productivity before effective management is applied is not being restored to predisease state ➤ This further suggests that intervention is necessary at the earliest stage of RA to minimize the level of productivity loss and to lessen the financial burden associated with RA ➤ In a study involving a Swedish patient population with RA, the estimated cost of sick leave and disability in 2007 was €391 million versus €177 million for the cohort without RA ➤ This study shows that the average patient with RA in Sweden accounts for an additional €9000 annually for social services compared with those without RA

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Among patients with “established RA, previous studies have shown substantial productivity losses,” the researchers stated. In this cost analysis Swedish survey, “productivity losses were reported to constitute greater than 50% of the total cost of RA,” they noted. In addition to addressing the potential impact of recently available biologic medications on the treatment of RA, the goal of this study was to expand the scope of the analysis to the entire population of patients with RA in Sweden. “[We] are unaware of any previous study reporting nationwide productivity data for patients with RA,” the researchers wrote.

The data were drawn from the Swedish Rheumatology Quality Register and the National Patient Register for the period between 1999 and 2007.

The data set comprised information from 2 patient cohorts—3029 patients with RA who were initially diagnosed during the study period, and 25,922 patients with RA diagnosed as of 2007. All patients were aged 19 to 64 years; in each cohort, 73% of the patients were women.

In addition to the medical records, the researchers collected data from the Social Insurance Office regarding sick leave, unemployment benefits, and disability pension allocations for the period between 1996 and 2010, as well as information regarding the patient’s level of education.

Data for both patient cohorts were matched for age, education, and sex.

The results showed that in the time leading up to a diagnosis of RA, the number of days associated with sick leave and/or a disability pension increased from 43 days in the second year before RA diagnosis to 77 days in the year just before RA diagnosis.

A further dramatic increase in lost productivity was seen in the first year after RA diagnosis, which translates to patients with RA being absent from work for a median of 147 days annually; in the postdiagnosis treatment-initiation period, a plateau of 116 days absentee was reached at year 4 versus 71 days annually in the control group. During this period, a decline in sick days was observed for patients with RA; however, this seeming benefit was completely offset by an increase in permanent disability applications.

Of note, a relative increase in the need for social services/disability

compensation was associated with reduced levels of education, perhaps reflecting job skills that are more physically demanding.

Economic Burden Associated with Sick Leave and Disability Excluding sick-leave episodes of less than 14 days, the estimated cost of sick leave and disability pensions in 2007 for the Swedish patient population with RA was €391 million versus €177 million for the cohort of those without RA. The average patient with RA in Sweden accounts for an additional €9000 annually in social services expenditures relative to the general population.

Productivity loss constitutes a significant proportion of the financial burden associated with arthritis; early intervention is necessary to minimize the cost to the patient and to society at large.

The researchers concluded that, “The large differences in sick leave and disability pensions between the patient with RA and the general population reveals a substantial unmet need already present at the time of RA diagnosis. This also indicates that early, effective treatment has the potential to prevent major economic losses for society.”

The researchers add that sustained work productivity through earlier treatment will help offset the substantial costs related to RA treatment with biologics, which constituted 5% of total drug expenditures in Sweden in 2009.

Can Biologics Save the Day? The second study from the same group assessed long-term, real-world data on sick leave and disability in relation to the initiation of different RA treatments (Neovius M, et al. Ann Rheum Dis. 2011;70:1407-1414).

This study used the same data sources as the first study, augmented with records from the Swedish Biologics Registry. The 3 cohorts of

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patients with RA (ages, 19-60 years) in this study included 2796 patients receiving 1 disease-modifying antirheumatic drug (DMARD), 973 patients receiving combination DMARDs, and 4787 patients taking biologic agents. The study period was from 1999 to 2007. Cohort selection was based on treatment initiation; therefore, the same patient may be included in more than 1 cohort.

Results showed that diminished work capacity correlated with assigned treatment intensity: during the year before the start of a therapy in any of these 3 treatment groups, the percentages of patients who received disability benefits were 10% for the single DMARD cohort, 12% for the combination DMARDs, and 43% for those receiving biologics; the combined annual sick leave and disability days were 78, 132, and 190, respectively.

Regardless of the treatment type, effective therapy was strongly associated with a break in this trajectory.

However, as in the first study, successful treatment only stabilized levels of lost productivity rather than restored productivity to predisease state.

Even for patients with early-stage RA who were selected for biologic drug therapy and demonstrated clinical improvement after treatment initiation, sick leave and disability still amounted to more than 150 days annually. “Given the increase observed already before treatment starts, there is an obvious need to identify patients at risk of work ability deterioration much earlier than is currently done,” the researchers stated. “These observations provide an additional argument for the earlier and more precise identification of arthritis patients with a bad prognosis.”

The researchers emphasized that the study was not intended to compare efficacy of treatment modalities but to provide some insight as to when in the disease process— according to loss of work function before diagnosis—the treatments are being used.

Of note, although these cost estimates are country-specific and may reflect differences in social safety nets, a recent literature review (Burton W, et al. Occup Med [Lond]. 2006;56:18027) showed similar rates of sick and work disability in patients with RA in the United States. ■

www.ValueBasedRheumatology.com

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Economic Issues in RA

Biologic Agents Are Changing the Landscape of Rheumatoid Arthritis, Improving Outcomes, Lowering Disability Pharmacy cost now the key driver of RA expenditures

By David Hawk

T

he total incremental costs for the treatment of patients with rheumatoid arthritis (RA) in the United States accounted for $22.3 billion in 2008, according to a new cost analysis. In addition to the growing economic burden of managing patients with RA, this study also revealed a shift in diseaserelated costs, with the lion’s share of the financial burden attributed to the growing cost of pharmaceutical therapies (Kawatkar AA, et al.

Arthritis Care Res [Hoboken]. 2012 Jun 5. Epub ahead of print).

“A decade ago, the key driver of expenditure for nearly all diseases was inpatient hospitalization,” said lead investigator Aniket A. Kawatkar, PhD, MS, a health economist at the Department of Research and Evaluation, Southern California Permanente Medical Group. “This was especially true for RA. But now, in a short period of time, with the introduction of biologics, the driver of the expenditures has become the pharmaceuticals.”

This study represents one of the few RA-specific cost analyses. “In 2007, Yelin and colleagues did some work in conjunction with the CDC [Centers for Disease Control and Prevention] looking at expenditures for arthritis and rheumatic conditions in general, but their analysis included hundreds of

at a glance ➤ In 2008, the total incremental costs for treating patients with RA in the United States accounted for $22.3 billion ➤ The introduction of biologic therapies in RA has shifted the key cost driver from hospitalization to drug therapy ➤ This economic trend, however, may also signal improved treatments and patient outcomes ➤ Improved therapies may reduce the rate of disability and loss of productivity in this patient population

10

study was representative of the US population. The primary outcome was the direct total annual expenditure for patients with RA.

“The key finding here is that in the postbiologic era, the primary driver of the incremental total expenditure associated with rheumatoid arthritis has shifted from hospital stays to pharmacy expenditure.”

—Aniket A. Kawatkar, PhD, MS

different conditions,” Dr Kawatkar told Value-Based Care in Rheumatology.

“RA is a key disease because of the tremendous disability associated with it—and I did not see any prior literature that quantified the incremental effect of managing these patients, especially from nationally representative samples.”

The data for the present analysis were derived from the 2008 Medical Expenditure Panel Survey (MEPS), a set of large-scale surveys of families and individuals, their medical providers, and employers across the United States. MEPS is purported to be the most comprehensive source of US-based data on the cost and use of healthcare and health insurance coverage, including demographics, health conditions, health status, the use of medical care services, charges and payments, access to care, employment, and patient satisfaction with care.

Using clinical classification coding, Dr Kawatkar and colleagues identified 585 adults with RA in the MEPS data set and matched them with 18,892 adults without RA, who were used as controls. The weighted sample of this

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Key Findings Dr Kawatkar and colleagues found that the average unadjusted expenditure of patients with RA was from 1.5fold to 3-fold higher than for individuals without RA. Overall, pharmacy costs for patients with RA averaged 39.9% versus 29% for patients without RA of the total expenditures; patients with RA also spent more on hospitalizations, with 9.4% of total costs versus 5.8% for those without RA. The total annual expenditure for a patient with RA ranged from $1737 to as high as $47,081 (mean, $13,012) compared with between $567 and $17,425 (mean, $4950) for the control cohort without RA. The cost of pharmaceuticals ranged from $446 to $30,998 for patients with RA compared with $86 to $6358 in the cohort without RA. Expenditures for office visits were on average higher by $587 in the RA cohort; however, expenditures for inpatient and emer-

“The key finding is not a bad thing, per se, because better treatment may lead to lower disability in the future.”

—Aniket A. Kawatkar, PhD, MS

gency department care were only slightly higher for those with RA— $258 and $13, respectively.

“The key finding here is that in the postbiologic era, the primary driver of the incremental total expenditure associated with rheumatoid arthritis has shifted from hospital stays to pharmacy expenditure,” said Dr Kawatkar.

However, Dr Kawatkar is quick to point out that this has a positive side as well. “The key finding is not a bad thing, per se,” he said, “because better treatment may lead to lower disability in the future.”

Dr Kawatkar believes that this shift in the cost trend is likely related to early, aggressive use of disease-modifying antirheumatic drugs (DMARDs), as well as the introduction of expensive biologic DMARDs. Comparative Cost-Benefit Analyses Needed However, although the data imply that some disabilities, and therefore hospitalizations, are being prevented with the early use of DMARDs and biologics, this study was not designed to address that issue.

The study was also not designed to examine productivity losses that may, in aggregate, dwarf the economic burden of direct medical expenditures. The magnitude of this issue is illustrated by one of the characteristics of the study cohort— 62% of the RA population was unemployed.

“These results were striking,” Dr Kawatkar noted, “but not unexpected, given the high disability of RA. I would say I was surprised by the magnitude of the differences.”

Previous studies have estimated that productivity losses are 2 to 3 times higher than direct medical expenditures.

Dr Kawatkar noted that with the efficacy of biologic agents and with the rigorous application of current RA treatment guidelines that emphasize the early treatment of patients with RA, “unemployment rates may go down in this population.”

Analyses that consider the cost versus benefits of biologics in relation to productivity issues in patients with RA and the potential prevention of disability with these high-cost agents are clearly needed to measure the overall economic impact of biologics in RA. Budgets are finite, and although the calculus to address these issues may seem daunting, even the richest nation cannot afford unbridled spending for healthcare. “As the spending has reached into trillions of dollars annually, we have to consider what’s going to be the best bang for our buck, because it’s unsustainable for us to keep spending this way,” warns Dr Kawatkar. ■

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In The Literature Biologic Agents Improve Work Status in Patients with Rheumatoid Arthritis Rheumatoid arthritis (RA) often leads to work disability, early retirement, or self-perceived disability. The introduction of biologic agents, or anti– tumor necrosis factor (TNF)-alpha, has changed the outcomes for patients with RA by slowing disease progression and controlling disease activity.

But the high cost associated with these agents has increased the overall cost of treating RA, despite reducing hospitalization costs. The positive effects of biologics on work participation could potentially offset the increased drug cost, but the impact of these agents on work status has not been studied until now. A new study reviewed the published literature to examine the effect of biologic agents on the employment status, absenteeism, and presenteeism of patients with RA, showing that the introduction of anti–TNF-alpha for the treatment of RA has improved the work status of patients with RA (Wee MM, et al. Ann Rheum Dis. 2012; 71:161-171).

In this systematic review, 19 studies met the inclusion criteria of RA, biologic agents, and work participation.

A total of 11,295 patients were treated with biologic agents in these studies.

Of the 19 studies, 6 were randomized controlled trials (RCTs), 6 were uncontrolled cohorts, and 7 were controlled cohort studies. The results showed that absenteeism was reduced in all 10 studies that involved this outcome, and presenteeism improved in 7 of the 9 studies involving that outcome.

Improvement in employment status as a result of treatment with biologic agents was seen in 50% of the studies on early-stage RA. In one controlled cohort study, employed patients receiving anti-TNF therapy worked an additional 0.61 years compared with the control group, and in another controlled study, 20% more patients remained employed while taking biologics compared with the control group receiving nonbiologic treatment.

The results were more mixed in the RCTs, showing the positive effect of biologic treatment on employment status after 52 and 104 weeks, but some of the studies showed no such results.

Reduction in absence from work was the most frequent positive effect seen from treatment with biologic agents compared with disease-modifying antirheumatic drugs (DMARDs) treatment or work status before the initiation of treatment. Overall, almost all of the studies showed some positive effects of treatment with biologic agents on work absenteeism or presenteeism.

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Nurse-Led Gout Care Improves Outcomes Gout affects joints via the accumulation of uric acid in the blood. The management of patients with gout is far from optimal, with only 33% to 50% of patients receiving urate-lowering therapy (ULT). The fixed dose of allopurinol, 300 mg daily, that is often

prescribed for gout has been insufficient for many patients. In addition, few patients receive information on the lifestyle changes needed to reduce gout flare. Nurse delivery of care has been successful in the management of chronic conditions, such as diabetes, in the United Kingdom. To improve the treatment of gout, a pilot observa-

tional study tested the effectiveness of a package of care delivered by nurses in a hospital-based gout clinic (Rees F, et al. Ann Rheum Dis. 2012 June 7. Epub ahead of print).

In the 106 participants, mean baseline serum uric acid was 456 (98) µmol/L. Patients received a nurseContinued on page 16

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©2012 Engage Healthcare Communications, LLC www.AHDBonline.com

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

Readers are invited to submit articles that aim at improving the quality of patient care and patient well-being while reducing or controlling costs, enhancing the health of communities and patient populations, as well as other topics relevant to benefit design with specific implications to policymakers, payers, and employers.

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AUGUST 2012

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www.ValueBasedRheumatology.com

11

Psoriatic Arthritis

Obesity a Marker for Poor Treatment Outcomes in Psoriatic Arthritis

By Neil Canavan Berlin, Germany—A pair of complementary studies presented at the 2012 European League Against Rheumatism Congress of patients with psoriatic arthritis who have just started anti–tumor necrosis factor (TNF) therapy illustrate that (1) obesity is a negative predictor of achieving minimal disease activity, and (2) patients with psoriatic arthritis who are able to lose weight by adhering to a hypocaloric, fiber-enriched diet can reverse the negative disease outcomes associated with being overweight.

“A study presented at the 2009 meeting of the Society for Investigative Dermatology alerted us to the fact that patients with psoriatic arthritis have an increased prevalence of obesity,” said Matteo Nicola Dario Di Minno, MD, Regional Reference Centre for Coagulation Disorders, Rheumatology Research Unit, Psoriatic Arthritis Clinic, University of Naples Federico II, Italy, the lead investigator of both studies. His objectives in these 2 investigations were to firmly establish the link between obesity on poor treatment outcomes and whether weight loss alone could reverse that suspected correlation.

In the first study, Dr Di Minno and

colleagues recorded the treatment outcomes for 135 obese (body mass index [BMI], >30 kg/m2) patients with psoriatic arthritis and 135 patients with normal weight who were used as a control group. All patients were treated with anti-TNF agents and were followed for 24 months. Patients were evaluated at baseline, at 12 months, and at 24 months for achieving minimal disease activity.

“The results of our study suggest that obese patients with psoriatic arthritis who stick to a hypocaloric diet have a greater chance of achieving treatment goals.”

—Matteo Nicola Dario Di Minno, MD

After 12 months, 64% of the patients not achieving minimal disease activity were obese compared with 26% nonobese patients; beyond the defined obesity threshold, weight-associated outcomes worsened as patient BMI increased.

Among the 98 patients in the entire cohort who achieved minimal disease activity at 12 months, the obese patients were twice as likely to lose disease activity after 24 months.

An Apple a Day The second study enrolled 138 obese patients with psoriatic arthritis.

After all patients began receiving anti-TNF therapy, 69 patients were maintained on a hypocaloric diet (intervention group), and the remaining 69 were allowed to self-manage their food intake. Patients were followed for 6 months.

Results showed that at follow-up, the hypocaloric-diet cohort was associated with significantly improved laboratory values for systemic inflammation (evidence of psoriatic arthritis) compared with the self-managed cohort, and that the prevalence of successful weight loss through dietary intervention showed a significantly higher prevalence in minimal disease activity compared with the patients who self-managed their food intake.

Overall, patients with psoriatic arthritis who were using a hypocaloric diet were almost 5 times as likely to achieve minimal disease activity as their more liberally eating

at a glance ➤ Obesity is a negative predictor of achieving disease activity in patients with psoriatic arthritis ➤ After 12 months of observation, 64% of those patients not achieving minimal disease activity were obese compared with 26% nonobese patients ➤ Patients who were using a hypocaloric diet were almost 5 times as likely to achieve minimal disease activity and had a great chance of achieving treatment goals ➤ Patients with psoriatic arthritis who lose weight by adhering to a hypocaloric diet can reverse the negative treatment outcomes associated with being overweight counterparts. “The results of our study suggest that obese patients with psoriatic arthritis who stick to a hypocaloric diet have a greater chance of achieving treatment goals,” Dr Di Minno concluded. ■

Psoriasis Drug Safe and Effective for Treating Psoriatic Arthritis Berlin, Germany—The biologic drug ustekinumab (Stelara), which is already approved for use in patients with moderate-to-severe plaque psoriasis, has demonstrated promise in treating psoriatic arthritis, according to data from the late-stage PSUMMIT-1 clinical trial. Lead investigator Iain B. McInnes, MD, PhD, Director of the Institute of Infection, Immunity, and Inflammation at the University of Glasgow, Scotland, discussed these results at the 2012 European League Against Rheumatism Congress.

“There are a number of patients with psoriatic arthritis who do not respond to currently available treatment options, including biologic medicines targeting tumor necrosis factor,” said Dr McInnes. “As physicians, we struggle to manage such people as

12

“There are a number of patients with psoriatic arthritis who do not respond to currently available treatment options, including biologic medicines targeting tumor necrosis factor. As physicians, we struggle to manage such people as well as we would like, so the development of this new medicine is a welcome step forward.”

—Iain McInnes, MD, PhD

well as we would like, so the development of this new medicine is a welcome step forward.”

Dr McInnes emphasized that the importance of new treatment options in this setting cannot be understated.

VALUE-BASED CARE IN RHEUMATOLOGY

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AUGUST 2012

Approximately 10% to 15% of patients with psoriasis go on to develop inflammation of the synovium, enthesis, and periosteum, resulting in deforming and debilitating arthritis.

To investigate the use of ustekin-

umab in patients with psoriatic arthritis, the PSUMMIT-1 investigators recruited 615 patients with the disease who were still experiencing active disease despite treatment with disease-modifying antirheumatic drugs, including biologics. Patients randomized to 45 mg of ustekinumab, 90 mg of ustekinumab, or to placebo.

Treatments were administered at the beginning of the trial, again at week 4, and then every 12 weeks thereafter.

Patients in any of the treatment groups were allowed to use concomitant methotrexate as needed.

If no therapeutic response was observed at 16 weeks, patients were allowed to switch to another treatment arm in a blinded fashion.

Results for PSUMMIT-1 showed Continued on page 15

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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 during the double-blind, placebo-controlled portion of Studies RA-I, RA-II, RA-III and RA-IV was 7% for patients taking HUMIRA and 4% for placebo-treated patients. The most common adverse reactions leading to discontinuation of HUMIRA were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%).

Infections In the controlled portions of the 32 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD and Ps, the rate of serious infections was 4.7 per 100 patient-years in 6694 HUMIRA-treated patients versus a rate of 2.7 per 100 patient-years in 3749 control-treated patients. Serious infections observed included pneumonia, septic arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis [see Warnings and Precautions].

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

rate of positive PPD conversion was 0.07 per 100 patient-years. In a subgroup of 8940 U.S. and Canadian HUMIRA-treated patients, the rate of reported active TB was 0.07 per 100 patient-years and the rate of positive PPD conversion was 0.06 per 100 patient-years. These trials included reports of miliary, lymphatic, peritoneal, and pulmonary TB. Most of the TB cases occurred within the first eight months after initiation of therapy and 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 cases of serious opportunistic infections and TB have been fatal [see Warnings and Precautions].

Autoantibodies In the rheumatoid arthritis controlled trials, 12% of patients treated with HUMIRA and 7% of placebo-treated patients that had negative baseline ANA titers developed positive titers at week 24. Two patients out of 3046 treated with HUMIRA developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms. The impact of long-term treatment with HUMIRA on the development of autoimmune diseases is unknown.

Liver Enzyme Elevations There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of HUMIRA (40 mg SC every other week) in patients with RA, PsA, and AS with control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULN occurred in 3.5% of HUMIRA-treated patients and 1.5% of control-treated patients. Since many of these patients in these trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between HUMIRA and the liver enzyme elevations is not clear. In controlled Phase 3 trials of HUMIRA (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on Days 1 and 15, respectively, followed by 40 mg every other week) in patients with Crohn’s disease with control period duration ranging from 4 to 52 weeks, ALT elevations ≥ 3 x ULN occurred in 0.9% of HUMIRA-treated patients and 0.9% of control-treated patients.

In controlled Phase 3 trials of HUMIRA (initial dose of 80 mg then 40 mg every other week) in patients with plaque psoriasis with control period duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of HUMIRA-treated patients and 1.8% of control-treated patients.

Immunogenicity Patients in Studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab during the 6- to 12-month period. Approximately 5% (58 of 1062) of adult rheumatoid arthritis patients receiving HUMIRA developed low-titer antibodies to adalimumab at least once during treatment, which were neutralizing in vitro. Patients treated with concomitant methotrexate had a lower rate of antibody development than patients on HUMIRA monotherapy (1% versus 12%). No apparent correlation of antibody development to adverse reactions was observed. With monotherapy, patients receiving every other week dosing may develop antibodies more frequently than those receiving weekly dosing. In patients receiving the recommended dosage of 40 mg every other week as monotherapy, the ACR 20 response was lower among antibody-positive patients than among antibody-negative patients. The long-term immunogenicity of HUMIRA is unknown.

In patients with juvenile idiopathic arthritis, adalimumab antibodies were identified in 16% of HUMIRA-treated patients. In patients receiving concomitant methotrexate, the incidence was 6% compared to 26% with HUMIRA monotherapy.

In patients with ankylosing spondylitis, the rate of development of antibodies to adalimumab in HUMIRA-treated patients was comparable to patients with rheumatoid arthritis. In patients with psoriatic arthritis, the rate of antibody development in patients receiving HUMIRA monotherapy was comparable to patients with rheumatoid arthritis; however, in patients receiving concomitant methotrexate the rate was 7% compared to 1% in rheumatoid arthritis. In patients with Crohn’s disease, the rate of antibody development was 3%. In patients with plaque psoriasis, the rate of antibody development with HUMIRA monotherapy was 8%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 ug/ml. Among the patients whose serum adalimumab levels were < 2 ug/ml (approximately 40% of total patients studied), the immunogenicity rate was 20.7%. In plaque psoriasis patients who were on HUMIRA monotherapy and subsequently withdrawn from the treatment, the rate of antibodies to adalimumab after retreatment was similar to the rate observed prior to withdrawal.

Other Adverse Reactions The data described below reflect exposure to HUMIRA in 2468 patients, including 2073 exposed for 6 months, 1497 exposed for greater than one year and 1380 in adequate and well-controlled studies (Studies RA-I, RA-II, RA-III, and RA-IV). HUMIRA was studied primarily in placebo-controlled trials and in long-term follow up studies for up to 36 months duration. The population had a mean age of 54 years, 77% were female, 91% were Caucasian and had moderately to severely active rheumatoid arthritis. Most patients received 40 mg HUMIRA every other week.

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

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

Placebo

(N=690)

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 pediatric patients in the juvenile idiopathic arthritis (JIA) trial were similar in frequency and type to those seen in adult patients [see Warnings and Precautions, Adverse Reactions]. Important findings and differences from adults are discussed in the following paragraphs.

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

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

In the first 48 weeks of treatment, non-serious hypersensitivity reactions were seen in approximately 6% of children and included primarily localized allergic hypersensitivity reactions and allergic rash.

Isolated mild to moderate elevations of liver aminotransferases (ALT more common than AST) were observed in children with JIA exposed to HUMIRA alone; liver enzyme test elevations were more frequent among those treated with the combination of HUMIRA and MTX than those treated with HUMIRA alone. In general, these elevations did not lead to discontinuation of HUMIRA treatment.

In the JIA trial, 10% of patients treated with HUMIRA who had negative baseline anti-dsDNA antibodies developed positive titers after 48 weeks of treatment. No patient developed clinical signs of autoimmunity during the clinical trial.

Approximately 15% of children treated with HUMIRA developed mild-to-moderate elevations of creatine phosphokinase (CPK). Elevations exceeding 5 times the upper limit of normal were observed in several patients. CPK levels decreased or returned to normal in all patients. Most patients were able to continue HUMIRA 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

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 after the introduction of biologic agents for the treatment of psoriatic arthritis, the direct healthcare costs related to psoriatic arthritis management rose from approximately $3600 annually to an annual expenditure exceeding $16,000.

“This estimate of new economic burden of illness may further aid decision makers in assessing the costeffectiveness 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 costs related to the company’s biologic drug golimumab (Simponi), which was approved by the US Food and

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Drug Administration in 2009 for the treatment of psoriatic arthritis.

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.

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

—Chureen T. Carter, PharmD, MS

The study included 211 patients (average age, 50 years) with psoriatic arthritis who were taking 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, after patients began using

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golimumab, the costs rose 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 researchers stressed that the largest cost component of the total costs was the loss of

at a glance ➤ After the introduction of biologics, such as golimumab, for the treatment of psoriatic arthritis, direct healthcare costs rose by more than 4.5-fold ➤ 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

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. ■

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Lupus

Cancer Drug Shows Promise...

“We showed that the proteasome inhibitor bortezomib, which is approved for the treatment of relapsed multiple myeloma, eliminates plasma cells, including longlived ones, and ameliorates lupus nephritis in systemic lupus erythematosus,” stated Dr Voll. It is these long-lived, antibody-producing plasma cells that are considered to be the root cause of SLE. Previous experiments using bortezomib in mouse models suggested the efficacy of the drug in the setting of SLE, prompting investigators to proceed with this limited investigation in humans.

The trial, which was conducted at 3 different university medical centers in Germany, included 13 patients with SLE who had a history of nonresponse or intolerance to conventional SLE drugs; they all received intravenous (IV) bortezomib.

Over the course of study, all the patients underwent treatment cycles of 11 days; IV bortezomib was dosed at 1.3 mg/m2 and was administered on days 1, 2, and 8, and for some

patients on day 11 of the cycle (4 doses of bortezomib per cycle is the standard regimen for hematologic malignancies). In addition, most patients also received 20 mg of dexamethasone.

“We showed that the proteasome inhibitor bortezomib, which is approved for the treatment of relapsed multiple myeloma, eliminates plasma cells, including long-lived ones, and ameliorates lupus nephritis in systemic lupus erythematosus.”

—Reinhard E. Voll, MD Treatment cycles were repeated up to 4 times, with a time interval of 10 to 14 days between cycles. Treatment was stopped when disease activity was substantially reduced or when severe side effects developed. After

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treatment with bortezomib was finished, patients received maintenance therapy with standard SLE drugs, generally mycophenolate mofetil, and hydroxychloroquine.

The treatment results showed that disease activity scores for SLE (SLEDAI) and laboratory levels of anti-dsDNA antibody (a signature of lupus) significantly decreased in all patients. “In a few patients, antidsDNA nearly disappeared,” stated Dr Voll and colleagues. In all patients with active lupus nephritis, proteinuria declined within 6 weeks of treatment, and 1 patient reached normal protein excretion within 4 months.

Bortezomib treatment had to be stopped in 3 patients because of adverse events: 2 for polyneuropathy (a well-known side effect of bortezomib, which is reversible if treatment is discontinued) and 1 for fever.

Despite these treatment interruptions, however, all 3 patients were still able to experience major reductions in SLEDAI scores and anti-dsDNA antibody levels.

One patient developed reversible

thrombocytopenia after 4 treatment cycles, but no other relevant hematologic toxicities were observed. Other non–treatment-limiting side effects included myalgia and headache.

Reductions in vaccine coverage as a result of treatment were tested for a potential problem with bortezomib that leaves some patients vulnerable to infections against which they were previously immunized, but serum values remained in the protective range for this study population.

Improvements in SLE symptoms with bortezomib were maintained to 6 months of follow-up.

As Dr Voll stressed, treatment with bortezomib in the setting of SLE is considered off-label use; however, in this investigation the cost of the drug (approximately $1300 per injection) was covered by the patients’ insurers or the treating hospitals.

Dr Voll stated that the next step after the positive results of this pilot study should be a formal clinical trial that he hopes will be sponsored by Millennium Pharmaceuticals, which is the manufacturer of bortezomib. ■

Psoriatic Arthritis

Psoriasis Drug Safe and Effective for Treating...

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that both doses of ustekinumab were superior to placebo at 24 weeks, with significant improvements in ACR20 (American College of Rheumatology criteria 20% response to treatment), ACR50, and the most favorable outcome of ACR70. An ACR50 response was seen in 24.9% of patients receiving the 45-mg dose and in 27.9% of patients receiving 90 mg of ustekinumab compared with 8.7% of those given placebo. ACR70 responses were seen in 12.2% and 14.2% for the 45-mg and 90-mg ustekinumab groups, respectively, compared with 2.4% of patients in the placebo group.

For skin involvement—a condition that precedes joint disease in patients with psoriatic arthritis, often by years—patients in the active-treat-

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ment arms experienced a 57.2% and a 62.4% improvement in Psoriasis Area and Severity Index (PASI) scores

“The real test in this trial was whether the treatment also worked in the joints, and the answer, at least in comparison with placebo, was that it does.”

—Iain McInnes, MD, PhD for 45 mg and 90 mg of ustekinumab, respectively.

“The improvement in Psoriasis Area and Severity Index was expected,” said Dr McInnes, “because uste-

at a glance ➤ Ustekinumab, which is already approved for moderate-tosevere plaque psoriasis, shows great promise as a treatment for psoriatic arthritis ➤ Significant improvements were seen with ustekinumab in ACR20, ACR50, and the most favorable outcome of ACR70 response rates ➤ In addition to the expected improvement in skin involvement, ustekinumab demonstrated benefits as a treatment for the joints

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kinumab is already licensed and in clinical use for psoriasis. The real test in this trial was whether the treatment also worked in the joints, and the answer, at least in comparison with placebo, was that it does.”

Through week 16, the proportion of patients experiencing ≥1 adverse events was similar between all treatment groups, with infection being the most common side effect (>2%).

No malignancies, serious infections, tuberculosis, opportunistic infections, or deaths occurred during the course of the trial.

“These results highlight not only ustekinumab’s efficacy, but also its promising safety profile. We look forward now to seeing how it compares in trials with standard treatments.”—NC ■

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Ankylosing Spondylitis

New Biomarkers Predict Disease Progression in Ankylosing Spondylitis

See also Personalized Medicine

By Neil Canavan Berlin, Germany—Several biomarkers have been identified that are predictive of structural damage in patients with ankylosing spondylitis who are at high risk for disease progression, according to data presented at the 2012 European League Against Rheumatism Congress.

Biomarkers that can be used to guide treatment decision-making are among the hallmarks of the evolving paradigm of personalized medicine in rheumatic diseases.

“Knowing more about why certain patients have disease progression is hugely important,” said lead investigator Denis Poddubnyy, MD, from Charité-Universitätsmedizin Berlin, Germany. “Not only will this help us stratify our patients due to risk, but in the future it may pave the way for more treatment options to be developed that target these specific markers.”

The presence of radiographic spinal damage (ie, syndesmophytes) is the strongest predictor of further radiographic progression in patients with ankylosing spondylitis. In recent years, several biomarkers have been found to be associated with radiographic spinal progression/syndesmophyte formation.

To determine whether the biomarkers had predictive potential, Dr Poddubnyy and colleagues recruited 64 patients with ankylosing spondylitis who were deemed eligible to participate in this analysis because of the presence of syndesmophytes at baseline examination.

Radiographs of the lumbar and cer-

vical spine were obtained for all patients at baseline and after 2 years of follow-up. Based on these measures, patients were assigned to 1 of 2 groups

“Knowing more about why certain patients have disease progression is hugely important. Not only will this help us stratify our patients due to risk, but in the future it may pave the way for more treatment options to be developed that target these specific markers.”

—Denis Poddubnyy, MD

for further analysis—(1) group I, consisting of 26 patients with syndesmophytes at baseline and a new syndesmophyte or syndesmophyte’s growth after 2 years (defined as pro-

gressors), or (2) group II, which consisted of 38 patients with syndesmophytes at baseline but with no evidence of progression at 2 years (defined as nonprogressors).

These data were then correlated with serum levels for a battery of biomarker candidates for disease progression, including C-reactive protein (CRP), matrix metalloproteinase-3 (MMP-3), sclerostin, Dickkopf 1 (DKK1), bone morphogenetic protein (BMP)-2, BMP-7, osteoprotegerin, vascular endothelial growth factor, periostin, and others.

The results showed significant differences between group I and group II in baseline serum levels of CRP and MMP-3, confirming the predictive value of these markers regarding active inflammation demonstrated as spinal radiographic progression. Conversely, protective trends were found for the biomarkers sclerostin, DKK1, and periostin.

“In ankylosing spondylitis, patients develop inflammation and pain, and eventually stiffness of the spine,” said Dr Poddubnyy. “We know that the presence of syndesmophytes on xrays is the strongest predictor of further spine damage in ankylosing spondylitis. This process moves quickly in some patients but can take years in others.”

The ability to predict which patients may experience disease progression is particularly important in terms of treatment. Clinical experience suggests that biologic therapy with anti–tumor necrosis factor agents does not inhibit radiographic

at a glance ➤ New biomarkers have been identified that can predict structural damage in patients with ankylosing spondylitis who are at high risk for disease progression ➤ CRP and MMP-3 were found to have predictive value regarding active inflammation demonstrated as spinal radiographic progression ➤ Conversely, the biomarkers sclerostin, DKK1, and periostin were found to have protective trends ➤ Knowing why some patients have disease progression can help to stratify patients according to risk and may also pave the way for new treatment options to target these specific markers

progression in patients who already have disease damage. However, other studies have shown that treatment with the conventional nonsteroidal anti-inflammatory drug (NSAID) diclofenac does seem to be beneficial in slowing syndesmophyte progression. For patients with the biomarkers associated with a high risk of disease progression identified in this study, NSAIDs may be a better treatment option. ■

In The Literature Nurse-Led Gout Care Improves... Continued from page 11 delivered intervention that included education, individualized lifestyle advice, and appropriate ULT. Of the participants, 92% achieved the therapeutic target level of uric acid of ≤360 µmol/L and 85% had a uric acid level <300 µmol/L. Allopurinol was the most frequently used ULT, requiring a median dose of 400 mg daily to achieve the uric acid target level. Pain measurement by the 36-Item Short Form Health Survey (SF-36) scores indicated signif-

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icant improvement in body pain after 1 year of treatment.

Using an intervention led by a nurse based on the elements of best practices—including patient education, lifestyle advice, and slow upward titration of ULT after serial serum uric acid measurements— resulted in good adherence to ULT therapy for 12 months, with more than 90% of patients achieving their recommended uric acid level. Such an excellent outcome using a nurse-led service suggests that this strategy can result in cost-effective care delivery.

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The Evidence for Tight Control in Early Arthritis There has been increasing evidence to support aggressive therapeutic intervention in patients with early RA. A recent review addresses the need for early treatment, based on the concepts of tight control and the treatto-target paradigm, leading to the ultimate goal of disease remission (Sen D, Brasington R. Rheum Dis Clin North Am. 2012;38:327-343).

Early RA is believed to be a time when the disease process is more receptive to treatment, which can posi-

tively affect the disease course. Furthermore, good response in early disease predicts good long-term outcomes.

The concept of treat to target requires understanding of what the target is. Remission is now thought to be an achievable target. Remission does not suggest the absence of inflammation in RA; joint damage progresses even during clinical remission. A variety of disease indices are used to measure disease activity and clinical remission and to guide the treatment of RA to target.

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Personalized Medicine in Rheumatology

Tailoring Therapy for the Needs of the Individual... an individually tailored treatment approach, Dr Krieckaert and colleagues administered the human monoclonal antibody adalimumab to 272 patients with RA during a 3-year period; after the first 6 months of treatment, the patients were assessed for adalimumab serum drug levels, the presence of antiadalimumab antibodies, and the EULAR response (a change in disease activity over time as measured by the disease activity score in 28 joints [DAS28] calculator).

Using these determinations, the protocol dictated whether adalimumab treatment continued unchanged, whether dosing of the drug was then altered, or even discontinued, or, as in the case of the lack of a response to adalimumab treatment, if the patient was

switched to a different biologic agent.

At the end of the study period, the EULAR response was established; in addition, the patients completed a health assessment questionnaire (HAQ), an instrument designed to gauge health-related quality of life through measuring a patient’s ability to perform everyday tasks.

Using a patient-level Markov model, outcomes regarding DAS28, HAQ, and the use of adalimumab for a personalized-care group were simulated over a 3-year period and then compared with historical data for observed drug use and related disease activity in RA. The mean direct and indirect costs, QALYs (both based on DAS28 and HAQ), and the incremental cost-effectiveness ratios (ICERs)

“With careful monitoring and testing of disease activity at 6 months, costs for rheumatoid arthritis treatment can be reduced, and treatment effectiveness can actually increase.”

—Charlotte L.M. Krieckaert, MD from a societal and healthcare perspective were then calculated.

The results of this analysis showed that costs were saved in the personalized-care group compared with the usual-care group, with mean savings of €667,513 and €665,630 for direct

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Furthermore, a total of €643,275 was saved on biologic drug costs, whereas the tests to monitor the patients’ drug levels, antiadalimumab antibodies, and EULAR responses only amounted to €12,116.

As the costs decreased, the effectiveness of treatment was shown to increase with personalized care, at a benefit of an extra 3.32 QALYs, which resulted in an average ICER of –€200,916 per QALY gained.

Commenting on the results of the study, Dr Krieckaert stated that although the tests that were used were specific to adalimumab, her findings in general underline the potential costeffectiveness of personalized treatment in RA with biologic agents. ■

Research on Pain Medicines Seeks a Genetic-Trait Link Personal factors will be studied to determine which drugs are safe or effective

By Ron Winslow

A

n international research team is launching an ambitious effort to determine whether everyday painkillers like Celebrex and Aleve could be made safer and more effective through personalized medicine, which involves tailoring treatments to patients based on genetic traits.

More than 30 types of such pain medications, known as nonsteroidal anti-inflammatory drugs, or NSAIDs, are on the market, but how well they work varies widely among patients.

Many carry increased risk of such problems as stomach bleeding or heart attacks, and it is hard to predict who is at risk of such side effects and who is likely to benefit from the drugs. The medicines generally are prescribed and used on a trial-anderror basis.

for the first five years of what is expected to be a 10-year project. The scientists plan a comprehensive look at genetic and other factors that affect how people respond to the medicines in hopes of finding biological signals that could predict efficacy or side effects. The hope is that individual patients could, say, plug their own data into a smartphone app to help decide which medicines to take, at what doses and for how long.

“They’re the common questions that people ask,” says Garret FitzGerald, director of the Institute for Translational Medicine & Therapeutics at the university, who is heading the project. “We’re trying to put some science behind the answers.”

Personalized medicine already is transforming cancer treatment for

Pain Pills

The risks and benefits of two widely used nonsteroidal anti-inflammatory drugs: Drug Type Uses Risks Celebrex (shown above)

Prescription

Pain from arthritis, rheumatoid arthritis, menstrual periods and other causes

Heart attack, stroke, gastrointestinal bleeding

Naproxen

Prescription and over-thecounter as Aleve and in generic versions

Pain from arthritis, rheumatoid arthritis, tendinitis, shoulder inflammation

Gastrointestinal bleeding, heart attack

Sources: NHLBI; Garret FitzGerald, University of Pennsylvania.

The National Heart Lung and Blood Institute has awarded the University of Pennsylvania an $18 million grant

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some patients whose tumors are fueled by genetic mutations that can be attacked with targeted treatments.

But researchers are finding that many diseases involve multiple genetic drivers and a host of other factors that makes predicting the risks and benefits of drugs especially challenging.

For instance, certain genetic mutations are known to limit the effectiveness of the blood-thinner Plavix (known generically as clopidogrel) and increase patients’ risk of a heart attack. But studies so far have turned up little evidence that using a test for the mutation to guide treatment makes any difference in how patients fare. “All of these things are oversimplified when you look at one test” or one gene, says Susan B. Shurin, acting director of the NHLBI, part of the National Institutes of Health.

NSAIDs work by blocking two enzymes known as Cox-1 and Cox-2.

While prescribing labels for all NSAIDs generally warn of both heart and bleeding risks, research suggests there are differences among them.

An international research team is launching an effort to determine whether everyday painkillers could be made safer and more effective through personalized medicine.

Naproxen, an over-the-counter pill available in many generic versions as well as under the brand Aleve, marketed by Bayer AG, blocks Cox-1. It is associated with a high risk of gastrointestinal bleeding in some patients, but based on limited studies, it doesn't appear to increase risk of heart attack, Dr. FitzGerald says. Naproxen also is available through a prescription.

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Celebrex, marketed by Pfizer Inc., is a Cox-2 inhibitor. Bleeding risk is generally low, Dr. FitzGerald says, but Celebrex is a cousin of the Cox-2 drug Vioxx, which Merck & Co. withdrew from the market in 2004 because of an increased risk of heart attack and stroke.

The researchers will test Celebrex and naproxen on five different biological systems: yeast, mammalian cells, mice, zebrafish and humans. They will hunt for patterns among various elements—genetic variants, metabolic processes, even bacteria known as the microbiome that affect human biology—that might be associated with risk or benefit of the medicines.

Researchers will then attempt to link any such patterns to risks or benefit in randomized trials involving Celebrex and naproxen as well as other NSAIDs. Researchers hope the process eventually will be applied to other classes of drugs such as cholesterol-lowering statins.

The project will require expertise from a variety of disciplines, says Dr. FitzGerald, who has enlisted colleagues from institutions including Harvard, Stanford and Duke universities in the U.S. and Cambridge University in the U.K. “There is a dominant pathway by which these drugs work, but it’s occurring in a context,” he says. “And everybody’s context is different.

That’s the basis of why people respond differently.” ■ Reprinted with permission from the Wall Street Journal, August 5, 2012.

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Comparative Effectiveness Research

A Head-to-Head Comparison of 2 Biologic Agents for the Treatment of Rheumatoid Arthritis

By David Hawk Berlin, Germany—Competition is heating up between the rheumatoid arthritis (RA) drugs known as “biologics,” with data for one of the first head-to-head comparisons presented at the 2012 European League Against Rheumatism Congress. Results for the Abatacept Versus Adalimumab Comparison in BiologicNaive RA Subjects with Background Methotrexate (AMPLE) trial suggest that abatacept, a first-in-class drug that works to reduce costimulation of the T-cells that drive RA inflammation, has an equivalent efficacy in treating RA as adalimumab, a member of the anti–tumor necrosis factor drug class.

AMPLE, a randomized, investigator-blinded, 2-year clinical trial compared the safety and efficacy of abatacept and adalimumab in patients with RA, with both drugs being used in combination with methotrexate. “There have been very few head-to-head trials in rheumatoid arthritis,” said AMPLE lead investigator Michael H. Schiff, MD, FACR, Clinical Professor of Medicine, Rheumatology Division, University of Colorado, Boulder.

“To date, there have been no randomized, controlled studies directly comparing the safety and efficacy of different biologic disease-modifying antirheumatic drugs using the combination of a biologic medication and methotrexate, which is the most commonly prescribed treatment approach

in moderate-to-severe rheumatoid arthritis,” said Dr Schiff.

The trial enrolled 646 patients with active RA who had already experienced an inadequate therapeutic response to methotrexate, but who had not yet been treated with

“Results from AMPLE provide important information comparing the efficacy of abatacept and adalimumab, including kinetics of response.”

—Michael H. Schiff, MD, FACR

any of the biologic agents. Patients were stratified by disease activity and randomized to either subcutaneous injections of 125-mg abatacept weekly, or 40-mg adalimumab biweekly, with both drugs being used in combination with a stable dose of methotrexate.

The results showed that after 4 weeks of treatment, 42.5% of patients in the abatacept group achieved ACR20 (American College of Rheumatology criteria, 20% improvement in disease activity) versus 47.6% in the adalimumab group, with a slight (but not statistically significant) advantage for adalimumab. This

treatment response equivalence was sustained to 12 months.

Also at 12 months, ACR50 responses were nearly identical between the 2 groups: 46.2% for abatacept versus 46% for adalimumab. ACR70 responses were also similar, with 29.2% versus 26.2% for abatacept and adalimumab patient cohorts, respectively.

No significant differences were observed between the 2 patient groups in terms of side effects.

“Results from AMPLE provide important information comparing the efficacy of abatacept and adalimumab, including kinetics of response,” said Dr Schiff. “The results demonstrate comparability between the 2

“It really is a great leap forward for us and our patients, as it shows there is another treatment option that is as effective and as safe as adalimumab.”

at a glance ➤ The AMPLE trial is the first randomized controlled study comparing the safety and efficacy of 2 biologic drugs in combination with methotrexate in RA ➤ Treatment responses were similar for the 2 drugs and were sustained to 12 months ➤ No significant differences in side effects were observed between the 2 groups ➤ These findings show that abatacept can be a safe and effective alternative to adalimumab treatment

there is another treatment option that is as effective and as safe as adalimumab,” he said.

agents for the primary end point of ACR20 and provide relevant data on ACR50 and ACR70.”

“It really is a great leap forward for us and our patients, as it shows

More Comparisons to Come?

Going forward, it will be interesting to see if head-to-head clinical trials such as AMPLE will proliferate as stakeholders in the pharmaceutical industry vie for favorable positioning in light of advancing healthcare reform legislation. As drug prices come under increasing scrutiny, comparative effectiveness studies will inevitably play a large role in ensuring payers that they are getting the value for what they paid for. ■

evidence is strong in favor of tight control, with early initiation of DMARD or biologic DMARD therapy.

In patients with mild disease, however, aggressive tight control may not be the best strategy.

It is important to remember that the real-world population of patients with RA is more heterogeneous than the clinical trial population. The data suggest that treating patients based on a treatment protocol is preferable to

physician-based decision-making. The use of standardized disease indices is important to achieve a treat-to-target goal of low disease activity or clinical remission.

Providers are advised to apply intensive therapy early in patients with RA, except in patients with mild disease, and follow the treat-to-target strategy, with the understanding that clinical remission is the goal of therapy. ■

—Michael H. Schiff, MD, FACR

In The Literature The Evidence for Tight Control... Continued from page 16 With the advent of biologic therapies in RA, clinical trials comparing DMARD monotherapy versus a combination of a DMARD plus a biologic agent have demonstrated that early, intensive treatment can have significant benefits on limiting disability in patients with RA. A head-to-head comparison of step-up versus initial combination therapy with conven-

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tional DMARD or biologic therapy also favored an initial intensive regimen with subsequent step-down rather than step-up therapy.

Other trials suggest that step-up therapy can yield good results if patients are closely monitored and if treatments are modified to achieve rapid remission.

The concept of tight control in patients with RA is analogous to tight control in patients with diabetes. The

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Rheumatology Practice Management

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Medicare Part D: Considerations for Rheumatology Practices

By Kip Piper, MA, FACHE President, Health Results Group, LLC, Washington, DC

T

he Medicare Part D drug benefit has important implications for rheumatology practices. As Part D continues to evolve, so do its challenges and opportunities. This article outlines some of the basic details of Medicare Part D and the challenges it poses.

Today, the Medicare program provides $591 billion in healthcare services to 48 million beneficiaries. In 2012, Medicare benefits include $130.7 billion worth of physician services and $69.4 billion in prescription drugs.

To understand Medicare Part D (the Medicare prescription drug benefit), it is necessary to be familiar with all 4 parts of Medicare, and how care is delivered through fee-for-service (FFS) or health insurance plans.

Medicare Part A provides coverage for inpatient hospital services. Part B covers physician services, outpatient services, and physician-administered drugs; Part B is optional, but most beneficiaries elect to participate. Parts A and B can be received through an FFS basis or through Part C, which is better known as Medicare Advantage (MA).

Medicare Part D was established in 2006 to provide outpatient prescription drug coverage for all Medicare beneficiaries. Participating in Part D is voluntary, but this benefit is available through health plans only. Beneficiaries must select a drug plan to receive Part D coverage.

If Medicare beneficiaries enroll in the Part D benefit but wish to receive their other Medicare benefits (Parts A and B) through an MA health plan, they may sign up for the prescription drug plan of their HMO or PPO. Approximately 32.7 million Americans are enrolled in Medicare Part D. Most Part D enrollees pay a monthly premium and are subject to an annual deductible, copayments, and a coverage gap. Approximately 11 million low-income Medicare beneficiaries receive subsidies to cover Medicare Part D costs. Of these, approximately 7 million are also enrolled in their state’s Medicaid program and may also receive all Medicaid-covered services.

Rules Regarding Drugs Often Used in Rheumatology Practices Medicare Part D is available to

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everyone who is aged ≥65 years, those with permanent disabilities, and those with severe kidney disease (ie, end-stage renal disease). This also includes all individuals who already are enrolled in Medicare Part A or Part B. You should be aware of the availability of drugs frequently taken by patients in the practice, because each Part D plan can have different coverage and cost-sharing requirements.

Part D formularies are devised based on the appropriate use of pharmaceutical agents and their cost.

You should be aware of the availability of drugs frequently taken by patients in the practice, because each Part D plan can have different coverage and cost-sharing requirements.

Stand-alone (ie, drug only) Part D plans may be particularly sensitive to drug cost, because they are at risk for pharmacy expenses alone. Unlike stand-alone Part D plans, MA plans also provide medical benefits, and therefore are potentially able to realize hospital-related and other net medical

Table

savings from improved medication therapy.

Before your patients enroll in a Medicare prescription drug plan, encourage them to first determine whether they are eligible for the plan and whether the plan is suitable for their needs (Table). Urge them to secure a list of prescription drugs covered by the plan and to determine the cost of the prescription drugs that they take in the plan.

Patients receiving medication for a chronic disease should be urged to find a plan that will offer them continued use of a necessary drug at a reasonable cost and without undue restrictions on quantity. If monthly quantity limitations become an issue (usually with mail-order pharmacies), it may be necessary to prescribe smaller quantities that could be filled at a local retail pharmacy. To ensure adherence, practice managers should have a system in place to provide timely prescriptions when necessary to prevent patients from going without their medications.

Be aware that if a patient is enrolled in a Medicare plan that provides prescription drug coverage and then enrolls in a drug-only prescription drug plan, the patient will be disenrolled from their MA plan and be returned to Medicare FFS for Part A and Part B services. This may have consequences for the patient, because many MA plans offer lower premi-

Advising Rheumatology Patients on Part D Enrollment

Instruct your patients to: • Make a list of all prescription medications they are taking, including chemotherapy agents • Examine the plan options carefully, because the plan premiums, drug coverage, and patient cost-sharing can vary substantially • Check the Medicare plan finder for health, prescription drug, and Medigap plans (www.medicare.gov/find-a-plan/) to see which of the patient’s prescription drugs are on the formulary of the plan of their choice; if patients do not have access to a computer, conducting the search for them will facilitate their being able to afford a necessary drug later and will help ensure compliance • Speak with their rheumatology practice administrator, especially if they are unsure whether a drug they are taking is covered by a specific plan • Obtain the prescribed drug from a pharmacy that participates in the network of the patient’s Medicare Part D plan; often, Part D enrollees may also use a mail-order pharmacy service offered by their drug plan

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ums or other cost-sharing features— sometimes with added benefits—than traditional FFS Medicare.

Medicare prescription drug plan enrollees must choose a specific benefit option (offered by private insurers) to help pay for their prescription drugs. The annual open enrollment period is from November 15 to December 31. Joining or changing a plan can be done only during this open enrollment period. The plan a patient chooses will become effective on January 1. For further information, direct patients to www.medicare.org/ medicare-basics/23-medicare-basics/ 287-medicare-enrollment-periods. html.

Encourage your patients to read their plan coverage carefully on annual renewal or to bring questions about drug coverage to your attention, because changes can occur that may affect their coverage or choice of drugs, such as formulary changes or changes related to plan premiums, deductibles, copayments, and member pharmacies where prescriptions can be filled.

Educate Patients on How Medicare Part D Works Your patients may have questions about the Medicare prescription drug benefit. This article provides information about the topics listed below that will be helpful for them. By answering patient questions and serving as a knowledgeable source of information, you have an opportunity to improve patient satisfaction and retention.

A potential customer should first review the prescription drug formulary that lists which drugs a plan covers to be sure his/her current drugs are on that insurer’s formulary.

Educate patients about what to look for in a plan, such as the following: • The formulary (the list of prescription drugs covered by the insurer) • The premium (monthly fee for the plan) • The deductible (amount you must pay before your plan begins to pay for drugs); no plan may have a deductible >$320; some plans have no deductible • The copay (amount you must pay toward the cost of each prescription you fill) Continued on page 20

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Rheumatology Practice Management

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Medicare Part D: Considerations for Rheumatology...

• The member pharmacies that can fill the patient’s prescriptions • The coverage gap, the amount of extra coverage provided during the “doughnut hole.”

Explain How a Formulary Works The formulary lists drugs that are covered by a Part D plan. Plans are often flexible with regard to benefits with cost-sharing. Levels of cost-sharing vary for generics, preferred drugs, and nonpreferred drugs.

All Medicare drug plans are required to cover at least 2 outpatient drugs in every therapeutic class. In addition, these plans are required to cover all drugs in 6 classes—anticonvulsants, antidepressants, antineoplastics, antipsychotics, antiretrovirals, and immunosuppressants for the treatment of transplant rejection.

Patients should be alerted to check not only the formulary but also the formulary tiers of each plan, because this affects the cost of each drug.

Remind patients that drugs in a lower tier will cost less than drugs in a higher tier. However, if the rheumatologist prescribes a drug in a higher tier, your patient may be able to ask the drug plan for an exception or to arrange for a lower copayment.

Patients or prescribers must contact the drug plan before certain prescriptions can be filled. All drugs must be medically necessary, and quantity limits on how much medication can be purchased at one time will apply.

Quantity limits usually apply for selfadministered drugs. Part D covers all commercially available vaccines and all drugs deemed necessary to prevent illness; however, each plan varies regarding which drugs are considered preventive.

The Coverage Gap All Medicare Part D plans have a temporary limit on coverage for prescription drugs, which is called a “coverage gap” (also known as the “doughnut hole”). The coverage gap begins after a plan has spent a certain amount of money for drugs covered in the plan on a beneficiary. Because each Part D plan varies, rheumatology practices should instruct their patients to call their plan to get information about the coverage cap.

In general, when the patient and the insurer pay a combined total of $2930 in drug spending, the coverage gap comes into play. After spending an additional $4700 out of pocket (OOP), or $6658 in total drug

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costs under the standard benefit, the plan once again pays a share of the drug cost. These amounts are updated annually.

Under the Affordable Care Act, the Part D coverage gap will be gradually reduced, until total beneficiary costsharing for brand-name and generic drugs purchased during the coverage gap reaches 25% by 2020. This is funded through a combination of a new, mandatory 50% discount provided by branded drug manufacturers and increased federal government subsidies for both branded and generic drugs.

Patients should be alerted to check not only the formulary but also the formulary tiers of each plan, because this affects the cost of each drug.

For beneficiaries in the coverage gap, branded drugs are discounted by 50% in 2012. Medicare will provide an additional 2.5% discount in 2013 and 2014. This added discount (in addition to the 50% discount provided by drug makers) will increase until it reaches 25% in 2020 and after. Thus, by 2020, the combined discounts from manufacturers and the government will amount to 75%. Medicare Part D beneficiaries will be responsible for the remaining 25%, which is the same amount of cost-sharing as in the initial coverage phase.

Although the patient in the coverage gap pays only 50% of the cost of a branded drug in 2012, the entire pharmacy price of the drug will count as an OOP expense. This helps to remove patients from the coverage gap faster.

While in the coverage gap, Medicare Part D patients receive a 14% discount on the cost of generic drugs in 2012. Medicare will cover an additional 7% in subsidies annually until, in 2020 and thereafter, the subsidy reaches 75% of the cost of generic drugs in the coverage gap.

When requirements and cost thresholds of the coverage gap are met, “catastrophic coverage” begins, meaning that patients will pay only a small coinsurance or copayment for covered drugs for the remainder of the year (5% or $2.60 for generic or preferred multisource drugs and the

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greater of 5% or $6.50 for all other drugs in 2012).

Medicare Part D enrollees who are also enrolled in Medicaid (ie, dualeligible) are exempt from Part D premiums, deductibles, and the coverage gap, and they have lower copayments.

How Your Patients Can Save Money during the Coverage Gap Patients have several options to help them manage prescription drug costs during the coverage gap: 1. Switching to generic or lower-cost drugs where possible 2. Using a mail-order pharmacy 3. Applying for Medicaid; Medicare Part D enrollees who are also enrolled in Medicaid are exempt from Part D premiums, deductibles, and the coverage gap, and they have lower copayments 4. Checking out pharmaceutical assistance programs: many drug manufacturers offer such programs for people enrolled in Medicare Part D; patients can determine whether this program is offered by a particular drug manufacturer by visiting www.medicare.gov/pharmaceuticalassistance-program/index.aspx 5. Seeking assistance from a possible state pharmaceutical assistance program (www.medicare.gov/pharma ceutical-assistance-program/stateprograms.aspx) 6. Continuing to use the Medicare drug plan each time they fill a prescription to ensure they are getting the correct coverage and manufacturer discounts; this will count toward OOP costs 7. Exploring national and communitybased charitable programs that might offer financial help with drug costs (www.benefitscheckup.org) 8. Contacting Social Security about qualifying for the Extra Help program to help pay for prescription drugs.

OOP costs that contribute to the maximum threshold and therefore help patients move out of the coverage gap include the annual deductible, the costs of drugs, coinsurance or copayments, manufacturers’ discounts, and any fees paid during the coverage gap.

Are Your Patients Qualified for Extra Help?

Patients who are unable to continue taking necessary medications because of cost may qualify for a governmentsponsored Extra Help program.

Continued from page 19

Individuals earning <$16,335 (single) or <$22,065 (married, with no other dependents) may qualify for the prescription drug low-income subsidy.

Rules vary from state to state, and there also may be restrictions based on a person’s cash resources in savings or checking accounts. Individuals who are already enrolled in state Medicaid programs or Supplemental Security Income benefits will automatically qualify for the Extra Help program and need not apply for the benefit.

Extra Help will subsidize the beneficiary’s Part D premium, as well as any copayments, coinsurance, and deductibles, and will pay from $1 to $6 for each drug. Patients who qualify for Extra Help will not have a coverage gap.

Rheumatology practice administrators can play an important role by helping patients navigate the Medicare system and identify plans that will cover necessary drugs.

Specialty Tier for High-Cost Drugs Some higher-cost drugs are included in what is called a “specialty tier.”

Although enrollees can request an exception when a plan designates a drug as nonpreferred, exceptions cannot be made for drugs in the specialty tier. Cost-sharing for drugs listed in the specialty tier typically is approximately 25% coinsurance but may be as high as 50% coinsurance.

As of 2007, all drugs that cost >$500 monthly are eligible for the specialty tier. Today, an increasing number of drugs on the specialty tier (eg, biologics) cost >$1000 monthly.

There are concerns that the specialty tier may limit patient access to prescription drugs. In 2010, New York became the first state to prohibit the use of specialty drug tiers.

Several states are in the process of following suit.

Rheumatology practice administrators can play an important role by helping patients navigate the Medicare system and identify plans that will cover necessary drugs, prioritizing their patients’ drugs, and being proactive regarding high-cost drugs. ■

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Gout

Gout Studies Presented at ISPOR

By Barbara Schwedel Washington, DC—Gout affects approximately 1% to 2% of the US population. The results of 2 recent studies involving patients with gout were presented at a poster session during the 2012 International Society for Pharmacoeconomics and Outcomes Research (ISPOR) annual meeting.

Uric Acid Levels Linked to Patient Medication Adherence Patients who are not adhering to their uric acid–lowering therapy are more likely to not reach their uric acid goals than patients who are adherent to therapy, according to the results of the first study on gout that was presented at ISPOR. This study was a retrospective analysis of the potential link between patient adherence to allopurinol therapy and the attainment of uric acid goals. Urate-lowering therapies are effective in lowering uric acid levels in patients with gout, but evidence has shown that their use is often suboptimal, and that many patients with gout have poor outcomes.

Allopurinol is the most often prescribed medication used for the management of uric acid levels in this patient population. Nevertheless, many patients who are prescribed this medication do not reach the goal serum urate of <6.0 mg/dL, the level that is associated with improved outcomes in patients with gout.

Nazia Rashid, PharmD, MS, Outcomes Research Pharmacist, and colleagues of Kaiser Permanente, Downey, CA, evaluated the characteristics of patients, prescribers, and adherence patterns of patients with gout who were initiating treatment with allopurinol.

The investigators identified 9288 patients (mean age, 60 years; men, 78%) who were newly diagnosed with gout between January 1, 2007, and June 31, 2010, and were new users of allopurinol. All patients had ≥1 comorbid

condition. Patients were followed for at least 12 months after the initiation of allopurinol therapy.

The mean medication possession ratio (MPR) was 92% for patients who were at goal compared with 77% for patients not at goal.

Approximately 60% of patients with gout who are prescribed allopurinol and are not adherent to the treatment regimen are not achieving their goal uric acid levels (<6.0 mg/dL).

Among all the patients who had more than 1 allopurinol prescription and were adherent to therapy (MPR >80%), 1793 (65%) reached their goal uric acid level (<6.0 mg/dL) and 2604 (40%) did not reach that goal. By contrast, among the patients who were not adherent to allopurinol therapy (MPR <80%), only 956 (35%) reached the goal uric acid level of <6.0 mg/dL compared with 3935 (60%) patients who did not reach that goal uric acid level.

Overall, men who were older and patients who visited a rheumatologist within 6 months preceding their first allopurinol prescription or measurement of their first uric acid level were more adherent to the regimen and were at goal (odds ratio [OR], 1.21; 95% confidence interval [CI], 1.021.43). Older patients (OR, 1.02; 95% CI, 1.01-1.02) and those who were at least 80% adherent (OR, 2.82; 95% CI, 2.56-3.11) were more likely to be at uric acid goal.

At the end of the study, 2749 (30%) of the patients (mean age, 63 years; men, 71%) achieved the goal uric acid level

of <6.0 mg/dL and 6539 (70%) of the patients (mean age, 59 years; men, 81%) did not achieve that goal.

This study shows that 60% of new allopurinol users are not adherent to uric acid–lowering therapy, resulting in patients not reaching their goal uric acid levels. Patient factors such as age, care by a rheumatologist, and adherence were associated with achieving uric acid goal levels.

The investigators suggest that new strategies, such as targeting specific factors to improve the care of patients with gout and to enhance patient adherence to therapy, are needed.

Validating Patient-Reported Outcomes in Gout Patient-reported outcomes (PROs) are gaining in importance in clinical studies and in medical research overall.

The goal of the second study on gout was to use a direct-to-patient strategy that combines information reported by patients (ie, PROs) and medical record information to evaluate the validity of PROs, based on data contained in the patients’ medical records.

Elisa Cascade, MBA, Vice President of MediGuard.org, Rockville, MD, and her colleagues compared PROs and medical record information of 50 patients with gout from MediGuard.org to see if the information will match.

Adult members (aged 18-80 years) of MediGuard.org, a free medication monitoring service, were randomly invited to participate by e-mail if they had a self-reported gout diagnosis or self-reported use of a gout medication. The first 50 eligible and consenting participants completed an online survey and a release form. The release forms were provided to Ms Cascade’s colleagues at Outcomes Health Information Solutions in Marietta, GA, who then requested a copy of the participants’ medical charts from their physicians.

A total of 120 US members (10% of

1250 invitees) clicked on the e-mail link provided (before the study closed with 50 consenting participants). Of these 120 invitees, 5 (4%) declined to participate because of the medical record release requirement. Up to 33% of additional patients discontinued by closing their browser window, with reasons not provided.

The collected age and sex data compare favorably to US national data, and 38 (76%) of the 50 requested medical charts were obtained. Of the 38 total available charts, 35 (92%) contained a gout diagnosis, 2 mentioned a gout medication (ie, allopurinol or colchicine), and 1 chart did not contain any mention of gout or a gout medication.

Although concerns exist regarding the validity of self-reported diagnoses, nearly all medical charts confirmed the study’s patient-reported data.

These results indicate, the investigators noted, that “patients can be successfully recruited directly for observational study designs that include PRO and medical record data.” Furthermore, these results show that PROs match well with information in the patient’s medical records.

Although concerns exist regarding the validity of self-reported diagnoses, nearly all medical charts confirmed the study’s patient-reported data; based on this small study, data completeness or validation of data can reach a level of more than 75%. New studies with more patients are ongoing to see if these results could be confirmed with more participants. ■

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ISPOR Annual Meeting

A New Approach to Estimating Healthcare Costs in Rheumatology Applying medical expenditure data to disease severity scores

By Barbara Schwedel Washington, DC—Mapping disease severity into a panel of economic data can help to predict the marginal economic effects of increasing severity of rheumatoid arthritis (RA), according to a first economic analysis of its type presented at a poster session during the 2012 International Society for Pharmacoeconomics and Outcomes Research annual meeting.

Using information from the Consortium of Rheumatology Researchers of North America (CORRONA) Registry, a patient registry that routinely collects clinical outcomes data from rheumatology practices across the United States, Michael Ingham, MSc, Health Economics & Outcomes Research Rheumatology Lead, at Janssen Scientific Affairs, LLC, in Horsham, PA, and colleagues compared data from CORRONA with cost data from a large cohort of patients

with RA in the Medical Expenditure Panel Survey (MEPS).

to patients with RA. Total healthcare costs for predetermined RA disease

Combining RA disease severity data and economic parameters can help to predict the economic effects of increases in disease severity. Patients with RA who can reach and maintain lower disease activity are likely to save substantial costs to the US healthcare system.

Data were collected on 19,011 patients with RA from the CORRONA Registry and were compared with expenditure data from MEPS. A mapping algorithm was developed by applying the Clinical Disease Activity Index (CDAI) and modified Health Assessment Questionnaire (HAQ) severity scores in the CORRONA data set on a list of clinical factors relevant

severity were then estimated based on data in MEPS. Results showed that the annual costs of prescription medications represented from 10% to 30% of total healthcare expenditures for patients with RA. Based on CDAI scores for patients with low RA activity, the incremental increase in total healthcare cost for

patients with moderate disease activity was $3051 (95% confidence interval [CI], $1274-$4828) and $6221 (95% CI, $2110-$10,332) for patients with high disease activity.

Based on modified HAQ scores for patients with low RA activity, the incremental increases in total healthcare costs was $4149 (95% CI, $1194$7104) for patients with moderate disease activity and $6102 (95% CI, $1870-$10,335) for those with high disease activity.

The researchers noted combining RA disease severity data and economic parameters can help to predict the economic effects of increases in disease severity. The results of this particular analysis indicate that patients with RA who can reach and maintain lower disease activity are likely to save substantial costs to the US healthcare system. ■

Patient-Reported Outcomes Support the Treat-to-Target Paradigm in RA Washington, DC—National and international rheumatology groups have defined the goals of the treat-to-target strategy in rheumatoid arthritis (RA) as achieving disease remission or as low disease activity level. A new analysis presented at the 2012 International Society for Pharmacoeconomics and Outcomes Research annual meeting focused on the difference in patient-reported outcomes between patients with RA who achieved the treat-to-target disease activity goals and those who did not.

For this post-hoc analysis, Michael Ingham, MSc, Health Economics & Outcomes Research Rheumatology Lead, Janssen Scientific Affairs, LLC, Horsham, PA, used information from RESTART, a phase 4 clinical trial of 203 methotrexate-treated patients with active RA who responded inadequately to treatment with etanercept or with adalimumab and were switched to infliximab therapy for 22 weeks.

Given RESTART’s high baseline Clinical Disease Activity Index (CDAI) scores, the definitions for responder subgroups were based on

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real-world goals of low or moderate RA activity rather than on remission, regardless of any improvement in CDAI scores. Patients were divided into subgroups based on real-world CDAI response thresholds at week 26: • Subgroup A: CDAI ≤19.6 (moderate

Table

disease activity) • Subgroup B: CDAI ≤19.6 and CDAI reduction of ≥10 points (moderate disease activity with significant improvement) • Subgroup C: CDAI ≤7.6 (low disease activity).

Mean Change from Baseline in SF-36 Domains at Week 26 in Subgroup Ba Mean change from baseline Attaining Not attaining treat-to-target treat-to-target goals goals (N = 76) (N = 75)

SF-36 domain Bodily pain

23.5

8.3

P value <.0001

General health

9.4

2.6

<.01

Mental health

7.7

3.2

NS

Physical functioning

13.4

4.6

<.01

Role emotional

18.4

20.5

NS

Role physical

31.6

14.7

<.01

Social functioning

16.1

5.8

<.01

Vitality

18.7

6.8

<.0001

In subgroup B, the response thresholds at week 26 were as follows: CDAI ≤19.6 and CDAI reduction of ≥10 points (moderate disease activity with significant improvement).

CDAI indicates Clinical Disease Activity Index; NS, not significant; SF-36, 36-Item Short Form Health Survey.

a

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Health Assessment Questionnaire (HAQ) scores and the 36-Item Short Form Health Survey (SF-36) domains were used to compare responders and nonresponders in each subgroup.

By week 26, compared with nonresponders, those who showed response to treatment typically achieved 2- to 3fold better improvement from baseline in most SF-36 domains and 2- to 8-fold greater improvement on the HAQ, with the greatest differences seen in subgroup C. In subgroup B, where responders and nonresponders had the most comparable baseline scores, the mean change from baseline was significant in most SF-36 domains at week 26 (Table).

In addition to the significantly greater improvement of responders than nonresponders in subgroup B on most end points, patients who did not achieve prespecified treat-to-target goals by week 26 still improved on health status and functionality; therefore, the researchers suggest, considering the patient functional status within the treat-to-target goals may also be warranted.—BS ■

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