VBCR December Vol 3 No 6

DECEMBER 2014 VOL 3 • NO 6

www.ValueBasedRheumatology.com VBCR PERSPECTIVE

ACR CONFERENCE HIGHLIGHTS

Treat-to-Target Optimal Approach in Early Active RA

By Phoebe Starr

Incorporating Educational Interventions into the Treatment Regimen for Patients with RA

By Howard Blumstein, MD, FACR Dr Blumstein is a Rheumatologist at the Rheumatology Associates of Long Island, Smithtown, NY

R

heumatoid arthritis (RA) is a chronic, systemic inflammatory illness with significant potential for morbidity and disability.

Although treatment options have sig-

Boston, MA—Early aggressive management of rheumatoid arthritis (RA) with a treat-to-target approach resulted in similar 10-year mortality compared with the general Dutch population, according to results of the BeST randomized trial reported

at the American College of Rheumatology 2014 Annual Meeting.

No matter which medications or sequence of medications was used in this 4-arm study, as long as the treatment target was low disease activity, measured by the Disease Continued on page 24

RHEUMATOLOGY UPDATE

New Measures for Infusible Medication Adherence Effective

nificantly expanded in the past 15 years, we are still faced with patients who do not achieve full remission and have persistent symptoms.

Educating our patients about their Continued on page 11

THE Rheumatology NURSE™

SLE and Pregnancy: Considerations in the Care of High-Risk Populations

By Deanna L. Owens, MSN, RN Ms Owens is Director, Infusion and Clinical Services, Low Country Rheumatology, Charleston, SC; and Member, Board of Directors, Rheumatology Nurses Society

S

ystemic lupus erythematosus (SLE), often seen in women of childbearing age, is an autoimmune disease that affects multiple

organ systems. To ensure optimal maternal and fetal health outcomes, proper disease management is key when caring for this high-risk populaContinued on page 20

By Leslie Wyatt Boston, MA—With patient cost-sharing becoming an increasingly common strategy in managed care, the amalga-

mation of our economy and high drug costs can impact decisions made by patients in the name of cost-cutting.

Continued on page 24

INSIDE VALUE PROPOSITIONS. . . . . . . . . . . 4 Ultrasound more effective than clinical evaluation for RA relapse

RHEUMATOLOGY UPDATE. . . . 22 Herpes zoster vaccine may benefit patients with RA

4

DRUG UPDATE. . . . . . . . . . . . . . . . . . . 25 Rasuvo (methotrexate) once-weekly SQ with flexible dosing approved by the FDA

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

Novel program improves quality of care in RA, reduces cost

LUPUS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Use of belimumab may be contro­ versial in SLE PSORIATIC ARTHRITIS. . . . . . . . . 21 Cost-cutting behaviors linked to poor outcomes in PsA © 2014 Engage Healthcare Communications, LLC

IN THE LITERATURE. . . . . . . . . . . . 27 Prioritization tool for RA referrals improves access

Don’t Face the Maze of Changes in Rheumatology Alone

NORM Keeps You Informed National Organization of Rheumatology Managers

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

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

“NORM, by far, surpasses the benefits of any other organization I have ever belonged to. Through the listserv, NORM members willingly assists each other by providing solutions to everyday issues that arise while managing a rheum practice. We share experiences, ideas, protocols and procedures specific to a rheumatology practice. The annual NORM conference in September is definitely the icing on the cake as we all come away with practical ideas and tools we can implement.” Mary Jo Wideman, RN, BSN, Practice Manager

Do you have questions about coding, biologics, insurance carrier denials or personnel issues? Join NORM to help find your answers. Are your questions state specific, MAC specific or national coverage issues? NORM offers rheumatology managers the opportunity to connect across the Nation. Through our listserv you receive expert advice from professionals in rheumatology!

Join NORM and network with experienced managers through our listserv, gain access to our members only section which contains sample practice forms, job descriptions, and other documents that have been shared on this listserv, a list of our members, and in the future educational resources. NORM also hosts webinars throughout the year to continue supporting the education of our members.

Membership is open to rheumatology professionals including physicians and those who hold a management position in a rheumatology practice.

Save the Date for our 2015 2014 Annual Conference September 12 18 & 13, 19, 2014 2015 ~ Louisville, Bellevue, WA KY

NORM ~ www.normgroup.org ~ info@normgroup.org

In This Issue Value-Based Care in Integrating Rheumatologists, NPs/PAs, Practice Managers & Payers

PUBLISHING STAFF Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Director, Client Services Zach Ceretelle zceretelle@the-lynx-group.com Editorial Directors Dalia Buffery dbuffery@the-lynx-group.com Frederique H. Evans, MBS fevans@the-lynx-group.com

TM

VALUE PROPOSITIONS

RHEUMATOLOGY UPDATE

Ultrasound more effective than clinical evaluation for RA relapse Comparing the efficacy of Tai Chi with physical therapy in the treatment of OA

Herpes zoster vaccine may benefit patients with RA Rethinking the herpes zoster vaccine in patients with RA taking biologics Secukinumab promising in AS and PsA

HEALTH ECONOMICS Novel program improves quality of care in RA, reduces in cost

DRUG UPDATE

Copyeditor Hina Khaliq

READER POLL

Editorial Assistant Cara Guglielmon

Do you provide patient education to pregnant patients with rheumatic diseases?

Rasuvo (methotrexate) once-weekly subcutaneous injection with flexible dosing approved by the FDA for rheumatoid arthritis, poly­ articular juvenile idiopathic arthritis, and severe psoriasis

LUPUS

IN THE LITERATURE

Associate Editor Lara J. Lorton

Production Manager Marie RS Borrelli THE LYNX GROUP President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Associate Director, Content Strategy & Development John Welz Director, Quality Control Barbara Marino

Use of belimumab may be controversial in SLE

Prioritization tool for RA referrals improves access to care

PSORIATIC ARTHRITIS Cost-cutting behaviors linked to poor outcomes in PsA

Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs

VBCR Editorial Advisory Board

Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Jr Digital Media Specialist Charles Easton IV Web Content Manager Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Managers Alyson Bruni Jini Gopalaswamy Project Manager Deanna Martinez Project Coordinator Mike Kodada IT Manager Kashif Javaid Administrative Services Team Leader Rachael Baranoski Office Coordinator Robert Sorensen Engage Healthcare Communications, LLC 1249 South River Road, Ste 202A Cranbury, NJ 08512 Telephone: 732-992-1880 Fax: 732-992-1881

Value-Based Care in Rheumatology, ISSN (applied), is published 6 times a year by Engage Healthcare Com­ munications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2014 by Engage Health­ care Communications, LLC. All rights reserved. Value-Based Care in Rheumatology is a 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 pho­ tocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Print­ ed 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 adver­ tisement 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.

Howard B. Blumstein, MD Rheumatology Associates of Long Island, Smithtown, NY Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield New York, NY Sheree C. Carter, PhD, RN Assistant Clinical Professor The University of Alabama in Huntsville; President, Rheumatology Nurses Society

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

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

Gary M. Owens, MD President, Gary Owens Associates Philadelphia, PA Kim A. Papp, MD, PhD Founder and President Probity Medical Research Waterloo, Ontario, Canada

John Kolstoe, MD Kolstoe Rheumatology Musculoskeletal Medicine East Lansing, MI

Gary R. Feldman, MD, FACR Private Practice, Pacific Rheumatology, Los Angeles, CA

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

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

Joel M. Kremer, MD Pfaff Family Professor of Medicine Albany Medical College Director of Research, Center for Rheumatology, Albany, NY

Atheer A. Kaddis, PharmD Vice President, Managed Markets Diplomat Specialty Pharmacy Swartz Creek, MI Shelly P. Kafka, MD, FACR Rheumatologist, Mountain State Rheumatology, Medical Director, Mountain State Clinical Research Clarksburg, WV Clinical Assistant Professor West Virginia University School of Medicine, Morgantown, WV

Jeffrey S. Peller, MD Practicing Rheumatologist Harbin Clinic/Rheumatology Rome, GA Edmund J. Pezalla, MD, MPH National Medical Director for Pharmacy Policy and Strategy Aetna, Hartford, CT

Alan Menter, MD Director, Baylor Psoriasis Research Center Dallas, TX Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Murray, UT

William A. Sunshine, MD, FACR Rheumatology Practice Boca Raton & Delray Beach, FL Ronald van Vollenhoven, MD, PhD Associate Professor Karlinska University Hospital Solna Stockholm, Sweden F. Randy Vogenberg, RPh, PhD Principal, Institute of Integrated Healthcare, Greenville, SC

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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.

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Value Propositions Ultrasound More Effective Than Clinical Examination to Determine RA Remission

To identify a clear method of assessing remission in patients with rheumatoid arthritis (RA), investigators conducted a systematic review of the literature and found that ultrasounds may be more effective than clinical examination. Previous data indicated that the use of musculoskeletal ultrasound may be effective in the assessment of synovitis, effusion, and bone damage. “Remission is the ultimate goal of the treatment of rheumatoid arthritis,” the authors explained. “However, the diagnosis of remission is still vague.”

A literature search was performed using MEDLINE and Scopus, and included the key words “remission,” “rheumatoid arthritis,” and “ultrasound.” Among 56 articles that were identified in the review process, 12 articles on the assessment of remission in patients with RA were selected for analysis. Remission criteria varied between the articles as well as the number of joints evaluated using ultrasound.

In addition, the authors of the studies included in the analysis all demonstrated that ultrasounds detected positive synovitis in patients who were in remission. They also found that structural damage and flare-ups of RA could be predicted using power Doppler ultrasounds of synovitis.

The researchers noted that although ultrasonography was more efficacious than clinical examinations of patients in remission, it is important for remission in RA to be defined. Ben Abdelghani K, et al. Diagn Interv Imaging. 2014 September 11 (Epub ahead of print)

Trial Assessing the Efficacy of Tai Chi in Knee OA Under Way

There are a limited number of effective treatments available for knee osteoarthritis (OA), which has led to more than $185 billion in annual healthcare costs in the United States. Using a 52-week, randomized controlled trial design, investigators are seeking to evaluate the efficacy of Tai Chi compared with physical therapy in adults ≥40 years with symptomatic and radiographic knee OA at an urban tertiary care medical center in Boston, MA. Patients were randomized to 12 weeks of physical therapy (2 times a week for 6 weeks, and then 6 weeks of carefully supervised exercise at home) or Tai Chi (2 times a week). At week 12, primary outcomes will be measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale.

Secondary outcomes measured at weeks 12, 24, and 52, in a variety of assessments, include evaluation of WOMAC stiffness and function domain scores, strength of lower extremities, health-related quality of life, and psychosocial and psychological functioning.

“When completed, the study will be the largest mind-body therapy study which compares to a standardized physical therapy regimen on symptomatic knee OA population with long-term follow up,” the investigators concluded. “Our robust and well-designed randomized comparative-effectiveness trial will fill a critical knowledge gap in this field, and results of this study are likely to have significant public health implications.” Wang C, et al. BMC Complement Altern Med. 2014;14:333

Health Economics

Novel Program Improves Quality of Care in RA, Reduces Cost

By Phoebe Starr Boston, MA­—The AIM FARTHER program developed at Geisinger Health System in Pennsylvania is a unique initiative designed to improve the quality of care for patients with rheumatoid arthritis (RA) and reduce costs. The program has been successful after 22 months. The cost of care for patients with RA was reduced by $1 million in 2014. “AIM FARTHER is a new value-based, population-care model,” explained Eric Newman, MD, Director of Rheumatology, Geisinger Health System and designer of AIM FARTHER. “We’ve improved the lives of more than 2300 RA patients, redefined the role of the rheumatologist to include a primary specialist role and provide management, advice, and be the steward of registry data.”

Starting with an RA Model “This model can be adapted to other chronic conditions, including gout. We are starting a gout program at our center,” he said at a press conference during the American College of Rheumatology 2014 Annual Meeting. “We are setting ourselves up for

4

the future, so no matter how the environment and regulations change, we will be able to handle it.”

Why choose RA for rollout of this model? RA is a complex, common, and costly condition that affects an estimated 1.3 million Americans. The disease is associated with an effect on employability, longevity, and quality of life.

The program has several objectives, including improving quality of care through a strategic approach, measuring disease activity and reporting, and reducing costs of care including variable use of biologics. The program also aims to integrate rheumatologists with primary care practices.

In addition, the new model incorporates several components, such as developing a registry; defining roles and attribution; integration of primary and specialty care; and creating a new strategic approach to RA care.

The new program also seeks to establish RA quality measure bundle management, as well as task management and performance reporting, and a new financial incentive model.

The RA quality measure bundle comprises 8 measures: RA on dis-

VALUE-BASED CARE IN RHEUMATOLOGY

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DECEMBER 2014

ease-modifying antirheumatic drug (DMARD), active RA on DMARD, RA with Clinical Disease Activity Index measurement, RA at low disease activity, tuberculosis testing if on a biologic, influenza vaccine, pneumococcal vaccine, and low-density lipoprotein level checked.

As an example, he elaborated on the task management and performance reporting component, which is a 4-step process. (1) Programming of quality measures using a specialized software system that collects information from patients via a touch-screen questionnaire. The data are integrated with electronic records and stored in a database, and the nurse and physician to interact in real time. (2) Patient-level scorecard that lists specific quality measures in stoplight format: green = met; yellow= not yet met; red = not met. (3) Develop task management. The scorecard is presented at each visit to define care gaps and close them. (4) Develop performance reporting. Each patient is assigned to a specific provider. Quality reports are generated at the provider level and division level to help engage providers in reporting change.

Results of the New Model Testing the new model involved all members of a multidisciplinary team who cared for patients with RA. “This moves team members from engagement in the process to ownership,” Dr Newman explained.

At 22 months, 40% of the 2378 RA patients tracked had achieved 100% of their applicable quality measures compared with only 22% at the beginning of the study in August 2012. Significant improvement was observed in all quality measures tracked, except active RA on DMARD, which was 92% at the beginning of the study and 93% at 22 months. “The improvement in quality measures at 22 months resulted in levels not achieved by any other group in the country,” he stated.

“The difference in this program is that doctors are coming together to make quality improvement changes rather than MBAs,” said Monique Hinchcliff, MD, Feinberg School of Medicine at Northwestern University of Chicago, IL. “The rheumatology team involves everyone who participates in the process.” n

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DISCOVER A DIFFERENT STATE OF MIND WHEN YOU CAN’T PRESCRIBE MTX When MTX is no longer an option for your DMARD-IR RA patients, consider ACTEMRA The benefits and risks of treatment should be considered prior to initiating ACTEMRA. Patients should be monitored during treatment with ACTEMRA. Please see following brief summary of Prescribing Information, including Boxed WARNING, for additional important safety information.

MTX=methotrexate; DMARD-IR=disease-modifying antirheumatic drug inadequate responder.

Indication ACTEMRA is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs).

Important Safety Information BOXED WARNING Serious Infections Serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial, invasive fungal, viral, and other opportunistic infections, have occurred in patients receiving ACTEMRA. ACTEMRA should not be administered during an active infection, including localized infections.

If a serious infection develops, ACTEMRA should be interrupted until the infection is controlled.

Prior to initiating ACTEMRA, a test for latent TB should be performed.

If the test is positive, treatment for TB should be started prior to starting ACTEMRA. All patients should be monitored for active TB during treatment, even if initial latent TB test is negative.

The benefits and risks of treatment should be considered prior to initiating ACTEMRA in patients: • with chronic or recurrent infection • who have been exposed to TB • who have a history of serious or opportunistic infections • who have resided or traveled in areas of endemic TB or mycoses • with underlying conditions that may predispose them to infection Patients should be closely monitored for signs and symptoms of infection during and after treatment with ACTEMRA. Please see following pages for full Important Safety Information and brief summary of Prescribing Information.

®

WHEN MTX IS NO LONGER AN OPTION FOR YOUR DMARD-IR RA PATIENTS, CONSIDER ACTEMRA

Contact a rep at ActemraHCP.com for more information

ACTEMRA DELIVERED RAPID RESPONSE AT WEEK 2 AS A SINGLE AGENT AMBITION: ACR20 Responses Over Time (24 Weeks)1,2 100 ACTEMRA 8 mg/kg IV (every 4 weeks)* (n=286) MTX (n=284)

80

P<0.001

70

ACTEMRA MONOTHERAPY: RAPID RESPONSE AT WEEK 2

Patients (%)

60

53 40

20

AMBITION: Pivotal, randomized, double-blind, Phase III clinical study in MTX-naïve/-free† patients with moderate to severe RA. The primary endpoint was ACR20 response at Week 24. Patients were treated with ACTEMRA 8 mg/kg IV (every 4 weeks)* or an escalating dose of MTX. MTX dose was initiated at 7.5 mg/week and increased to a maximum dose of 20 mg/week within 8 weeks.

The treatment period was 24 weeks. *The recommended starting dose for ACTEMRA IV is 4 mg/kg followed by an increase to 8 mg/kg based on clinical response. † ACTEMRA is not indicated for the treatment of MTX-naïve patients with rheumatoid arthritis (RA). ACTEMRA is indicated for the treatment of adult patients with moderately to severely active RA who have had an inadequate response to one or more DMARDs.

Select Important Safety Information Primary endpoint: ACR20 response at Week 24

0 BL

2

4

8

12

16

20

24

Contraindication ACTEMRA is contraindicated in patients with known hypersensitivity to ACTEMRA.

Time (weeks)

MTX=methotrexate.

Please see following pages for full Important Safety Information and brief summary of Prescribing Information.

ACTEMRA PROVIDED SIGNIFICANT ACR50 AND ACR70 RESPONSES VS MTX AT WEEK 24 *The recommended starting dose for ACTEMRA IV is 4 mg/kg followed by an increase to 8 mg/kg based on clinical response.

Select Important Safety Information

AMBITION: ACR Responses at Week 241,2 100 ACTEMRA 8 mg/kg IV (every 4 weeks)* (n=286) MTX (n=284)

Patients (%)

80

P=0.002

60

44 %

40

Laboratory Monitoring Laboratory monitoring is recommended due to potential consequences of treatmentrelated laboratory abnormalities in neutrophils, platelets, lipids, and liver function tests. Dosage modifications or interruptions may be required.

Please see full Prescribing Information for more information.

P<0.001

34 %

28 % 15 %

20 0 ACR50

ACR70

ACTEMRA + MTX NOT SUPERIOR TO ACTEMRA ALONE ACT-RAY (Supportive Study): DAS28 <2.6 Responses at Week 243 100 ACTEMRA 8 mg/kg IV monotherapy (every 4 weeks)* (n=276) ACTEMRA 8 mg/kg IV (every 4 weeks)* + MTX (n=277)

Patients (%)

80

60

40

Primary endpoint not met Non-significant P=0.19

40 %

ACT-RAY: Supportive, Phase IIIb clinical trial in MTX-IR patients with moderate to severe RA. The study was designed to evaluate the superiority of combination ACTEMRA IV 8 mg/kg + MTX vs monotherapy ACTEMRA IV 8 mg/kg.* Patients received ACTEMRA IV + MTX or ACTEMRA IV every 4 weeks. The primary endpoint was the proportion of patients achieving DAS28 <2.6 at Week 24.

ACT-RAY primary endpoint was not met. *The recommended starting dose for ACTEMRA IV is 4 mg/kg followed by an increase to 8 mg/kg based on clinical response.

35 %

20

0 DAS28 <2.6 DAS=disease activity score.

速

Indication

ACTEMRA is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs).

Important Safety Information

BOXED WARNING Serious Infections Serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial, invasive fungal, viral, and other opportunistic infections, have occurred in patients receiving ACTEMRA. ACTEMRA should not be administered during an active infection, including localized infections. If a serious infection develops, ACTEMRA should be interrupted until the infection is controlled.

Prior to initiating ACTEMRA, a test for latent TB should be performed. If the test is positive, treatment for TB should be started prior to starting ACTEMRA. All patients should be monitored for active TB during treatment, even if initial latent TB test is negative.

The benefits and risks of treatment should be considered prior to initiating ACTEMRA in patients: • with chronic or recurrent infection • who have been exposed to TB • who have a history of serious or opportunistic infections • who have resided or traveled in areas of endemic TB or mycoses • with underlying conditions that may predispose them to infection Patients should be closely monitored for signs and symptoms of infection during and after treatment with ACTEMRA. CONTRAINDICATION ACTEMRA is contraindicated in patients with known hypersensitivity to ACTEMRA. WARNINGS AND PRECAUTIONS Gastrointestinal Perforations Use ACTEMRA with caution in patients who may be at increased risk for gastrointestinal (GI) perforation. Promptly evaluate patients presenting with new-onset abdominal symptoms for early identification of GI perforation.

Laboratory Monitoring Laboratory monitoring is recommended due to potential consequences of treatmentrelated laboratory abnormalities in neutrophils, platelets, lipids, and liver function tests.

Dosage modifications may be required. Please see full Prescribing Information for more information.

Immunosuppression The impact of treatment with ACTEMRA on the development of malignancies is not known, but malignancies were observed in clinical studies with ACTEMRA. ACTEMRA is an immunosuppressant, and treatment with immunosuppressants may result in an increased risk of malignancies.

Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, have been reported in association with ACTEMRA and anaphylactic events with a fatal outcome have been reported with intravenous infusion of ACTEMRA. ACTEMRA for intravenous use should only be infused by a healthcare professional with appropriate medical support to manage anaphylaxis.

For ACTEMRA subcutaneous injection, advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If anaphylaxis or other hypersensitivity reaction occurs, stop administration of ACTEMRA immediately and discontinue ACTEMRA permanently. Do not administer ACTEMRA to patients with known hypersensitivity to ACTEMRA. Anaphylaxis and other hypersensitivity reactions that required treatment discontinuation were reported in 0.1% (3 out of 2644) of patients in the 6-month controlled trials of intravenous ACTEMRA, 0.2% (8 out of 4009) of patients in the intravenous all-exposure RA population, 0.7% (8 out of 1068) in the subcutaneous 6-month controlled RA trials, and in 0.7% (10 out of 1456) of patients in the subcutaneous all-exposure population.

Demyelinating Disorders Monitor patients for signs and symptoms of demyelinating disorders. Prescribers should exercise caution in considering the use of ACTEMRA in patients with preexisting or recent-onset demyelinating disorders.

Active Hepatic Disease and Hepatic Impairment Treatment with ACTEMRA is not recommended in patients with active hepatic disease or hepatic impairment.

Vaccinations Avoid use of live vaccines concurrently with ACTEMRA. Patients should be brought up to date on all recommended vaccinations prior to initiation of ACTEMRA therapy.

ADVERSE REACTIONS

The most common serious adverse reactions were serious infections. In the ACTEMRA-IV monotherapy clinical study, the rate of serious infections was 3.6 per 100 patient-years in the ACTEMRA group and 1.5 per 100 patient-years in the methotrexate group. The rate of serious infections in the 4 mg/kg and 8 mg/kg ACTEMRA plus DMARD groups was 4.4 and 5.3 events per 100 patient-years, respectively, compared to 3.9 events per 100 patient-years in the placebo plus DMARD group.

In the 5 Phase III clinical trials, the most common adverse reactions (≥5% of patients treated with ACTEMRA-IV) through 6 months were: ACTEMRA-IV ACTEMRA-IV ACTEMRA-IV 8 mg/kg 4 mg/kg 8 mg/kg Placebo Monotherapy Methotrexate + DMARDs + DMARDs + DMARDs (%) (%) (%) (%) (%) URTI

7

5

6

8

6

Nasopharyngitis

7

6

4

6

4

Headache

7

2

6

5

3

Hypertension

6

2

4

4

3

Increased ALT

6

4

3

3

1

The safety observed for ACTEMRA administered subcutaneously was consistent with the known safety profile of intravenous ACTEMRA, with the exception of injection-site reactions, which were more common with ACTEMRA-SC compared with placebo-SC injections (IV-arm).

In the 6-month control period, in SC-I, the frequency of injection-site reactions was 10.1% (64/631) and 2.4% (15/631) for the weekly ACTEMRA-SC and placebo-SC (IV-arm) group, respectively. In SC-II, the frequency of injection-site reactions was 7.1% (31/437) and 4.1% (9/218) for the every other week ACTEMRA-SC and placebo-SC groups, respectively. These injection-site reactions were mild to moderate in severity. The majority resolved without any treatment and none necessitated drug discontinuation.

USE IN PREGNANCY: PREGNANCY CATEGORY C Adequate and well-controlled studies with ACTEMRA have not been conducted in pregnant women. ACTEMRA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ACTEMRA during pregnancy.

Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.

PATIENT COUNSELING INFORMATION Advise patients of the potential benefits and risks of ACTEMRA. Physicians should instruct their patients to read the Medication Guide before starting ACTEMRA therapy.

Inform patients that ACTEMRA may lower their resistance to infections and instruct patients of the importance of contacting their doctor immediately when symptoms of an infection appear. Inform patients that some patients receiving ACTEMRA have had serious side effects in the stomach and intestines and instruct patients of the importance of contacting their doctor immediately when symptoms of severe, persistent abdominal pain appear. Assess patient suitability for home use for SC injection. Inform patients that some patients have had serious allergic reactions including anaphylaxis and advise them to seek immediate medical attention if symptoms occur.

Please see following brief summary of Prescribing Information, including Boxed WARNING, for additional important safety information.

References 1. Jones G, et al. Ann Rheum Dis. 2010;69:88-96. 2. Data on file.

AMBITION Clinical Study Report. Genentech Inc. 3. Dougados M, et al. Presented at EULAR Annual European Congress of Rheumatology; June 6-9, 2012; Berlin, Germany.

Poster THU0093.

®

© 2014 Genentech USA, Inc. All rights reserved. ACT/110614/0039

ACTEMRA® (tocilizumab) Injection, for intravenous use Injection, for subcutaneous use This is a brief summary. Before prescribing, please refer to the full Prescribing Information.

WARNING: RISK OF SERIOUS INFECTIONS

Patients treated with ACTEMRA are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions, Adverse Reactions]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. If a serious infection develops, interrupt ACTEMRA until the infection is controlled.

Reported infections include: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before ACTEMRA use and during therapy. Treatment for latent infection should be initiated prior to ACTEMRA use.

• Invasive fungal infections, including candidiasis, aspergillosis, and pneumocystis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.

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

The risks and benefits of treatment with ACTEMRA 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 ACTEMRA, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy [see Warnings and Precautions].

INDICATIONS AND USAGE ACTEMRA® (tocilizumab) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs).

ACTEMRA is indicated for the treatment of active polyarticular juvenile idiopathic arthritis (PJIA) in patients 2 years of age and older.

ACTEMRA is indicated for the treatment of active systemic juvenile idiopathic arthritis (SJIA) in patients 2 years of age and older.

DOSAGE AND ADMINISTRATION ACTEMRA may be used alone or in combination with methotrexate: and in RA, other non-biologic DMARDs may be used.

Recommended Intravenous (IV) Adult RA Dosage Patients who have had an inadequate response to one or more DMARD

When used in combination with DMARDs or as monotherapy the recommended starting dose is 4 mg per kg followed by an increase to 8 mg per kg based on clinical response

• Reduction of dose from 8 mg per kg to 4 mg per kg is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia [see Warnings and Precautions and Adverse Reactions].

• Doses exceeding 800 mg per infusion are not recommended in RA patients [see Clinical Pharmacology].

Recommended Subcutaneous (SC) Adult RA Dosage Patients less than 100 kg weight

162 mg administered subcutaneously every other week, followed by an increase to every week based on clinical response

Patients at or above 100 kg weight

162 mg administered subcutaneously every week

When transitioning from ACTEMRA intravenous therapy to subcutaneous administration administer the first subcutaneous dose instead of the next scheduled intravenous dose.

Interruption of dose or reduction in frequency of administration of subcutaneous dose from every week to every other week dosing is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia (see Dosage and Administration, Warnings and Precautions, and Adverse Reactions).

CONTRAINDICATIONS ACTEMRA is contraindicated in patients with known hypersensitivity to ACTEMRA [see Warnings and Precautions].

WARNINGS AND PRECAUTIONS

Serious Infections Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including ACTEMRA for rheumatoid arthritis.

The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis [see Adverse Reactions]. Among opportunistic infections, tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis were reported with ACTEMRA. Other serious infections, not reported in clinical studies, may also occur (e.g., histoplasmosis, coccidioidomycosis, listeriosis). Patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids which in addition to rheumatoid arthritis may predispose them to infections.

Do not administer ACTEMRA in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating ACTEMRA in patients: • with chronic or recurrent infection • who have been exposed to tuberculosis • with a history of serious or an opportunistic infection

• who have resided or traveled in areas of endemic tuberculosis or endemic mycoses • with underlying conditions that may predispose them to infection

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with ACTEMRA, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants [see Dosage and Administration, Adverse Reactions and Patient Counseling Information].

Hold ACTEMRA if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with ACTEMRA should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.

Tuberculosis Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating ACTEMRA. Consider anti-tuberculosis therapy prior to initiation of ACTEMRA 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.

Closely monitor patients for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy.

It is recommended that patients be screened for latent tuberculosis infection prior to starting ACTEMRA. The incidence of tuberculosis in worldwide clinical development programs is 0.1%. Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before initiating ACTEMRA. Viral Reactivation Viral reactivation has been reported with immunosuppressive biologic therapies and cases of herpes zoster exacerbation were observed in clinical studies with ACTEMRA. No cases of Hepatitis B reactivation were observed in the trials; however patients who screened positive for hepatitis were excluded.

Gastrointestinal Perforations

Events of gastrointestinal perforation have been reported in clinical trials, primarily as complications of diverticulitis in RA patients. ACTEMRA should be used with caution in patients who may be at increased risk for gastrointestinal perforation.

Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation [see Adverse Reactions].

Laboratory Parameters

Rheumatoid Arthritis Neutropenia Treatment with ACTEMRA was associated with a higher incidence of neutropenia. Infections have been uncommonly reported in association with treatment-related neutropenia in long-term extension studies and postmarketing clinical experience.

– It is not recommended to initiate ACTEMRA treatment in patients with a low neutrophil count i.e., absolute neutrophil count (ANC) less than 2000/mm3. In patients who develop an absolute neutrophil count less than 500/mm3 treatment is not recommended.

– Monitor neutrophils 4 to 8 weeks after start of therapy and every 3 months thereafter. For recommended modifications based on ANC results, please consult the full Prescribing Information.

Thrombocytopenia Treatment with ACTEMRA was associated with a reduction in platelet counts. Treatment-related reduction in platelets was not associated with serious bleeding events in clinical trials [see Adverse Reactions].

– It is not recommended to initiate ACTEMRA treatment in patients with a platelet count below 100,000/mm3. In patients who develop a platelet count less than 50,000/mm3 treatment is not recommended.

– Monitor platelets 4 to 8 weeks after start of therapy and every 3 months thereafter. For recommended modifications based on platelet counts, please consult the full Prescribing Information.

Elevated Liver Enzymes Treatment with ACTEMRA was associated with a higher incidence of transaminase elevations. These elevations did not result in apparent permanent or clinically evident hepatic injury in clinical trials [see Adverse Reactions].

Increased frequency and magnitude of these elevations was observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with ACTEMRA.

In one case, a patient who had received ACTEMRA 8 mg/kg monotherapy without elevations in transaminases experienced elevation in AST to above 10x ULN and elevation in ALT to above 16x ULN when MTX was initiated in combination with ACTEMRA. Transaminases normalized when both treatments were held, but elevations recurred when MTX and ACTEMRA were restarted at lower doses. Elevations resolved when MTX and ACTEMRA were discontinued.

– It is not recommended to initiate ACTEMRA treatment in patients with elevated transaminases ALT or AST greater than 1.5x ULN. In patients who develop elevated ALT or AST greater than 5x ULN treatment is not recommended.

– Monitor ALT and AST levels 4 to 8 weeks after start of therapy and every 3 months thereafter. When clinically indicated, other liver function tests such as bilirubin should be considered. For recommended modifications based on transaminases, please consult the full Prescribing Information.

Lipid Abnormalities Treatment with ACTEMRA was associated with increases in lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol [see Adverse Reactions].

– Assess lipid parameters approximately 4 to 8 weeks following initiation of ACTEMRA therapy, then at approximately 24 week intervals.

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

Immunosuppression The impact of treatment with ACTEMRA on the development of malignancies is not known but malignancies were observed in clinical studies [see Adverse Reactions]. ACTEMRA is an immunosuppressant, and treatment with immunosuppressants may result in an increased risk of malignancies.

Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions, including anaphylaxis and death, have been reported in association with ACTEMRA [see Adverse Reactions] and anaphylactic events with a fatal outcome have been reported with intravenous infusion of ACTEMRA. Anaphylaxis and other hypersensitivity reactions that required treatment discontinuation were reported in 0.1% (3 out of 2644) of patients in the 6-month controlled trials of intravenous ACTEMRA, 0.2% (8 out of 4009) of patients in the intravenous all-exposure RA population, 0.7% (8 out of 1068) in the subcutaneous 6-month controlled RA trials, and in 0.7% (10 out of 1465) of patients in the subcutaneous all-exposure population. Injection site reactions were categorized separately [see Adverse Reactions].

In the postmarketing setting, events of hypersensitivity reactions, including anaphylaxis and death, have occurred in patients treated with a range of doses of intravenous ACTEMRA, with or without concomitant arthritis therapies. Events have occurred in patients who received premedication. Hypersensitivity, including anaphylaxis events, have occurred both with and without previous hypersensitivity reactions and as early as the first infusion of ACTEMRA [see Adverse Reactions]. ACTEMRA for intravenous use should only be infused by a healthcare professional with appropriate medical support to manage anaphylaxis.

For ACTEMRA subcutaneous injection, advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If anaphylaxis or other hypersensitivity reaction occurs, administration of ACTEMRA should be stopped immediately and ACTEMRA should be permanently discontinued. Do not administer ACTEMRA to patients with known hypersensitivity to ACTEMRA [see Contraindications and Adverse Reactions].

Demyelinating Disorders The impact of treatment with ACTEMRA on demyelinating disorders is not known, but multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in RA clinical studies. Patients should be closely monitored for signs and symptoms potentially indicative of demyelinating disorders. Prescribers should exercise caution in considering the use of ACTEMRA in patients with preexisting or recent onset demyelinating disorders.

Active Hepatic Disease and Hepatic Impairment Treatment with ACTEMRA is not recommended in patients with active hepatic disease or hepatic impairment [see Adverse Reactions, Use in Specific Populations].

Vaccinations Avoid use of live vaccines concurrently with ACTEMRA as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving ACTEMRA. No data are available on the effectiveness of vaccination in patients receiving ACTEMRA. Because IL-6 inhibition may interfere with the normal immune response to new antigens, it is recommended that all patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating ACTEMRA therapy. The interval between live vaccinations and initiation of ACTEMRA therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

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

Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Intravenous ACTEMRA (ACTEMRA-IV) The ACTEMRA-IV data in rheumatoid arthritis (RA) includes 5 double-blind, controlled, multicenter studies. In these studies, patients received doses of ACTEMRA-IV 8 mg per kg monotherapy (288 patients), ACTEMRA-IV 8 mg per kg in combination with DMARDs (including methotrexate) (1582 patients), or ACTEMRA-IV 4 mg per kg in combination with methotrexate (774 patients).

The all exposure population includes all patients in registration studies who received at least one dose of ACTEMRA-IV. Of the 4009 patients in this population, 3577 received treatment for at least 6 months, 3309 for at least one year; 2954 received treatment for at least 2 years and 2189 for 3 years. All patients in these studies had moderately to severely active rheumatoid arthritis. The study population had a mean age of 52 years, 82% were female and 74% were Caucasian. The most common serious adverse reactions were serious infections [see Warnings and Precautions]. The most commonly reported adverse reactions in controlled studies up to 24 weeks (occurring in at least 5% of patients treated with ACTEMRA-IV monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT. The proportion of patients who discontinued treatment due to any adverse reactions during the double-blind, placebocontrolled studies was 5% for patients taking ACTEMRA-IV and 3% for placebo-treated patients. The most common adverse reactions that required discontinuation of ACTEMRA-IV were increased hepatic transaminase values (per protocol requirement) and serious infections.

Overall Infections In the 24 week, controlled clinical studies, the rate of infections in the ACTEMRA-IV monotherapy group was 119 events per 100 patient-years and was similar in the methotrexate monotherapy group. The rate of infections in the 4 mg per kg and 8 mg per kg ACTEMRA-IV plus DMARD group was 133 and 127 events per 100 patient-years, respectively, compared to 112 events per 100 patient-years in the placebo plus DMARD group. The most commonly reported infections (5% to 8% of patients) were upper respiratory tract infections and nasopharyngitis.

The overall rate of infections with ACTEMRA-IV in the all exposure population remained consistent with rates in the controlled periods of the studies.

Serious Infections In the 24 week, controlled clinical studies, the rate of serious infections in the ACTEMRA-IV monotherapy group was 3.6 per 100 patient-years compared to 1.5 per 100 patient-years in the methotrexate group. The rate of serious infections in the 4 mg per kg and 8 mg per kg ACTEMRA-IV plus DMARD group was 4.4 and 5.3 events per 100 patient-years, respectively, compared to 3.9 events per 100 patient-years in the placebo plus DMARD group.

In the all-exposure population, the overall rate of serious infections remained consistent with rates in the controlled periods of the studies. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of opportunistic infections have been reported [see Warnings and Precautions].

Gastrointestinal Perforations During the 24 week, controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient-years with ACTEMRA-IV therapy.

In the all-exposure population, the overall rate of gastrointestinal perforation remained consistent with rates in the controlled periods of the studies. Reports of gastrointestinal perforation were primarily reported as complications of diverticulitis including generalized purulent peritonitis, lower GI perforation, fistula and abscess. Most patients who developed gastrointestinal perforations were taking concomitant nonsteroidal anti-inflammatory medications (NSAIDs), corticosteroids, or methotrexate [see Warnings and Precautions]. The relative contribution of these concomitant medications versus ACTEMRA-IV to the development of GI perforations is not known.

Infusion Reactions In the 24 week, controlled clinical studies, adverse events associated with the infusion (occurring during or within 24 hours of the start of infusion) were reported in 8% and 7% of patients in the 4 mg per kg and 8 mg per kg ACTEMRAIV plus DMARD group, respectively, compared to 5% of patients in the placebo plus DMARD group. The most frequently reported event on the 4 mg per kg and 8 mg per kg dose during the infusion was hypertension (1% for both doses), while the most frequently reported event occurring within 24 hours of finishing an infusion were headache (1% for both doses) and skin reactions (1% for both doses), including rash, pruritus and urticaria. These events were not treatment limiting.

Anaphylaxis Hypersensitivity reactions requiring treatment discontinuation, including anaphylaxis, associated with ACTEMRA-IV were reported in 0.1% (3 out of 2644) in the 24 week, controlled trials and in 0.2% (8 out of 4009) in the all-exposure population.

These reactions were generally observed during the second to fourth infusion of ACTEMRA-IV. Appropriate medical treatment should be available for immediate use in the event of a serious hypersensitivity reaction [see Warnings and Precautions].

Laboratory Abnormalities Neutropenia In the 24 week, controlled clinical studies, decreases in neutrophil counts below 1000 per mm3 occurred in 1.8% and 3.4% of patients in the 4 mg per kg and 8 mg per kg ACTEMRA-IV plus DMARD group, respectively, compared to 0.1% of patients in the placebo plus DMARD group. Approximately half of the instances of ANC below 1000 per mm3 occurred within 8 weeks of starting therapy. Decreases in neutrophil counts below 500 per mm3 occurred in 0.4% and 0.3% of patients in the 4 mg per kg and 8 mg per kg ACTEMRA-IV plus DMARD, respectively, compared to 0.1% of patients in the placebo plus DMARD group. There was no clear relationship between decreases in neutrophils below 1000 per mm3 and the occurrence of serious infections. In the all-exposure population, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 24 week controlled clinical studies [see Warnings and Precautions].

Thrombocytopenia In the 24 week, controlled clinical studies, decreases in platelet counts below 100,000 per mm3 occurred in 1.3% and 1.7% of patients on 4 mg per kg and 8 mg per kg ACTEMRA-IV plus DMARD, respectively, compared to 0.5% of patients on placebo plus DMARD, without associated bleeding events.

In the all-exposure population, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 24 week controlled clinical studies [see Warnings and Precautions].

Elevated Liver Enzymes Liver enzyme abnormalities are summarized in Table 1. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of ACTEMRA-IV, or reduction in ACTEMRA-IV dose, resulted in decrease or normalization of liver enzymes [see Dosage and Administration].

These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic insufficiency [see Warnings and Precautions].

Table 1 Incidence of Liver Enzyme Abnormalities in the 24 Week Controlled Period of Studies I to V* ACTEMRA 8 mg per kg MONOTHERAPY

Methotrexate

ACTEMRA 4 mg per kg + DMARDs

ACTEMRA 8 mg per kg + DMARDs

Placebo +

N = 288 (%)

N = 284 (%)

N = 774 (%)

N = 1582 (%)

N = 1170 (%)

AST (U/L) > ULN to 3x ULN 22 26 34 41 17 > 3x ULN to 5x ULN 0.3 2 1 2 0.3 > 5x ULN 0.7 0.4 0.1 0.2 <0.1 ALT (U/L) > ULN to 3x ULN 36 33 45 48 23 > 3x ULN to 5x ULN 1 4 5 5 1 > 5x ULN 0.7 1 1.3 1.5 0.3 ULN = Upper Limit of Normal. *For a description of these studies, see Section 14, Clinical Studies in the full Prescribing Information.

In the all-exposure population, the elevations in ALT and AST remained consistent with what was seen in the 24 week, controlled clinical trials Lipids Elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were first assessed at 6 weeks following initiation of ACTEMRA-IV in the controlled 24 week clinical trials. Increases were observed at this time point and remained stable thereafter. Increases in triglycerides to levels above 500 mg per dL were rarely observed. Changes in other lipid parameters from baseline to week 24 were evaluated and are summarized below: – Mean LDL increased by 13 mg per dL in the ACTEMRA 4 mg per kg+DMARD arm, 20 mg per dL in the ACTEMRA 8 mg per kg+DMARD, and 25 mg per dL in ACTEMRA 8 mg per kg monotherapy.

– Mean HDL increased by 3 mg per dL in the ACTEMRA 4 mg per kg+DMARD arm, 5 mg per dL in the ACTEMRA 8 mg per kg+DMARD, and 4 mg per dL in ACTEMRA 8 mg per kg monotherapy.

– Mean LDL/HDL ratio increased by an average of 0.14 in the ACTEMRA 4 mg per kg+DMARD arm, 0.15 in the ACTEMRA 8 mg per kg+DMARD, and 0.26 in ACTEMRA 8 mg per kg monotherapy.

– ApoB/ApoA1 ratios were essentially unchanged in ACTEMRA-treated patients.

Elevated lipids responded to lipid lowering agents.

In the all-exposure population, the elevations in lipid parameters remained consistent with what was seen in the 24 week, controlled clinical trials.

Immunogenicity In the 24 week, controlled clinical studies, a total of 2876 patients have been tested for anti-tocilizumab antibodies. Forty-six patients (2%) developed positive anti-tocilizumab antibodies, of whom 5 had an associated, medically significant, hypersensitivity reaction leading to withdrawal. Thirty patients (1%) developed neutralizing antibodies.

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

For these reasons, comparison of the incidence of antibodies to tocilizumab with the incidence of antibodies to other products may be misleading.

Malignancies During the 24 week, controlled period of the studies, 15 malignancies were diagnosed in patients receiving ACTEMRAIV, compared to 8 malignancies in patients in the control groups. Exposure-adjusted incidence was similar in the ACTEMRA-IV groups (1.32 events per 100 patient-years) and in the placebo plus DMARD group (1.37 events per 100 patient-years).

In the all-exposure population, the rate of malignancies remained consistent with the rate observed in the 24 week, controlled period [see Warnings and Precautions].

Other Adverse Reactions Adverse reactions occurring in 2% or more of patients on 4 or 8 mg per kg ACTEMRA-IV plus DMARD and at least 1% greater than that observed in patients on placebo plus DMARD are summarized in Table 2.

Table 2 Adverse Reactions Occurring in at Least 2% or More of Patients on 4 or 8 mg per kg ACTEMRA-IV plus DMARD and at Least 1% Greater Than That Observed in Patients on Placebo plus DMARD

Preferred Term Upper Respiratory Tract Infection Nasopharyngitis Headache Hypertension ALT increased Dizziness Bronchitis Rash Mouth Ulceration Abdominal Pain Upper Gastritis Transaminase increased

ACTEMRA 8 mg per kg Monotherapy

Methotrexate

ACTEMRA 4 mg per kg + DMARDs

ACTEMRA 8 mg per kg + DMARDs

Placebo +

N = 288 (%)

N = 284 (%)

N = 774 (%)

N = 1582 (%)

N = 1170 (%)

7

5

6

8

6

7 7 6 6 3 3 2 2 2 1 1

6 2 2 4 1 2 1 2 2 2 5

4 6 4 3 2 4 4 1 3 1 2

6 5 4 3 3 3 3 3 3 2 2

4 3 3 1 2 3 1 1 2 1 1

Other infrequent and medically relevant adverse reactions occurring at an incidence less than 2% in rheumatoid arthritis patients treated with ACTEMRA-IV in controlled trials were: Infections and Infestations: oral herpes simplex Gastrointestinal disorders: stomatitis, gastric ulcer Investigations: weight increased, total bilirubin increased Blood and lymphatic system disorders: leukopenia General disorders and administration site conditions: edema peripheral Respiratory, thoracic, and mediastinal disorders: dyspnea, cough Eye disorders: conjunctivitis Renal disorders: nephrolithiasis Endocrine disorders: hypothyroidism Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Subcutaneous ACTEMRA (ACTEMRA-SC) The ACTEMRA-SC data in rheumatoid arthritis (RA) includes 2 double-blind, controlled, multicenter studies. Study SC-I was a non-inferiority study that compared the efficacy and safety of tocilizumab 162 mg administered every week subcutaneously (SC) and 8 mg/kg intravenously (IV) every four weeks in 1262 adult subjects with rheumatoid arthritis. Study SC-II was a placebo controlled superiority study that evaluated the safety and efficacy of tocilizumab 162 mg administered every other week SC or placebo in 656 patients. All patients in both studies received background non-biologic DMARDs. The safety observed for ACTEMRA administered subcutaneously was consistent with the known safety profile of intravenous ACTEMRA, with the exception of injection site reactions, which were more common with ACTEMRA-SC compared with placebo SC injections (IV arm).

Injection Site Reactions In the 6-month control period, in SC-I, the frequency of injection site reactions was 10.1% (64/631) and 2.4% (15/631) for the weekly ACTEMRA-SC and placebo SC (IV-arm) groups, respectively. In SC-II, the frequency of injection site reactions was 7.1% (31/437) and 4.1% (9/218) for the every other week SC ACTEMRA and placebo groups, respectively.

These injection site reactions (including erythema, pruritus, pain and hematoma) were mild to moderate in severity. The majority resolved without any treatment and none necessitated drug discontinuation.

Immunogenicity In the 6-month control period in SC-I, 0.8% (5/625) in the ACTEMRA-SC arm and 0.8% (5/627) in the IV arm developed anti-tocilizumab antibodies; of these, all developed neutralizing antibodies. In SC-II, 1.6% (7/434) in the ACTEMRASC arm compared with 1.4 % (3/217) in the placebo arm developed anti- tocilizumab antibodies; of these, 1.4% (6/434) in the ACTEMRA-SC arm and 0.5% (1/217) in the placebo arm also developed neutralizing antibodies.

A total of 1454 (>99%) patients who received ACTEMRA-SC in the all exposure group have been tested for anti-tocilizumab antibodies. Thirteen patients (0.9%) developed anti-tocilizumab antibodies, and, of these, 12 patients (0.8%) developed neutralizing antibodies.

The rate is consistent with previous intravenous experience. No correlation of antibody development to adverse events or loss of clinical response was observed.

Laboratory Abnormalities Neutropenia During routine laboratory monitoring in the 6-month controlled clinical trials, a decrease in neutrophil count below 1 × 109/L occurred in 2.9% and 3.7% of patients receiving ACTEMRA-SC weekly and every other week, respectively.

There was no clear relationship between decreases in neutrophils below 1 x 109/L and the occurrence of serious infections.

Thrombocytopenia During routine laboratory monitoring in the ACTEMRA-SC 6-month controlled clinical trials, none of the patients had a decrease in platelet count to ≤ 50 × 103/mcL. ACTEMRA® (tocilizumab) Genentech USA, Inc., A Member of the Roche Group South San Francisco, California 94080-4990 Copyright © 2014 Genentech USA, Inc. All rights reserved. ACT/102714/0030

Elevated Liver Enzymes During routine laboratory monitoring in the 6-month controlled clinical trials, elevation in ALT or AST ≥ 3x ULN occurred in 6.5% and 1.4% of patients, respectively, receiving ACTEMRA-SC weekly and 3.4% and 0.7% receiving ACTEMRA SC every other week.

Lipids During routine laboratory monitoring in the ACTEMRA-SC 6-month clinical trials, 19% of patients dosed weekly and 19.6% of patients dosed every other week and 10.2% of patients on placebo experienced sustained elevations in total cholesterol > 6.2 mmol/l (240 mg/dL), with 9%, 10.4% and 5.1% experiencing a sustained increase in LDL to 4.1 mmol/l (160 mg/dL) receiving ACTEMRA-SC weekly, every other week and placebo, respectively.

DRUG INTERACTIONS

Other Drugs for Treatment of Rheumatoid Arthritis Population pharmacokinetic analyses did not detect any effect of methotrexate (MTX), non-steroidal anti-inflammatory drugs or corticosteroids on tocilizumab clearance.

Concomitant administration of a single dose of 10 mg per kg ACTEMRA with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure.

ACTEMRA has not been studied in combination with biological DMARDs such as TNF antagonists [see Dosage and Administration].

Interactions with CYP450 Substrates Cytochrome P450s in the liver are down-regulated by infection and inflammation stimuli including cytokines such as IL-6.

Inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. In vitro studies showed that tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Its effects on CYP2C8 or transporters is unknown. In vivo studies with omeprazole, metabolized by CYP2C19 and CYP3A4, and simvastatin, metabolized by CYP3A4, showed up to a 28% and 57% decrease in exposure one week following a single dose of ACTEMRA, respectively. The effect of tocilizumab on CYP enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of ACTEMRA, in patients being treated with these types of medicinal products, therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) should be performed and the individual dose of the medicinal product adjusted as needed. Exercise caution when ACTEMRA is coadministered with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy [see Clinical Pharmacology].

Live Vaccines Avoid use of live vaccines concurrently with ACTEMRA [see Warnings and Precautions].

USE IN SPECIFIC POPULATIONS

Pregnancy Pregnancy Category C. Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ACTEMRA during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.

Risk Summary Adequate and well-controlled studies with ACTEMRA have not been conducted in pregnant women. In animal reproduction studies, administration of tocilizumab to cynomolgus monkeys during organogenesis caused abortion/embryofetal death at dose exposures 1.25 times the human dose exposure of 8 mg per kg every 2 to 4 weeks. The incidence of malformations and pregnancy loss in human pregnancies has not been established for ACTEMRA. However, all pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy loss.

ACTEMRA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations In general, monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester.

Animal Data An embryo-fetal developmental toxicity study was performed in which pregnant cynomolgus monkeys were treated intravenously with tocilizumab (daily doses of 2, 10, or 50 mg per kg from gestation day 20-50) during organogenesis. Although there was no evidence for a teratogenic/dysmorphogenic effect at any dose, tocilizumab produced an increase in the incidence of abortion/ embryo-fetal death at 10 mg per kg and 50 mg per kg doses (1.25 and 6.25 times the human dose of 8 mg per kg every 2 to 4 weeks based on a mg per kg comparison). Testing of a murine analogue of tocilizumab in mice did not yield any evidence of harm to offspring during the pre-and postnatal development phase when dosed at 50 mg per kg intravenously with treatment every three days from implantation until day 21 after delivery (weaning). There was no evidence for any functional impairment of the development and behavior, learning ability, immune competence and fertility of the offspring.

Nursing Mothers It is not known whether tocilizumab is excreted in human milk or if it would be absorbed systemically in a breastfed infant after ingestion. IgG is excreted in human milk, and therefore it is expected that tocilizumab could be present in human milk.

Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ACTEMRA, 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 ACTEMRA by intravenous use is indicated for the treatment of pediatric patients with: • Active systemic juvenile idiopathic arthritis in patients 2 years of age and older • Active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older Safety and effectiveness of ACTEMRA in pediatric patients with conditions other than PJIA or SJIA have not been established.

Children under the age of two have not been studied. SC administration has not been studied in pediatric patients. Testing of a murine analogue of tocilizumab did not exert toxicity in juvenile mice. In particular, there was no impairment of skeletal growth, immune function and sexual maturation.

Geriatric Use Of the 2644 patients who received ACTEMRA in Studies I to V [see Clinical Studies], a total of 435 rheumatoid arthritis patients were 65 years of age and older, including 50 patients 75 years and older. Of the1069 patients who received ACTEMRA-SC in studies SC-I and SC-II there were 295 patients 65 years of age and older, including 41 patients 75 years and older. The frequency of serious infection among ACTEMRA treated subjects 65 years of age and older was higher than those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.

Hepatic Impairment The safety and efficacy of ACTEMRA have not been studied in patients with hepatic impairment, including patients with positive HBV and HCV serology [see Warnings and Precautions].

Renal Impairment No dose adjustment is required in patients with mild renal impairment. ACTEMRA has not been studied in patients with moderate to severe renal impairment [see Clinical Pharmacology].

OVERDOSAGE

There are limited data available on overdoses with ACTEMRA. One case of accidental overdose was reported in which a patient with multiple myeloma received a dose of 40 mg per kg. No adverse drug reactions were observed. No serious adverse drug reactions were observed in healthy volunteers who received single doses of up to 28 mg per kg, although all 5 patients at the highest dose of 28 mg per kg developed dose-limiting neutropenia.

In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions.

Patients who develop adverse reactions should receive appropriate symptomatic treatment.

PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Medication Guide) Patient Counseling Advise patients and parents or guardians of minors with PJIA or SJIA of the potential benefits and risks of ACTEMRA. Physicians should instruct their patients to read the Medication Guide before starting ACTEMRA therapy.

• Infections: Inform patients that ACTEMRA may lower their resistance to infections. Instruct the patient of the importance of contacting their doctor immediately when symptoms suggesting infection appear in order to assure rapid evaluation and appropriate treatment.

• Gastrointestinal Perforation: Inform patients that some patients who have been treated with ACTEMRA have had serious side effects in the stomach and intestines. Instruct the patient of the importance of contacting their doctor immediately when symptoms of severe, persistent abdominal pain appear to assure rapid evaluation and appropriate treatment.

• Hypersensitivity and Serious Allergic Reactions: Assess patient suitability for home use for SC injection. Inform patients that some patients who have been treated with ACTEMRA have developed serious allergic reactions, including anaphylaxis. Advise patients to seek immediate medical attention if they experience any symptom of serious allergic reactions.

Instruction on Injection Technique Perform the first injection under the supervision of a qualified healthcare professional. If a patient or caregiver is to administer subcutaneous ACTEMRA, instruct him/her in injection techniques and assess his/her ability to inject subcutaneously to ensure proper administration of subcutaneous ACTEMRA and the suitability for home use [See Patient Instructions for Use].

Prior to use, remove the prefilled syringe from the refrigerator and allow to sit at room temperature outside of the carton for 30 minutes, out of the reach of children. Do not warm ACTEMRA in any other way.

Advise patients to consult their healthcare provider if the full dose is not received.

A puncture-resistant container for disposal of needles and syringes should be used and should be kept out of the reach of children. Instruct patients or caregivers in the technique as well as proper syringe and needle disposal, and caution against reuse of these items.

VBCR Perspective

Incorporating Educational Interventions into the Treatment Regimen for Patients with RA Continued from page 1

disease state, medications, side effects, and healthy habits is an impor­ tant component of comprehensive medical care. An informed, educated patient will often have better outcomes through improved treatment adherence, 1 reduced symptoms through self-management techniques,2 and will likely be in a better position to recognize possible drug or disease side effects. Unfortunately, formal educational interventions are not skills that are typically discussed in medical school, residency, or subspecialty training in a formal, substantive way.

One possible explanation for this absence of formalized instruction is that there is little in the way of rigorous, validated methods for educating patients.3 Clinical studies have typically yielded mixed results with regard to the outcomes and durability of various educational interventions.4-8 In addition, there are numerous practical barriers to patient education programs, including the considerable time constraints of a typical patient encounter, potential language barriers, an individual patient’s educational level, and health literacy.9 Further, there may be differences in physician and patient priorities in terms of relevant educational content and focus.

Despite these obstacles, the following approaches and principles may be incorporated into clinical practice to help facilitate improved education of patients with RA. 1. Have a Formal Process Employ a set curriculum with essential topics to cover, including RA medications, disease state understanding, nutritional interventions, healthy habits such as exercise and sleep, communication with doctors and family, nonmedical pain man­ agement techniques (eg, mindfulness training10), coping, and stress management.11 Institute a systematic practice with checkpoints along the way to ensure that educational goals are met to enhance and make the educational process a routine part of rheumatologic care. By dividing the task into smaller elements and viewing the process as an ongoing effort, the teaching process can be made more practical

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and achievable within the constraints of a busy clinical practice. I would suggest reserving a small portion of the office visit for the specific agenda of patient education. Necessary features of a comprehensive educational intervention include12: • Needs assessment to determine a patient’s current needs and willingness to learn. Ask general open-ended questions about what the patient’s current understanding of his or her disease

diseases for patients and their families. This also represents an opportunity to invite your own patients to get additional information about their disease state without the typical time limitations of an office visit.

4. Use a Patient Educator Trained patient educators who specialize in RA have successfully been used in medical school curricula to enhance the effectiveness of teaching musculoskeletal examination

RA can assist patients in achieving better health outcomes and increase treatment satisfaction. Although there are hurdles to overcome, by incorporating a focused and systematic method of delivering patient education, we can enhance our effectiveness as physicians.

Looking to the future, more studies are needed to develop and refine educational interventions to achieve the highest yield and retention rate for such efforts. n References

The addition of educational interventions and self-management modalities to the treatment approach for RA can assist patients in achieving better health outcomes and increase treatment satisfaction.

—Howard Blumstein, MD, FACR

state is, what they currently do to help themselves, how confident they are with their ability to help themselves and self-manage their symptoms • Periodic assessments to ensure outcome goals are being achieved • Reteaching and reinforcement.

2. Use Patient Information Leaflets Multiple studies have demonstrated that patients often do not recall the specifics of information provided during an office visit, but their retention can increase if supplemented by written material.13 Investigators from one interventional trial evaluating the benefit of patient reading materials found that patients who were provided with an informational leaflet about RA also demonstrated reduced pain and depression compared with the control group.14 3. Participate in Patient-Focused Educational Programs Whether disease-specific or in the venue of broader patient advocacy groups such as the Arthritis Foundation, there are numerous opportunities for physicians to provide informative lectures about rheumatologic

skills as well as improve students’ sensitivity and awareness of the major life impact of chronic inflammatory arthritis.15 In addition, there may be a role for a trained patient educator in the office setting to improve patient education. Branch and colleagues conducted a trial with 108 patients randomized to standard care versus follow-up education with a trained patient educator.16 The treatment group had improved information recall, were more capable of identifying self-help aids, and generally demonstrated a higher degree of satisfaction with their care compared with the control group.

5. Use a Nurse Educator In 2011, the European League Against Rheumatism published guidelines to incorporate nurses into the interdisciplinary rheumatology team and achieve treat-to-target goals and better health outcomes. Of the 4 grade A category strength of recommendations from this position paper, the first called for providing patient access to a nurse for education about the disease and its management.17 The addition of educational interventions and self-management modalities to the treatment approach for

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1. Hill J, Bird H, Johnson S. Effect of patient education on adherence to drug treatment for rheumatoid arthritis: a randomised controlled trial. Ann Rheum Dis. 2001;60:869-875.

2. Superio-Cabuslay E, Ward MM, Lorig KR. Patient education interventions in osteoarthritis and rheumatoid arthritis: a meta-analytic comparison with nonsteroidal antiinflammatory drug treatment. Arthritis Care Res. 1996;9:292-301.

3. Cooper H, Booth K, Fear S, Gill G. Chronic disease patient education: lessons from meta-analyses. Patient Educ Couns. 2001;44:107-117.

4. Li LC. If knowledge is power, why don't rheumatoid arthritis education programs show better outcomes?

J Rheumatol. 2007;34:1645-1646.

5. Giraudet-Le Quintrec JS, Mayoux-Benhamou A, Ravaud P, et al. Effect of a collective educational program for patients with rheumatoid arthritis: a prospective 12-month randomized controlled trial. J Rheumatol. 2007;34:1684-1691.

6. Akl EA, Kamath G, Kim SY, et al. Oral anticoagulation for prolonging survival in patients with cancer. Cochrane Database Syst Rev. 2007;(2):CD006466.

Review. Update in: Cochrane Database Syst Rev. 2010;(12):CD006466.

7. Riemsma RP, Taal E, Kirwan JR, Rasker JJ. Patient education programmes for adults with rheumatoid arthritis. BMJ. 2002;325:558-559.

8. Niedermann K, Fransen J, Knols R, Uebelhart D. Gap between short- and long-term effects of patient education in rheumatoid arthritis patients: a systematic review. Arthritis Rheum. 2004;51:388-398.

9. Buchbinder R, Hall S, Youd JM. Functional health literacy of patients with rheumatoid arthritis attending a community-based rheumatology practice.

J Rheumatol. 2006;33:879-886.

10. Fogarty FA, Booth RJ, Gamble GD, et al. The effect of mindfulness-based stress reduction on disease activity in people with rheumatoid arthritis: a randomised controlled trial. Ann Rheum Dis. 2014 Nov 18 [Epub ahead of print].

11. Tucker M, Kirwan JR. Does patient education in rheumatoid arthritis have therapeutic potential? Ann Rheum Dis. 1991;50 (Suppl 1) 3:422-428.

12. Redman BK. The practice of patient education: overview, motivation and learning. In: Redman BK, ed. The practice of patient education: a case study approach. 10th ed. Maryland Heights, MO: Mosby; 2006: 1-25.

13. Kenny T, Wilson RG, Purves IN, et al. A PIL for every ill? Patient information leaflets (PILs): a review of past, present and future use. Fam Pract. 1998;15:471479.

14. Barlow JH, Wright CC. Knowledge in patients with rheumatoid arthritis: a longer term follow-up of a randomized controlled study of patient education leaflets.

Br J Rheumatol. 1998;37:373-376.

15. Gruppen LD, Branch VK, Laing TJ. The use of trained patient educators with rheumatoid arthritis to teach medical students. Arthritis Care Res. 1996;9:302308.

16. Branch VK, Lipsky K, Nieman T, Lipsky PE. Positive impact of an intervention by arthritis patient educators on knowledge and satisfaction of patients in a rheumatology practice. Arthritis Care Res. 1999;12:370-375.

17. Kruithof E, Van den Bosch F, Baeten D, et al.

Repeated infusions of infliximab, a chimeric antiTNFalpha monoclonal antibody, in patients with active spondyloarthropathy: one year follow up. Ann Rheum Dis. 2002;61:207-212.

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Continuing Education

The Evolving Management of Rheumatoid Arthritis and Psoriatic Arthritis

By Sy Schlager, MD, PhD

T

he past decade has witnessed significant, practice-changing developments in the management of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), not only in terms of the advent of novel biologic agents, but also in the outcomes we have come to expect from therapeutic approaches. Healthcare professionals need to be aware of new ways in which to assess disease severity; understand the rationale for using aggressive therapy in early disease; utilize objective measures to assess patient prognosis and disease activity, and to drive treatment decisions; and fully appreciate the concepts of treat-to-target and disease remission, while bearing in mind the costs associated with therapy.

This review will focus on the evolution of value-based care in RA and PsA based on presentations from the 2014 Annual Meeting of the American College of Rheumatology (ACR)/ Association of Rheumatology Health Professionals (ARHP), held in Boston, MA, November 14-19, 2014, and perspectives on key data from thoughtleaders in the field. This year, the ACR/ARHP meeting comprised a broad range of presentations: • Molecular biomarkers and objective measures of disease activity • Safety and efficacy of existing and emerging biologic disease-modifying antirheumatic drugs (bDMARDs) • Evaluation of competing therapies, including conventional DMARDs

Release date: December 22, 2014 Expiration date: December 31, 2015 Estimated time to complete activity: 1.25 hours Target Audience This educational program is directed toward rheumatologists, rheumatology nurses, pharmacists, and other healthcare professionals involved in the delivery of care to patients with RA and PsA. Educational Objectives After completing this activity, the participant should be better able to: • Integrate emerging data from ACR/ARHP 2014 into personalized treatment strategies for patients with RA and PsA • Distinguish biologic agents used in RA/PsA based on their mechanisms of action and appropriate usage in patients with different patient and disease characteristics • Employ the most recent safety and efficacy data on existing and emerging biologic agents in formulating evidence-based, personalized treatment decisions for patients with RA/PsA • Utilize objective, quantifiable disease measures to guide therapeutic decisions in RA/PsA

System Requirements PC Windows 7 or above Flash Player v10.0 or higher Internet Explorer v9.0 or higher Latest version of Firefox, Google Chrome, or Safari Adobe Acrobat Reader v7.0 or higher*

(cDMARDs) compared with bDMARDs and different bDMARDs compared with each other • New definitions of the treat-to-target paradigm in RA • Ways of improving the value associated with bDMARDs, including the role played by biosimilars, new approaches to minimizing therapy with biologic agents, and the impact of bDMARDs on healthcare resource utilization and work productivity.

Rheumatoid Arthritis RA is a progressive, debilitating autoimmune disorder characterized by inflammation of synovial tissue and bone erosion, eventually leading to de-

MAC MAC OS X 10.6 or higher Flash Player v10.0 or higher Latest version of Firefox, Google Chrome, or Safari Adobe Acrobat Reader v7.0 or higher*

*Required to view printable (PDF) version of the lesson.

Disclosure of Conflicts of Interest Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high-quality CME/CE activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.

Faculty Alan Brown, MD Clinical Associate Professor of Medicine Medical University of South Carolina Charleston, SC

The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME/CPE activity: Name of Faculty or Presenter

Reported Financial Relationship

Ronald F. van Vollenhoven, MD, PhD Professor and Chief, Unit for Clinical Therapy Research, Inflammatory Diseases (ClinTRID) Karolinska Institute Stockholm, Sweden

Alan Brown, MD

On Speaker’s Bureau for AbbVie, Genentech, and Questcor.

Consultant for AbbVie, Biotest, Bristol-Myers Squibb, Glaxo Smith Kline, Janssen, Lilly, Merck, Pfizer, Roche, UCB, and Vertex; research support from AbbVie, Bristol-Myers Squibb, Glaxo Smith Kline, Pfizer, Roche, and UCB.

Ronald F. van Vollenhoven, MD, PhD

Physician Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Postgraduate Institute for Medicine and Center of Excellence Media, LLC. Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Physician Credit Designation Postgraduate Institute for Medicine designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

The following PIM planners and managers—Laura Excell, ND, NP, MS, MA, LPC, NCC; Trace Hutchison, PharmD; Samantha Mattiucci, PharmD, CCMEP; and Jan Schultz, MSN, RN, CCMEP—hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.

formity due to irreversible joint destruction, disability, loss of productivity and the ability to perform daily functions of life, and premature death.

Significant advances in the diagnosis, assessment, and use of value-based therapy in RA were presented at ACR/ ARHP 2014.

Molecular Biomarkers—Predictive and Prognostic Value Extensive research is under way in the field of RA to identify molecular biomarkers that can predict response to certain therapies, particularly with respect to guiding value-based care with expensive bDMARDs. In a genetic substudy of the OPTIMA (Optimal Protocol for Methotrexate and Adalimumab

Center of Excellence Media, LLC: Susan Berry and Sy Schlager, MD, PhD, hereby state that they or their spouse/life partners do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.

Disclosure of Unlabeled Use This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Postgraduate Institute for Medicine and Center of Excellence Media, LLC, do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

Instructions for Credit There is no fee for this activity. To receive credit after reading this CME activity in its entirety, participants must complete the posttest and evaluation. The posttest and evaluation can be completed online at http://ce.lynxcme.com/ COE184. Upon completion of the evaluation and scoring 75% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 75% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records.

If you have any questions regarding the CME certification for this activity, please contact Postgraduate Institute for Medicine at: information@pimed.com or 303-799-1930.

Media: Printed report

To obtain a digital version, download a free QR code app on your SmartPhone and then scan this code.

Jointly provided by Postgraduate Institute for Medicine and Center of Excellence Media, LLC.

This activity is supported by an educational grant from Lilly USA, LLC. For further information concerning Lilly grant funding visit www.lillygrantoffice.com.

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Continuing Education Combination Therapy in Early Rheumatoid Arthritis) trial, Skapenko and colleagues identified multiple singlenucleotide polymorphisms in the APOH, MAP2K6, ABCB1, and STAT4 genes that were significantly associated with a positive response to adalimumab plus methotrexate (MTX) in 413 patients with early RA.1 These results may prove useful for the development of approaches to the personalized treatment of patients with early RA with adalimumab-plus-MTX combination therapy.

Similarly, Sode and colleagues found a significant association between singlenucleotide polymorphisms in the TLR5 locus and improved European League Against Rheumatism (EULAR) responses to anti–tumor necrosis factor (TNF) therapy in 538 bDMARD-naïve patients with RA.2 No statistically significant correlation was demonstrated, however, between the TLR5 single-nucleotide polymorphisms and American College of Rheumatology 50% improvement (ACR50) responses.2 A disintegrin and metalloproteinases (ADAMs), a family of transmembrane and secreted proteins, are reported to be responsible for the release of a number of chemokines and cytokine receptors; in fact, ADAM-10 has been shown to be overexpressed on RA synovial tissue endothelial cells.

Based on a presentation by Isozaki and colleagues, 35 patients with RA were treated with either adalimumab (n = 15) or tocilizumab (n = 20); ADAM-10 levels were assessed via enzyme-linked immunosorbent assay.3 In tocilizumab-treated patients who experienced a significant decrease in Disease Activity Score in 28 joints (DAS28) at 12 and 24 weeks compared with baseline, a significant decrease in ADAM-10 levels was observed (138 pg/mL at 54 weeks vs 408 pg/mL at baseline; P < .05); however, no significant changes in ADAM-10 levels were reported with adalimumab treatment, including in patients who demonstrated significant decreases in disease activity.3 These results suggest that ADAM-10 levels may be a good predictor of response to tocilizumab therapy.

A challenge faced by many rheumatologists is distinguishing between early RA and other inflammatory arthritides. In a study by Ai and colleagues, genomic DNA from fibroblast-like synoviocytes was isolated from arthroscopic biopsies of patients with early RA, long-standing RA, undifferentiated arthritis that progressed to osteoarthritis or RA, juvenile idiopathic arthritis, and spondyloarthritis; DNA methylation signatures were assessed in these samples.4 Unique methylation signatures were found in long-standing RA, with patterns that could be differentiated from spondyVOL. 3

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loarthritis and juvenile idiopathic arthritis. Patients with undifferentiated arthritis who ultimately developed RA had a long-standing RA pattern, whereas those with early RA had a distinct, but overlapping differentially methylated locus gene pattern compared with patients with long-standing RA.4 These results are important for several reasons: (1) they show that differential methylation of RA fibroblast-like synoviocytes occurs early and evolves over time; (2) understanding the transition from early to established disease may provide new molecular targets involved in RA disease progression; and (3) these DNA methylation signatures may be useful in distinguishing early RA from spondyloarthritis, juvenile idiopathic arthritis, or other inflammatory arthritides, for individualized therapy to be initiated. Although the data from these studies are interesting and exciting, the challenge remains in making these assays widely available and affordable so they may be applied in routine clinical practice.

Imaging Techniques and Clinical Assessment Tools Kaeley and colleagues reported results from the MUSICA study—a double-blind, randomized, controlled trial of 2 different dosages of adalimumab plus MTX in 309 patients with RA who had had an inadequate response to MTX alone.5 Synovial vascularization was assessed by power Doppler ultrasonography (PDUS) at 10 joints (bilateral dorsal and volar views of 3 metacarpophalangeal joints; dorsal images alone of metatarsophalangeal joint 5 and both wrists) after 24 weeks of treatment. Joint swelling was assessed clinically for the same 10 joints (SJC10 score). At week 24, for the 10 joints selected, 68% of the patients in DAS28–C-reactive protein (CRP) remission and 55% of those in Simplified Disease Activity Index (SDAI) remission had a positive PDUS score (≥2). A poor correlation was observed between PDUS scores and clinical disease scores, including swollen joint count (10 joints; SJC10).5 These results suggest that PDUS may provide additional information beyond that obtained from clinical disease measures, which may be used to inform therapy. These conclusions were in agreement with the findings by Kirino and colleagues, who reported PDUS to be useful as an independent predictor of joint destruction in patients with RA.6 As time goes on, modifications and refinements in the use of PDUS will occur, rendering this tool easier and more valid in the detection of joint inflammation. For example, data were presented by Hanova and colleagues that determined it is possible to detect a high percentage of

subclinical synovitis in patients with RA in clinical remission with the use of a 7-joint ultrasound scoring system of the dominant hand and foot, assessing joint erosions and tenosynovitis.7 The challenge for rheumatologists is to decide what to do with these data.

Should a patient with RA who is in remission based on clinical criteria but exhibits subclinical synovitis according to PDUS receive additional treatment, or is a wait-and-watch scenario appropriate? Should these patients undergo serial PDUS evaluations, or are frequent clinical follow-ups sufficient?

These questions involve both clinical and economic considerations, and it is hoped that the true value of PDUS and other imaging modalities will become more apparent as additional imaging studies are undertaken.

The Clinical Disease Activity Index (CDAI), routine assessment of patient index data 3 Routine Assessment of Patient Index Data 3 (RAPID3), and other patient- and physician-reporting instruments have been in clinical use for some time. At ACR 2014, data on several unique scoring systems were presented. For example, the Rheumatoid Arthritis Impact of Disease (RAID) score is a relatively new patient-derived composite score that assesses the 7 most important domains of the impact of RA, including pain, functional disability, fatigue, sleep disturbances, coping, overall assessment of physical well-being, and overall assessment of psychological well-being. In a report by Nordberg and colleagues, RAID scores were compared with other disease measures in 229 patients with RA who had had symptoms for <2 years, were DMARD-naïve, and had clinical indications for DMARD treatment.8 Patients were stratified according to level of RAID score at baseline, with a score ≤3 considered low, >3 to 6 moderate, and >6 high. Correlation analysis revealed statistically significant associations between RAID scores and several patient-reported and objective disease measures, including DAS44, 44-swollen joint count, erythrocyte sedimentation rate (ESR), CRP, Ritchie tender joint score, patient and physician visual analog scale (VAS) scores, gray-scale ultrasound score, EQ-5D, pain VAS, fatigue VAS, and Short Form-36 (SF-36) physical and mental component summaries. No statistically significant correlation was observed, however, between RAID scores and PDUS scores.8 These data support the use of RAID as a valid patient-reported outcome measure in patients with early RA. The prediction of radiographic progression of disease in patients with early RA is key to optimal treatment. In this regard, another important presentation at ACR 2014 demonstrated a corDECEMBER 2014

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relation between the multi-biomarker disease activity (MBDA) score and radiographic progression of disease.9 MBDA consists of a blood test that measures the concentrations of 12 serum proteins by customized immunoassays—serum amyloid A, interleukin-6 (IL-6), TNF receptor superfamily member 1A (TNF-RI), vascular endothelial growth factor A, matrix metalloproteinase-1, human cartilage glycoprotein 39, MMP-3, epithelial growth factor, vascular cell adhesion molecule 1, leptin, resistin, and CRP. In the SWEFOT trial, the MBDA score at baseline was shown to be predictive of radiographic disease progression over the first year of treatment in patients with early RA; the current study evaluated the MBDA score at different time points during treatment with MTX as a predictor of radiographic progression over the first 2 years of treatment in patients with early RA. Median MBDA scores for year-1 progressors and nonprogressors were 70 and 58, respectively (P = .001).9 After 3 months of MTX therapy, the progressor and nonprogressor median MBDA scores were 48 and 40 (P = .001).9 In all cases, MBDA scores at baseline, and at 3 and 12 months of therapy, as well as change in MBDA category (from low to moderate to high), were predictive of subsequent radiographic progression during the 2-year duration of the study.9 For patients with early RA, MTX is recommended as first-line therapy; in those who do not respond to MTX monotherapy, triple therapy with cDMARDs or treatment with an antiTNF agent is the next step. Identification of patients who are more likely to respond to one or the other of these treatments would lead to more personalized therapy; if triple cDMARD therapy is a viable option, this could lead to more cost-effective therapy. Hambardzumyan and colleagues presented results of their investigation into whether MBDA can predict responsiveness to triple cDMARD therapy versus anti-TNF therapy in patients with early RA who have not responded to MTX monotherapy.10 The authors evaluated the patient population from the SWEFOT trial, in which patients with early RA received MTX monotherapy for 3 months, at which time clinical nonresponders (DAS28 >3.2) were randomized to receive triple cDMARD therapy (Arm A) or infliximab treatment (Arm B). In a subanalysis of SWEFOT, 129 nonresponders at month 3 were analyzed by MBDA scores at baseline and at 3 months. Among those who did not achieve low disease activity on MTX monotherapy, 67% of the patients with large decreases in MBDA scores (>20 points) from baseline to month 3 were the most likely to respond to triple

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Continuing Education therapy with cDMARDs, whereas only 37% of these patients responded to anti-TNF therapy.10 Conversely, patients with small (≤6 points) or moderate (7-20 points) decreases in MBDA scores were more likely to respond to anti-TNF therapy.10 These results are potentially quite useful in guiding therapy in patients with early RA who have failed to achieve low disease activity on MTX monotherapy.

Updates on Existing Biologic Therapies Although use of bDMARDs has been well documented in patients with early RA, Kodama and colleagues analyzed the safety and efficacy of etanercept therapy in 45 patients with established RA (mean disease duration, 17 years) who were ≥75 years of age, 84% of whom had such significant comorbidities as hypertension, diabetes mellitus, osteoporosis, interstitial pneumonia, or amyloidosis.11 Patients were treated with etanercept doses ranging from 20 to 50 mg per week. All patients exhibited significant reductions in tender and swollen joint counts, CRP, ESR, MMP-3, and rheumatoid factor levels; 34% of the patients achieved disease remission or low disease activity score, and 50% achieved SDAI remission or low disease activity. Whereas adverse events occurred in 10 patients (6 had to discontinue therapy), the authors concluded that etanercept is an effective and relatively safe treatment for elderly patients with long-standing RA.11 One of the controversial topics in the management of RA is whether antiTNF therapy can be tapered or discontinued when patients achieve remission or low disease activity both from a clinical perspective, in terms of reducing the likelihood of adverse events, and from an economic standpoint.

Emery and colleagues presented data on patients with previously untreated early moderate to severe RA who received etanercept 50 mg plus MTX 10 to 25 mg (phase 1).12 Patients who achieved DAS28 ≤3.2 at week 39 and <2.6 at week 52 were randomized to receive MTX alone, etanercept 25 mg plus MTX, or placebo for 39 weeks (phase 2). Patients who experienced a rapid and robust response to etanercept 50 mg plus MTX in phase 1 (first DAS28 remission within 179 days; mean DAS28 ≤1.91 at week 52) exhibited sustained remission in response to the reduced-dose combination (phase 2).12 These data are important, in that they provide a way to identify patients who may be amenable to downward adjustments in anti-TNF therapy while retaining remission or low disease activity.

Golimumab is another TNF antagonist approved for the treatment of patients with moderate to severe RA. A presentation by Han and colleagues

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provided 5-year data on the impact of golimumab on physical function and employability in patients with RA.13 Subanalyses were conducted from 3 pivotal clinical trials with golimumab (GO-BEFORE, GO-FORWARD, and GO-AFTER), in which patients with RA who were MTX-naïve (GO-BEFORE; N = 637), MTX–inadequate responders (GO-FORWARD; N = 444), or TNF antagonist–experienced (GO-AFTER; N = 445) were treated with placebo, golimumab 100 mg plus placebo (GO-BEFORE and GO-FORWARD), or golimumab 50 or 100 mg, every 4 weeks. At baseline, 88% to 92% of the patients exhibited disability (Health Assessment Questionnaire Disability Index [HAQ-DI] scores >0.5), and 8% to 13% of the patients were unemployable because of their disability.13 After treatment with golimumab, 28% to 47% of the patients who had had a disability at baseline had no disability at week 256 (HAQ-DI score ≤0.5), and among those who were unemployable at baseline, 5% to 30% had regained employability at week 256.13 It is interesting to note that the highest reductions in disability and increased employability occurred in the MTX-naïve group, and those with the lowest responses were in the TNFinhibitor–experienced group.

The efficacy and safety of certolizumab pegol plus MTX versus MTX alone in MTX-naïve Japanese patients with early RA and poor prognostic factors were discussed in a presentation by Atsumi and colleagues.14 In this multicenter study, 316 MTX-naïve patients with moderate to severe RA (DAS28ESR ≥3.2 and high-positive anti-cyclic citrullinated peptide antibody), who were either rheumatoid factor-positive or had bone erosions on radiographs of the hands or feet, were randomized in a 1:1 ratio to receive certolizumab plus MTX or MTX alone.14 SDAI remission rates at week 52 were significantly higher among patients treated with certolizumab plus MTX versus MTX alone (58% vs 34%, respectively; P < .001). Additionally, the percentage of patients with no radiographic progression at week 52 was significantly higher in the certolizumab-plus-MTX group than in the MTX-alone group (83% vs 71%, respectively; P = .011).14 Although the use of TNF antagonists has revolutionized the treatment of patients with RA, a number of individuals still exhibit an inadequate response to these agents. At ACR 2014, the response of these patients to several non– anti-TNF bDMARDs was discussed.

Rituximab is a chimeric monoclonal anti-CD20 antibody. In a presentation of data from the REPEAT study by Ancuta and colleagues, 1087 patients with active RA despite treatment with ≥1

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TNF antagonist (adalimumab, etanercept, or infliximab) were treated with rituximab every 6 months.15 At 6, 12, 24, 30, and 36 months, DAS28 scores improved significantly over baseline in the rituximab-treated patients, regardless of which anti-TNF agent they had received originally and whether they had been treated with ≥1 TNF antagonist.15 In a study by Opris and colleagues, however, significant differences were reported in the clinical response of patients, depending on the number of prior anti-TNF agents that had been used, such that patients appeared to respond better to rituximab when they had been previously treated with ≥2 anti-TNF agents (P = .009).16 These data actually support the EULAR guidelines that recommend the use of rituximab as second-line therapy under certain circumstances in patients with RA after failure of ≥2 TNF antagonists.17 Recent recommendations support shared decision-making between the patient and the rheumatologist, emphasizing more patient-focused outcomes to assess treatment targets.17 In this regard, Furst and colleagues presented results of the AVERT trial, in which 351 patients with RA of ≤2 years’ onset, who were MTX-naïve, anti-cyclic citrullinated peptide-positive, and had active synovitis in ≥2 joints, were treated with abatacept plus MTX, abatacept alone, or MTX alone for 12 months.18 Patient-reported outcomes at 12 months and at 18 months (ie, 6 months after discontinuation of therapy) included fatigue, HAQ-DI scores, SF-36 scores, activity limitation, work time missed, impairment while working, overall work impairment, and activity impairment. All 3 treatment groups showed improvements in patient-reported outcomes, with greater improvements reported in the abatacept-plus-MTX group versus the MTX-alone group at 12 months.

Patient-reported outcomes worsened over the 6 months after treatment withdrawal but remained below baseline levels.18 The investigators support the use of abatacept in patients with early RA (and prior to treatment with MTX) for improvements in patientreported outcomes.18 The early use of abatacept was further advocated in an analysis by Turesson and colleagues, who presented observational data on 1291 patients with RA from the National Swedish Rheumatology Quality Register.19 According to the investigators, in abatacept-treated patients in clinical practice, a higher proportion of bio-naïve individuals exhibited a significant clinical response and remained on treatment, compared with those with a previous inadequate response to other bDMARDs. The data from these 2

studies (Furst et al18; Turesson et al19) maintain that a substantial number of patients with RA who are treated with abatacept as their first biologic agent in clinical practice would experience a favorable outcome.

In contrast, the use of abatacept following treatment with another biologic agent may not be as effective. Finckh and colleagues presented pooled data from 9 registries of 1994 patients with RA, 24% of whom received abatacept after inadequate response to rituximab and 76% after inadequate response to ≥1 anti-TNF agents, but not rituximab.20 Response rates to abatacept at 1 year were lower in rituximab-inadequate responders compared with anti-TNF–inadequate responders (73% EULAR good or moderate response rate vs 83%, respectively; P = .001).20 These data suggest that abatacept is a reasonable choice in patients with RA who are inadequate responders to ≥1 TNF antagonists but may not be an ideal choice in rituximab-inadequate responders.

Tocilizumab is a recombinant, humanized monoclonal antibody against the IL-6 receptor. The FUNCTION trial was a randomized, controlled study of treatment with tocilizumab plus MTX, tocilizumab monotherapy, or MTX monotherapy in MTX-naïve patients with early RA.21 Patients were randomized to receive tocilizumab 8 mg/kg alone or combined with MTX (TCZ8 monotherapy or TCZ8 + MTX), tocilizumab 4 mg/kg plus MTX (TCZ4 + MTX), or MTX alone for 104 weeks. Patients who received TCZ8 plus MTX or TCZ8 monotherapy for the duration of the study exhibited sustained improvement in disease activity (as measured

by DAS28 scores <2.6 and ACR 20/50/70 scores) and maintained joint damage inhibition (as measured by changes from baseline in mean van der Heijde–modified Total Sharp scores) over 104 weeks; these treatments were superior to TCZ4 plus MTX and to MTX alone.21 For example, at 104 weeks, DAS scores <2.6 were achieved by 48% and 44% of patients treated with tocilizumab plus MTX or tocilizumab alone, respectively, compared with 16% of those receiving MTX. Similarly, ACR70 scores were achieved by 47% and 39% of patients treated with tocilizumab plus MTX or tocilizumab alone, respectively, compared with 17% of those receiving MTX alone.

Mean changes from baseline at 104 weeks in mean van der Heijde–modified Total Sharp scores were 0.19, 0.62, and 1.88 in patients who had received tocilizumab plus MTX, tocilizumab alone, and MTX alone, respectively. In patients who switched from MTX monotherapy or from TCZ4 plus MTX to TCZ8 plus MTX at week 52, efficacy improved further to levels observed in VOL. 3

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Continuing Education Figure 1 ACR20 response rates over time in phase 3 studies.24

ACR indicates American College of Rheumatology; BID, twice daily.

Reprinted with permission from Bird P, et al.

patients treated with TCZ8 plus MTX for the entire 104 weeks of the trial.21 This study highlights the importance of initiating appropriate therapy as early as possible in patients with early RA, to achieve optimal outcomes.

Highlighting the ability of tocilizumab to inhibit radiographic progression of disease, Sagawa demonstrated that TCZ8 plus MTX or another cDMARD can prevent radiographically determined joint destruction for up to 3 years in 75% of patients with long-standing RA (median duration of disease, 10.9 years) and active disease (mean DAS28-ESR, 5.31) despite prior treatment with other bDMARDs.22 Rheumatologists are often faced with a choice in their patients with RA who have active disease despite adequate therapy with an anti-TNF agent: Should a second anti-TNF agent be used, or, alternatively, a bDMARD with a different molecular target? In a presentation

by Choquette and colleagues, one possible answer was suggested based on retention data.23 In this study, 259 patients who had failed an anti-TNF agent were treated with tocilizumab, adalimumab, etanercept, or infliximab as second-line biologic therapy. (The 4-year retention rates with tocilizumab, VOL. 3

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adalimumab, etanercept, and infliximab were 44%, 27%, 37%, and 34%, respectively; log rank P = .0249).23 The authors concluded that switching to tocilizumab in patients with RA who fail treatment with their first anti-TNF agent may be a better alternative than cycling to a second anti-TNF agent.23 Tofacitinib is an oral, synthetic Janus kinase (JAK) inhibitor. A comprehensive summary of the efficacy and safety data on tofacitinib in patients with RA and an inadequate response to prior DMARDs was presented by Bird and colleagues.24 In their review, week 12 efficacy and safety data for tofacitinib 5 mg administered orally twice daily were compiled from 5 phase 3 studies (ORAL Solo [tofacitinib monotherapy], or ORAL Sync, ORAL Standard, ORAL Scan, and ORAL Step [all with background cDMARDs]). Patients in ORAL Standard and ORAL Scan exhibited an inadequate response to MTX, whereas those in ORAL Step had an inadequate response to a TNF antagonist, those in ORAL Solo had an inadequate response to a cDMARD or a biologic agent, and those in ORAL Sync were cDMARD treatment failures.24 Regardless of prior therapy, short-term treatment with tofacitinib significantly re-

duced the signs and symptoms of RA, as assessed by ACR20/50/70, DAS284-ESR, and HAQ-DI, compared with placebo (see Figure 1 for ACR20 response rates).24 The safety profile of this agent was as described previously, and included serious and opportunistic infections and adverse cardiovascular events.25 Treatment with tofacitinib in patients with RA was also shown to lessen the impact of the disease on daily and work-related activities compared with individuals receiving placebo.26 Optimal Use of Existing Biologics In a comprehensive review presented at ACR 2014, Sawyer and colleagues conducted an indirect comparison of 16 randomized clinical trials that assessed the efficacy of several biologic agents in patients with early, active RA.27 Understanding that the fallacy of such a comparison across clinical trials is accompanied by such issues as different RA patient populations, different treatment regimens, and different end points, the data illustrated in Figures 2A and B are interesting, in that the efficacy of bDMARDs plus MTX, tofacitinib and tocilizumab monotherapy, and triple cDMARD DECEMBER 2014

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therapy appears to be comparable in patients with early RA. Although the authors attempt to draw conclusions about which agent is better than the other, this is difficult because of the problems noted above.27 Currently, there is growing interest in optimizing biologic therapy by tapering treatments in patients with low disease activity, to reduce the incidence of drug-related adverse reactions, and to control costs. In a retrospective, observational study of 2 groups of patients (N = 144) with RA and DAS28 <3.2 being treated with a TNF antagonist (adalimumab, etanercept, or infliximab), 1 group (n = 67) was treated with a tapering strategy and the other group (n = 77) continued to receive fulldose (standard) therapy.28 Tapering therapy consisted of prolongation of dosing interval (increased dosing interval of 33%, 53%, and 53% in infliximab-, adalimumab- and etanercept-treated patients, respectively).28 At the 1-year conclusion of the study, no significant difference in DAS28 scores was reported between the 2 groups (DAS28 2.7 and 2.5 in the tapered and full-dose groups, respectively; P = .1).28 In a similar fashion, a systematic review and meta-analysis of 6 controlled

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Continuing Education Figure 2 ACR response and DAS28 remission in 16 clinical trials.27

A

Table Clinical Efficacy Measures: All Patients31

ACR response; median relative treatment effects (95% credible intervals).

SSZ 0.09 (–0.18 to 0.37) SSZ + MTX –0.11 (–0.45 to 0.23)

SSZ + HCQ + MTX –0.4 (–0.61 to –0.18) SSZ + MTX + PRD –0.39 (–0.6 to –0.18) TCZ –0.26 (–0.39 to –0.12) ETN –0.15 (–0.36 to 0.06) ADA 0.18 (0.01 to 0.35) aTNF 0.06 (–0.07 to 0.19)a TCZ + MTX –0.41 (–0.58 to –0.25) ETN + MTX –0.48 (–0.61 to –0.35) ADA + MTX –0.43 (–0.54 to –0.33) IFX + MTX –0.4 (–0.54 to –0.28) GOL + MTX –0.3 (–0.51 to –0.08) aTNF + MTX –0.43 (–0.5 to –0.37)a Tofa –0.5 (–0.69 to –0.31)b ABA + MTX –0.4 (–0.6 to –0.2)b RTX + MTX –0.46 (–0.62 to –0.3)b –0.8

–0.6

–0.4 Favors Drug

–0.2

0

0.2

Favors MTX

0.4

0.6

Treatment Effect Versus MTX on Probit Scale

B

Parts A & B Week 24a N=201

Part C: Week 76 (NRI)b N=201

Part D: Week 128 (NRI)c N=144

ACR20

149 (74%)

137 (65%)

101 (70%)

ACR50

83 (41%)

92 (43%)

68 (47%)

ACR70

43 (21%)

50 (25%)

34 (24%)

Boolean Remission

21 (10%)

29 (14%)

21 (15%)

CDAI Remission ≤2.8

34 (17%)

38 (19%)

31 (22%)

SDAI Remission ≤3.3

32 (16%)

38 (19%)

30 (21%)

DAS28-ESR ≤2.6

35 (17%)

44 (22%)

37 (26%)

DAS28-ESR ≤3.2

55 (27%)

69 (34%)

56 (39%)

DAS28-CRP ≤2.6

61 (30%)

76 (38%)

56 (39%)

DAS28-CRP ≤3.2

97 (48%)

100 (50%)

74 (51%)

Clinical Efficacy Measures

a

Observed data for patients entering Part C at Week 24.

NRI imputes non-response for discontinuing prior to Week 76, but not for dose-escalation.

NRI imputes non-response for discontinuing prior to Week 128 for patients entering Part D. ACR indicates American College of Rheumatology; CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; SDAI, Simple Disease Activity Index.

Reprinted with permission from Keystone EC, et al.

DAS28 remission: median relative treatment effects (95% credible intervals).

b c

TCZ 4.99 (3.54 to 7.08) ADA 1.04 (0.72 to 1.5) aTNF 1.02 (0.71 to 1.44)a TCZ + MTX 7.93 (5.4 to 11.8) ETN + MTX 2.58 (1.81 to 3.72) ADA + MTX 2.5 (2.02 to 3.12) IFX + MTX 2.01 (1.36 to 3.04) GOL + MTX 2.3 (1.34 to 4.1) aTNF + MTX 2.41 (2.05 to 2.84)a Tofa 2.13 (1.17 to 4.12)b ABA + MTX 2.33 (1.59 to 3.44)b RTX + MTX 2.66 (1.77 to 4.1)b 0 Favors MTX

2 Favors Drug

4

6

8

10

12

14

Odds Ratio Versus MTX

a

Sensitivity analysis pooling all aTNFs. Sensitivity analysis including unlicensed novel disease-modifying antirheumatic drugs. aTNF indicates tumor necrosis factor antagonist; ABA, abatacept; ACR, American College of Rheumatology; ADA, adalimumab; ETN, etanercept; IFX, infliximab; GOL, golimumab; HCQ, hydroxychloroquine; MTX, methotrexate; PRD, prednisolone; RTX, rituximab; SSZ, sulfasalazine; Tofa, tofacitinib; TCZ, tocilizumab.

Reprinted with permission from Sawyer L, et al. b

trials compared TNF antagonist withdrawal (n = 725) versus TNF antagonist dose reduction and dose continuation (n = 694) in patients with RA who achieved remission or low disease activity.29 The odds ratio (OR) for maintenance of remission or low disease activity was significantly higher with anti-TNF continuation versus anti-TNF withdrawal (P < .00001), whereas the OR for maintenance of remission or low disease activity did not differ significantly between anti-TNF continuation and anti-TNF dose reduction.

Thus, anti-TNF dose reduction appears to be a reasonable strategy for maintenance of low disease activity or even remission, whereas complete anti-TNF withdrawal in patients with RA who achieve low disease activity or remission seems to be a risky strategy.

Emerging Biologic Agents Data on the safety and efficacy of a number of novel agents were presented at ACR 2014. We will focus this review on selected agents in late-stage clinical development, although preclinical or early clinical data on a num-

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ber of promising and interesting agents were also presented.

Baricitinib is an oral JAK1/JAK2 signaling inhibitor that has been associated with clinically meaningful improvements as early as week 2 and up to 12 weeks compared with placebo in patients with active RA receiving stable doses of MTX.30 At ACR 2014, Keystone and colleagues presented an update on the safety and efficacy of baricitinib through 128 weeks in an open-label, long-term extension study.31 In the original phase 2b study, patients had been randomized to placebo or to 1 of 4 doses of baricitinib, but in the long-term, open-label extension, all patients received baricitinib 4 mg once daily. As illustrated in the Table,31 among patients completing 128 weeks of the phase 2b study extension, all clinical improvements observed at week 24 were maintained or enhanced.

In addition, no new safety signals were observed with baricitinib therapy through 128 weeks that had not been seen at week 24.

One of the treatment-related adverse events associated with barici-

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tinib therapy is dose- and time-dependent changes in serum lipids (increases in low-density lipoprotein [LDL] particle size, and in high-density lipoprotein [HDL] and very-low-density lipoprotein particle numbers).32 Interestingly, the increases in serum HDL cholesterol, but not LDL cholesterol, associated with baricitinib treatment correlated with improvements in DAS28-CRP scores. Further studies are warranted to determine whether the positive effects of baricitinib therapy on RA disease activity are accompanied by long-term positive cardiovascular outcomes.

Sarilumab, a fully human monoclonal antibody against the IL-6 receptor, was recently investigated in the randomized, double-blind, placebo-controlled, international, phase 3 MOBILITY study; 52-week results were presented at ACR 2014.33 Patients with active, moderate to severe RA and an inadequate response to MTX were randomized to receive MTX alone, sarilumab 150 mg plus MTX, or sarilumab 200 mg plus MTX every 2 weeks. Compared with MTX alone, sarilumab at both dosages plus MTX provided significant, clinically meaningful improvements in ACR20 response, HAQ-DI, and mean van der Heijde– modified Total Sharp scores (the primary study end points), as well as ACR50/70 responses and reductions in DAS28-CRP and CDAI (secondary end points) at week 52.33 At week 52, 31% to 34% of sarilumab-plus-MTXtreated patients were in clinical remission (DAS28-CRP <2.6), compared with 9% of those treated with MTX alone (P < .0001), and 48% to 56% demonstrated no radiographic progression of disease, compared with 39% in the MTX-alone group (P < .01).33 Similarly, at week 52, the mean change from baseline in HAQ-DI scores was

-0.7 to -0.8 in those receiving sarilumab plus MTX versus -0.5 in those treated with MTX alone (P < .0001). In an accompanying presentation, patients with RA who were treated with sarilumab plus MTX demonstrated significant improvements in health-related quality of life (as assessed by SF-36 scores) and fatigue scores (using the Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F] scale) at 24 weeks, compared with those treated with MTX alone.34 Mavrilimumab, a first-in-class monoclonal antibody that inhibits the granulocyte-macrophage colony-stimulating factor receptor α, was assessed for efficacy and safety in a 24-week, phase 2b, randomized, double-blind, placebo-controlled multicenter study.37 Patients with active RA and an inadequate response to ≥1 DMARDs were randomized to receive MTX alone or MTX plus 1 of 3 subcutaneous doses of mavrilimumab (30 mg, 100 mg, or 150 mg) every 2 weeks for 24 weeks.

Dose-dependent, statistically significant improvements in DAS28-CRP scores were reported at weeks 12 and 24 in patients treated with mavrilimumab plus MTX, compared with MTX alone. For example, at week 24 of therapy, the mean change from baseline in DAS28-CRP scores were -2.18, -1.98, and -1.74 in patients treated with mavrilimumab 150 mg, 100 mg, and 30 mg, respectively, compared with -0.96 for those receiving placebo (P < .001 for all comparisons of mavrilimumab vs placebo).35 Similar results were observed with ACR20 and ACR50 scores at week 24, and with ACR70 scores at the highest mavrilimumab dose; 73%, 41%, and 14% of patients treated with mavrilimumab 150 mg achieved ACR20, ACR50, and ACR70 scores, respectively, compared VOL. 3

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Continuing Education with 25%, 12%, and 4% of placebo-treated patients (P < .001 or ACR20 and ACR50 scores of mavrilimumab vs placebo, and P < .05 for ACR70 scores of mavrilimumab vs placebo).35 An acceptable tolerability profile was demonstrated over the 24-week study period.

Treat-to-Target Strategies—Where Are We Now? The treat-to-target strategy has become the new paradigm for the treatment of RA. Although this strategy works well in controlled clinical studies, the question remains as to whether it is feasible in routine clinical practice.

In a presentation by Waimann and colleagues, 535 DMARD-naïve patients with early RA (<2 years’ disease duration) were followed every 3 months for a mean of 24 months, and mean HAQ-DI and DAS28 scores were compiled.36 In this cohort, patients did not achieve remission in 68% of the clinic visits, but a change in drug treatment was registered in only 42% of these visits. Many of the changes in patients not in remission included the addition or dose escalation of a nonsteroidal anti-inflammatory drug or an intra-articular steroid injection, whereas the addition or change of a biologic agent in those not in remission was reported in <1% of cases.36 Similar results were presented by Maksymowych and colleagues from a 2-year prospective study using the RA Biomarkers as Predictors of Structural Damage in Rheumatoid Arthritis registry.37 In accordance with the results above, the investigators followed 500 patients with active RA who were trying to achieve a DAS target of ≤2.4. According to the authors, nonadherence to the treat-to-target protocol occurred in 42% of the clinic visits, most often due to physician decision that the current treatment was acceptable. For those patients who did follow the protocol, improvements in swollen/tender joint counts, HAQ-DI scores, SF-36 scores, and rates of remission by SDAI, CDAI, or DAS scores were significantly greater than in those who were nonadherent to treat-to-target.37 Thus, although this study demonstrates that adherence to treat-to-target is associated with consistent improvements in RA outcomes and increased rates of remission, a substantial gap in the implementation of this strategy still exists, even in protocol-specified clinical settings.

Biosimilars Over the past 5 years, the number of biosimilars in development for the treatment of RA has increased, as the original etanercept, infliximab, adalimumab, and rituximab near the expiraVOL. 3

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tion of their original patents.38 Overall, 14 biosimilars are now in development, 4 each for adalimumab and etanercept, and 3 each for infliximab and rituximab. For example, Udata and colleagues presented data on the biosimilar PF-06438179 compared with infliximab sourced from the United States and from the European Union.39 According to the investigators, the 3 agents had comparable immunogenicity profiles, with a somewhat lower incidence of antidrug antibodies reported with the biosimilar. Overall, PF06438179 demonstrated similar pharmacokinetics, and comparable safety and immunogenicity profiles, to infliximab in healthy subjects, with additional phase 3 studies planned in patients with RA.39 In a similar fashion, Becker and colleagues presented efficacy data on a rituximab biosimilar in 220 patients with active RA.40 Comparing PF05280586 with rituximab sourced from the United States or from the European Union, the authors demonstrated that the 3 compounds had comparable efficacy in reducing DAS28-CRP scores and exhibited similar safety profiles.40 Bae and colleagues presented data from a randomized, double-blind, phase 3 equivalence trial of an etanercept biosimilar in 294 patients with active RA.41 Patients were randomly assigned to receive MTX plus the etanercept biosimilar HD203 25 mg or etanercept 25 mg administered subcutaneously twice weekly for 48 weeks. The proportion of patients achieving an ACR20 response (the primary end point) with HD203 and reference etanercept was 83% versus 81%, respectively, at 24 weeks (P = .6706) and 86% versus 82%, respectively, at 48 weeks (P = .3905). No statistically significant differences were observed between the 2 groups with respect to changes in DAS28 and EULAR responses at 24 and 48 weeks, or in the number of treatment-emergent adverse events.41 Will the use of biosimilars really result in cost savings? A presentation by Kim and colleagues analyzed the 5-year budget impact of an infliximab biosimilar in the European Union.42 Biosimilar infliximab has been approved by the European Medicines Agency for use in the European Union, based on a quality, safety, and efficacy profile comparable to that of infliximab for the management of RA, ankylosing spondylitis, PsA, Crohn’s disease, and ulcerative colitis. The authors evaluated the budget impact of the biosimilar infliximab in the treatment of RA from both payer and patient perspectives.42 Since the price of the biosimilar infliximab is not yet known, 3 different discount scenarios (10%, 20%, and 30% discounts on biosimilar acquisition cost) were ap-

plied, with varying market uptake growth rate (20%-40%) and an assumed 25% market share. Based on these analyses, the introduction of a biosimilar infliximab as a treatment option for patients with RA would result in a 5-year cost savings in the European Union of €96 million to €433 million.42 Value-Based Treatment of RA One issue facing payers and providers is to assess the value of biologic agents—that is, the cost per effectively treated patient—to determine whether value-based care is being delivered.

Cannon and colleagues approached this question via a presentation in which national Veterans Affairs pharmacy and administrative claims for US veterans initiating biologic therapies (abatacept, adalimumab, etanercept, infliximab, or rituximab) were evaluated.43 Clinical effectiveness was estimated using an algorithm based on claims data; a total of 4696 patients were included in the analysis. The investigators found that the percentage of patients categorized as effectively treated was highest with adalimumab (33%) and etanercept (32%), and the cost per effectively treated patient was lowest with etanercept ($39,400) and adalimumab ($41,500).43 The study fell short of providing substantive evidence of value-based therapy, however, as it did not address the cost per effectively treated patient when nonbiologic DMARDs were used, including triple therapy, or if a treat-to-target algorithm was utilized.

Several presentations focused on approaches for reducing the costs associated with providing value-based care to patients with RA. One powerful approach was discussed by Matsumoto and colleagues, who reported on a payer-initiated collaboration between CareFirst BlueCross BlueShield and Cardinal Health, and private rheumatology practices, in which a committee of 12 community-based rheumatologists was organized to create a treatment pathway for patients with RA based on published evidence and a community standard of care.44 Practices that achieved 80% compliance with the program were offered increased reimbursements to offset the cost of data collection and program compliance. Compliance with the program included prescribed patient visits at 3- to 6-month intervals, with a CDAI recorded at each visit; use of a cDMARD for 3 months prior to initiation of biologic therapy; and changes in biologic therapy mandated only by objective measures based on CDAI scores.44 Over the first 12 months of the program, 80 physicians from 37 practices were recruited and 1800 patients were entered into the pathway. During this DECEMBER 2014

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time, >90% of patients and 74% of practices were compliant with the program, and 70% of the patients were in remission or exhibited low disease activity based on CDAI scores.44 This is an interesting, first-of-its-kind model in which payers and providers got together to ensure appropriate biologic use and to objectively assess clinical outcomes in patients with RA. The authors recommend this program as a model for improving cost and clinical effectiveness of treatment strategies for patients with RA.44 Psoriatic Arthritis The treatment of PsA has changed dramatically over recent years, despite the lack of sufficient knowledge on disease etiology and detailed pathogenesis. Observations that proinflammatory cytokines may play an important pathogenetic role have led to the evaluation of novel therapies; indeed, new synthetic and biologic DMARDs are now widely used in patients with PsA, with additional treatment options anticipated in the near future.

Updates on Existing Therapies Certolizumab, ustekinumab, and apremilast are the 3 major biologic therapies approved for the treatment of patients with PsA. Numerous presentations at ACR 2014 discussed emerging data with these agents.

Kavanaugh and colleagues reported on 96-week, open-label extension data from the RAPID-PsA trial.45 A total of 409 patients with PsA were randomized, of whom 138 were treated with certolizumab 200 mg every 2 weeks and 135 received certolizumab 400 mg every 4 weeks.45 The 96-week data mirrored those of the initial 24-week results, in that compared with baseline, patients in both groups exhibited fewer missed work days due to arthritis, less decreased workplace productivity, and greater household productivity and social participation (measured as days missed from family, social, or leisure activities).45 These results suggest longterm productivity benefits of certolizumab treatment in patients with PsA. A companion presentation by Mease and colleagues of RAPID-PsA data at 96 weeks showed that patients benefited from certolizumab therapy, regardless of whether they were TNF inhibitor–naïve or TNF inhibitor–experienced, and that no new safety signals were observed with certolizumab at the 96-week mark that had not been observed at 24 weeks.46 Ustekinumab is an anti–IL-12/IL-23 monoclonal antibody that was evaluated in PSUMMIT—a phase 3, multicenter, double-blind, placebo-controlled study. Kavanaugh and colleagues reported on 108-week data from a sub-

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Continuing Education Faculty Perspectives “Key leaders in the industry provided up-to-date research on current health trends in the rheumatic population. The meeting offered an opportunity to network and assess our own healthcare standards in current practice to ensure that we are delivering cutting-edge care to our patients. For example, musculoskeletal ultrasound [MSUS] has proven to be a valued tool when diagnosing, differentiating, and following rheumatic disease. Our clinical practice recently adopted the use of MSUS, and the ACR 2014 provided a clearer understanding of the clinical relevance of this resource to improve patient care.”

-Alan Brown, MD “One of the big stories in rheumatologic therapeutics at ACR 2014 was the possibility of tapering down, or even stopping, certain therapies once a good result has been obtained and patients are doing well. For example, in the DRESS study from the Netherlands (Abstract 500), investigators reported that a large majority of patients who were in remission after treatment with adalimumab or etanercept could reduce the frequency of injections without experiencing a major flare. If a flare did occur, patients were able to recapture the remission by resuming prior effective treatments. Perhaps even more surprising are results from the German RETRO trial (Abstract 940). In this trial, patients in remission were randomized to continue treatment, reduce the dose of all of their antirheumatic medications by 50% (including biologics, cDMARDs, and glucocorticoids), or completely halt all of their antirheumatic medications. The dose reduction worked well for greater than 50% of patients, and amazingly, approximately 40% of those who completely halted therapy had sustained remission. As in the DRESS trial, remissions could be recaptured by resuming prior effective treatments. These results and other data presented at ACR 2014 make it clear that rheumatologists may confidently make attempts to lower dosages or dosing frequencies, and sometimes even halt treatment completely, leading to less complicated treatment for patients, potentially fewer side effects, and a more favorable pharmacoeconomic balance.

IL-17 antagonism was another very hot topic at ACR 2014. Several monoclonal antibodies targeting this mechanism are being developed and have generally shown very good results in the skin disorder psoriasis. It is now becoming clear that these agents are also effective for PsA and spondyloarthritis. As some of these drugs are already nearing approval for the dermatological indication, it will be interesting to see to what extent rheumatologists may start using them off-label for their most refractory patients with PsA or spondyloarthritis.”

-Ronald F. van Vollenhoven, MD, PhD

group of patients with PsA from PSUMMIT, who had physician-diagnosed spondylitis and peripheral joint involvement, and were treated with ustekinumab.47 The 186 patients who were evaluated had active disease (≥5 swollen and tender joints; CRP ≥0.3 mg/dL), despite DMARD therapy, and were randomized to ustekinumab 45 mg, ustekinumab 90 mg, or placebo at week 0 and week 4, and then every 12 weeks thereafter, until week 88.47 At week 24, significantly greater proportions of ustekinumab-treated patients exhibited improvements in dactylitis/ enthesitis measurements, HAQ-DI scores, and ACR20/50/70 responses than did placebo-treated patients, with these improvements generally maintained through week 100. Psoriasis Area and Severity Index 75 (PASI75) responses in these patients were also significantly better with ustekinumab than with placebo, with these responses being maintained through week 100 as well.47 Adverse events were similar in the ustekinumab and placebo groups. Fatigue (measured using FACIT-Fatigue and SF-36 Vitality [VT] scores) was also significantly improved in these patients compared

18

with the placebo controls (P = .002 for FACIT-Fatigue and P = .004 for SF-36 VT at week 24), often within 3 doses of ustekinumab therapy.48 Apremilast, an oral phosphodiesterase-4 inhibitor, helps to regulate the immune response that causes the inflammation and skin disease associated with PsA. The PALACE 4 study was a phase 3, randomized, controlled trial that compared the safety and efficacy of apremilast with placebo in DMARD-naïve patients with active PsA.49 Patients were randomized to placebo, apremilast 20 mg twice daily (APR20), or apremilast 30 mg twice daily (APR30). At week 16, significantly greater proportions of apremilast-treated patients achieved a modified ACR20 response (31% with APR30 [P = .0010 vs placebo], 28% with APR20 [P = .0062 vs placebo], and 16% with placebo) and a modified ACR50 response (11%, 11%, and 5% with APR30 [P < .0181 vs placebo], APR20 [P = .0173 vs placebo], and placebo).49 ACR70 response and tender and swollen joint counts were also significantly better in patients treated with apremilast than with placebo. All these responses were sustained over 52 weeks.49 In a latebreaking presentation on 104-week data

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from the PALACE 4 study, Wells and colleagues showed that apremilast monotherapy at both doses—20 mg and 30 mg twice daily— was associated with sustained responses, as well as improvements in PsA signs and symptoms, enthesitis, dactylitis, physical function, and psoriasis.50 At the APR20 dose, ACR20/50/70 scores, median percent changes in tender and swollen joint counts, mean change from baseline in HAQ-DI, PASI-50 and -70 scores, the Maastricht Ankylosing Spondylitis Entheses Score (MASES) and the mean count of dactylitis all improved at week 104 compared with week 52, demonstrating the durability of apremilast in influencing a broad range of responses in patients with PsA. For example, comparing week 52 with week 104 in patients treated with APR20, ACR70 scores were achieved by 14% and 28% of patients, PASI75 scores were achieved by 41% and 47% of patients, MASES of 0 was achieved by 40% and 60% of patients, and absence of dactylitis was achieved by 69% and 83% of patients, respectively, at 52 and 102 weeks. Similar results were observed with APR30.50 Emerging Biologic Agents Brodalumab is a human anti-IL-17 receptor A monoclonal antibody.

Genovese and colleagues presented data from an open-label extension of a phase 2 study of this agent in adult patients with active PsA.51 The significantly higher ACR20/50 response rates reported in brodalumab-treated patients (n = 113) versus placebotreated patients (n = 55) at week 12 continued through week 52, with similar improvements in DAS28, CDAI, and several ACR components. Exposure-adjusted serious adverse event rates were similar in the brodalumab and placebo treatment groups.51 Brodalumab remains a promising new agent for individuals with PsA. Secukinumab is a human anti– IL-17A monoclonal antibody. In a late-breaking presentation by McInnes and colleagues, the investigators presented data from FUTURE 2—a phase 3, randomized, multicenter, double-blind, placebo-controlled study of secukinumab administered subcutaneously.52 In this study, 397 adult patients with active PsA were randomized to receive subcutaneous secukinumab 300 mg, secukinumab 150 mg, secukinumab 75 mg, or placebo at baseline, week 1, week 2, week 3, week 4, and every 4 weeks thereafter. Two-thirds of the subjects were TNF-inhibitor–naïve; the remaining one-third were TNFinhibitor–inadequate responders.

ACR20 responses at week 24—the primary end point—were significantly higher with secukinumab than with placebo (54%, 51%, and 29% with

secukinumab 300 mg, secukinumab 150 mg, and secukinumab 75 mg, respectively, compared with 15% with placebo; P < .0001 for the 300- and 150-mg doses vs placebo; P < .05 for the 75-mg dose vs placebo).52 Secukinumab therapy also improved ACR50/70 responses, PASI75/90 scores, DAS28CRP, SF-36 physical component summary scores, HAQ-DI scores, dactylitis, and enthesitis compared with placebo.

With the 150-mg and 300-mg doses of secukinumab, many of these responses were observed as early as 3 weeks. Similar responses were observed with secukinumab in TNF-inhibitor-naïve subjects and TNF-inhibitor–inadequate responders.52 Treatment with secukinumab was shown to inhibit structural joint damage in patients with active PsA from the FUTURE 1 study.53 Approximately two-thirds of patients with PsA experience progressive joint damage, which is often associated with varying degrees of disability. FUTURE 1 was a phase 3, randomized, double-blind, placebo-controlled study of 606 adults with moderate to severe PsA who received placebo or secukinumab 10 mg/kg administered intravenously, followed by either secukinumab 75 mg or secukinumab 150 mg administered subcutaneously.53 From baseline to week 24, secukinumab-treated patients exhibited significantly lower van der Heijde– modified Total Sharp scores, and erosion and joint space narrowing scores, than did the placebo group, with these differences maintained through week 52. The effects of secukinumab on the inhibition of joint structural damage were observed regardless of whether the patients were receiving concomitant MTX therapy or had previously been treated with a TNF inhibitor.53 Value-Based Treatment of PsA As with RA, value-based therapy for PsA is often couched in terms of an assessment of a cost per analysis. Strand and colleagues presented such an analysis, which compared the cost per responder value of adalimumab, MTX, and apremilast in MTX-naïve patients with PsA.54 A systematic literature review of response rates from clinical trials with approved biologic agents, MTX, and apremilast, and a subanalysis of the phase 3 ADEPT trial of adalimumab versus placebo, were conducted. A meta-analysis was performed to indirectly compare the efficacy outcomes at 16 weeks between approved therapies for PsA, and the number needed to treat was calculated using the inverse of absolute risk reduction. Using data from the MIPA trial for MTX, PALACE 4 for apremilast, and ADEPT for adalimumab, the numbers needed to treat for MTX, VOL. 3

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Continuing Education apremilast, and adalimumab were 8.31, 6.69, and 2.63, respectively.54 The 16-week drug costs were $436, $6844, and $10,010, respectively, for MTX, apremilast, and adalimumab. Thus, the calculated cost per ACR20 responders were $3622 with MTX, $45,808 with apremilast, and $26,316 with adalimumab, suggesting that among MTX-naïve patients, MTX is the most cost-effective and apremilast is the least cost-effective therapy at 16 weeks for patients with PsA.54 As with RA, the cost of treating patients with PsA with TNF antagonists can be reduced if the biologic agent is withdrawn at some point during treatment. In a presentation by Huynh and associates, data were presented from an observational cohort study of PsA in the CORRONA registry of patients who discontinued TNF inhibitor use after achieving low disease activity (defined as CDAI ≤10 and skin psoriasis physician global assessment ≤20/100).55 Of the 5945 patients with PsA in the CORRONA database, 325 discontinued TNF-inhibitor therapy while exhibiting low disease activity and had follow-up data available.

These were patients with well-established PsA (mean disease duration, 9.8 years), with a mean duration of TNF inhibitor use of 1.5 years.55 Of these, 146 patients (45%) lost clinical benefit upon TNF inhibitor discontinuation because of increased CDAI, initiation of, or increase in, DMARD use, TNF inhibitor restart, initiation of, or increase in, prednisone, or worsening skin disease. The median time to loss of benefit was 29.2 months. The other 179 patients (55%) still exhibited persistent benefit at their last clinic visit. Patients with PsA who had less success stopping TNF-inhibitor therapy tended to be those with higher disease activity (CDAI >3.2; patient global assessment >5/10) at the time of discontinuation and smokers.55 n References

1. Skapenko A, Schulze-Koops H, Devanarayan V, et al.

Identification of genetic variants associated with re-

sponse to adalimumab plus methotrexate in patients with early rheumatoid arthritis. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 1131.

2. Sode J, Vogel U, Bank S, et al. Genetic variation in the TLR5 locus is associated with anti-TNF response among rheumatoid arthritis patients. Arthritis Rheumatol (ACR/ ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 2500.

3. Isozaki T, Isojima T, Tokunaga T, et al. ADAM-10 as a tocilizumab predictive factor in rheumatoid arthritis.

Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 2509.

4. Ai R, Whitaker JW, Boyle DL, et al. Distinctive DNA methylation signatures in early rheumatoid arthritis (RA) synoviocytes compared with longstanding (RA) and other inflammatory arthritides. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl): Abstract 2816.

5. Kaeley GS, Nishio MJ, Goyal J, et al. The use of ultra-

sound to detect residual joint inflammation in patients with rheumatoid arthritis in clinical disease remission.

Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 122.

6. Kirino Y, Hama M, Minegishi-Takase K, et al. Combination with joint power Doppler signals with anti-citrullinated peptide antibody predicts joint destruction in rheumatoid arthritis. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 123.

7. Hanova P, Zavada J, Hurnakova J, et al. Seven joints ultrasound scoring system may be useful and effective in assessing disease activity in patients with rheumatoid arthritis in the state of remission in daily clinical practice. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 129.

8. Nordberg LB, Lie E, Aga A-B, et al. The rheumatoid arthritis impact of disease score is associated with disease activity by clinical, laboratory, and ultrasonographic measures: validation in an inception cohort of DMARD-naïve patients with rheumatoid arthritis. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts).

2014;66(suppl):Abstract 356.

9. Hambardzumyan K, Bolce RJ, Saevarsdottir S, et al.

In early rheumatoid arthritis, the multi-biomarker disease activity score at different time-points is predictive of subsequent radiographic progression. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014; 66(suppl):Abstract 364.

10. Hambardzumyan K, Bolce RJ, Saevarsdottir S, et al.

In early rheumatoid arthritis patients with non-response to methotrexate monotherapy the change in multi-biomarker disease activity score is differentially associated with subsequent response to non-biological versus biological therapy. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 367.

11. Kodama S, Ito S, Murasawa A, Nakazono K, Kobayashi D. Efficacy and safety of etanercept in rheumatoid arthritis patients over 75 years old. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl): Abstract 481.

12. Emery P, Pedersen R, Bukowski J, Marshall L. Early response to full-dose etanercept-plus-methotrexate induction therapy predicts sustained remission with reduced-dose combination therapy in early rheumatoid arthritis patients. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 2503.

13. Han C, Keystone EC, Fleischmann R, et al. Impact of golimumab on physical function and employability of patients with rheumatoid arthritis: 5-year data from 3 phase III clinical trials. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 2495.

14. Atsumi T, Yamamoto K, Takeuchi T, et al. The first multicenter, double-blind, randomized, parallel-group study of certolizumab pegol in early rheumatoid arthritis demonstrates inhibition of joint damage progression.

Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014; 66(suppl):Abstract 2472.

15. Ancuta I, Ionescu R, Codreanu C, et al. Sustained clinical benefit with multiple courses of rituximab in second line for all rheumatoid arthritis patients irrespective to the inhibitor of tumour necrosis factor previously used. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 1538.

16. Opris D, Mazilu D, Bojinca V, et al. Relation between number of previous anti-TNF agents and clinical response in rheumatoid arthritis patients treated with rituximab. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 1539.

17. Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73:492-509.

18. Furst DE, Bykerk VP, Burmester G, et al. Patient-reported outcomes following 12 months of therapy with abatacept (plus methotrexate or as monotherapy) or methotrexate and up to 6 months after treatment withdrawal in patients with early rheumatoid arthritis. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts).

2014;66(suppl):Abstract 2486.

19. Turesson C, Stawiarz L, Lindblad S, Saevarsdottir S. Bio-naïve patients with rheumatoid arthritis benefit more from abatacept treatment compared to those who are inadequate responders to other biologics—results from the National Swedish Rheumatology Quality Register. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 501.

20. Finckh A, Neto D, Hernández MV, et al. Abatacept after rituximab in rheumatoid arthritis: a pan-European collaboration of RA registries. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 504.

21. Burmester G, Rigby W, van Vollenhoven RF, et al.

Tocilizumab combination therapy or monotherapy or methotrexate monotherapy in methotrexate-naïve patients with early rheumatoid arthritis: 2-year clinical and radiographic results from a randomized, placebocontrolled trial. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl): Abstract 1845.

22. Sagawa A. Long-term treatment with tocilizumab (TCZ) strongly suppresses joint destruction in biolog-

ic-naïve patients with rheumatoid arthritis (RA) regardless of inflammation status. Arthritis Rheumatol (ACR/ ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 2505.

23. Choquette D, Payette M-P, Raynauld J-P, et al. Tocilizumab use in patients with rheumatoid arthritis having failed one previous anti-TNF agent: comparison with adalimumab, etanercept and infliximab. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts).

2014;66(suppl): Abstract 502.

24. Bird P, Bensen W, El-Zorkany B, et al. Comprehensive summary of the efficacy and safety of tofacitinib 5mg twice daily in patients with rheumatoid arthritis and an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 461.

25. Wollenhaupt J, Silverfield J, Lee EB, et al. Safety and efficacy of tofacitinib, an oral janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies. J Rheumatol. 2014;41:837-852.

26. Strand V, Riese R, Gerber R, et al. Effects of tofacitinib on health care resource utilization and work productivity in US patients with rheumatoid arthritis. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts).

2014;66(suppl):Abstract 2487.

27. Sawyer L, Chang S, Diamantopoulos A, Dejonckheere F. Efficacy of biologic treatments in early active rheumatoid arthritis: an indirect comparison. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts).

2014;66(suppl):Abstract 1527.

28. Plasencia-Rodriguez C, Wolbink GJ, Krieckaert CLM, et al. Comparing a tapering strategy to the standard dosing regimen of TNF inhibitors in patients with rheumatoid arthritis in remission or with low disease activity. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014; 66(suppl):Abstract 2400.

29. Henaux S, Barnetche T, Witrand AR, Fautrel B, Cantagrel AG, Constantin A. Treatment adjustment strategy after achieving remission or low disease activity in rheumatoid arthritis: a systematic review and meta-analysis. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 2483.

30. Smolen JS, Schlichting DE, Sterling KL, et al. 12- and 24-week patient-reported outcomes from a phase 2b dose-ranging study of baricitinib, an oral Janus kinase 1/Janus kinase 2 inhibitor, in combination with traditional disease-modifying antirheumatic drugs in patients with rheumatoid arthritis. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2012;64(suppl):Abstract 490.

31. Keystone EC, Taylor PC, Genovese MC, et al. Safety and efficacy of baricitinib through 128 weeks in an open-label, long-term extension study in patients with rheumatoid arthritis. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 2822.

32. Kremer JM, Genovese MC, Keystone EC, et al. Increases in serum cholesterol with baricitinib treatment are associated with favorable changes in apolipoprotein content and with improvement in DAS28-CRP in patients with rheumatoid arthritis. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 488.

33. Kavanaugh A, Decktor DL, Fan C, van Adelsberg J, Martincova R, Genovese MC. A profile of the efficacy of sarilumab plus methotrexate in rheumatoid arthritis patients: results of a 52-week, phase 3, randomized, double-blind, placebo-controlled, international study.

Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 2824.

34. Strand V, Joseph G, van Hoogstraten H, et al. Impact of sarilumab on health related quality of life (HRQoL), fatigue, and sleep in rheumatoid arthritis patients at week 24 – results of a phase 3, randomized, double-blind, placebo-controlled, multicenter study. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts).

2014;66(suppl):Abstract 1522.

35. Burmester G, McInnes IB, Kremer JM, et al. Efficacy and safety/tolerability of mavrilimumab, a human GM-CSFRα monoclonal antibody in patients with rheumatoid arthritis. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 2821.

36. Waimann CA, Citera G, Dal Pra F, et al. Adherence to a treat-to-target (T2T) strategy in early rheumatoid arthritis. Is it feasible in daily clinical practice? Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts).

2014;66(suppl):Abstract 2381.

37. Maksymowych WP, Østergaard M, Elkayam O, et al. Impact of failure to adhere to treat-to-target of rheumatoid arthritis in real world practice: data from the International Rheumatoid Arthritis Biomarker Program. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 2912.

38. Goel N, Chance K. The biosimilar landscape: a systematic review of its current status. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 1505.

39. Udata C, Yin D, Cai, C, et al. Immunogenicity assessment of PF-06438179, a potential biosimilar to infliximab, in healthy volunteers. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 1501.

40. Becker J-CP, Yin D, Melia LA, et al. A phase I trial comparing PF-05280586 (a potential biosimilar) and rituximab in subjects with active rheumatoid arthritis. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 1502.

41. Bae S-C, Kim J, Choe J-Y, et al. A randomized, double-blind, phase 3 equivalence trial comparing the etanercept biosimilar, HD203, with Etanercept (Enbrel®), in combination with methotrexate (MTX) in patients with rheumatoid arthritis (RA). Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl): Abstract 2825.

42. Kim JS, Hong JA, Kudrin A. 5-year budget impact analysis of biosimilar infliximab for the treatment of rheumatoid arthritis in UK, Italy, France, and Germany.

Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 1166.

43. Cannon GW, Teng C-C, He T, et al. Estimation of cost per effectively treated patients with biologic disease modifying anti-rheumatic drugs in US veterans with rheumatoid arthritis. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 494.

44. Matsumoto AK, Baraf HSB, Feinberg B, Miller P, Winn D. Collaboration between a third party payer and community rheumatologists to create a clinical pathway for the treatment of rheumatoid arthritis to assure proper use of biologics and quality of care. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl): Abstract 1356.

45. Kavanaugh A, Gladman DD, van der Heijde D, Purcaru O, Mease P. Sustained improvements in workplace and household productivity and social participation with certolizumab pegol over 96 weeks in patients with psoriatic arthritis. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 1552.

46. Mease P, Fleischmann R, Wollenhaupt J, et al. Longterm safety and efficacy of certolizumab pegol over 96 weeks in patients with psoriatic arthritis with and without prior tumor necrosis factor inhibitor exposure. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts).

2014;66(suppl):Abstract 545.

47. Kavanaugh A, Sanz LP, Gottlieb AB, et al. Efficacy and safety of ustekinumab in psoriatic arthritis patients with spondylitis and peripheral joint involvement: results from a phase 3, multicenter, double-blind, placebo-controlled study. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 539.

48. Ritchlin CT, Rahman P, Sanz LP, et al. Treatment effect of ustekinumab on fatigue in patients with psoriatic arthritis: results from a phase 3 clinical trial. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts).

2014;66(suppl):Abstract 1548.

49. Wells A, Adebajo AO, Aelion JA, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, is associated with long-term (52-week) improvement in the signs and symptoms of psoriatic arthritis in DMARD-naïve patients: results from a phase 3, randomized, controlled trial. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 1543.

50. Wells A, Edwards C, Adebajo AO, et al. Long-term (104-week) safety and efficacy of monotherapy with apremilast in DMARD-naïve patients with psoriatic arthritis: a phase 3, randomized, controlled trial and open-label extension (PALACE 4). Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract L22.

51. Genovese MC, Mease PJ, Greenwald MW, et al. Clinical response in subjects with psoriatic arthritis following one year of treatment with brodalumab, an anti-interleukin-17 receptor antibody. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 1557.

52. McInnes IB, Mease PJ, Kirkham B, et al. Secukinumab, a human anti-interleukin-17A monoclonal antibody, improves psoriatic arthritis: 24-week efficacy and safety data from a phase 3 randomized, multicenter, double-blind, placebo-controlled study using subcutaneous dosing. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract L1.

53. van der Heijde D, Landewe RBM, Mease P, et al.

Secukinumab, a monoclonal antibody to interleukin-17A, provides significant and sustained inhibition of joint structural damage in active psoriatic arthritis regardless of prior TNF inhibitors or concomitant methotrexate: a phase 3 randomized, double-blind, placebo-controlled study. Arthritis Rheumatol (ACR/ ARHP Annual Meeting Abstracts). 2014;66(suppl): Abstract 954.

54. Strand V, Griffith J, Betts K, Friedman A, Signorovitch J, Ganguli A. An indirect comparison and cost per responder analysis of adalimumab, methotrexate (MTX), and apremilast in the treatment of MTX-naïve psoriatic arthritis (PsA) patients. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 1555.

55. Huynh DH, Etzel CJ, Cox V, Mease P, Kavanaugh A. Persistence of low disease activity after tumor necrosis factor inhibitor withdrawal in patients with psoriatic arthritis. Arthritis Rheumatol (ACR/ARHP Annual Meeting Abstracts). 2014;66(suppl):Abstract 1594.

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SLE and Pregnancy: Considerations in the Care... tion. Ideally, providers and patients should work together to plan a pregnancy when the disease is in remission. Adequate disease control is crucial as the risk for a flare seems to relate to the level of maternal disease activity in the 6 to 12 months before conception.1 Healthcare providers should be well versed in pertinent issues related to SLE management throughout pregnancy because of the increased risk for disease-related mortality and morbidity. Immunologic and hormonal changes related to pregnancy may lead to increased frequency of SLE

for preeclampsia can be challenging, a recent review pertaining to the use of low-dose aspirin during SLE pregnancy suggests a 20% risk reduction for preeclampsia in patients with lupus.

Additional risks during SLE pregnancies include preterm birth, hy­ pertension, premature rupture of membranes, diabetes mellitus, antiphospholipid syndrome, retina damage or detachment, deep vein thrombosis, and stroke. All SLE pregnancies are considered high risk, and labs should be obtained as soon as pregnancy is confirmed: 24-hour urine protein, urinalysis, complete blood

Healthcare providers should be well versed in pertinent issues related to SLE management throughout pregnancy because of the increased risk for diseaserelated mortality and morbidity.

—Deanna L. Owens, MSN, RN

flares; however, the severity of symptoms remains unchanged. Increases in cortisol, progesterone, and estradiol during pregnancy may lead to Th1/ Th2 cytokine shifts.1 With SLE being a predominantly Th2-driven disease, some researchers believe these shifts contribute to symptomatic relapse during pregnancy.

One of the major risks for women with SLE during pregnancy is preeclampsia, marked by elevated blood pressure and proteinuria. Mothers are approximately 30% more likely to develop preeclampsia during pregnancy compared with 5% in the general population.2 Although lowering the risk

count, creatinine, liver function test, antideoxyribonucleic acid, anti-SSA/ Ro and anti-SSB/La antibodies, and antiphospholipid antibodies.

Antibody screening is an important predictor of potentially harmful maternal and fetal complications, including antiphospholipid syndrome (APS) and neonatal lupus. APS is an autoimmune thrombolytic syndrome with clinical manifestations that include recurrent miscarriage, fetal prematurity, maternal and/or fetal thrombosis, HELLP syndrome (H, hemolysis; EL, elevated liver enzymes; LP, low platelet count), fetal distress, and intrauterine growth restrictions.3 The

preferred treatment regimen includes low-dose aspirin and heparin in combination with frequent prenatal visits for necessary monitoring. With appropriate management, >70% of patients will deliver a viable, live baby.

Infants born to SLE mothers with positive anti-SSA/Ro and anti-SSB/ La antibodies are at risk for symptoms associated with neonatal lupus. Maternal antibodies begin crossing the placenta as early as 11 weeks and can lead to rash, various blood or liver abnormalities, and permanent cardiac abnormalities in the infant.4 Congenital heart block develops in approx­ imately 2% of infants and requires frequent fetal echocardiograms throughout the pregnancy to help determine if pacemaker implantation will be warranted postdelivery.

Medication Safety Common medications in the treatment of SLE include combinations of methotrexate, hydroxychloroquine, leflunomide, azathioprine, mycophenolate, corticosteroids, various nonsteroidal anti-inflammatory drugs, and belimumab. Careful consideration should be taken when educating patients on the teratogenic effects of specific medications associated with the management of SLE. In particular, methotrexate must be discontinued at least 3 to 6 months prior to conception, and leflunomide should be stopped at least 2 years prior to pregnancy.5 Ideally, patients should discuss pregnancy options with their healthcare providers because of the delicate balance of maintaining low-disease activity and the discontinuation of potentially teratogenic medications. Although corticosteroids are considered a Category C medication, low doses up to 15 mg daily are

Continued from page 1

considered safe throughout pregnancy, and are often used to lessen the severity of SLE symptoms.5 Hydroxychloroquine—although compatible with pregnancy—is still considered Category C because of associated congenital malformations seen with chloroquine. Intravenous belimumab is a b-lymphocyte-specific inhibitor used to treat adult patients with moderate-to-severe SLE who are also on a combination of disease maintenance medications. Providers should discuss the potential risks versus benefits of continuing belimumab (Category C) therapy with patients as there are no human studies or pregnancy data available.

Another teaching point for both providers and patients is the availability of pregnancy exposure registries.

The Organization of Teratology Information Specialists is dedicated to providing evidence-based information to mothers, healthcare providers, and the general public about medication exposures during pregnancy. n Ms Owens is Director, Infusion and Clinical Services, Low Country Rheumatology, Charleston, SC; and Member, Board of Directors, Rheumatology Nurses Society.

References

1. Doria A, Incani A, Lockshin M. Challenges of lupus pregnancies. Rheumatology (Oxford). 2008;47(suppl 3): iii9-12.

2. Stanhope TJ, White WM, Moder KG, et al. Obstetric nephrology: lupus and lupus nephritis in pregnancy.

Clin J Am Soc Nephrol. 2012;7:2089-2099.

3. Fosca D, Valenti O, Hyseni E, et al. Antiphospholip­ id syndrome during pregnancy: the state of the art.

J Prenat Med. 2011;5:41-63.

4. Capone C, Buyon J, Friedman D, et al. Cardiac manifestations of neonatal lupus: a review of autoantibodyassociated congenital heart block and its impact in an adult population. Cardiol Rev. 2012;20:72-76.

5. Hazes JM, Coulie PG, Geenen V, et al. Rheumatoid arthritis and pregnancy: evolution of disease activity and pathophysiological considerations for drug use.

Rheumatology (Oxford). 2011;50:1955-1968.

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Lupus

Use of Belimumab May Be Controversial in SLE

By Phoebe Starr Boston, MA—Belimumab is the first new drug for systemic lupus erythematosus (SLE) in more than 50 years and the first in its class to be approved by the US Food and Drug Administration (FDA).

The effectiveness and value of be­ limumab in the treatment of SLE was the subject of debate at the recent American College of Rheumatology 2014 Annual Meeting. On the pro side, a presenter indicated that belimumab met its primary end points in 2 large, pivotal, phase 3 trials and has gained FDA approval. On the con side, however, a researcher argued that other trials in SLE had lackluster findings, and the drug is expensive.

Belimumab Effective in SLE Belimumab is a monoclonal antibody that binds the soluble form of B lymphocyte stimulator (BLyS), which is released from B cells, and is thought to reduce the number of abnormal B cells in SLE. Belimumab is FDA-approved for the treatment of active, autoantibody-positive SLE in patients who are receiving standard therapy.

Taking the pro position, Bevra H. Hahn, MD, Professor Emeritus at the University of California, Los Angeles, first discussed the mechanism of action (ie, destroying B cells). “This is the soluble form of BLyS, and inhibition of BLyS results in autoreactive B-cell apoptosis,” she told listeners.

More important than how it acts is whether it is effective, she continued.

Two large, multicenter, prospective, randomized controlled studies compared belimumab plus standard therapy versus infused placebo plus standard therapy: BLISS-52 and BLISS-76.

The studies included a total of 1684 patients with active SLE. The studies excluded patients who had received prior B-cell targeted therapy, or intravenous cyclophosphamide, and those who had active lupus involving the kidneys or central nervous system (CNS).

The studies showed a significant effect on severe flares, fatigue, and improved function and quality of life, and increased the number of patients who could reduce the dose of prednisone (ie, steroid-sparing effect). The studies included 2 patients who committed suicide, and there were serious infusion-related reactions.

Dr Hahn said that these findings influenced her decision not to initiate belimumab in patients who are severely depressed or expressing suicidal thoughts. Also, belimumab should not be given with other live vaccines.

She deemed the cost of treatment, estimated at $28,000 to $35,000 annually, “acceptable” considering the therapeutic effects.

Belimumab Too Costly David A. Isenberg, MD, Academic Director of Rheumatology at Univer-

sity College, London, UK, disagreed.

First he presented findings from a cohort of 600 patients with SLE, mainly women, that he and his colleagues have been following for more than 30 years. Disease duration was more

“One third of patients continue on this drug at $30,000 a year, and it is not even working.”

—David A. Isenberg, MD

than 10 years and patients were of mixed ethnicity. In addition to the common manifestations of arthritis and rash, renal involvement was present in 30% of the cases and CNS involvement in 20%.

“These are the patients excluded from BLISS-52 and BLISS-76 [ie, renal involvement and CNS involvement],” he stated. Dr Isenberg finds it exciting that therapies like belimumab are targeted to the immune system based on better understanding of how it works.

But does that translate to effectiveness and value, he asked.

He discussed 2 other studies of belimumab. One was a posthoc review of both BLISS trials and the other was a more extensive 52-week, placebo-con-

at a glance ➤ Belimumab is a monoclonal antibody that binds the soluble form of B lymphocyte stimulator ➤ The drug met its primary end points in 2 large, pivotal, phase 3 trials and has gained FDA approval ➤ In addition to the common manifestations of arthritis and rash, renal involvement has been seen in 30% of the patients evaluated, and CNS involvement in 20% of patients trolled study called LBSL-2. LBSL-2 did not reach its primary endpoints: percent change in SELENA/SLEDAI (ie, measure of disease activity in SLE) from day 0 to week 24, and time to first mild/moderate or severe disease flare.

A post hoc review of both BLISS trials did not show a significant steroid-sparing effect of reduction in the risk of severe flares. Moreover, qualityof-life improvement was minimal or transient in both trials, he said.

Most objectionable, in his view, is the cost of treatment. “One third of patients continue on this drug at $30,000 a year, and it is not even working,” he concluded. n

Psoriatic Arthritis

Cost-Cutting Behaviors Linked to Poor Outcomes in PsA

By Leslie Wyatt Boston, MA—The method used to administer medication to patients can also heavily impact their medication adherence, placing a lot of importance on the quality and clinical relevance of adherence measures. At the Academy of Managed Care Pharmacy 2014 Nexus meeting, investigators brought attention to medication nonadherence in patients with psoriatic arthritis (PsA).

Identifying Patients with CostCutting Behaviors Overall, 306 patients aged ≥18 years with a diagnosis of PsA were recruitVOL. 3

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ed for the study. Investigators sought to measure cost-cutting behaviors as they relate to loss of work productivity and health conditions. Roxanne Meyer, PharmD, Janssen Scientific Affairs, LLC, Titusville, NJ, and colleagues, conducted cross-sectional, online questionnaires and examined the cost-cutting behaviors of study participants as they related to any health condition from the prior 6 months.

Cost-cutting behaviors were divided into 3 categories: nonadherent cost-cutting behaviors (ie, filling pre-

scriptions less often or not at all, decreasing medication intake, purchasing fewer tablets, cutting tablets in half), adherent cost-cutting behaviors (use of samples or generic brand medications, using coupons or discount cards, ordering medicines by mail on a multimonth basis), and no cost-cutting behaviors.

The results of patients who displayed nonadherent cost-cutting behaviors were compared with those of patients who either engaged in adherent cost-cutting behaviors only, or had no cost-cutting behaviors. Health conDECEMBER 2014

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ditions and loss of work productivity were measured using the Short Form36 questions version 2 survey and the Work Productivity and Activity Impairment questionnaire, respectively.

Adherent Patients Have Better Mental, Physical Health Overall, 64% (n = 197) of patients engaged in ≥1 cost-cutting behaviors, whereas 27% (n = 85) reported participating in ≥1 nonadherent cost-cutting behaviors. Among adherent cost-cutting behaviors, purchasing generic brands, using samples, and bulk buyContinued on page 22

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Rheumatology Update

Herpes Zoster Vaccine May Benefit Patients with RA

By Rosemary Frei, MSc Atlanta, GA—An analysis presented at the Society for Medical Decision Making’s 36th Annual North American Meeting suggests that it may be beneficial to routinely immunize patients with rheumatoid arthritis (RA) against herpes zoster (HZ).

The HZ vaccine is contraindicated for patients with RA and patients who

comorbid conditions and not RA, according to lead investigator Marc Vacquier, MSc, Division of Health Policy and Management, University of Minnesota, Minneapolis, and colleagues.

Without the vaccination, the risk for HZ in patients with RA is approximately double that of the general population, the investigators added.

“Based on the literature and results of our decision-analytic model, the HZ vaccine could be beneficial for RA patients…after they have discussed the implications of [taking] this course of action with their rheumatologist.”

—Marc Vacquier, MSc, and colleagues

are immunosuppressed because it increases the risk for an acute HZ episode, which may lead to vaccine-related visceral dissemination. Although vaccine-related visceral dissemination is potentially life-threatening, the literature suggests that death only occurs in severely immunocompromised patients treated for multiple

Mr Vacquier and colleagues used a mathematical Markov model to simulate a hypothetical cohort of patients with RA aged 60 years receiving traditional nonbiologic disease-modifying antirheumatic drugs and who did or did not receive the HZ vaccination. The model was created with a 30% risk for vaccine-in-

duced visceral dissemination.

“This is a conservative estimate considering that in 2 studies where a combined 19,197 immunocompromised patients received off-label use of the vaccine there were no reports of vaccine-induced visceral dissemination,” said Mr Vacquier. The vaccine’s effectiveness in reducing the incidence of postherpetic neuralgia, which is the most common HZ complication, was not included in the analysis.

“We intentionally excluded the potential reduction in the incidence of postherpetic neuralgia to allow us to conservatively estimate the benefit of reducing the incidence of HZ alone as a baseline measure of vaccine effectiveness in RA,” Mr Vacquier told Value-Based Care in Rheumatology.

As long as the risk of vaccineinduced visceral dissemination is less than 1/250,000, the benefits of vaccination outweigh the risks, the investigators reported. Vaccination was associated with an increase of 0.3 quality-adjusted months per patient—a measure of remaining lifeyears and the quality of life associated with those years, the investigators found. Furthermore, increasing the patients’ risk for HZ raised the threshold whether to vaccinate.

“Based on the literature and results of our decision-analytic model, the HZ vaccine could be beneficial for RA patients…after they have discussed the implications of [taking] this course of action with their rheumatologist,” the investigators concluded. “If both the RA patient and their provider agree on vaccination, then the patient should report any adverse events to their rheumatologist and should be ready to start antiviral treatment within 72 hours if [vaccine-related dissemination occurs].” n

at a glance ➤ The HZ vaccine is contraindicated in people with RA and patients who are immunosuppressed, because it places them at risk of an acute HZ episode resulting in vaccine-related visceral dissemination ➤ Without the vaccination, risk for HZ in patients with RA is approximately double that of the general population

Psoriatic Arthritis

Cost-Cutting Behaviors Linked... ing for months at a time via mail or­der were reported most frequently.

Choosing to not fill an expensive prescription was the most frequently reported tactic for patients engaging in nonadherent cost-cutting behavior.

Patients with no or adherent

cost-cutting behaviors displayed better mental and physical health than patients participating in nonadherent cost-cutting behaviors, according to investigators. Results also indicated that patients who engaged in nonadherent cost-cutting behaviors were

22

younger and from households with lower incomes, compared with patients who were adherent.

Absenteeism, presenteeism, activity impairment, and overall work impair-

Although the cross-sectional methodology used in this study is a limitation, these data indicate that a considerable number of patients with PsA use nonadherent cost-cut-

“Nonadherent cost-cutting behaviors…are associated with worsening health status, decreased work productivity, and more [emergency department] and hospital visits.”

at a glance ➤ Cost-cutting behaviors were divided into several categories, including nonadherent costcutting behaviors and adherent cost-cutting behaviors ➤ Patients with no or adherent costcutting behaviors displayed better mental and physical health than

Continued from page 21

patients participating in non­ adherent cost-cutting behaviors ➤ Work productivity habits were notably worse in patients who participated in nonadherent costcutting behaviors compared with patients who did not engage in such behaviors

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DECEMBER 2014

—Roxanne Meyer, PharmD, and colleagues

ment were measured for the 7 days prior to the study. Work productivity habits were notably worse in patients who participated in nonadherent cost-cutting behaviors compared with patients who did not engage in such behaviors.

ting methods. “Nonadherent costcutting behaviors…are associated with worsening health status, decreased work productivity, and more [emergency department] and hospital visits,” Dr Meyer and colleagues reported. n VOL. 3

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Rheumatology Update

Rethinking Herpes Zoster Vaccine in Patients with RA Taking Biologics

By Phoebe Starr Boston, MA—A single-center study found the herpes zoster (HZ) vaccine was safe in patients taking biologics for rheumatoid arthritis (RA) and other arthritic disease. In more than 150 patients given the vaccine, not a single case of disseminated HZ was observed over follow-up, according to investigators at the American College of Rheumatology (ACR) 2014 Annual Meeting.

Guidelines for HZ Vaccination in RA Current ACR and Advisory Committee on Immunization Practices (ACIP) guidelines recommend that the HZ vaccine be withheld from patients on biologic therapy. However, results of this single-center trial, as well as from a population-based study showing sharply increased rates of HZ infection in patients with RA and systemic lupus erythematosus (SLE) as early as in their 20s and 30s, have led the National Institutes of Health to fund a pilot study followed by a larger phase 3, controlled trial to determine the safety of the HZ vaccine in patients with RA on biologic therapy. Patients in those trials will be continued on biologics during HZ vaccination. The

population-based study found at least a 2-fold increase in risk of HZ in patients with RA, SLE, and inflammatory bowel disease compared with the general population.

“HZ can be serious,” explained Jeffrey Curtis, MD, University of Alabama, Birmingham, senior author of the population-based study. “About 15% of people develop serious post-herpetic neuralgia at the rash site, and about 1 in 6 will need lifelong medication. Herpes zoster reactivation can be disseminated and threaten vision.”

The study by Dr Curtis and colleagues was based on data from the 2007 to 2010 Multi-Payer Claims Database to determine the influence of HZ in a non-Medicare younger population of more than 50,000 patients with 7 different autoimmune inflammatory diseases, including RA, SLE, and inflammatory bowel disease; these patients were compared with more than 330,000 healthy controls.

The findings suggest that the HZ vaccine would be beneficial starting at age 30 years for patients with RA, SLE, and inflammatory bowel disease. The vaccine is currently recommended over the age of 60 years in the general

population and for RA patients prior to starting nonbiologic or biologic drugs, or on nonbiologic disease modifying antirheumatic drugs. ACR does not recommend the vaccine for patients on biologics.

Single-Center Experience Stephen Lindsey, MD, Ochsner Health Center, Baton Rouge, LA, was inspired to conduct his study because a number of arthritis patients coming in his practice had very painful shingles, and a study published in JAMA in 2012 by Zhang and colleagues reported the safety of the HZ vaccine in 630 patients on biologics who were vaccinated inadvertently.

After July 2012, Dr Lindsey assessed 302 patients with RA, psoriatic arthritis, and spondyloarthritis taking biologic therapy as candidates for the vaccine. Among 160 patients on infusional biologics, 110 (68%) received therapy, and of 142 patients on subcutaneous biologics, 42 (32%) received therapy. Overall, 152 patients were vaccinated. Patient age, previous HZ infection, and lack of informed consent were key reasons for patients not being vaccinated.

No cases of HZ infection were re-

at a glance ➤ Current ACR and ACIP guidelines recommend that the HZ vaccine be withheld from patients on biologic therapy ➤ Using a cautious approach, investigators only vaccinated patients with RA, psoriatic arthritis, and spondyloarthritis who were stable on biologics

ported 6 weeks postvaccination, and no cases of disseminated HZ infection have occurred to date.

Dr Lindsey emphasized that he took a cautious approach, including only patients with RA, psoriatic arthritis, and spondlyoarthritis who were stable on biologics. The vaccine was given instead of a biologic at a regularly scheduled visit, and biologic therapy was resumed at the next scheduled visit. No other vaccines were given at the same time as the HZ vaccine.

He has since vaccinated more patients on biologics and it remains safe. n

Secukinumab Promising in Ankylosing Spondylitis and PsA Boston, MA—Secukinumab, an interleukin (IL)-17A inhibitor, was found effective in pivotal phase 3 studies among patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA). The drug was recently approved by the US Food and Drug Administration, and with the new phase 3 data, approval is expected for AS and PsA in 2015.

Two groups of phase 3 studies presented at the American College of Rheumatology (ACR) 2014 Annual Meeting: MEASURE 1 and MEASURE 2 in patients with AS, and FUTURE 1 and FUTURE 2 in patients with PsA. Two other IL-17A antibodies— brodalumab and ixekizumab—are under way and both have had positive results in phase 3 studies of PsA. “Secukinumab is the first non-TNF [tumor necrosis factor] drug to demonstrate responses in AS, and responses were seen in both TNF-exposed and VOL. 3

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non-TNF-exposed patients,” said lead author of MEASURE 1, Dominique Baeten, MD, PhD, Professor of Clinical Immunology and Rheumatology at the Academic Medical Center, University of Amsterdam, the Netherlands. “We saw rapid and sustained relief in signs and symptoms of AS.” MEASURE 1 and MEASURE 2 had similar designs and both studies compared subcutaneous 75 mg and 150 mg of secukinumab; the 150-mg dose was found to be the most effective.

The primary end point of MEASURE 1 (N = 482), which was a 20% improvement in signs and symptoms according to Assessment of SpondyloArthritis International Society criteria (ASAS20) was 60.8% for the 150mg dose and 59.7% for the 75-mg dose, versus 28% for placebo at week 16 (P <.0001). ASAS40, which is a 40% improvement, was achieved in 41.6% and 33.1% of the treated groups ver-

sus 13.1%, respectively (P <.001). All secondary end points were met for both treatment arms versus placebo, including high-sensitivity C-reactive protein, Bath AS Disease Activity Index, quality of life as assessed by the 36-Item Short Form Health Survey and the AS Quality of Life, and Assess Spondyloarthritis partial remission.

After week 24, all of the patients were randomized to 1 of the 2 doses of secukinumab during an open-label phase. At week 52, responses were maintained in both treatment arms, both in anti–TNF-exposed and anti– TNF-naïve patients.

Secukinumab was well tolerated; a higher number of adverse events and serious adverse events were reported in the placebo group. No serious infections were reported, and immunogenicity was low.

MEASURE 2 results were similar for secukinumab in patients with AS. DECEMBER 2014

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FUTURE 1 and FUTURE 2 are the first phase 3 studies of a selective IL17A inhibitor in PsA. FUTURE 1 compared 75 mg and 150 mg of secukin­ umab of with placebo, and FUTURE 2 compared 75 mg, 150 mg, and 300 mg with placebo.

Both studies met the primary end point of the ACR 20% (ACR20) improvement from baseline at week 24.

In FUTURE 1, ACR20 was achieved in 50.5% and 50% of the 75-mg and 140mg arms, respectively, versus 17.3% for placebo (P <.0001). In FUTURE 2, ACR20 was achieved in 29.3% for secukinumab 75 mg (P <.05); 51% and 54% for secukinumab 150 mg and 300 mg, respectively, versus 15.3% for placebo (P <.0001).

Secukinumab was well tolerated in both studies, with a similar adverse event profile as in the MEASURE 1 and MEASURE 2 studies.—PS n

www.ValueBasedRheumatology.com

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ACR Conference Highlights

Treat-to-Target Optimal Approach in Early...

Activity Score (DAS) <2.4, mortality remained similar to that of the gen­ eral population, the researchers emphasized.

Between 2000 and 2002, BeST enrolled 508 Dutch patients with recentonset active RA and randomized them to 1 of 4 treatment arms: sequential monotherapy starting with methotrexate (MTX); stepped-up combina-

at a glance ➤ The BeST trial included patients with recent-onset active RA who were randomized to 1 of 4 treatment arms ➤ Independent risk factors for mortality included age, gender, smoking, and disability ➤ Study results are reassuring because many studies suggest that RA patients are at higher risk of dying due to their disease

tion therapy starting with MTX; initial combination therapy with prednisone starting with MTX plus cyclosporine plus prednisone; and initial combination therapy with infliximab starting with infliximab plus MTX. For each of these strategies, patients were assessed every 3 months and, if the target of DAS <2.4 was not met, treatment was intensified according to preplanned steps that differed in each strategy. If DAS remained <2.4, patients were put on maintenance therapy.

These results are reassuring, said the Dutch researchers, because many studies suggest that RA patients are at higher risk of dying due to their disease. By treating with targeted therapy and suppressing inflammation, this risk was reduced in the BeST trial, they said.

“We wanted to see whether survival was improved by treating early severe RA with treat to target strategies compared to the general population,” said presenting author Iris Markusse, MD, Leiden University Medical Cen-

Continued from page 1

ter, the Netherlands. “Our results suggest that treatment targeted to DAS <2.4 prevents increased mortality previously associated with RA and that the medication used in these strategies does not increase mortality.”

“Our results suggest that treatment targeted to DAS <2.4 prevents increased mortality previously associated with RA and that the medication used in these strategies does not increase mortality.”

—Iris Markusse, MD

At baseline, mean age was approximately 54 years and mean DAS was 4.4. The study population was ageand gender-matched from the general Dutch population. There was no sta-

tistically significant difference in mortality between these 2 cohorts.

The number of overall deaths in patients with RA was 72: 16, 15, 21, and 20, in the 4 treatment arms, respectively. In the general Dutch population, 62 deaths were expected and 72 occurred, resulting in an overall standardized mortality ratio (SMR) of 1.16 (95% confidence interval [CI], 0.92-1.46).

When each treatment arm was compared with the general Dutch population, the SMR was 1 (95% CI, 0.611.64) for arm 1; 1.02 (95% CI, 0.61-1.69) for arm 2; 1.30 (95% CI, 0.85-1.99) for arm 3; and 1.32 (95% CI, 0.85-2.04) for arm 4. In the RA cohort, independent risk factors for mortality included age, gender, smoking, and disability as measured by the Health Assessment Questionnaire.

“Patients remained in the study because they wanted to contribute to science. They also developed a good relationship with their researcher, which may have helped with compliance,” Dr Markusse noted. n

Rheumatology Update

New Measures for Infusible Medication Adherence...

The method used to administer medication to a patient can also heavily impact their medication adherence, placing a lot of importance on the quality and clinical relevance of adherence measures. At the Academy of Managed Care Pharmacy 2014 Nexus meeting, new adherence mea-

at a glance ➤ Medication adherence measures, including medication possession ratio and proportion of days covered, share the extent of a patient’s nonadherence ➤ The new medication adherence measures investigated in this study included days of uninterrupted use, observed versus expected refill ratio, and cumulative time off treatment

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sures for patients with rheumatoid arthritis (RA) receiving infusible biologics were presented.

Medication adherence measures such as the medication possession ratio and proportion of days covered share the extent of a patient’s nonadherence, but do not provide details about clinically relevant nonadherence patterns.

Seeking to investigate new, clinically focused adherence measures for patients with RA receiving infusible biologic agents, Roxanne Meyer, PharmD, Janssen Scientific Affairs, LLC, Titusville, NJ, and colleagues, carried out a study involving 2 regularly prescribed infusible therapeutic agents, infliximab and abatacept.

A total of 848 insured patients aged ≥18 years with a diagnosis of RA were selected from the Optum Clinformatics Data Mart database. Starting with the induction infusion, the study spanned 1 year, and involved 7 novel adherence measures calculated over the course of the maintenance phase.

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DECEMBER 2014

Patients received abatacept (n = 431) every 4 weeks and patients received infliximab (n = 417) every 8 weeks.

“Nearly all measured adherence outcomes were significantly different between groups, with [patients receiving infliximab] showing a greater level of medication adherence.”

—Roxanne Meyer, PharmD, and colleagues

The fourth dose of each respective medication denoted the start of the maintenance phase.

The new medication adherence measures included days of uninter-

Continued from page 1

rupted use, observed versus expected refill ratio, and cumulative time off treatment. These measures were only applied to maintenance infusions.

“Nearly all measured adherence outcomes were significantly different between groups, with [patients receiving infliximab] showing a greater level of medication adherence,” reported Dr Meyer and colleagues.

Patients given abatacept had a higher chance of being women (83.7% vs 77.4%) and were more likely to have been treated with biologics in the past than their counterparts receiving infliximab, the investigators noted. Patients receiving treatment with abatacept were also significantly more prone to cumulative time off treatment compared with patients taking infliximab (79.6 vs 41.2 days), but had a considerably lower number of days of uninterrupted use (160.4 vs 283.7 days) and observed versus expected refill ratio (0.75 vs 0.99) than their counterparts. n VOL. 3

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Drug Update

Rasuvo (Methotrexate) Once-Weekly Subcutaneous Injection with Flexible Dosing Approved by the FDA for Rheumatoid Arthritis, Polyarticular Juvenile Idiopathic Arthritis, and Severe Psoriasis

By Loretta Fala, Medical Writer

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nflammatory autoimmune conditions can affect different body systems, resulting in a variety of diseases involving the joints, skin, brain, and other organs. Rheumatoid arthritis, gout, juvenile idiopathic arthritis, psoriasis, and psoriatic arthritis are among the common chronic inflammatory autoimmune diseases affecting millions of Americans annually.

Rheumatoid Arthritis Rheumatoid arthritis, a chronic inflammatory, autoimmune disorder that affects the lining (synovium) of the joints, affects 1.3 million people in the United States.1 Aside from causing painful swelling that may eventually lead to bone erosion and joint deformity, rheumatoid arthritis can also affect other organs of the body, including the skin, eyes, lungs, and blood vessels.1,2 Patients with rheumatoid arthritis have a high risk for disability and mortality, and they are twice as likely to die as people of the same age without rheumatoid arthritis.3 Approximately 40% of all deaths associated with rheumatoid arthritis are attributed to cardiovascular causes, including ischemic heart disease and stroke.3 Rheumatoid arthritis has a substantial impact on a patient’s functional status and quality of life.3 In addition, this disease is associated with substantial direct and indirect costs. According to one study, rheumatoid arthritis accounted for $19.3 billion (2005 dollars) in societal costs, excluding intangible costs, which rose to $39.2 billion when intangible costs were added.4 The management goals for patients with rheumatoid arthritis include reducing joint pain and swelling, alleviating stiffness, and preventing joint damage.1 According to the 2012 American College of Rheumatology (ACR) recommendations for the use of disease-modifying antirheumatic drugs (DMARDs) and biologic agents in the treatment of rheumatoid arthritis, “The goal for each rheumatoid arthritis patient should be low disease activity or remission. In ideal circumstances, rheumatoid arthritis remission should be the target of therapy, but in

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others, low disease activity may be an acceptable target.”5 The ACR recommendations also state that decisions about treating to target are left to the clinician caring for the individual patient, based on the patient’s preferences, comorbid conditions, and other relevant factors. Moreover, treatment plans involve patient-tailored risk– benefit analysis based on the clinician’s assessment and collaboration with the patient.5 The early diagnosis and treatment of rheumatoid arthritis are vital.1 More aggressive treatment in early rheumatoid arthritis may improve outcomes, prevent irreversible joint damage, and preserve physical function and health-related quality of life.5 Therapies for rheumatoid arthritis include nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, DMARDs (ie, methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine), immunosuppressants, tumor necrosis factor (TNF)-alpha inhibitors, and other biologic anti-inflammatory agents.2 Polyarticular Juvenile Idiopathic Arthritis Rheumatoid arthritis characteristically develops in adults, but it can affect people of all ages. When rheumatoid arthritis affects young individuals aged <16 years, the condition is called juvenile arthritis. Although juvenile arthritis generally develops in children before age 16 years, symptoms may start as early as 6 months of age.6 Approximately 300,000 children in the United States have been diagnosed with some form of juvenile arthritis.7 An estimated 40% of all cases of juvenile arthritis are polyarticular disease.8 Polyarticular juvenile idiopathic arthritis (pJIA) is characterized by the involvement of many joints (≥5), which may include the large and small joints of the legs and arms, as well as the jaw and neck. The polyarticular form of juvenile arthritis may eventually evolve into rheumatoid arthritis.

The symptoms of pJIA include swollen or warm joints, limping, rash, sudden high fever, joint stiffness or pain, and swollen glands.6 Other dis-

ease manifestations may include red eyes, eye pain, photophobia, or vision changes. The severity of disease cor­ responds with the number of major joints affected.6 Complications of pJIA include erosion or destruction of the joints, a slow rate of growth, vision loss from chronic uveitis, anemia, and pericarditis.6 Moreover, children affected with pJIA may have poor school attendance as a result of chronic pain.6 In addition to its substantial health impact on young patients, juvenile arthritis diseases in the United States account for an estimated $285 million annually in direct costs, based on 1989 data from the Centers for Disease Control and Prevention.8 The treatment goal for patients with pJIA is to control symptoms, prevent joint damage, and help them maintain function.7 First-line therapy for pJIA includes NSAIDs, which are admin­ istered in a dose appropriate for the child’s weight. If a response is not achieved with NSAIDs, DMARDs are used as second-line therapy. These DMARDs include methotrexate and biologic agents, which consist of several TNF-alpha inhibitors.7 Psoriasis Psoriasis is a chronic, inflammatory autoimmune skin disease that is often accompanied by thick, itchy, red patches that can be painful.9 In some cases, the disease is disfiguring and disabling. The most prevalent autoimmune disease in the United States, psoriasis affects an estimated 7.5 million people.9 Severe psoriasis is characterized by involvement of more than 10% of the body.10 Individuals with psoriasis have an increased risk for developing psoriatic arthritis, eye disorders, obesity, type 2 diabetes, and hypertension.11 They also have an elevated risk for cardiovascular disease, Parkinson’s disease, kidney disease, and other autoimmune diseases.11 Moreover, psoriasis has a dramatic impact on a patient’s quality of life and self-esteem. It can lead to depression, social isolation, and problems at work.11 Psoriasis also imposes a substantial financial burden on affected individuals, as well as DECEMBER 2014

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on the national healthcare costs. The annual US costs attributable to psoriasis totaled a staggering $11.25 billion in 2008.9 The treatment goals for patients with psoriasis include slowing the speed of skin growth to reduce in-­ flammation and plaque formation, removing skin scales, and smoothing the skin.11 Topical treatments include topical corticosteroids, vitamin D analogs, anthralin, topical retinoids, calcineurin inhibitors, salicylic acid, and coal tar.12 Phototherapy (artificial ultraviolet A and ultraviolet B lights) is sometimes used alone or in combination with other medications. Oral or injectable therapies for psoriasis include methotrexate, retinoids, cyclosporine, and biologic immunomod­ ulator agents, including several TNF-alpha inhibitors (ie, etanercept, infliximab, adalimumab) and the interleukin-12/interleukin-23 inhibitor, ustekinumab.12 Methotrexate Injection Approved in 10 Dosage Strengths for 3 Autoimmune Conditions Oral methotrexate has been available for the treatment of inflammatory autoimmune disorders for many years. In fact, for more than 2 decades, methotrexate has been recognized as a cornerstone therapy for patients with rheumatoid arthritis and severe psoriasis. The first once-weekly subcutaneous formulation of methotrexate (Otrexup; Antares Pharma) was approved by the US Food and Drug Administration (FDA) in 2013 for adults with severe active rheumatoid arthritis who do not respond to or cannot tolerate first-line therapy, for children with active pJIA, and for adults with severe, refractory psoriasis.13 In July 2014, the FDA approved a new once-weekly subcutaneous injection of methotrexate (Rasuvo; Medac Pharma) for the treatment of patients with rheumatoid arthritis, pJIA, or psoriasis.14 The new methotrexate injection is administered once weekly subcutaneously via an autoinjector pen. Methotrexate injection is not indicated for the treatment of neoplastic diseases.15 Eric Ruderman, MD, Professor of Continued on page 26

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Drug Update

Rasuvo (Methotrexate) Once-Weekly Subcutaneous...

Continued from page 25

Table Starting Doses for the Subcutaneous Injection of Methotrexate Indication

Starting dosea

Rheumatoid arthritis

7.5 mg once weeklyb

Polyarticular juvenile idiopathic arthritis

10 mg/m2 once weekly

Psoriasis

10-25 mg once weeklyc

The dose should be adjusted gradually to achieve an optimal response.

Oral formulation is a potential alternative. c Oral, intramuscular, or intravenous formulation is a potential alternative.

Source: Rasuvo (methotrexate) injection prescribing information; July 2014. a

b

Medicine, Northwestern University Feinberg School of Medicine, said in a press release from Medac Pharma, “As a rheumatologist, I believe Rasuvo will offer patients the opportunity to maximize the benefit they get from methotrexate. Rasuvo’s dosing flexibility, in particular, will be very helpful, as RA patients do not all respond equally to methotrexate, making it important to select a treatment regimen that is appropriate for the patient’s condition.”14 The subcutaneous delivery of methotrexate injection and its availability in 10 dosage strengths (ranging from 7.5 mg to 30 mg) was designed to improve its bioavailability, according to the manufacturer.14 Results of a clinical study showed that subcutaneous methotrexate administration with a prefilled autoinjector pen led to a higher relative bioavailability compared with oral administration of the drug.16 The use of oral methotrexate is associated with gastrointestinal side effects, including nausea and abdominal pain.17 Studies suggest that the subcutaneous pen administration of methotrexate is associated with fewer, less intense gastrointestinal adverse events than oral methotrexate.16,17 Mechanism of Action Methotrexate works by inhibiting dihydrofolic acid reductase.15 Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be used as carriers of one-carbon groups in synthesizing purine nucleotides and thymidylate. Methotrexate interferes with the synthesis and repair of DNA, as well as cellular replication. In general, actively proliferating tissues (eg, malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder) are more sensitive to this effect of methotrexate.15 The mechanism of action of methotrexate in patients with rheumatoid arthritis is unknown, but it may affect immune function. The production rate of epithelial cells in the skin is greatly

26

increased in patients with psoriasis versus patients with normal skin. This differential in proliferation rates serves as the basis for using methotrexate to control the process of psoriasis.15 Dosing and Administration Methotrexate injection is administered once weekly subcutaneously in the abdomen or the thigh. A different formulation of methotrexate should be used instead of the subcutaneous form for patients requiring oral, intramuscular, intravenous, intra-arterial, or intrathecal dosing; doses of <7.5 mg weekly; doses >30 mg weekly; high-dose regimens; or dose adjustments of <2.5-mg increments.

The starting doses of methotrexate are listed in the Table. The dose should be adjusted gradually in the individual patient to achieve an optimal response.

Methotrexate injection is available as a single dose from a manually triggered autoinjector pen that delivers the drug. It is available in 10 different dosage strengths, ranging from 7.5 mg to 30 mg, including 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, and 30 mg.14,15 Clinical Studies In patients with rheumatoid arthritis, clinical trials were performed using other formulations of methotrexate. The effects of methotrexate on articular swelling and tenderness can be seen as early as 3 to 6 weeks after the start of treatment in patients with rheumatoid arthritis. Most studies of methotrexate in patients with rheumatoid arthritis have been of relatively short duration (3-6 months). Based on limited data from long-term studies, an initial clinical improvement should be maintained for at least 2 years with continuous therapy with subcutaneous methotrexate.15 Clinical trials in patients with pJIA were performed using formulations other than subcutaneous methotrexate.15 Treatment with methotrexate was evaluated in a 6-month, dou-

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ble-blind, placebo-controlled study in 127 pediatric patients with pJIA (mean age, 10.1 years; mean duration of disease, 5.1 years).15,18 This study showed that in patients receiving background NSAIDs and/or prednisone, methotrexate given weekly at an oral dose of 10 mg/m2 resulted in significant clinical improvement compared with placebo as measured by the physician’s global assessment or by a patient composite (ie, 25% reduction in the articular severity score plus improvement based on parent and physician global assessments of disease activity).15,18 More than 66% of the patients in this study had pJIA; the numerically greatest response was seen in this subgroup of patients who received 10 mg/m2 per week of methotrexate.15,18 The overwhelming majority of the remaining patients had systemic-course juvenile idiopathic arthritis. All patients were unresponsive to NSAIDs; approximately 33% were receiving low-dose corticosteroids.15,18 The 5-mg/m2 dose of weekly methotrexate was not significantly more effective than placebo.15,18 Safety The most common adverse reactions associated with methotrexate injection are nausea, abdominal pain, dyspepsia, stomatitis/mouth sores, rash, nasopharyngitis, diarrhea, liver function test abnormalities, vomiting, headache, bronchitis, thrombocytopenia, alopecia, leukopenia, pancytopenia, dizziness, photosensitivity, and burning of skin lesions.15 Contraindications Methotrexate injection is contraindicated in pregnant women, nursing mothers, and in patients affected by alcoholism or those with liver disease, immunodeficiency syndromes, preexisting blood dyscrasias, or hypersensitivity to methotrexate.15 Drug Interactions Aspirin, NSAIDs, and steroids. The concomitant use of methotrexate injection with aspirin, NSAIDs, and steroids may elevate and prolong serum methotrexate levels and may cause increased toxicity.15 Proton pump inhibitors. The concomitant use of methotrexate injection with proton pump inhibitors may prolong serum methotrexate levels and may cause increased toxicity.15 Hepatotoxins. Patients receiving concomitant treatment with methotrexate and potential hepatotoxins (eg, azathioprine, retinoids, and sulfasal­

azine) should be monitored closely for the possible increased risk for hepatotoxicity.15 Theophylline. Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when taken concurrently with methotrexate.15 Folic acid and antifolates. Vitamin preparations containing folic acid or its derivatives may decrease the response to systemically administered methotrexate.15 Mercaptopurine. Methotrexate increases the plasma levels of mercaptopurine. The combination of methotrexate and mercaptopurine may therefore require dose adjustment.15 Other drugs. Methotrexate is partially bound to serum albumin, and its toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides. The use of methotrexate with probenecid should be monitored carefully, because renal tubular transport is also diminished by probenecid.15 Warnings and Precautions Boxed warnings. The prescribing information for methotrexate injection carries a boxed warning stating that serious toxic reactions and death have been reported with its use, and that patients should be monitored closely for bone marrow, liver, lung, skin, and kidney toxicities. Methotrexate has been reported to cause fetal death and/or congenital anomalies and is contraindicated in pregnancy. Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) with some NSAIDs.15 The boxed warning also notes the risk for hepatotoxicity, fibrosis, and cirrhosis, which may occur after prolonged use of methotrexate. Methotrexate may cause interstitial pneumonitis at any time during therapy; this has been reported at low doses. Consequently, pulmonary symptoms—especially a dry, nonproductive cough— may require interruption of treatment and careful investigation.15 In addition, diarrhea, ulcerative stomatitis, hemorrhagic enteritis, and death from intestinal perforation may occur, as well as potentially fatal opportunistic infections. Severe, occasionally fatal, skin reactions have also been reported.15 Organ system toxicity. Serious VOL. 3

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Drug Update toxic reactions are possible with this medication. Methotrexate should only be used by physicians who are experienced in antimetabolite therapy.15 Embryofetal toxicity. Methotrexate is not recommended for women of childbearing potential unless medical evidence shows that the benefits will outweigh the risks. Women of childbearing potential should not start taking methotrexate until pregnancy is excluded and should be counseled about the serious risk to the fetus if they become pregnant while undergoing treatment. Pregnancy should be avoided if the man or the woman is receiving methotrexate (a minimum of 3 months for men, and for at least 1 ovulatory cycle after therapy for women).15 Effects on reproduction. Methotrexate may cause infertility, oligospermia, and menstrual dysfunction; these effects should be discussed with all patients.15 Laboratory tests. Patients using subcutaneous methotrexate injection should be monitored closely to detect any toxic effects promptly. Complete blood counts, renal function, and liver function tests should be performed at the intervals recommended in the prescribing information.15 Risks from improper dosing. The physician and the pharmacist should emphasize to the patient that subcutaneous methotrexate is administered once weekly and that mistaken daily use has led to fatal toxicity.15 Patients with impaired renal function, ascites, or pleural effusions. Because methotrexate elimination is reduced in patients with impaired renal

function, ascites, or pleural effusions, such patients require especially careful monitoring for toxicity as well as dose reduction or, in some cases, the discontinuation of methotrexate.15 Dizziness and fatigue. Adverse reactions from methotrexate, such as dizziness and fatigue, may affect the ability to drive or operate machinery.15 Malignant lymphomas. Non-Hodg­ kin’s lymphoma and other tumors have been reported in patients receiving low-dose oral methotrexate; however, some cases of malignant lymphoma related to low-dose oral methotrexate have regressed completely after the withdrawal of methotrexate, without requiring active antilymphoma treatment. Methotrexate should be discontinued, and if the lymphoma does not regress, ap­ propriate treatment should be instituted.15 Tumor lysis syndrome. Like other cytotoxic drugs, methotrexate may induce tumor lysis syndrome in patients with rapidly growing tumors.15 Concomitant radiation therapy.

Methotrexate given concomitantly with radiotherapy may increase the risk for soft-tissue necrosis and osteonecrosis.15

years to determine whether they respond to it differently from younger patients. In general, dose selection for an elderly patient should be done cautiously, reflecting the greater frequency of decreased hepatic and renal functions, decreased folate stores, and concomitant disease or other drug therapy (ie, that interfere with renal function, methotrexate, or folate metabolism) in this population.15

Use in Specific Populations Pediatric use. The safety and efficacy of methotrexate injection have not been established in pediatric patients with psoriasis or in pediatric patients with malignancy.15 Geriatric use. Clinical studies of methotrexate did not include sufficient numbers of patients aged ≥65

References

Conclusion The recent FDA approval of methotrexate subcutaneous injection marks the availability of a new once-weekly therapeutic option for patients with severe rheumatoid arthritis or pJIA who do not tolerate or respond to firstline treatment, and for patients with severe psoriasis who do not respond to other treatments.14 Methotrexate subcutaneous injection is available in 10 dosage strengths, providing a wide range of patient-tailored dosing options. In clinical studies, the subcutaneous delivery of once-weekly methotrexate via an autoinjector pen resulted in a higher relative bioavailability than oral methotrexate; furthermore, it is associated with fewer, less severe gastrointestinal adverse events than oral methotrexate.16,17 n 1. Ruderman E, Tambar S; for the American College of Rheumatology. Rheumatoid arthritis. Updated August 2012. www.rheumatology.org/practice/ clinical/patients/diseases_and_conditions/ra.asp.

Accessed November 10, 2014.

2. Mayo Clinic. Rheumatoid arthritis. October 29, 2014. www.mayoclinic.org/diseases-conditions/rheu matoid-arthritis/basics/definition/con-20014868.

Accessed November 10, 2014.

3. Centers for Disease Control and Prevention.

Rheumatoid arthritis. Updated November 6, 2014. www.cdc.gov/arthritis/basics/rheumatoid.htm.

Accessed November 10, 2014.

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

5. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res. 2012;64:625-639.

6. MedlinePlus. Juvenile rheumatoid arthritis. Updated April 20, 2013. www.nlm.nih.gov/medlineplus/ency/ article/000451.htm. Accessed October 15, 2014.

7. Abramson LS; for the American College of Rheumatology. Arthritis in children. Updated May 2013. www.rheumatology.org/practice/clinical/patients/ diseases_and_conditions/juvenilearthritis.asp.

Accessed October 15, 2014.

8. Centers for Disease Control and Prevention. Childhood arthritis. Updated October 23, 2013. www. cdc.gov/arthritis/basics/childhood.htm. Accessed October 15, 2014.

9. National Psoriasis Foundation. Psoriasis and comorbid conditions issue brief. Executive summary. January 2012. www.psoriasis.org/document. doc?id=793. Accessed October 17, 2014.

10. National Psoriasis Foundation. Psoriasis severity. www.psoriasis.org/about-psoriasis/treatments/ severity. Accessed October 17, 2014.

11. Mayo Clinic staff. Psoriasis. April 11, 2014. www. mayoclinic.org/diseases-conditions/psoriasis/ basics/symptoms/con-20030838?p=1.

Accessed October 17, 2014.

12. National Psoriasis Foundation. Moderate to severe psoriasis: biologic drugs. www.psoriasis. org/about-psoriasis/treatments/biologics. Accessed October 17, 2014.

13. Brooks M. FDA OKs methotrexate autoinjector (Otrexup). October 18, 2013. Medscape. www.medscape. com/viewarticle/812821. Accessed October 22, 2014.

14. Medac Pharma, Inc. Medac Pharma, Inc. secures FDA approval of Rasuvo (methotrexate) injection for rheumatoid arthritis, poly-articular-course juvenile idiopathic arthritis and psoriasis. Press release. July 14, 2014. www.medacpharma.com/u-s-district-court-forthe-district-of-delaware-concurrently-denies-motionfor-preliminary-injunction-filed-by-antares-pharmainc/. Accessed November 10, 2014.

15. Rasuvo (methotrexate) injection [prescribing information]. Chicago, IL: Medac Pharma, Inc; July 2014.

16. Pichlmeier U, Heuer KU. Subcutaneous administration of methotrexate with a prefilled autoinjector pen results in a higher relative bioavailability compared with oral administration of methotrexate. Clin Exp Rheumatol. 2014;32:563-571.

17. Rutkowska-Sak L, Rell-Bakalarska M, Lisowska B. Oral vs. subcutaneous low-dose methotrexate treatment in reducing gastrointestinal side effects.

Reumatologia. 2009;47:207-211.

18. Giannini EH, Brewer EJ, Kuzmina N, et al; for the Pediatric Rheumatology Collaborative Study Group, and the Cooperative Children’s Study Group.

Methotrexate in resistant juvenile rheumatoid arthritis: results of the U.S.A.–U.S.S.R. double-blind, placebo- controlled trial. N Engl J Med. 1992;326:1043-1049.

In the Literature

Prioritization Tool for RA Referrals Improves Access

R

esults from a recent prospective analysis indicated that the use of a prioritization tool for rheumatoid arthritis (RA) referrals improves access when rheumatologists are scarce (Cummins L, et al. Arthritis Care Res (Hoboken). 2014 Aug 22. Epub ahead of print).

Over the course of 8 months, investigators evaluated new adult rheumatology referrals with possible inflammatory arthritis to determine whether the VOL. 3

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2010 American College of Rheumatology (ACR)/European League Against Rheumatology (EULAR) Classification Criteria for RA improved triage decisions and reduced waiting times. Data concerning rheumatologist diagnosis, use of disease-modifying antirheumatic drugs (DMARDs), and waiting times were also collected.

Approximately 450 referrals were screened: 180 met criteria for inclusion, 143 provided sufficient data after

information was requested, and 71 referrals met triage criteria. Forty percent of the 63 patients who attended their appointments received diagnoses of RA by a rheumatologist. Mean wait times were 7.9 weeks for referrals who fulfilled triage criteria and 45.4 weeks for referrals who did not meet triage criteria. The sensitivity and specificity of the diagnostic tool were 96% and 56%, respectively. In addition, the positive predictive value was DECEMBER 2014

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40%, whereas the negative predictive value was 98%.

Cummins and colleagues found that implementing the 2010 ACR/ EULAR Classification Criteria for RA as a prioritization tool could improve the wait time of patients diagnosed with RA. “Waiting time was reduced for RA patients,” they concluded.

“Applying this strategy in areas of rheumatology scarcity may permit earlier DMARD treatment.” n

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Supplement

Evolution in the Value-Based Care of Rheumatologic Diseases: A Prospectus for Managed Care Pharmacists Faculty Douglas Burgoyne, PharmD President VRx Pharmacy Services, LLC Salt Lake City, UT

Joseph F. Merola, MD, MMSC Director of Clinical Trials Co-Director, Center for Skin and Related Musculoskeletal Diseases Brigham and Women’s Hospital Instructor, Harvard Medical School Boston, MA

Release date: December 15, 2014 Expiration date: December 31, 2015 Estimated time to complete activity: 1.0 hour

Latest version of Firefox, Google Chrome, or Safari Adobe Acrobat Reader v7.0 or higher*

Target Audience This activity is directed toward pharmacists who are involved in the management of patients with rheumatologic diseases.

*Required to view printable (PDF) version of the lesson.

Disclosure of Conflicts of Interest Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high-quality CME/CE activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.

Educational Objectives After completing this activity, the participant should be better able to: • Review the current management options in rheumatoid arthritis and psoriatic arthritis • Discuss the potential clinical implications of existing and emerging novel biologic therapies on the treatment paradigm for rheumatologic diseases • Utilize optimal, value-based management approaches to patients with rheumatoid arthritis and psoriatic arthritis • Provide accurate and appropriate counsel as part of the treatment team

The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME/CPE activity:

Faculty Douglas Burgoyne, PharmD President, VRx Pharmacy Services, LLC Salt Lake City, UT

Name of Faculty or Presenter

Joseph F. Merola, MD, MMSC Director of Clinical Trials Co-Director, Center for Skin and Related Musculoskeletal Diseases Brigham and Women’s Hospital Instructor, Harvard Medical School, Boston, MA

Reported Financial Relationship

Douglas Burgoyne, Consultant to AstraZeneca, BristolPharmD Myers Squibb, Novo Nordisk, Purdue, Sanofi, and XenoPort.

Joseph F. Merola, Advisory Board for AbbVie, Amgen, MD, MMSC Eli Lilly, and Novartis; Consultant to AbbVie, Amgen, Biogen Idec, Eli Lilly, and Novartis; Investigator for Amgen, Biogen Idec, and Pfizer; Licensed Outcome Measure for AbbVie; Research funding from Biogen Idec.

Jonathan Kay, MD Consultant to AbbVie, Alexion Pharmaceuticals, Amgen, AstraZeneca, Bristol-Myers Squibb, Crescendo Bioscience, Eli Lilly, Epirus Biopharmaceuticals, Genentech, Hospira, Janssen Biotech, PanGenetic B.V., Pfizer, Roche Laboratories, Samsung Bioepis, and UCB Inc.

Jonathan Kay, MD Director of Clinical Research, Rheumatology Professor of Medicine University of Massachusetts Medical School UMass Memorial Medical Center, Worcester, MA Pharmacist Continuing Education Accreditation Statement Postgraduate Institute for Medicine is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Credit Designation Postgraduate Institute of Medicine designates this continuing education activity for 1 contact hour(s) (0.1 CEU) of the Accreditation Council for Pharmacy Education. (Universal Activity Number 0809-9999-14-227-H01-P) Type of Activity: application System Requirements PC Windows 7 or above Flash Player v10.0 or higher Internet Explorer v9.0 or higher

Google Chrome, or Safari Adobe Acrobat Reader v7.0 or higher*

The following PIM planners and managers—Laura Excell, ND, NP, MS, MA, LPC, NCC; Trace Hutchison, PharmD; Samantha Mattiucci, PharmD, CCMEP; and Jan Schultz, MSN, RN, CCMEP—hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.

MAC MAC OS X 10.6 or higher Flash Player v10.0 or higher Latest version of Firefox,

Center of Excellence Media, LLC: Susan Berry hereby states that she or her spouse/life partner do not have any financial relation-

Jonathan Kay, MD Director of Clinical Research, Rheumatology Professor of Medicine University of Massachusetts Medical School UMass Memorial Medical Center Worcester, MA ships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.

Disclosure of Unlabeled Use This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Postgraduate Institute for Medicine and Center of Excellence Media, LLC, do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

Instructions for Credit There is no fee for this activity. To receive credit after reading this CE activity in its entirety, participants must complete the posttest and evaluation. The posttest and evaluation can be completed online at http://ce.lynxcme.com/COE175. Upon completion of the evaluation and scoring 75% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 75% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records.

If you have any questions regarding the CE certification for this activity, please contact Postgraduate Institute for Medicine at: information@pimed.com or 303-799-1930.

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To obtain a digital version, download a free QR code app on your SmartPhone and then scan this code.

This activity is supported by an independent educational grant from Celgene.

Jointly provided by Postgraduate Institute for Medicine and Center of Excellence Media, LLC.

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heumatologic diseases, such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), are chronic inflammatory disorders that are associated with severe disability and, consequentially, negative impact on quality of life (QOL). Dramatic advancements seen in the treatment of rheumatoid diseases largely stem from the advent of biologic agents. However, the costs of therapy are significant, underscoring the importance and need for the practice of value-based care. This educational activity provides highlights of a live symposium from the Academy of Managed Care Pharmacy meeting held in Boston, MA, on October 7-10, 2014, which focused on the evolution of value-based care of rheumatologic diseases, including clinical and pharmacoeconomic assessments of conventional and biologic disease-modifying antirheumatic drugs (DMARDs) in the treatment of patients with RA or PsA.

In addition, the current treatment armamentarium of bDMARDs includes 5 US Food and Drug Administration (FDA)-approved tumor necrosis factor (TNF) inhibitors (adalimumab, certolizumab, etanercept, golimumab,

Dramatic advancements seen in the treatment of rheumatoid diseases largely stem from the advent of biologic agents. and infliximab), the cytotoxic T-lymphocyte–associated protein-4 T-cell costimulation blocker abatacept, the anti-CD20 monoclonal antibody (mAb) rituximab, the interleukin (IL)-1 receptor antagonist inhibitor anakinra, the anti–IL-6 receptor mAb tocilizumab, and the oral Janus kinase/signal transducer and activator of transcription inhibitor tofacitinib (Table 1).4-11 Over the last decade, the treatment paradigms for RA have evolved significantly, with authoritative guidelines and emerging clinical data advocating the initiation of intensive therapy earlier in the course of disease and the use of a treat-to-target management strategy. To attain

Optimization of Conventional and Biologic Disease-Modifying Antirheumatic Drug Use in Rheumatoid Arthritis RA is an autoimmune disease characterized by inflammation of the joints, accompanied by proliferation of the synovium and the progressive erosion of cartilage and bone, leading to severe disability and premature mortality.1 In 2010, a colTable 1 Biologic Disease-Modifying Antirheumatic Drugs Approved for Management of Rheumatoid Arthritis and Psoriatic Arthritis laboration between the American College of Rheumatology (ACR) and Drug Mechanism of action FDA approval year the European League Against RheuRheumatoid arthritis4-9 matism (EULAR) resulted in new Anti-TNF 2002 Adalimumab classification criteria for RA that emAnti-TNF 2008 Certolizumab pegol phasized the need for early diagnosis Anti-TNF 1998 Etanercept based on the extent of joint involveAnti-TNF 2009 Golimumab ment, serology (rheumatoid factor Anti-TNF 1999 and anticitrullinated protein antiInfliximab CD28 2005 body), acute-phase reactants (erythAbatacept rocyte sedimentation rate [ESR] and Anti-CD20 1997 Rituximab C-reactive protein), and duration of IL-1 receptor 2001 Anakinra symptoms (<6 weeks or ≥6 weeks).2 IL-6 receptor 2010 Tocilizumab Based on the important pathogenJAK/STAT TKI 2012 Tofacitinib ic roles of proinflammatory cytokines Psoriatic arthritis4,5,10,11 in RA, a number of powerful convenAnti-TNF 2002 tional DMARDs (cDMARDs) and Etanercept Anti-TNF 2005 biologic DMARDs (bDMARDs) Adalimumab have become available. In this era of Anti-TNF 2005 Infliximab targeted biologic therapies, methoAnti-TNF 2009 Golimumab trexate (MTX) still reigns as an “anAnti-TNF 2013 Certolizumab pegol chor drug” and the gold standard for PDE4 inhibitor 2014 Apremilast treatment of RA, either as monotherAnti–IL-12/IL-23 2013 Ustekinumab apy or in combination with various biologic agents, attesting to its efficaFDA indicates US Food and Drug Administration; IL, interleukin; JAK, Janus kinase; PDE4, phosphodiesterase 4; STAT, signal transducer and activator of cy, acceptable safety profile, low cost, 3 transcription; TKI, tyrosine kinase inhibitor; TNF, tumor necrosis factor. and decades of clinical experience.

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Table 2 Radiographic Progression During 2 Years in the TEAR Trial Patients, n

Baseline (mean ± SD)

Immediate combination therapy

330

7.0 ± 14.9

7.9 ± 15.9

7.5 ± 15.7

1.1 ± 6.4

Step-up to combination therapy

236

6.2 ± 13.4

7.3 ± 14.6

6.2 ± 8.7

1.2 ± 4.1

MTX monotherapy

84

2.9 ± 3.5

2.9 ± 3.6

2.6 ± 2.9

0.2 ± 1.1

Treatment group

Week 102 (mean ± SD)

Difference in modified Sharp score at week 102

Week 48 (mean ± SD)

(mean ± SD)

P values across treatment groups were significant at week 48 (P=.0321) and week 102 (P=.0074), as was the change in modified Sharp score at week 102 (P=.0467).

MTX indicates methotrexate; SD, standard deviation; TEAR, Treatment of Early Aggressive Rheumatoid Arthritis.

Sources: O’Dell JR, et al. Arthritis Rheum. 2013;65:1985-1994; Moreland LW, et al. Arthritis Rheum. 2012;64:2824-2435.

the treatment goal of remission or low disease activity, therapy should be adjusted when no improvement is noted by at most 3 months after the start of treatment or when the target has not been reached by 6 months.12 The 2013 EULAR guidelines clarified that intensive therapy in early RA does not imply commencing therapy with bDMARDs before cDMARDs, and advised that cDMARD monotherapy or a combination of cDMARDs should be used in DMARD-naive patients, and that MTX should be part of the first treatment strategy.12

Currently, tocilizumab is the only biologic agent that has demonstrated superiority as monotherapy over MTX in MTX-naive patients with RA. The guidelines further state that bDMARDs may be initiated in combination with MTX if treatment target is not achieved with cDMARD approaches or if poor prognostic factors are present.12 In addition, the EULAR guidelines broadly consider that abatacept, tocilizumab, rituximab, and the 5 FDA-approved TNF inhibitors exhibited similar efficacy and safety and recommended switching to another bDMARD upon failure of a first bDMARD. The guidelines further recommend the preferential use of a bDMARD in combination with MTX over bDMARD monotherapy,12 because the approved biologic agents have demonstrated reduction of disease activity, improvement of functional disability, and retardation of radiographic progression, either alone13 or in combination with MTX.14,15 Currently, tocilizumab is the only biologic 30

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agent that has demonstrated superiority as monotherapy over MTX in MTX-naive patients with RA.16 Several trials have assessed whether it is better to intensively treat all patients with early RA using combination therapy comprising bDMARD plus MTX or triple therapy with cDMARDs, such as MTX, sulfasalazine, and hydroxychloroquine immediately, or to delay administration of combination therapy following an inadequate response to MTX monotherapy.17-20 The 2-year follow-up assessment of the randomized SWEFOT (Swedish Farmacotherapy) trial involving patients with MTX-refractory early RA showed that the proportion of patients who achieved a EULAR-defined good response was numerically higher in those who were treated with MTX plus infliximab compared with those who received cDMARD triple therapy, although this difference was not significant (38% vs 31%, respectively; P=.204).17 However, the radiologic disease progression was significantly greater in patients treated with conventional therapy compared with those who were treated with biologic therapy (change in modified Sharp score mean, 7.23 vs 4.00; P=.009).17 The randomized, 4-arm TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) trial of 755 patients with early, poor-prognosis RA evaluated 2 immediate treatment approaches with either cDMARD triple therapy (MTX + sulfasalazine + hydroxychloroquine) or MTX plus etanercept combination therapy, and 2 delayed treatment approaches in which treatment escalation to one of the combination therapies was applied at 24 weeks after inadequate response to MTX monotherapy, based on a disease activity score in 28 joints using the ESR (DAS28ESR) ≥3.2.18,19 Overall, no differences were seen in the mean DAS28-ESR between patients randomized to triple therapy and those randomized to MTX plus etanercept, VOL. 3

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Figure Response Rates at 1 Year in the AMPLE Trial 100

Primary end point

90 Proportion of patients with ACR20 response, %

regardless of whether patients received immediate combination therapy or step-up from MTX monotherapy. In this trial, approximately 28% of patients continued to use MTX monotherapy based on a DAS28-ESR â&#x2030;¤3.2, confirming that a subset of patients attain disease control with MTX alone. However, at 102 weeks, immediate combination therapy with either strategy was more effective than initial MTX monotherapy, underscoring the benefits of combination therapy. Of note, patients who received initial MTX monotherapy and subsequent step-up to combination therapy had DAS28-ESR values at week 48 and radiographic progression at week 102 similar to those who received immediate combination therapy, which validated the traditional step-up approach (Table 2).18,19 Along the same vein, the 48-week, double-blind, noninferiority RACAT (RA: Comparison of Active Therapies) trial concluded that triple therapy (MTX + sulfasalazine + hydroxychloroquine) was noninferior to MTX plus etanercept in terms of DAS28 response at 48 weeks, in patients with active RA who had an inadequate response to MTX (DAS28 â&#x2030;Ľ4.4).20 In this study, patients who did not show an improvement in DAS28 at 24 weeks (DAS28 decrease <1.2) were allowed to switch from one arm to the other, resulting in significant improvements in both groups. Taken together, the findings from the TEAR and the RACAT trials support the use of cDMARD triple therapy as a low-cost alternative to the combination of MTX plus bDMARD. In addition, in patients with early RA, the initial use of MTX monotherapy with a biologic or a nonbiologic DMARD added on as needed after 6 months of disease persistence is a rational approach.18-20 Recently, in treating patients with bDMARDs, there has been interest in evaluating the potential withdrawal of the biologic agent when reaching low disease activity or remission. Understandably, this paradigm shift in the treatment of RA would have favorable pharmacoeconomic implications in addition to obvious safety and convenience benefits.21 For example, a systematic review of 10 eligible studies evaluating discontinuation of TNF inhibitors in patients achieving low disease activity or remission suggested that this approach was possible in 24% to 81% of patients without a resultant increase in disease activity; heterogeneous inclusion criteria and highly variable outcome definitions across studies contributed to the wide range of the results.22 However, there are currently no markers to predict which patients may be candidates for discontinuation of anti-TNF therapy once desirable clinical outcomes are achieved.

A number of studies have compared bDMARDs directly. For example, the AMPLE (Abatacept Versus Adalimumab Comparison in Biologic-Naive RA Subjects with Background Methotrexate) trial concluded that subcutaneous abatacept or adalimumab (adminis-

80

64.8%

63.4%

206/318

208/328

Abatacept

Adalimumab

70 60 50 40 30 20 10 0

ACR indicates American College of Rheumatology; AMPLE, Abatacept Versus Adalimumab Comparison in Biologic-Naive RA Subjects with Background Methotrexate.

Sources: Schiff M, et al. Ann Rheum Dis. 2014;73:86-94; Weinblatt ME, et al. Arthritis Rheum. 2013;65:28-38.

tered with MTX) showed comparable ACR improvement responses (Figure), as well as improvement in functional disability and inhibition of radiographic progression at 2 years.23,24 Although the rates of adverse events and serious adverse events were similar between the 2 treatment groups, adalimumab therapy was associated with a higher rate of discontinuation and a higher

Recently, in treating patients with bDMARDs, there has been interest in evaluating the potential withdrawal of the biologic agent when reaching low disease activity or remission. incidence of serious infections (including 2 cases of tuberculosis) compared with abatacept therapy.23 Conversely, the randomized, double-blind, phase 4 ADACTA (Tocilizumab Monotherapy Versus Adalimumab Monotherapy for Treatment of Rheumatoid Arthritis) trial reported that tocilizumab monotherapy was superior to adalimumab monotherapy in producing a significantly greater change from baseline in DAS28, DAS28 remission, and DAS28 low disease activity at week 24 in patients with RA for whom MTX was deemed ineffective or inappropriate.25 The safety profiles were consistent with those previously reported for these 2 agents.25 However, it must be noted that a higher dose of tocilizumab (8 mg/kg DECEMBER 2014

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intravenous monthly) was used in this trial than the doses used in other trials with this agent, and adalimumab monotherapy is known to be less effective than adalimumab plus MTX; both of these factors may have skewed the results in favor of tocilizumab.15,26

Treatment Paradigms in Psoriatic Arthritis PsA is a chronic, systemic, inflammatory disease that is associated with significant joint involvement (peripheral and spinal) in conjunction with a spectrum of extra-articular manifestations, including enthesitis and dactylitis, as well as involvement of the skin and nails.27 Such broad articular and nonarticular phenotypes of PsA have a debilitating impact on patientsâ&#x20AC;&#x2122; function and QOL, which were shown to be nearly equivalent to the function and QOL scores reported by patients with RA.28 Although the general prevalence of PsA in the United States is estimated to be 0.25%, it is considerably higher among patients with psoriasis, with a prevalence rate of up to 42%.29,30 Skin disease typically precedes joint disease in patients with PsA, with approximately 75% to 80% of affected patients developing joint complications 7 to 12 years from the onset of psoriasis to the diagnosis of PsA, although in 10% to 15% of patients, PsA may precede psoriasis.30 Moreover, PsA is associated with an elevated risk for cardiovascular disease and metabolic syndrome, conferring an increased risk for mortality.31 In fact, the prevalence of metabolic syndrome among patients with PsA in one study was observed to be higher (58.1%) than the prevalence among the general population (35.2%) reported by the Third National Health and Nutrition Examination Survey.32

The management of PsA can pose a clinical challenge as a result of diverse and often simultaneous clinical manifestations, requiring multidisciplinary treatment.

The heterogeneous clinical presentation of PsA is accompanied by a variable disease course, with some patients experiencing mild, chronic disease whereas others show severe, rapid, erosive joint disease.27 Timely diagnosis and appropriate therapeutic intervention are of paramount importance, because persistent inflammation, progressive joint damage, and marked functional impairment and disability can occur in the absence of effective therapy.17 However, the management of PsA can pose a clinical challenge as a result of diverse and often simultaneous clinical manifestations, requiring multidisciplinary treatment.

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Two treatment guidelines, 2012 EULAR and 2009 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis, have been released for the management of PsA.33,34 Whereas the immediate treatment target is to achieve clinical remission or at least low disease activity, long-term treatment goals are to maintain health-related QOL, reduce skin and joint signs and symptoms, and prevent or attenuate structural damage. Treatment recommendations from both guidelines indicate that patients with mild-to-moderate disease may be treated with nonsteroidal anti-inflammatory drugs and intra-articular corticosteroid injections as adjunctive therapy for control of joint (but not skin) symptoms. For patients with more severe disease, cDMARD therapy (ie, MTX, sulfasalazine, leflunamide, or cyclosporine) is indicated at an early stage, whereas biologic agents with or without cDMARDs may be considered if the response to cDMARDs is considered inadequate, and as first-line therapy in patients with extensive involvement of skin and joints. The 2012 EULAR guidelines in particular recommend switching to a second anti-TNF agent in patients whose disease fails to improve after treatment with a TNF inhibitor.33 However, in contrast to RA, current evidence does not support the use of a combination of TNF inhibitors and cDMARDs in patients with PsA.29,33 Currently, 5 TNF inhibitors (adalimumab, certolizumab, etanercept, golimumab, and infliximab), the antiIL-12/23 mAb ustekinumab, and the phosphodiesterase 4 inhibitor apremilast have shown efficacy in PsA and have been approved by the FDA for this indication.30,33 The guidelines note that despite the lack of direct head-tohead comparisons among the available TNF inhibitors, no apparent differences in efficacy for joint involvement have emerged with these agents, whereas the efficacy of etanercept on skin involvement may be lower than the other TNF antagonists.33 A meta-analysis of an indirect comparison of adalimumab, etanercept, golimumab, and infliximab in PsA revealed no significant differences in effectiveness among these agents.35 However, the study noted that golimumab yielded the highest relative risk for the PsA response criteria, whereas etanercept and infliximab showed the greatest benefit for Health Assessment Questionnaire improvements, and infliximab was most effective in yielding psoriasis area and severity index improvements.35 Taken together, these findings show that an individualized approach to drug selection, based on disease severity and tissue manifestations, is critical in the treatment of PsA.

Clinical and Pharmacoeconomic Assessments in Value-Based Care of Rheumatologic Diseases Although bDMARDs have redefined the treatment paradigm in rheumatologic diseases, it is undisputed that VOL. 3

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the treatment costs incurred by these agents are substantial. According to the 2014 CVS/Caremark Book of Business spending trend analysis, RA was the therapeutic category with the largest specialty drug spending.36 Currently, the 5 approved TNF inhibitors represent approximately $20 billion in annual sales.37 These facts have led to a growing interest in evaluating the value of bDMARDs in the treatment of RA and PsA, specifically, to determine whether the efficacy benefits, reductions in healthcare use, decreases in productivity losses, and improvements in QOL achieved with these agents warrant the increased drug costs compared with cDMARDs. Toward this end, several cost-effectiveness analyses of anti-TNF drugs for RA have been conducted.

Zalesak and colleagues recently published a systematic review of market research and cost-effectiveness studies designed to assess clinical, functional, and economic outcomes associated with specialty drug treatments versus the previous standard of care.38 They showed that compared with conventional DMARDs, bDMARDs had significant therapeutic benefit in addition to being costeffective, with incremental cost-effectiveness ratios (ICERs) of $47,500 per quality-adjusted life-year (QALY).38 Overall, whereas the costs of anti-TNF agents were clearly higher than those of traditional DMARDs, the former resulted in a higher number of QALYs.38 In another analysis that used the Birmingham Rheumatoid Arthritis Model, which takes into account QOL and mortality indices, TNF inhibitors were most costeffective when used as last active therapy after the use of less expensive conventional DMARDs, rather than firstline use.39 Comparing TNF inhibitors, the ICER for infliximab was significantly higher than the ICERs for etanercept or adalimumab, regardless of whether it was used as first-line therapy or later.39 In terms of first-line combination therapy, the ICERs associated with MTX plus a TNF inhibitor were considerably higher than those generated with monotherapy.39 Consistent with these results, the cost-effectiveness analysis of the SWEFOT trial showed that the infliximab-treated group accumulated higher drug and healthcare costs compared with the group randomized to conventional nonbiologic therapy, compounded by higher societal costs as a result of productivity losses being similar between the groups.40 Finally, sequential therapy with 2 TNF antagonists has been shown to have the same order of cost-effectiveness as single-agent therapy.39 Many of the conclusions from these cost-effectiveness analyses are consistent with emerging clinical data and guideline recommendations. A few persistent questions relevant to value-based care in rheumatologic diseases include: • Is there a significant clinical benefit of biologic agents over conventional agents?

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• Should biologic drugs be offered only after patients show inadequate response to less expensive conventional therapies?

• Can biologic drugs be discontinued once remission or low disease activity is achieved?

• Which patients should receive biologic agents instead of conventional therapies?

Taken together, these findings show that an individualized approach to drug selection, based on disease severity and tissue manifestations, is critical in the treatment of PsA. In addition to optimization of currently existing biologic agents to gain cost benefits, another approach is to develop effective but cheaper biologic alternatives. This has led to the development of biosimilars, which are biologic drugs that are structurally similar but not identical to the reference agent, and show no clinically meaningful differences in terms of safety, purity, and potency.41 This concept has taken root because the US patents for several biologic agents for RA (including abatacept, adalimumab, infliximab, rituximab, and tocilizumab) have expired or are expected to expire over the next few years.42 Although the efforts to introduce biosimilars for the treatment of RA are expected to provide cost-savings and, possibly, increased access to biologic agents, several hurdles remain to be overcome to achieve this goal. Foremost is the need to establish the clinical bioequivalence in terms of efficacy and safety of a biosimilar and its parent compound, followed by their interchangeability in clinical practice.41,42

Conclusion The advent of biologic DMARDs has brought us closer to being able to achieve disease remission and repair of structural damage in RA and PsA, but these agents incur significant costs, necessitating further cost-effectiveness analyses. Balancing the cost considerations with the clinical outcomes suggests that cDMARDs should remain as first-line therapies in RA and PsA within a treat-to-target framework, whereas biologic agents should be used subsequent to the failure of treatment with cDMARDs, to achieve optimal clinical, functional, and economic outcomes in rheumatologic diseases.

Acknowledgment Sabeeha Muneer, PhD, contributed to the development of this article.

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16. Jones G, Sebba A, Gu J, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010;69:88-96.

17. van Vollenhoven RF, Geborek P, Forslind K, et al. Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial.

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18. O’Dell JR, Curtis JR, Mikuls TR, et al. Validation of the methotrexate-first strategy in patients with early, poor-prognosis rheumatoid arthritis: results from a two-year randomized, double-blind trial. Arthritis Rheum. 2013;65:1985-1994.

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20. O’Dell JR, Mikuls TR, Taylor TH, et al. Therapies for active rheumatoid arthritis after methotrexate failure. N Engl J Med. 2013;369:307-318.

21. Kavanaugh A, Smolen JS. The when and how of biologic agent withdrawal in rheumatoid arthritis: learning from large randomised controlled trials. Clin Exp Rheumatol. 2013;31:S19-S21.

22. Navarro-Millan I, Sattui SE, Curtis JR. Systematic review of tumor necrosis factor inhibitor discontinuation studies in rheumatoid arthritis. Clin Ther. 2013;35:1850-1861, e1.

23. Schiff M, Weinblatt ME, Valente R, et al. Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: two-year efficacy and safety findings from AMPLE trial. Ann Rheum Dis. 2014;73:86-94.

24. Weinblatt ME, Schiff M, Valente R, et al. Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: findings of a phase IIIb, multinational, prospective, randomized study. Arthritis Rheum. 2013;65:28-38.

25. Gabay C, Emery P, van Vollenhoven R, et al. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet. 2013;381:1541-1550.

26. Besada E. Potential patient benefit of a subcutaneous formulation of tocilizumab for the treatment of rheumatoid arthritis: a critical review. Patient Prefer Adherence.

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34. Ritchlin CT, Kavanaugh A, Gladman DD, et al. Treatment recommendations for psoriatic arthritis. Ann Rheum Dis. 2009;68:1387-1394.

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39. Chen Y-F, Jobanputra P, Barton P, et al. A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness. Health Technol Assess.

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42. Scheinberg MA, Kay J. The advent of biosimilar therapies in rheumatology—“O brave new world.” Nat Rev Rheumatol. 2012;8:430-436.

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If only it were this easy to spot * SLE organ damage

33% to 50% of SLE patients experience permanent organ damage within the first 5 years of diagnosis.1,2

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SLE can affect nearly every major organ, including the skin, kidneys, joints, lungs, and heart.3 Even when minimal symptoms are present, organ damage can still occur. 2 *systemic lupus erythematosus

REFERENCES: 1. Chambers SA, Allen E, Rahman A, Isenberg D. Damage and mortality in a group of British patients with systemic lupus erythematosus followed up for over 10 years. Rheumatology (Oxford). 2009;48(6):673-675. 2. Urowitz MB, Gladman DD, Ibañez D, et al. Evolution of disease burden over five years in a multicenter inception systemic lupus erythematosus cohort. Arthritis Care Res (Hoboken). 2012;64(1):132-137. 3. Lopez R, Davidson JE, Beeby MD, Egger PJ, Isenberg DA. Lupus disease activity and the risk of subsequent organ damage and mortality in a large lupus cohort.

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All rights reserved. Printed in USA. BN2670R0 April 2014