VBCR February 2015, Volume 4, Number 1

FEBRUARY 2015 VOL 4 • NO 1

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CANADIAN RHEUMATOLOGY ASSOCIATION CONFERENCE HIGHLIGHTS

New Studies Help Clarify Relationship Between Pollution and Rheumatic Diseases

Patient Descriptions Deepen Understanding of Fibromyalgia Flares Rosemary Frei, MSc

F

ibromyalgia flares are associated with intense pain, flulike aches and exhaustion, and other phenomena such as “brain fog,” as confirmed by the first-ever qualitative analysis of these periods of symptom exacerbation. Furthermore, according to the 44 people who responded to the

investigators’ survey, the patients tried many coping techniques, from medications to massage and from meditation to humor.

One of the most common coping strategies described by the respondents is to avoid all forms of activity, which surprised the investigators.

Continued on page 15

Rheumatology PRACTICE MANAGEMENT

™

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pair of posters presented at this year’s Canadian Rheumatology Association Annual Scientific Meeting suggest that rheumatologic diseases are associ-

ated with proximity to major industrial emitters and exposure to sources of fine particulate matter air pollution.1,2 In one of the studies, Sasha Continued on page 16

Use of Colchicine Reviewed Rosemary Frei, MSc

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lthough colchicine has been used for centuries to treat gout, research on this drug is still revealing new treatment dimensions, according to a review article by Michael Pillinger, MD, and other clinician-researchers.1

Physicians can apply this new knowledge to help ensure their patients with gout and other rheumatic diseases are optimally treated, according to Pillinger, a professor in the Division of Rheumatology, NYU Hospital for Joint Diseases, New

Continued on page 19

Increasing the Understanding of Rheumatic Diseases Chase Doyle

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ttended by a plurality of the membership, the 12th annual meeting of the Tennessee Rheumatology Society (TRS) fulfilled the society’s stated mission of increasing and propagating the understanding of rheumatic diseases among physicians engaged in the ongoing practice of rheumatology.

“What made the meeting memorable,” said the president of TRS, Satish Odhav, MD, “was not only the quality

ICD-10 Coding Amiel Tokayer, MD, a rheumatologist from West Palm Beach, Florida, began the meeting Friday evening with a presentation on the coming mandatory ICD-10 coding.

“ICD-10 coding is a source of much

Continued on page 12

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

Costs of Biologic Therapies in Inflammatory Autoimmune Diseases

Rheumatology PRACTICE

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MANAGEMENT™ . . . . . . . . . . . . . . . . . 11 In Pursuit of Independence Electronic Medical Records Being Used Suboptimally for Osteoporosis Patients

© 2015 Engage Healthcare Communications, LLC

of the presentations but also the tremendous mix of interactive educational sessions for both clinician and academia.”

IN THE LITERATURE . . . . . . . . . . . 14 Acetaminophen Lacks Effectiveness in Knee Osteoarthritis CONFERENCE HIGHLIGHTS. . . 16 Systematic Review Showcases Benefits of Nonpharmaceutical Interventions for Juvenile Idiopathic Arthritis FDA UPDATE . . . . . . . . . . . . . . . . . . . . . 19 Secukinumab Approved for Psoriasis

Join Our Editorial Advisory Board Value-Based Care in RheumatologyTM is looking for practicing rheumatologists with a wide range of experience who are interested in joining our Editorial Advisory Board.

Now in its third year of publication, Value-Based Care in RheumatologyTM covers key developments from the rheumatology literature and from national and international rheumatology meetings.

Mission Statement Value-Based Care in RheumatologyTM provides a forum for providers, payers, 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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In This Issue Value-Based Care in

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Integrating Rheumatologists, NPs/PAs, Practice Managers & Payers

PUBLISHING STAFF

VALUE PROPOSITIONS

IN THE LITERATURE

Managing Editor Kristen Olafson kolafson@the-lynx-group.com

Costs of Biologic Therapies in Inflammatory Autoimmune Diseases Cost-effectiveness in the Treatment of Gout Vitamin D and Calcium Supplementation in the Treatment of Osteoporosis in the Elderly: A European Study

Copyeditor Rosemary Hansen

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Acetaminophen Lacks Effectiveness in Knee Osteoarthritis Adverse Events on Biologics Common in Juvenile Idiopathic Arthritis Increased Cardiovascular Risk in Psoriatic Arthritis More…

Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Director, Client Services Zach Ceretelle zceretelle@the-lynx-group.com Editorial Director Dalia Buffery dbuffery@the-lynx-group.com

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FDA UPDATE

Rheumatology PRACTICE MANAGEMENT™ In Pursuit of Independence Electronic Medical Records Being Used Suboptimally for Osteoporosis Patients More…

FDA Final Rule on Pregnancy and Lactation Labeling Getting Mixed Reviews Secukinumab Approved for Psoriasis

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

VBCR Editorial Advisory Board

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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 © 2015 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

Mission Statement

Value-Based Care in Rheumatology provides a forum for payers, providers, and the entire rheumatology team to consider the cost-value issues particular to rheumatology treatments. This unique focus is achieved through news coverage from major rheumatology meetings and the rheumatic diseases literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care.

Contact Information: For subscription information please contact: Telephone: 732-992-1880 Fax: 732-992-1881.

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POSTMASTER: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Care in Rheumatology, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

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Value Propositions Costs of Biologic Therapies in Inflammatory Autoimmune Diseases

With data from the Humana commercial claims database, researchers evaluated the use and annual costs of biologic agents in the treatment of several autoimmune diseases. In addition to biologic agents commonly reported on as treatment in rheumatoid arthritis (RA) and psoriasis (PsO), this analysis included recently approved biologic therapies and treatment for psoriatic arthritis (PsA) and ankylosing spondylitis (AS).

Patients eligible for the study had a diagnosis of RA, PsO, PsA, AS, or a combination of these diseases and recorded their index claim between February 1, 2008, and September 30, 2011, for abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, or ustekinumab. Continuing patients were those who had a claim for their index therapy within 180 days prior to the study index date; those without such a claim were defined as new patients.

The study included 1308 new patients and 1413 continuing patients.

The most frequently used biologic therapies were adalimumab, etanercept, and infliximab. Continuing patients had higher rates of persistence on index therapy than new patients. For new patients, the mean annual cost (standard deviation [SD]) across all disease indications was lowest for adalimumab, $20,916 [$7572]; infliximab was next, $22,516 [$8460]; and then etanercept, $23,567 [$8314]). For continuing patients, mean annual costs were etanercept, $21,508 [$6769]; infliximab, $22,852 [$11,674]; and adalimumab, $24,341 [$8906].

This analysis showed that use of new biologic agents was quite limited compared with established TNF blockers in the treatment of RA, PsO, PsA, AS, and combination conditions. The researchers concluded that data from commercial claims may help payers evaluate annual costs in a real-world setting. Howe A, et al. J Manag Care Pharm. 2014;20(12):1236-1244.

Cost-effectiveness in the Treatment of Gout

The 2012 American College of Rheumatology Guidelines for Management of Gout recommends xanthine oxidase inhibitor therapy with allopurinol or febuxostat as urate-lowering therapy (ULT) in the treatment of gout. By design, the guidelines do not address cost-effectiveness.

The objective of a recent study was to evaluate the cost-effectiveness of several ULT plans for the management of gout. Using a Markov model to calculate lifetime health benefits, costs, and incremental cost-effectiveness ratios, researchers examined 5 ULT strategies: no treatment; allopurinol- or febuxostat-only therapy; allopurinol-febuxostat sequential therapy; and febuxostat-allopurinol sequential therapy.

They evaluated a fixed-dose schedule of febuxostat 80 mg daily and allopurinol 300 mg daily and a dose-escalation schedule of febuxostat ≤120 mg daily and allopurinol ≤800 mg daily.

Results showed that allopurinol-only therapy was cost-saving. Although dose-escalation allopurinol-febuxostat sequential therapy was more effective than dose-escalation allopurinol therapy, it cost more, having an incremental cost-effectiveness ratio of $39,400 per quality-adjusted life-year.

The cost-effectiveness ratios of dose escalation with allopurinol-febuxostat sequential therapy remained lower than the willingness-to-pay threshold of $109,000 per quality-adjusted life-year. The authors concluded that allopurinol single therapy is cost-saving even compared with no treatment and dose-escalation allopurinol-febuxostat sequential therapy is cost-effective compared with accepted willingness-to-pay thresholds.

Jutkowitz E, et al. Ann Intern Med. 2014;161(9):617-626.

Vitamin D and Calcium Supplementation in the Treatment of Osteoporosis in the Elderly: A European Study

Osteoporosis is recognized as a growing problem in Europe. Approximately 3.5 million fragility fractures occur annually in the European Union. In 2010, fragility fractures cost €37 billion and were responsible for 43,000 deaths. Supplementation with vitamin D and calcium has been recommended, especially for those with increased risk of fractures who are older than 65 years. The current study assessed vitamin D/calcium supplementation in elderly women and men with osteoporosis to determine whether this supplementation is cost-effective.

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Using Belgian cost and epidemiological data and a validated model for economic assessment in osteoporosis, researchers compared vitamin D/ calcium supplementation with no treatment to estimate the cost per quality-adjusted life-year (QALY) gained. The cost per QALY gained with supplementation at age 60 years was estimated at €40,578 and €23,477, in women and men, respectively. These values decreased at age 70 years, and vitamin D/calcium supplementation was cost-saving at age 80 years, meaning that treatment cost was less than the costs of osteoporotic fractures of the no-treatment group.

Fracture risk and medication costs can be notably different within and across countries and could significantly impact the cost-effectiveness of vitamin D/calcium supplementation. The authors conclude, however, that vitamin D/calcium supplementation is cost-effective for women and men older than 60 years with osteoporosis and should therefore be administered in these patients including in those patients also taking other osteoporotic treatments. Hiligsmann M, et al. Eur J Public Health. 2015; 25(1):20-25.

New Model of Care for Patients With Rheumatoid Arthritis

A report presented at the recent American College of Rheumatology Annual Meeting in Boston describes a new strategic model of care delivery for patients with rheumatoid arthritis (RA). The program, called AIM FARTHER, which stands for Attribution, Integration, Measurement, Finances and Reporting of Therapies, was launched in August 2012 at the Geisinger Health System in central Pennsylvania.

As part of AIM FARTHER, 17 rheumatologists treated 2378 RA patients. RA patient care was evaluated using PACER, a specialized software system. With information collected from patients via a touch screen questionnaire and from physicians, nurses, and the electronic health record, rheumatologists created a patient scorecard that illustrated gaps in care that could be addressed at the clinic or between visits.

At 22 months of follow-up, quality of care showed significant improvement and costs were reduced. Slowing the use of costly biologic drugs resulted in savings of $720,000 for 2013, and researchers estimate a savings of $1.2 million for 2014.

“By using industry-vetted problem-solving techniques and quality improvement methodology, we were able to design, test, and implement a new model of care that has shown improvement in quality and reduction in cost beyond what I had hoped,” said Eric Newman, MD, director of rheumatology for the Geisinger Health System and designer of AIM FARTHER. American College of Rheumatology. ScienceDaily. November 16, 2014.

Medical Scribes

According to the Centers for Disease Control and Prevention, the use of electronic health record (EHR) systems continues to grow. In 2001, the number of office-based physicians using any type of EHR was 18%, but in 2013, use ranged from 66% in New Jersey to 94% in Minnesota. This growth is partially due to incentives offered by the Centers for Medicare & Medicaid Services. For many physicians, however, using an EHR system has become a time-consuming, inefficient chore that detracts from providing meaningful patient care. Often the doctor sees fewer patients and experiences a subsequent decline in income. A medical scribe can alleviate these problems by entering data such as notes and test results into the software program.

The Joint Commission has defined a medical scribe as “an unlicensed person hired to enter information into the electronic medical record (EMR) or chart at the direction of a physician or licensed independent practitioner.... [T]he scribe does not and may not act independently but can document the previously determined physician’s or practitioner’s dictation and/or activities.” Scribes usually accompany the physician or practitioner and record information into the medical record. They also help practitioners navigate the EHR to retrieve information.

“A medical scribe shares the provider’s burden of data gathering and EHR documentation,” explains Michael Murphy, MD, emergency physician and founder of ScribeAmerica, a scribe vendor. “In doing so, the physician’s individual productivity and patient throughput increase, so that the goal of providing cost-effective, quality medical care is achieved.”

Chesanow N. Medscape. February 27, 2014.

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WHAT

DO YOUR PATIENTS WANT FROM THEIR RA TREATMENT? INDICATION • XELJANZ (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). • Limitations of Use: Use of XELJANZ in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

IMPORTANT SAFETY INFORMATION Patients treated with XELJANZ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.

Lymphoma and other malignancies have been observed in patients treated with XELJANZ.

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

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

XELJANZ DELIVERS POWERFUL EFFICACY3,4 — In ORAL Start, XELJANZ demonstrated statistically significantly superior ACR70 response rates vs MTX at 6 months, 25% vs 12%, respectively, and were sustained at year 2, 34% vs 15%, respectively (P<0.001)3,5 — In ORAL Solo, ACR20/50/70 response rates for XELJANZ at 3 months were 59%,*† 31%,* 15% ‡ vs placebo 26%, 12%, 6% (*P<0.001, ‡ P<0.01)4,6,7

Statistically significantly superior efficacy to MTX at 6 months and sustained at 2 years1,4 INHIBITION OF THE PROGRESSION OF JOINT DAMAGE

REDUCTION OF THE PROGRESSION OF JOINT DAMAGE

IN MTX-NAÏVE PATIENTS WITH MODERATE TO SEVERE RA1,4,5

IN MTX-IR PATIENTS WITH MODERATE TO SEVERE RA4,8

*P<0.001 VS MTX

*P= 0.0792 (Not statistically significant)

* §|| *§ *

XELJANZ is not indicated in MTX-naïve patients.4 Patients treated with XELJANZ showed less progression from baseline in both erosion and joint space narrowing at 6 months compared to MTX.4 Mean change from baseline in mTSS was a co-primary endpoint at 6 months and was a secondary endpoint at 1 and 2 years. Erosion and joint space narrowing scores were secondary endpoints at all time points.1,4 Patient baseline clinical characteristics included mean disease duration of 2.9 years for XELJANZ 5 mg BID and 2.7 years for MTX; 37% of patients who received XELJANZ 5 mg BID had been treated with nonbiologic DMARDs other than MTX.1,3 MTX dose started at 10 mg/week, titrated by 5 mg every 4 weeks as tolerated to 20 mg/week by week 8. Mean methotrexate dose at end of titration (month 3) = 18.5 mg/week.1

Mean change from baseline in mTSS at 6 months was a co-primary endpoint.4 XELJANZ 5 mg twice daily + MTX reduced mean progression of structural damage vs placebo + MTX at 6 months (not statistically significant).

Analyses of erosion and joint space narrowing scores were consistent with the overall results.4 Patient baseline clinical characteristics included mean disease duration of 9 years: % of patients on prior medications: MTX, 100%; other nonbiologic DMARDs, 60%; TNFi, 19%.8 12- and 24-month data for ORAL Scan are not shown because all placebo patients transfer to active treatment at the end of month 6.8

IMPORTANT SAFETY INFORMATION (cont’d) WARNING: SERIOUS INFECTIONS AND MALIGNANCY SERIOUS INFECTIONS Patients treated with XELJANZ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.

If a serious infection develops, interrupt XELJANZ until the infection is controlled.

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

• Invasive fungal infections, including cryptococcosis and pneumocystosis.

Patients with invasive fungal infections may present with disseminated, rather than localized, disease.

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

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

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

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

CHOOSE XELJANZ FOR CLINICALLY MEANINGFUL OUTCOMES1,2 †

Primary endpoint.

In the absence of an acceptable radiograph, the results from previous radiographs have been extrapolated linearly.1 || In year 1, all x-rays were read by independent, blinded readers. In year 2, all x-rays were re-read by independent, blinded readers, beginning at study baseline.

Data not available in year 1 for a few patients became available for 2-year analyses.5 mTSS=modified Total Sharp Score, IR=inadequate responder. §

Study Designs ORAL Start (Study VI), a 24-month, randomized, multicenter, double-blind, parallel-group trial (N=952) that compared XELJANZ to MTX in patients with active RA who were MTX-naïve, and received XELJANZ 5 mg BID or 10 mg BID or MTX. MTX dose started at 10 mg/week, titrated by 5 mg every 4 weeks as tolerated to 20 mg/week by week 8.1 The co-primary endpoints at month 6 were mean change from baseline in van der Heijde-mTSS and ACR70 response rate. XELJANZ is not indicated in MTX-naïve patients.4 ORAL Scan (Study IV), a 24-month, randomized, double-blind, placebo-controlled, multicenter trial in which 797 patients with moderately to severely active RA who had an inadequate response to MTX received XELJANZ 5 mg BID or 10 mg BID or placebo added to background MTX. The co-primary endpoints were ACR20 response, mean change from baseline in mTSS, and DAS28-4(ESR) <2.6 at month 6, and HAQ-DI improvement at month 3.4 ORAL Solo (Study I), a 6-month, randomized, double-blind, controlled, multicenter monotherapy trial in which 610 patients with moderately to severely active RA who had an inadequate response to a biologic or nonbiologic DMARD received XELJANZ 5 mg BID or 10 mg BID or placebo. The endpoints at month 3 were ACR20 response, HAQ-DI improvement, and DAS28-4(ESR) <2.6.4 The approved dose of XELJANZ is 5 mg twice daily.4 For full Prescribing Information, visit XeljanzPI.com.

IMPORTANT SAFETY INFORMATION (cont’d) MALIGNANCIES Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virus–associated posttransplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications.

SERIOUS INFECTIONS The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, and urinary tract infection. Avoid use of XELJANZ in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment before initiating XELJANZ in patients: References: 1. Lee EB, Fleischmann R, Hall S, et al; for the ORAL Start Investigators. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. 2014;370(25):2377-2386. 2. Bruynesteyn K, van der Linden S, Landewé R, et al. Progression of rheumatoid arthritis on plain radiographs judged differently by expert radiologists and rheumatologists. J Rheumatol. 2004;31:1088-1094. 3. Supplement to Lee EB, Fleischmann R, Hall S, et al; for the ORAL Start Investigators. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. 2014;370(25):2377-2386. 4. XELJANZ® (tofacitinib) Prescribing Information. New York, NY: Pfizer Inc; 2014. 5. Data on file.

Pfizer Inc, New York, NY. 6. Fleischmann R, Kremer J, Cush J, et al; for the ORAL Solo Investigators. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367(6):495-507. 7. Supplement to: Fleischmann R, Kremer J, Cush J, et al; for the ORAL Solo Investigators. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367(6):495-507. doi: 10.1056/NEJMoa1109071. 8. van der Heijde D, Tanaka Y, Fleischmann R, et al; and the ORAL Scan Investigators. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate. Arthritis Rheum. 2013;65(3):559-570.

• with chronic or recurrent infection; • who have been exposed to tuberculosis (TB); • with a history of a serious or an opportunistic infection; • who have lived or traveled in areas of endemic TB or mycoses; or • with underlying conditions that may predispose them to infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ. XELJANZ should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis.

VISIT

IMPORTANT SAFETY INFORMATION WARNING: SERIOUS INFECTIONS AND MALIGNANCY SERIOUS INFECTIONS Patients treated with XELJANZ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.

If a serious infection develops, interrupt XELJANZ until the infection is controlled.

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

• Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.

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

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

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

MALIGNANCIES Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virus–associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications.

SERIOUS INFECTIONS The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, and urinary tract infection. Avoid use of XELJANZ in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment before initiating XELJANZ in patients: • with chronic or recurrent infection; • who have been exposed to tuberculosis (TB); • with a history of a serious or an opportunistic infection; • who have lived or traveled in areas of endemic TB or mycoses; or • with underlying conditions that may predispose them to infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ. XELJANZ should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis.

Tuberculosis Evaluate and test patients for latent or active infection before administration of XELJANZ. Consider anti-TB therapy prior to administration of XELJANZ in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection. Treat patients with latent TB with standard therapy before administering XELJANZ. Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (eg, herpes zoster), was observed in clinical studies with XELJANZ. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with XELJANZ. MALIGNANCY and LYMPHOPROLIFERATIVE DISORDERS Consider the risks and benefits of XELJANZ treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ in patients who develop a malignancy.

In the 7 controlled rheumatoid arthritis clinical studies, 11 solid cancers and 1 lymphoma were diagnosed in 3328 patients receiving XELJANZ with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure. Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with XELJANZ. In Phase 2B controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high-dose corticosteroids,

and mycophenolic acid products, Epstein Barr Virus–associated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of 111 patients treated with cyclosporine.

Non-Melanoma Skin Cancer Non-melanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

GASTROINTESTINAL PERFORATIONS Gastrointestinal perforations have been reported in rheumatoid arthritis clinical trials, although the role of JAK inhibition is not known. This happens most often in people who also take nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or methotrexate. XELJANZ should be used with caution in patients who may be at increased risk for gastrointestinal perforation (eg, patients with a history of diverticulitis).

LABORATORY ABNORMALITIES Lymphocyte Abnormalities Treatment with XELJANZ was associated with initial lymphocytosis at 1 month of exposure followed by a gradual decrease in mean lymphocyte counts of approximately 10% during 12 months of therapy. Counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections. Avoid initiation of XELJANZ treatment in patients with a count less than 500 cells/mm3. In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3, treatment with XELJANZ is not recommended. Monitor lymphocyte counts at baseline and every 3 months thereafter.

Neutropenia Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo. Avoid initiation of XELJANZ treatment in patients with an ANC less than 1000 cells/mm3. For patients who develop a persistent ANC of 500-1000 cells/mm3, interrupt XELJANZ dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with XELJANZ is not recommended. Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Anemia Avoid initiation of XELJANZ treatment in patients with a hemoglobin level less than 9 g/dL. Treatment with XELJANZ should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment. Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Liver Enzyme Elevations Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy.

Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury.

If drug-induced liver injury is suspected, the administration of XELJANZ should be interrupted until this diagnosis has been excluded.

Lipid Elevations Treatment with XELJANZ was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks.

Assess lipid parameters approximately 4-8 weeks following initiation of XELJANZ therapy, and manage patients according to clinical guidelines for the management of hyperlipidemia.

VACCINATIONS Avoid use of live vaccines concurrently with XELJANZ. Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ therapy.

HEPATIC IMPAIRMENT Use of XELJANZ in patients with severe hepatic impairment is not recommended.

ADVERSE REACTIONS The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions during the first 3 months in controlled clinical trials with XELJANZ 5 mg twice daily and placebo, respectively, (occurring in greater than or equal to 2% of patients treated with XELJANZ with or without DMARDs) were upper respiratory tract infections (4.5%, 3.3%), headache (4.3%, 2.1%), diarrhea (4.0%, 2.3%), and nasopharyngitis (3.8%, 2.8%).

USE IN PREGNANCY There are no adequate and well-controlled studies in pregnant women. XELJANZ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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

TRA678018-01

© 2014 Pfizer Inc.

August 2014

All rights reserved.

XELJANZ® (tofacitinib) BRIEF SUMMARY OF PRESCRIBING INFORMATION. SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION. WARNING: SERIOUS INFECTIONS AND MALIGNANCY SERIOUS INFECTIONS Patients treated with XELJANZ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

If a serious infection develops, interrupt XELJANZ until the infection is controlled.

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

• Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.

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

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

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

MALIGNANCIES Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virusassociated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications.

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

• Limitations of Use: Use of XELJANZ in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Serious Infections Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving XELJANZ. The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster and urinary tract infection. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus, and BK virus were reported with XELJANZ. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids.

Other serious infections that were not reported in clinical studies may also occur (e.g., histoplasmosis, coccidioidomycosis, and listeriosis).

Avoid use of XELJANZ in patients with an active, serious infection, including localized infections. The risks and benefts of treatment should be considered prior to initiating XELJANZ in patients: •

with chronic or recurrent infection

•

who have been exposed to tuberculosis

•

with a history of a serious or an opportunistic infection

•

who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or

•

with underlying conditions that may predispose them to infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ. XELJANZ should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with XELJANZ should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.

Tuberculosis Patients should be evaluated and tested for latent or active infection prior to administration of XELJANZ.

Anti-tuberculosis therapy should also be considered prior to administration of XELJANZ in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confrmed, and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection.

Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient.

Lipid Elevations Treatment with XELJANZ was associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.

Patients should be closely monitored for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy.

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

Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering XELJANZ.

Vaccinations No data are available on the response to vaccination or on the secondary transmission of infection by live vaccines to patients receiving XELJANZ. Avoid use of live vaccines concurrently with XELJANZ.

Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with XELJANZ. The impact of XELJANZ on chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or C were excluded from clinical trials. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with XELJANZ. Malignancy and Lymphoproliferative Disorders Consider the risks and benefts of XELJANZ treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ in patients who develop a malignancy.

Malignancies were observed in clinical studies of XELJANZ. In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one lymphoma were diagnosed in 3328 patients receiving XELJANZ with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the frst 12 months of exposure.

Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with XELJANZ. In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high-dose corticosteroids, and mycophenolic acid products, Epstein Barr Virus-associated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of 111 patients treated with cyclosporine.

Non-Melanoma Skin Cancer Non-melanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

Gastrointestinal Perforations Events of gastrointestinal perforation have been reported in clinical studies with XELJANZ in rheumatoid arthritis patients, although the role of JAK inhibition in these events is not known.

XELJANZ should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identifcation of gastrointestinal perforation.

Laboratory Abnormalities Lymphocyte Abnormalities Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean absolute lymphocyte counts below the baseline of approximately 10% during 12 months of therapy. Lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections.

Avoid initiation of XELJANZ treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm3). In patients who develop a confrmed absolute lymphocyte count less than 500 cells/mm3 treatment with XELJANZ is not recommended.

Monitor lymphocyte counts at baseline and every 3 months thereafter.

Neutropenia Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo.

Avoid initiation of XELJANZ treatment in patients with a low neutrophil count (i.e., ANC less than 1000 cells/mm3). For patients who develop a persistent ANC of 500-1000 cells/mm3, interrupt XELJANZ dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with XELJANZ is not recommended.

Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Anemia Avoid initiation of XELJANZ treatment in patients with a low hemoglobin level (i.e., less than 9 g/dL). Treatment with XELJANZ should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment.

Monitor hemoglobin at baseline and after 4–8 weeks of treatment and every 3 months thereafter.

Liver Enzyme Elevations Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy.

Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury. If drug-induced liver injury is suspected, the administration of XELJANZ should be interrupted until this diagnosis has been excluded.

Assessment of lipid parameters should be performed approximately 4-8 weeks following initiation of XELJANZ therapy.

Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ therapy.

ADVERSE REACTIONS Clinical Trial Experience 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.

Although other doses have been studied, the recommended dose of XELJANZ is 5 mg twice daily.

The following data includes two Phase 2 and fve Phase 3 double-blind, controlled, multicenter trials. In these trials, patients were randomized to doses of XELJANZ 5 mg twice daily (292 patients) and 10 mg twice daily (306 patients) monotherapy, XELJANZ 5 mg twice daily (1044 patients) and 10 mg twice daily (1043 patients) in combination with DMARDs (including methotrexate) and placebo (809 patients). All seven protocols included provisions for patients taking placebo to receive treatment with XELJANZ at Month 3 or Month 6 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Therefore some analyses that follow include patients who changed treatment by design or by patient response from placebo to XELJANZ in both the placebo and XELJANZ group of a given interval. Comparisons between placebo and XELJANZ were based on the frst 3 months of exposure, and comparisons between XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily were based on the frst 12 months of exposure.

The long-term safety population includes all patients who participated in a double-blind, controlled trial (including earlier development phase studies) and then participated in one of two long-term safety studies. The design of the long-term safety studies allowed for modifcation of XELJANZ doses according to clinical judgment. This limits the interpretation of the long-term safety data with respect to dose.

The most common serious adverse reactions were serious infections.

The proportion of patients who discontinued treatment due to any adverse reaction during the 0 to 3 months exposure in the double-blind, placebo-controlled trials was 4% for patients taking XELJANZ and 3% for placebo-treated patients.

Overall Infections In the seven controlled trials, during the 0 to 3 months exposure, the overall frequency of infections was 20% and 22% in the 5 mg twice daily and 10 mg twice daily groups, respectively, and 18% in the placebo group.

The most commonly reported infections with XELJANZ were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively).

Serious Infections In the seven controlled trials, during the 0 to 3 months exposure, serious infections were reported in 1 patient (0.5 events per 100 patient-years) who received placebo and 11 patients (1.7 events per 100 patient-years) who received XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confdence interval) was 1.1 (-0.4, 2.5) events per 100 patient-years for the combined 5 mg twice daily and 10 mg twice daily XELJANZ group minus placebo.

In the seven controlled trials, during the 0 to 12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 33 patients (2.7 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confdence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection.

Tuberculosis In the seven controlled trials, during the 0 to 3 months exposure, tuberculosis was not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ. In the seven controlled trials, during the 0 to 12 months exposure, tuberculosis was reported in 0 patients who received 5 mg twice daily of XELJANZ and 6 patients (0.5 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confdence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. Cases of disseminated tuberculosis were also reported. The median

XELJANZ exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days).

In a controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy.

Opportunistic Infections (excluding tuberculosis) In the seven controlled trials, during the 0 to 3 months exposure, opportunistic infections were not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ.

In the long-term safety population, elevations in lipid parameters remained consistent with what was seen in the controlled clinical trials.

In the seven controlled trials, during the 0 to 12 months exposure, opportunistic infections were reported in 4 patients (0.3 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 4 patients (0.3 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confdence interval) was 0 (-0.5, 0.5) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days).

Malignancy In the seven controlled trials, during the 0 to 3 months exposure, malignancies excluding NMSC were reported in 0 patients who received placebo and 2 patients (0.3 events per 100 patient-years) who received either XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confdence interval) was 0.3 (-0.1, 0.7) events per 100 patient-years for the combined 5 mg and 10 mg twice daily XELJANZ group minus placebo.

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

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

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

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

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

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

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

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

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

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

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

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

Lipid Elevations In the controlled clinical trials, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the frst 3 months of exposure in the controlled clinical trials are summarized below: • Mean LDL cholesterol increased by 15% in the XELJANZ 5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm.

• Mean HDL cholesterol increased by 10% in the XELJANZ 5 mg twice daily arm and 12% in the XELJANZ 10 mg twice daily arm.

• Mean LDL/HDL ratios were essentially unchanged in XELJANZ-treated patients.

Serum Creatinine Elevations In the controlled clinical trials, dose-related elevations in serum creatinine were observed with XELJANZ treatment. The mean increase in serum creatinine was <0.1 mg/dL in the 12-month pooled safety analysis; however with increasing duration of exposure in the long-term extensions, up to 2% of patients were discontinued from XELJANZ treatment due to the protocol-specifed discontinuation criterion of an increase in creatinine by more than 50% of baseline. The clinical signifcance of the observed serum creatinine elevations is unknown.

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

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

XELJANZ 10 mg Twice Daily*

N = 1336 (%) N = 1349 (%)

Placebo N = 809 (%)

Diarrhea

4.0

2.9

2.3

Nasopharyngitis

3.8

2.8

2.8

Upper respiratory tract infection

4.5

3.8

3.3

Headache

4.3

3.4

2.1

Hypertension

1.6

2.3

1.1

N refects randomized and treated patients from the seven clinical trials *The recommended dose of XELJANZ is 5 mg twice daily.

Other adverse reactions occurring in controlled and open-label extension studies included: Blood and lymphatic system disorders: Anemia Metabolism and nutrition disorders: Dehydration Psychiatric disorders: Insomnia Nervous system disorders: Paresthesia Respiratory, thoracic and mediastinal disorders: Dyspnea, cough, sinus congestion Gastrointestinal disorders: Abdominal pain, dyspepsia, vomiting, gastritis, nausea Hepatobiliary disorders: Hepatic steatosis Skin and subcutaneous tissue disorders: Rash, erythema, pruritus Musculoskeletal, connective tissue and bone disorders: Musculoskeletal pain, arthralgia, tendonitis, joint swelling Neoplasms benign, malignant and unspecifed (including cysts and polyps): Non-melanoma skin cancers General disorders and administration site conditions: Pyrexia, fatigue, peripheral edema Clinical Experience in Methotrexate-Naïve Patients Study VI was an active-controlled clinical trial in methotrexate-naïve patients. The safety experience in these patients was consistent with Studies I-V. DRUG INTERACTIONS Potent CYP3A4 Inhibitors Tofacitinib exposure is increased when XELJANZ is coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 (e.g., ketoconazole).

Moderate CYP3A4 and Potent CYP2C19 Inhibitors Tofacitinib exposure is increased when XELJANZ is coadministered with medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fuconazole).

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

Immunosuppressive Drugs There is a risk of added immunosuppression when XELJANZ is coadministered with potent immunosuppressive drugs (e.g., azathioprine, tacrolimus, cyclosporine). Combined use of multiple-dose XELJANZ with potent immunosuppressives has not been studied in rheumatoid arthritis. Use of XELJANZ in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic effects: Pregnancy Category C. There are no adequate and wellcontrolled studies in pregnant women. XELJANZ should be used during pregnancy only if the potential beneft justifes the potential risk to the fetus. Tofacitinib has been shown to be fetocidal and teratogenic in rats and rabbits when given at exposures 146 times and 13 times, respectively, the maximum recommended human dose (MRHD).

In a rat embryofetal developmental study, tofacitinib was teratogenic at exposure levels approximately 146 times the MRHD (on an AUC basis at oral doses of 100 mg/kg/day). Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively, and skeletal malformations or variations (absent cervical arch; bent femur, fbula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced.

No developmental toxicity was observed in rats at exposure levels approximately 58 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day). In the rabbit embryofetal developmental study, tofacitinib was teratogenic at exposure levels approximately 13 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects.

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

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

Pregnancy Registry: To monitor the outcomes of pregnant women exposed to XELJANZ, a pregnancy registry has been established.

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

Nursing Mothers Tofacitinib was secreted in milk of lactating rats.

It is not known whether tofacitinib is excreted in human milk.

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

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

Geriatric Use Of the 3315 patients who enrolled in Studies I to V, a total of 505 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older. The frequency of serious infection among XELJANZ-treated subjects 65 years of age and older was higher than among those under the age of 65.

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

Hepatic Impairment XELJANZ-treated patients with moderate hepatic impairment had greater tofacitinib levels than XELJANZ-treated patients with normal hepatic function. Higher blood levels may increase the risk of some adverse reactions; therefore, XELJANZ dose should be reduced to 5 mg once daily in patients with moderate hepatic impairment. XELJANZ has not been studied in patients with severe hepatic impairment; therefore, use of XELJANZ in patients with severe hepatic impairment is not recommended. No dose adjustment is required in patients with mild hepatic impairment. The safety and effcacy of XELJANZ have not been studied in patients with positive hepatitis B virus or hepatitis C virus serology.

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

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

There is no specifc antidote for overdose with XELJANZ. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate treatment.

This brief summary is based on XELJANZ® (tofacitinib) Prescribing Information LAB-0445-5.0 Issued: March 2014

©2014 Inc. © 2014 Pfzer Pfzer Inc.

All reserved.

All rights reserved.

August April 20142014

Rheumatology Practice Management

™

In Pursuit of Independence Kyle Harner, MD

I

f your rheumatology practice is physician owned, I am willing to bet that staying independent is very important to both the doctors and managers. In short, you do not want to “work for the man” that runs the health system, hospital, or multispecialty group down the street. You want to remain the boss even if that means extra headaches at times. In the current healthcare environment, remaining independent means being informed and staying proactive. In short, being your own boss is a lot of work and is becoming more work as the years go by.

The clinic where I work with my 2 partners is the only single-specialty rheumatology group in the city where we practice. There are other rheumatologists at a large multispecialty group and at an even larger hospital system. How do we stay independent in this environment? And believe me, we want to stay independent. The 3 partners in our practice control the destiny of our day-to-day operations, along with the managers and staff members that WE chose.

We do not answer to anyone (other than the insurance companies and the federal government and…but that is another story).

As a group, we try to be very proactive and to keep our eye on the medical landscape in the area. What

other groups are looking for new rheumatologists or adding physician extenders? Are we accepting patients from the best mix of insurance carriers? How are other practices adver-

the frustrating fluctuations in the accounts receivable process. Managers need to constantly monitor for changes in reimbursement from all the accepted carriers. At times,

Keeping patients happy is another key to staying independent. This means trying to minimize wait times, having a congenial staff, and offering a mix of ancillaries —Kyle Harner, MD

tising? Do we have the right ancillaries to offer our patients?

If a private practice rheumatology clinic is so busy that patients have to wait for months to be seen, those same patients are likely to see a competing rheumatologist. Your practice may need to recruit another physician or hire an extender to shorten wait times. Patients who are seen in a few weeks after a referral are much less likely to look for another doctor to address their problems.

Without a mix of accepted insurance carriers, it is hard to weather

poor-paying insurance providers may need to be dropped, or contracts may need to be renegotiated.

A practice may need to add a carrier if such a carrier starts to cover a larger percentage of the patient population in a given area. At best, this aspect of practice management is a constantly moving target.

Advertising aggressively is the key to staying busy if the wait time for your practice is too short or if you have too many unbooked appointments. This advertising can take several forms—print (both newspapers

and local magazines), radio, and TV. Advertising has to fit into your budget, and it has to reach the right audience. Another effective way to advertise is to give patient lectures or sponsor a booth at local health fairs.

Both doctors and extenders can give interesting patient talks to recruit patients. Such gatherings put a face with a name, and I believe that most patients appreciate these educational opportunities.

Keeping patients happy is another key to staying independent. This means trying to minimize wait times, having a congenial staff, and offering a mix of ancillaries. Patients will start to walk across the street if they have to wait every time they come to see the rheumatologist. They also want to hear “please” and “thank you” and to see smiles, especially when they are having a bad day. Also, if patients have to drive around town for labs, x-rays, and other ancillaries, they might start looking for a rheumatologist with one-stop shopping all under the same roof.

The quest for ongoing independence is becoming more difficult over time. Being proactive is the key to keeping control of your practice. No one has knocked on our door and tried to buy us out…yet. And we plan to do everything we can to keep it that way. n

Electronic Medical Records Being Used Suboptimally for Osteoporosis Patients Rosemary Frei, MSc

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lectronic medical records represent unfulfilled promise for identifying patients who are at elevated risk for osteoporosis and fragility fractures, according to a survey of the situation in Ontario, Canada. As reported at the American Medical Informatics Association 2014 Annual Symposium, electronic medical records (EMRs) from family physicians across the province of Ontario that were contributed to a database dubbed EMRALD (EMR AdministraVOL. 4

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tive Data Linked Database) contain widely varying report formats for bone mineral density (BMD) results.1 EMRALD was created in 2007 by Karen Tu, MD, and her colleagues from the Department of Family and Community Medicine, University of Toronto. It is housed at the Institute for Clinical Evaluative Sciences in Toronto.

“It’s encouraging that there are a lot of BMD exam results in EMRALD, but a bit discouraging to see how variably the results and other infor-

mation about osteoporosis are stored,” presenter Sonya Allin, PhD, told Value-Based Care in Rheumatology. For example, among the osteoporosis patients included in the electronic-record review “only about half had BMD exam results in the EMRs and less than two-thirds had their osteoporosis diagnosis coded in their patient profile.” Some members of the same research team showed in an earlier study that there is a woefully low rate of age-standardized BMD FEBRUARY 2015

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testing within 6 months of a fracture in Ontario patients.2 Allin, a researcher in the Department of Physical Therapy, University of Toronto, and Tu, and their coinvestigators focused on 15,365 patients in EMRALD who had diagnostic-imaging entries for BMD exams.

They found that, while the rate of BMD testing recorded in EMRALD does reflect the rate shown in records from the provincial health agency, pulling diagnoses and fracture risk

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Rheumatology Practice Management

™

Increasing the Understanding of Rheumatic…

Satish Odhav, MD

John M. Stuart, MD

trepidation to physicians,” said Tokayer, “particularly to rheumatologists, who often treat multiple complex problems on the same patient in a single office visit.”

According to Tokayer, rheumatoid arthritis must be specified as either RF positive or RF negative; gout must be specified as chronic, acute, with/without tophi; rheumatoid arthritis or connective tissue disorders must be further specified to include any major organ involvement; and drug-induced conditions must include an additional code that represents the drug itself.

Ultimately, Tokayer was able to “de-code and de-mystify” the ICD10, demonstrating how a 1-page tool can allow for multiple ICD-10 diagnostic codes in a simple but effective way.

Autoimmune Diseases Yehuda Shoenfeld, MD, director of the Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Aviv University, offered the audience 2 intellectually stimulating presentations. His first talk focused on the interactions between the human immune system and surrounding pathogens—or lack thereof—and how these fit in the mosaic of autoimmunity.

Shoenfeld’s second, more provocative presentation dealt with the recognition of a new autoimmune syndrome dubbed ASIA, or autoimmune inflammatory syndrome induced by adjuvants. This syndrome includes 4 enigmatic conditions affecting genetically predisposed individuals exposed to various factors that chronically stimulate the immune system.

Ruth Ann Vleugels, MD, MPH, from Harvard Medical School, also offered 2 presentations. First, she provided practical clinical pearls for the diagnosis and advanced management of cutaneous lupus erythematosus. In her second presentation, Vleugels described the dermatologic manifestations of dermatomyositis, systemic sclerosis, and other fibrosing disorders.

John M. Stuart, MD, from the University of Tennessee Health Science Center in Memphis, presented research into a common joint condition, namely osteoarthritis. Stuart described a means of detecting very early cartilage degradation and the potential to quantify these changes in real time using nondestructive procedures. He also described a novel delivery system for targeting cartilage or even specific cells within the tissue—a system that would allow for controlled release of therapeutic agents at the site of cartilage damage.

Finally, Linda Kay Myers, MD, a colleague of Stuart at the University of Tennessee, shared with the membership the results of years of research.

With long-term interest in the pathogenesis of juvenile rheumatoid arthritis, most of Myers’ research has centered on the hypothesis that an autoimmune response to a cartilage-specific protein (mainly type II collagen) contributes to the inflammation and destruction of cartilage in

Electronic Medical Records Being Used… information from EMRALD’s BMD reports was complicated by lack of standardization. Among all the patients with BMD exam entries in EMRALD, 27.8% did not have BMD results in searchable text format, and 8% did not mention the term T-score.

Even when text entries did contain a BMD exam result, the formats were “extremely varied,” noted the researchers: 27.3% were less than 200 characters long and many were short annotations from primary care physicians. Most of the BMD results were attached to the EMR either as an image or scan.

Furthermore, when members of the research team manually reviewed the EMRs of some of the patients, they

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found only 55.8% of osteoporosis patients’ BMD results were readily accessible. The most common place for a

Fortunately, the patients in EMRALD who experienced a fragility fracture did seem to be relatively well

—Sonya Allin, PhD

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that medical condition.

“If this hypothesis is true,” concluded Myers, “then oral administration of type II collagen may lead to T-cell tolerance and hopefully suppression of disease.”

Attendees also appreciated presentations by 2 fellows, Syed Islam, MD, from the University of Tennessee program, and Ami Joglekar, MD, from the Vanderbilt program, who described 2 interesting clinical cases, with a review of the relevant literature.

The Future of TRS The 12th annual meeting was funded by several corporate sponsors and vendors. The Tennessee Chapter of the Arthritis Foundation and the Lupus Foundation were both given the opportunity to highlight activities of their respective foundations.

“Thirteen years ago,” said Odhav, current TRS president, “the founding president envisioned the creation of an encompassing statewide rheumatology society. This and other meetings were definitive proof that their initial vision bore fruit.”

Looking toward the future, however, Odhav saw the potential for even greater influence. “The TRS modus operandi could be emulated by other rheumatology state societies in which relations between clinicians and academicians are less than stellar,” he suggested. n

Continued from page 11

“It’s encouraging that there are a lot of BMD exam results in EMRALD, but a bit discouraging to see how variably the results and other information about osteoporosis are stored.”

mention of the osteoporosis diagnoses in the EMRs, at 90.2%, was in a note from a primary care provider attached to an individual patient exam.

Continued from page 1

investigated for osteoporosis.

“In the future, we’d like to relate the representation of fragility fractures in the EMR to their representa-

tion in administrative data sources; this might tell us how many fractures are not communicated to primary care providers by patients,” reflected Allin. She also noted that comparable data quality issues are likely present in American primary care physicians’ EMRs and administrative databases. n References

1. Allin S, Munce S, Jaglal S, et al. Capture of osteoporosis and fracture information in an electronic medical record database from primary care. Presented at: American Medical Informatics Association 2014 Annual Symposium; November 15-19, 2014; Washington, DC. http://knowledge.amia.org/.

Accessed January 5, 2015.

2. Jaglal S, Hawker G, Croxford R, et al. Impact of a change in physician reimbursement on bone mineral density testing in Ontario, Canada: a population-based study. CMAJ Open. 2014;2(2):E45-E50. www.cmajopen. ca/content/2/2/E45.full. Accessed January 5, 2015.

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FDA Update

FDA Final Rule on Pregnancy and Lactation Labeling Getting Mixed Reviews Rosemary Frei, MSc

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he US Food and Drug Administration (FDA) is hoping that its December 4, 2014, final rule on pregnancy and breastfeeding labeling for prescription drugs and biological products will be helpful to patients and providers. Clinicians are also optimistic about the changes but are waiting to see whether sufficient data will be available to truly clarify the risks of using each medication during conception, pregnancy, and lactation.

The new regulations state that as of June 30, 2015, labels for newly approved medications must have 3 subsections—Pregnancy, Lactation, and Females and Males of Reproductive Potential—describing the medication’s effects on women who are pregnant or breastfeeding, on the fetus and breast-fed children, and on men and women who are attempting to conceive. Labels must no longer include a labor and delivery subsection or the currently used A, B, C, D, or X pregnancy category designation for classifying teratogenicity.

Over the subsequent 3 to 5 years, products approved from 2001 to June 2015 will be required to comply with the new labeling rules. Labeling for medications approved before June 30, 2001, will not be required to include the new changes, but the letter designation, if any, must be removed within 3 years of the final rule’s effective date.

“We’ve been long aware that this section of the medical product labeling is probably one of the least informative sections of the drug labeling there is. It is rarely up to date, [and]

we hear from clinicians that they don’t understand it [and that] there were long descriptions of animal data that were not interpreted well,” Sandy Walsh, FDA Press Officer, stated in an email to Value-Based Care in Rheumatology. “[A]nd studies... done by astute clinicians and re-

ent drugs are to the developing fetus or the child who’s breastfeeding, particularly with some of the new targeting drugs that we don’t have much experience with.”

A rheumatologist also expressed both optimism and caution. “It’s a great step forward. The old system

“It’ll be interesting to see what data get into the labels, because there aren’t a lot of data currently available, and the FDA hasn’t said what their process will be for approving data supplied by the pharma companies.”

—Megan Clowse, MD

searchers never made it to labeling.

We’re hoping this new rule will allow for much more useful information to be added consistently.”

Richard L. Schilsky, MD, Chief Medical Officer, American Society of Clinical Oncology, commended the FDA for moving forward with the changes but said a large data gap remains. “The rule seems to deal with how the information should be presented in the label,” Schilsky told Value-Based Care in Rheumatology. “[But] the bigger issue is how we get the information that needs to be in those sections of the label that actually provides the guidance that physicians and their patients are looking for. The problem is the lack of information about what the risks of differ-

was misleading and was too simplistic—for example, azathioprine was labeled as class D because there is some potential fetal toxicity, but we consider it our safest immunosuppressant—and also didn’t really change when new data became available,” said Megan Clowse, MD, Associate Professor of Medicine, Division of Rheumatology and Immunology, and director of the Duke Autoimmunity in Pregnancy Registry, Duke University Health System, Durham, North Carolina.

“It’ll be interesting to see what data get into the labels, because there aren’t a lot of data currently available, and the FDA hasn’t said what their process will be for approving data supplied by the pharma companies.”

The final rule stipulates that the Pregnancy subsection of the label will specify whether there is a scientifically acceptable pregnancy-exposure registry for the drug. This subsection also will include a summary of the risks to fetuses and mothers of using the drug during pregnancy, as well as any other available information to help clinicians counsel pregnant women about use of the medication.

The Lactation subsection will indicate whether the medication is absorbed systemically by the mother and, if so, what its effects are on milk production; how much of the drug reaches the breast milk; and what its effects are on breast-fed babies. Other information to be put in this subsection includes ways to minimize the amount of the drug ingested by children via breastfeeding and ways to monitor for and reduce side effects from the medication.

Information in the Females and Males of Reproductive Potential subsection will address whether pregnancy testing or contraception is needed or recommended before, during, or after medication use. Furthermore, if studies have indicated that the medication effects fertility, this data will also be included.

The opportunity for public comments regarding this measure closed on February 1, 2015. The FDA is now planning to finalize draft guidance for the industry. n Reference

Content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling. Federal Register website. https://federalreg ister.gov/a/2014-28241. Published December 4, 2015. Accessed February 4, 2015.

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Let us know if you discuss clinical trials with your patients. Submit your vote for this online poll. Results will be printed in an upcoming issue of VBCR.

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In the Literature Acetaminophen Lacks Effectiveness in Knee Osteoarthritis Despite being the most common over-the-counter treatment for pain related to knee osteoarthritis (OA), acetaminophen was found inferior to other commonly used pain medications in a large network meta-analysis. Intra-articular (IA) treatments were superior to oral nonsteroidal anti-inflammatory drugs (NSAIDs) for pain relief in this study.

Lead author Raveendhara R. Bannuru, MD, and colleagues at Tufts Medical Center in Boston, Massachusetts, wrote that the superiority of IA treatments is possibly due to a placebo effect. “The information from this study, along with the safety profiles and relative costs of included treatments, should be helpful to clinicians when making care decisions tailored to individual patient needs,” they wrote.

In the absence of definitive head-tohead trials of medications used to treat knee OA, the authors conducted a large meta-analysis to get a handle on the comparative effectiveness of commonly used drugs in this setting.

They reviewed a total of 33,243 participants in 137 randomized controlled trials published between 1980 and 2014; each trial compared 2 or more treatments for knee OA and reported at least 1 measure of pain, function, or stiffness. Studies were drawn from searches of MEDLINE, EMASE, Web of Science, Google, Scholar, and Cochrane Central Register of Controlled Trials, as well as unpublished data.

Treatments studied included acetaminophen, diclofenac, ibuprofen, naproxen, celecoxib, IA corticosteroids, IA hyaluronic acid, oral placebo, and IA placebo. An absolute change of 20 points on a scale from 0 to 100 on the OA Research Society International-Outcome Measures in Rheumatology responder criteria was deemed clinically significant.

Reported outcomes differed in these trials; 129 trials with 32,129 participants contributed to the analyses of pain-related outcomes, 76 trials (24,059 participants) contributed to the analyses of physical function outcomes, and 55 trials (18,267 participants) contributed to the analyses of stiffness outcomes. Age of participants ranged from 45 to 76 years, and the proportion of women ranged from 3% to 100%.

All interventions were statistically superior to placebo for pain-related outcomes. The most efficacious pain relief occurred with IA hyaluronic acid and the least efficacious was acetaminophen; effect sizes (standard mean differences) were 0.63 and 0.18, respectively. All treatments except ac-

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etaminophen met the prespecified criteria for clinically significant improvement. All active treatments except celecoxib were statistically superior to acetaminophen; IA treatments were more effective than oral treatments.

All interventions were significantly superior to oral placebo for function, except IA corticosteroids. Naproxen, ibuprofen, diclofenac, and celecoxib were statistically significantly better than acetaminophen for functional outcomes. IA hyaluronic acid was significantly better than IA placebo and IA corticosteroids.

All oral treatments were significantly superior to acetaminophen for stiffness. IA hyaluronic acid was significantly better than IA placebo for stiffness.

Traditional nonselective NSAIDs were associated with more gastrointestinal (GI) adverse events and withdrawals compared with oral placebo and acetaminophen; GI adverse events were similar between acetaminophen and celecoxib. The short exposure time of 2 to 3 months probably affected reporting on adverse cardiovascular events, the authors wrote.

Transient local reactions were the most commonly reported adverse events related to IA treatments, and the frequency was similar among IA therapies.

The network meta-analysis did not investigate combination therapies, even though these are commonly used to treat knee OA. “The large number of possible therapy combinations and scarcity of trials comparing these treatments prompted us to restrict our analysis to monotherapies,” the authors wrote.

Bannuru RR, et al. Ann Intern Med. 2015;162(1):46-54.

Adverse Events on Biologics Common in Juvenile Idiopathic Arthritis The occurrence of adverse events (AEs), including serious adverse events (SAEs), is more common in children with juvenile idiopathic arthritis (JIA) on biologic therapy than has been previously reported. More than 90% of children experienced at least 1 AE on biologics, and more than one-third suffered an SAE over longterm follow-up in a “real world,” retrospective, observational study reported online December 10, 2014, in Rheumatology. Although AEs and SAEs were more frequent than assumed, these events seldom led to drug discontinuation.

“Our data show a wide spectrum of AEs during biologic therapy as they appear in a real-life setting. One of the strengths of the study is that we included all AEs, whether known to be

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related to the biologic agent or not, regardless of how many times or when they appeared in a single patient.

Moreover, we did not rely on surveys or survey-based registries, but assessed all the available information in patient records, which seemed to be a more reliable method of collecting information,” wrote the authors.

Other strengths of the study included long-term follow-up of more than 4 years in the majority of patients. The main limitation was that it was retrospective and was not able to define causality of AEs with accuracy.

The study included 348 consecutive patients with JIA treated at 3 different tertiary centers in Finland. This amounted to 1516 patient-years: 710 patient-years on etanercept, 591 on infliximab, 188 on adalimumab, 8 on rituximab, 5.3 on anakinra, 6 on abatecept, 4 on tocilizumab, and 1 on golimumab. Median follow-up of an individual patient on biologics was 50.5 months (range, 1-154.7 months). Median age at end of follow-up was 15.9 years (range, 3.8-29 years). Ninety-five percent (n=330) were on disease-modifying antirheumatic drugs (DMARDs) prior to biologics, and 97% received DMARDs during treatment with biologics.

Ninety-two percent (n=319) reported at least 1 AE. Patients without an AE had a significantly shorter median follow-up compared with those who had an AE: 18.8 months versus 52.3 months, respectively (P<.0001). AEs totaled 2902 and 169/100 patient-years. Infections were the most common AE, reported in 274 patients (79%). Other common AEs included infusion or injection site reactions (n=105, 30.2%), flare of uveitis (n=43, 12.4%), and mild elevation of alanine aminotransferase (ALT) <3 times upper limit of normal (n=49, 14.1%).

SAEs were reported in 121 patients (35%) over follow-up, with a total of 173 events and 11.4/100 patient-years.

A total of 44 patients (12.6%) had a serious infectious AE. The occurrence of serious infections was significantly higher with ritixumab compared with all other anti-TNFs, with a relative risk of 6.16 (P=.008). A total of 32 patients had more than 1 SAE. Drug therapy was continued unchanged in 150 patients (87%) despite an SAE. In some of these cases, there was a short pause in therapy. No cases of malignancies or tuberculosis were found.

New onset uveitis was reported in 9 patients, psoriasis or psoriaform lesions in 13 patients, and inflammatory bowel disease in 6 patients.

Lead author Maarit Tarkiainen, MD, Children’s Hospital, University of Helsinki, Finland, said these data support the use of biologics in juve-

nile patients. “Most common SAEs were leucopenias and ALT elevations.

After these, drug therapy could most often be continued after a short pause.

SAEs during treatment with biologics in juvenile patients can mostly be controlled by experienced pediatric rheumatologists,” she said.

Tarkiainen M, et al. Rheumatology.

Published online: December 10, 2014.

Increased Cardiovascular Risk in Psoriatic Arthritis People with psoriatic arthritis (PsA) are at increased risk for cardiovascular disease (CVD) even at early stages of PsA, but the traditional method of estimating risk using the Framingham risk score (FRS) appears to greatly understimate the true risk of CVD in this population. A new study suggests that the FRS may underestimate CVD risk by as much as 50% in newly diagnosed patients with PsA. The population-based, retrospective study included 158 patients who fulfilled the ClASsification of Psoriatic ARthritis (CASPAR) criteria for PsA between 1989 and 2008. Mean age was 43.4 years (range, 19-74 years); 61% were men; 44% were obese (body mass index ≥30 kg/m2); and 94% had inflammatory joint disease. Fifty-four patients (34%) had at least 2 CVD risk factors at diagnosis of PsA. Medical records were reviewed to identify CVD risk factors and CVD events, and future risk of CVD was estimated using the FRS algorithm.

The 10-year risk of CVD was twice as high in PsA patients as that predicted by the FRS, especially for patients older than 40 years. Over 1 year of follow-up, 32 patients had at least 1 cardiovascular event, for a 17% 10-year cumulative incidence—twice as high as the incidence predicted by the FRS. Of 126 PsA patients aged 30 years or older with no CVD history, 18 developed CVD for a cumulative incidence of 17%—also twice as high as that predicted by the FRS. No differences between the groups were found for traditional CVD risk factors (ie, cholesterol level, smoking history, obesity, and blood pressure) and the FRS was not associated with disease activity as measured by traditional markers such as erythrocyte sedimentation rate.

The authors comment that the association between rheumatoid arthritis and CVD is well established, and risk factors such as disease activity, corticosteroid use, and inflammation have been implicated in the acceleration of CVD in this population. However, these associations are less well understood and studied in PsA, and subclinical atherosclerosis has been detected in PsA patients without Continued on page 15 VOL. 4

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Fibromyalgia

Patient Descriptions Deepen Understanding…

“Avoiding everything may indicate a lack of knowledge of or ability to use healthy coping strategies, and therefore, future research could evaluate the potential effects of teaching patients healthy coping strategies as one method to deal with symptom flare,” wrote Ann Vincent, MD, and her 2 coauthors.

Vincent, Associate Professor of Medicine, Mayo Clinic, Rochester, Minnesota, said her team administered the survey to Mayo Clinic fibromyalgia patients at a ratio of 4:1 of females:males to reflect the gender proportion of the illness; 77% of the respondents were female, and 93% were non-Hispanic white.

When queried by Value-Based Care in Rheumatology about what the specific clinical implications are with respect to optimizing coping strategies, Vincent responded, “This is a qualitative study and this [the survey results] is what patients reported they do.”

She and her coauthors suggest that future research could include a larger, more diverse patient population to assess the characteristics of fibromyalgia flares quantitatively.

The 7 items in the qualitative questionnaire were designed to probe the unique characteristics of flares. The questions included, “Do you experience any new symptoms during a fibromyalgia flare that are not typical of your everyday fibromyalgia symptoms?” and “How do you cope with a fibromyalgia flare?”

In the respondents’ descriptions of flare triggers, the most common theme was “stress, stress, stress” related to work and life in general. They also said “overdoing it” can cause flares; this included physical exercise and variations in normal activity such as attending social events. Inadequate or poor-quality sleep and weather changes were the other most common triggers. Sleep is particularly prob-

Continued from page 1

lematic for patients because flare-ups reduce sleep quality, causing a continuing feedback loop.

A key characteristic of flares is an intensification of symptoms to the point of being disabling. Many survey respondents described exhaustion, and also severe pain.

—Ann Vincent, MD, and colleagues

A key characteristic of flares is an intensification of symptoms to the point of being disabling. Many survey respondents described full-body ach-

ing and exhaustion, similar to having a flu, and also severe pain, which can be so intense that, as one patient described, it “makes me not want to move or be touched.” Respondents also described severe and disabling fatigue and other symptoms such as “fogginess in my head,” severe headaches or migraines, and difficulty with emotional regulation.

Among respondents, 77% turned to medications as treatment—principally acetaminophen and ibuprofen— and 22.7% reported using massage.

Many also reported using meditation, breathing exercises, and hot or cold therapy. Three other major coping strategies were getting more rest or staying home, avoiding all activities including social interactions, and “waiting it out.” n Reference

Vincent A, Whipple MO, Rhudy LM. Fibromyalgia flares: a qualitative analysis [published online January 13, 2015]. Pain Med.

Literature

In the Literature traditional cardiovascular risk factors.

The authors believe that the presence of PsA alone may account for increased CVD risk.

Limitations of the study include lack of a comparator group and relatively short follow-up.

Ernste FC, et al. Arthritis Care Res (Hoboken). Published online: January 7, 2015.

Early Treatment for Rheumatoid Arthritis Supported Treating rheumatoid arthritis (RA) early in the course of the disease can lead to improved outcomes, according to a large study published online in Annals of Rheumatic Disease January 5, 2015. The study suggests that there is a window of opportunity within a few months of symptom onset when treatment with disease-modifying antirheumatic drugs (DMARDs) can have an impact on joint erosion and inflammation, possibly reducing the need for orthopedic surgery, noted lead author VOL. 4

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Jessica A.B. van Nies, MD, Leiden University Medical Center, the Netherlands, and colleagues.

In more than 1200 RA patients receiving DMARDs, the authors found that early treatment led to more durable DMARD-free remissions compared with delayed treatment.

Patients often wait to consult a doctor when they first have symptoms of RA, and the authors say that strategies are needed to get patients to treatment earlier so as to capitalize on this notvery-broad window of opportunity.

The study explored the association between treatment onset and DMARD-free remission (primary outcome measure) in patients in 2 longitudinal observation cohorts: 738 patients enrolled in the Leiden Early Arthritis Clinic (EAC) cohort and 553 patients enrolled in the Evaluation et Suivi de Polyarthrites Indifférenciées Recentes (ESPOIR) cohort in Nimes, France. Log-hazard ratios were used to evaluate the relationship between

duration of symptoms before treatment and DMARD-free sustained remission in 5 years of follow-up.

At the time of enrollment in the cohort, median symptom duration was 18.7 weeks for EAC and 21.3 weeks for ESPOIR. Methotrexate was initiated in 76.3% of EAC patients and 67% of ESPOIR patients. The majority of the remaining patients in each cohort were started on either sulfasalazine or hydroxychloroquine.

Over 5 years of follow-up, 11.5% of EAC patients and 5.4% of ESPOIR patients enjoyed DMARD-free remissions. A nonlinear association was observed, with a decrease in DMARDfree sustained remission after about 15 to 19 weeks of symptom duration, suggesting that “a confined period in which the disease is more susceptible to treatment is present indeed,” the authors wrote.

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characteristic curves with DMARDfree sustained remission as the outcome, in both cohorts the area under the curve was relatively low, making it difficult to identify the optimum time window for initiation of treatment.

The 2 cohorts differed somewhat in this regard. For the EAC cohort, 14.9 weeks of symptom duration was able to discriminate between patients with DMARD-free remissions from those with persistent disease, whereas 19.1 weeks appeared to be the symptom duration that was most sensitive and specific in the ESPOIR cohort.

The authors did not suggest that treating after this “window of opportunity” is not effective but rather that treating early might lead to a better outcome. Patients who are diagnosed with RA after 15 or 20 weeks of persistent symptoms should definitely be treated, they wrote. van Nies JA, et al. Ann Rheum Dis. Published online: January 5, 2015. n

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Conference Highlights

New Studies Help Clarify Relationship Between…

Continued from page 1

Rosemary Frei, MSc Bernatsky, MD, PhD, and her coinvestigators looked at pollution exposures and positivity for certain autoantibodies. They used the CARTaGENE cohort of 20,000 people randomly drawn from 4 metropolitan areas in Quebec: Montreal, Quebec City, Sherbrooke, and Saguenay–Lac-Saint-Jean. The investigators focused on 3579 people that they randomly sampled from the cohort.

Subjects had more than a 9-fold increased risk of being positive for anti-cyclic citrullinated peptide (anti-CCP) antibodies per every 1000-tonne (1100-ton US) increase in fine particulate matter (PM2.5) emissions in their residential neighborhood. There was also a trend, albeit less dramatic, toward increased risk of positivity for anti-CCP antibodies with every unit increase in sulfur dioxide (SO2) emissions. Among those living near a major industrial emitter of SO2 or PM2.5, the chances of being positive for anti-CCP antibodies decreased with greater distance of their residence from the pollution source.

In the second poster, Bernatsky and her colleagues showed that the probability of having a systemic autoim-

mune rheumatic disease (SARD) is increased in individuals in Quebec and Alberta who are exposed to higher PM2.5 levels. This study, the first data ever produced on SARD and pollution, drew on administrative data

in these issues for several years, due to the incomplete picture of what specific environmental factors trigger rheumatic diseases.

“It is known that air pollution, upon entering the body through the lungs,

“It is known that air pollution, upon entering the body through the lungs, can stimulate the immune system and cause inflammation...it seemed a good idea to look further into the effects of pollution on rheumatic diseases.”

—Sasha Bernatsky, MD, PhD

her group had suggested that pollution in Montreal may correlate with disease activity in patients with systemic lupus erythematosus and that patterns of rheumatic diseases in Montreal appear to be related to traffic density.3 The more recent studies increase the scope of the investigation to other areas in Canada. She and the members of her team also noted in their SARD study that improved air quality across the continent could significantly lower the rates of chronic diseases, including SARD as well as respiratory and cardiac diseases.

“Next, we will expand our studies in other populations, using different approaches to capture pollution exposures,” Bernatsky said in her email. n References

from Alberta (1993-2007) and Quebec (1989-2010). The researchers found that females were more likely than males to suffer from SARD, as were people aged more than 45 years versus younger individuals.

Bernatsky told Value-Based Care in Rheumatology that her colleagues at McGill University and other institutions in Quebec have been interested

can stimulate the immune system and cause inflammation. This has been shown to provoke diseases like diabetes, asthma, and heart disease, so it seemed a good idea to look further into the effects of pollution on rheumatic diseases,” Bernatsky, Associate Professor, Department of Medicine, McGill University, Montreal, wrote in an email.

An earlier study by Bernatsky and

1. Bernatsky S, Fritzler M, Hudson M, et al. Industrial pollution emissions are associated with anti-CCP antibodies. Poster presented at: 2015 Canadian Rheumatology Association Annual Scientific Meeting; February 4-7, 2015; Quebec City, Quebec. Abstract 139.

2. Bernatsky S, Smargiassi A, Barnabe C, et al. Fine particulate air pollution and systemic autoimmune rheumatic disease in two Canadian provinces. Poster presented at: 2015 Canadian Rheumatology Association Annual Scientific Meeting; February 4-7, 2015; Quebec City, Quebec. Abstract 26.

3. Bernatsky S, Fournier M, Pineau CA, et al.

Associations between ambient fine particulate levels and disease activity in patients with systemic lupus erythematosus (SLE). Environ Health Perspect.

2011;119(1):45-49.

Systematic Review Showcases Benefits of Nonpharmaceutical Interventions for Juvenile Idiopathic Arthritis

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everal types of exercise regimens are useful in the management of juvenile idiopathic arthritis (JIA), according to a new review of the literature. A group from the University of Ottawa conducted a systematic literature search for nonpharmaceutical interventions that yielded 4 high-quality, randomized, controlled trials. They showed that individualized home exercise, strength training exercise, aquatic exercise, Pilates, and cardio-karate all have benefits for young people with arthritis.

Principal investigator Lucie Brosseau, PhD, has subsequently spearheaded the production of YouTube videos and other material on the internet to spread the word to youth, and their parents and healthcare provid-

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ers, about these forms of exercise.

“I think all the medical professionals agree that we need a combination of both medication and nonpharmaceutical interventions because chil-

ty of Ottawa, told Value-Based Care in Rheumatology when the results were presented at the Canadian Rheumatology Association’s 2015 Annual Scientific Meeting.

Individualized home exercise, strength training exercise, aquatic exercise, Pilates, and cardio-karate all have benefits for young people with arthritis.

dren with juvenile arthritis need to not just take medicine but to get out and be active,” Brosseau, Professor, School of Rehabilitation Sciences, Faculty of Health Sciences, Universi-

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Brosseau and her 13 co-authors, known as the Ottawa Panel, identified 47 full-text articles that addressed comparative controlled trials of different types of physical activity

in JIA. However, only 5 provided high-quality, level 1 evidence.

One of the randomized, controlled trials was a comparison between patients who were using an individualized home exercise program and controls who were not exercising for 3 months. It showed grade A evidence for improvement of functional ability and quality of life. Another trial provided grade A evidence for significantly more improvement of joint status with aquatic aerobic fitness training than with normal daily activities. The third trial, which compared exercise to no exercise, showed modest benefits associated with a strength-training program for muscle torque.

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Conference Highlights study of Pilates versus a low-intensity standard workout program yielded grade A evidence for improvement of health-related quality of life with Pilates, as well as of pain, functional ability, and range of motion. Cardio-karate was compared to qigong in another randomized, controlled trial that yielded grade C+ evidence for an improvement in range of motion and number of active joints.

Among all the patients in all 5 trials there was only 1 who dropped out due to exacerbated symptoms. None of the others experienced any adverse effects.

The results were compelling enough for the members of the Ottawa Panel to recommend physical activity for the management of JIA. Brosseau also helped create a ‘People Getting a Grip on Arthritis’ website

hosted by The Arthritis Society (www.arthritis.ca/peoplegettin gagrip and www.arthrite.ca/pren dreenmainvotrearthrite) and helped put together a video in French showing youth participating in a cardio-karate class. In addition, 2 of her graduate students are studying the best way to disseminate this new knowledge to patients, their parents, and healthcare providers across the

country using new technologies.

“I’m very proud of these online dissemination efforts,” said Brosseau.

“Because research isn’t useful it if just sits on the shelf.” —RF n Reference

Brosseau L, Cavallo S, Toupin-April K, et al.

Therapeutic exercises are effective strategies for pain management of juvenile idiopathic arthritis.

Poster presented at: 2015 Canadian Rheumatology Association Annual Scientific Meeting; February 4-7, 2015; Quebec City, Quebec. Abstract 133.

Strong Link Uncovered Between Some Statins and Reduced Risk of Developing Rheumatoid Arthritis sician-scientist, Jewish General Hospital, Montreal, and 2 colleagues sought to sort out the conflicting conclusions of previous studies.2,3 Using the large

the index date and similar proportions of males and females. The control group had a lower proportion of smokers and a higher average total

“You select people who have a family history and/or who have certain laboratory tests or other information that confirms they’re at high risk of developing RA. And then, if they’re candidates for statins, assign them to high- versus low-dose statins and see if they have different outcomes.”

—Koray Tascilar, MD

Clinical Practice Research Datalink (formerly General Practice Research Database), they identified patients with RA and controls without RA, in a large population-based cohort of individuals who had been taking statins.

There were 1357 incident RA cases and 13,570 controls. The cases and controls had similar average ages at

cholesterol level at cohort entry. The researchers controlled for these differences in their analysis: they adjusted the hazard ratios for treatment compliance, baseline cholesterol level, smoking, obesity, history of cardiovascular disease, non-iatrogenic hypothyroidism, and history of other autoimmune diseases.

The overall incidence of RA was 7.9/10,000 patient-years, and the mean follow-up duration was 39 months.

The results revealed a dose-response relationship between increased statin intensity and adjusted hazard ratio (HR) in those who developed and did not develop RA. Based on a reference HR of 1.0 for the lowest statin-intensity quintile, patients taking the high-intensity statins had an adjusted HR of 0.77 (95% CI, 0.63-0.95).

For the third and fourth quintiles, the adjusted HR was 0.94, but the 95% CI for each crossed 1.00, rendering these results non–statistically significant.

There also was a non–statistically significant adjusted HR of 0.86 for the second quintile. —RF n References

1. Tascilar K, Dell’Aniello S, Hudson M, et al. Statins and risk of rheumatoid arthritis: a nested case-control study. Poster presented at: 2015 Canadian Rheumatology Association Annual Scientific Meeting; February 4-7, 2015; Quebec City, Quebec. Abstract 122.

2. Chodick G, Amital H, Shalem Y, et al. Persistence with statins and onset of rheumatoid arthritis: a population-based cohort study. PLoS Med. 2010;7(9):e1000336.

3. de Jong HJ, Klungel OH, van Dijk L, et al. Use of statins is associated with an increased risk of rheumatoid arthritis. Ann Rheum Dis. 2012;71(5):648-654.

TAKE ACTION: Get Your Rheumatology Center Profiled We are interested in interviewing medical directors from rheumatology centers around the country.

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ertain statins may have the potential to reduce people’s risk of developing rheumatoid arthritis (RA), according to a case-control analysis presented at the Canadian Rheumatology Association’s 2015 Annual Scientific Meeting.1 There was a nearly one-quarter reduction of incident RA with the “high-intensity statins”—rosuvastatin 5-40 mg, atorvastatin 20-80 mg, and simvastatin 80 mg. The investigators noted, though, that a randomized, controlled trial must be done to determine causation.

“The advantage of these results is you could use them to design such a trial,” Koray Tascilar, MD, a postdoctoral fellow, Lady David Research Institute, Montreal, told Value-Based Care in Rheumatology. “Then you select people who have a family history and/or who have certain laboratory tests or other information that confirms they’re at high risk of developing RA. And then, if they’re candidates for statins, assign them to high- versus low-dose statins and see if they have different outcomes.”

Tascilar, Marie Hudson, MD, a phy-

Contact Kristen Olafson at kolafson@the-lynx-group.com for more information.

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Conference Highlights

Women Diagnosed With Systemic Lupus Erythematosus at Younger Age Partially Protected From Some Cancers

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new analysis points to lower rates of breast, ovarian, and uterine cancers in patients with systemic lupus erythematosus (SLE) who were diagnosed before age 40 years compared with expected rates in the general population.1 This analysis, which was presented at the Canadian Rheumatology Association’s 2015 Annual Scientific Meeting, fits with earlier research that uncovered lower-than-expected rates of breast and endometrial cancers in women with SLE.2,3 “The new results also combine cohorts from across the world and represent the largest ever sample, so I feel the data are robust. But we do have [even more] updated data which will help us eventually produce even more precise results,” lead investigator Sasha Bernatsky, MD, PhD, Associate Professor, Department of Medicine, McGill University, Montreal, Quebec, told Value-Based Care in Rheumatology.

Bernatsky, working with medical student Hiromi Tissera, focused on 5406 women diagnosed with SLE be-

fore age 40 from a large multicenter study conducted in 6 countries. The study was the result of collaborations with a global network of physicians from the Systemic Lupus International Collaborating Clinics and elsewhere.

Among the 5406 patients in the new analysis, the average age at SLE diagnosis was 26.8 years and the average length of follow-up after SLE diagnosis via outpatient clinic appointments was 8 years, yielding a total of 44,073 patient-years of observation. To ascertain cancer cases, the team linked tumor-registry information to the study patients’ records. The team used standardized incidence ratios (SIRs), which indicate whether observed cancer rates are higher or lower than expected for the general population, given the study patients’ age distribution and other characteristics.

There were 29 cases of breast cancer among the SLE subjects compared with the expected 76. This yielded an SIR of 0.38—suggesting a much lower breast cancer risk in these women with SLE versus the age- and sex-

matched general population. The numbers of observed uterine and ovarian cancers were also lower in these SLE patients versus numbers expected in the general population.

Overall, the SIRs were statistically significant for breast and uterine cancers.

There was “more uncertainty for the ovarian cancer results, given that it is a relatively uncommon tumor; only one ovarian cancer was found in the SLE patients,” Bernatsky said.

The researchers did not have information on all patients’ use of nonsteroidal anti-inflammatory drugs, hormone replacement therapy, and immunosuppressive drugs, or age of menopause, and therefore they could not analyze the influence of these factors.

Bernatsky pointed to another poster she and colleagues presented at the Canadian Rheumatology Association meeting, in which they attempted to analyze what the optimal approach is for SLE-patient cancer screening.4 They did not find any original research comparing cancer-screening

strategies in people with SLE, but the existing literature offered several screening recommendations, most of which were in line with those for the general population.

“Despite what appears to be a protective effect of SLE for breast and possibly endometrial and ovarian malignancies, women with SLE should still undergo mammograms and all other cancer screening as recommended by general population guidelines,” concluded Bernatsky. —RF n References

1. Tissera H, Clarke A, Ramsey-Goldman R, et al.

Breast, ovarian and endometrial cancers in women diagnosed with SLE before age 40. Poster presented at: 2015 Canadian Rheumatology Association Annual Scientific Meeting; February 4-7, 2015; Quebec City, Quebec. Abstract 1.

2. Bernatsky S, Boivin JF, Joseph L, et al. An international cohort study of cancer in systemic lupus erythematosus. Arthritis Rheum. 2005;52(5):1481-1490.

3. Bernatsky S, Ramsey-Goldman R, Labrecque J, et al. Cancer risk in systemic lupus: an updated international multi-centre cohort study. J Autoimmun.

2013;42:130-135.

4. Tessier-Cloutier B, Clarke A, Pineau C, et al.

What investigations are needed to optimally monitor for malignancies in SLE? Poster presented at: 2015 Canadian Rheumatology Association Annual Scientific Meeting; February 4-7, 2015; Quebec City, Quebec. Abstract 31.

Rheumatoid Arthritis and the Risk of Diabetes

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new study confirms that people with rheumatoid arthritis (RA) have a higher risk of developing diabetes mellitus (DM) compared with the general population.1 In a poster presented at the Canadian Rheumatology Association’s 2015 Annual Meeting, researchers analyzed data from an administrative database in British Columbia, finding a 1.62 adjusted hazard ratio for RA in people with DM versus those without diabetes.

An earlier administrative-database analysis of patients in British Columbia by Daniel Solomon, MD, MPH, and colleagues from Brigham and Women’s Hospital, Boston, Massachusetts, showed an adjusted hazard ratio of 1.5 for diabetes among individuals with RA compared to those without rheumatic disease.2 Solomon’s team expanded that work in a subsequent study of the British Columbia cohort and a group of patients in the United States; they showed that

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DM risk is lowest in people who use tumor necrosis factor inhibitors compared to nonbiologic disease-modifying antirheumatic drugs, and that risk also is lowered, albeit to a lesser extent, by use of methotrexate or hydroxychloroquine.3 The new analysis reviewed all cases of RA in British Columbia identified between January 1996 and March 2006.

The investigators defined diabetes as at least 1 physician visit or hospitalization with a diagnostic code for DM and at least 1 medication for DM. They matched the RA cases 1:1 with people in the database who did not have RA. There were 26,013 people with RA and 25,823 controls, with a mean follow-up of 4.8 and 5.3 years, respectively. The mean age was approximately 58 years in each group, and the ratio of females to males was 2 to 1 in each group.

They determined that a total of 1513 RA patients developed diabetes, translating into an incidence of DM of

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8.63 per 1000 patient-years. Conversely, 1065 controls developed diabetes, for an incidence of 5.53 cases per 1000

“We show the estimate of risk of DM in RA is consistent with that reported in a Chinese meta-analysis and the incidence of DM in the general-population controls is similar to that reported in the BC population.”

—Timothy Schmidt patient-years. The researchers calculated the hazard ratio for diabetes was

1.62, after adjusting for age, sex, the Romano modification of the Charlson comorbidity index, and whether the RA onset was before or after 2001.

“We are updating the results. We show the estimate of risk of DM in RA is consistent with that reported in a Chinese meta-analysis4 and the incidence of DM in the general-population controls is similar to that reported in the BC population,” lead investigator Timothy Schmidt told Value-Based Care in Rheumatology. —RF n References

1. Schmidt TJ, Avina-Zubieta A, Sayre E, et al.

Incidence of diabetes mellitus in rheumatoid arthritis: a British Columbia population based cohort study.

Poster presented at: 2015 Canadian Rheumatology Association Annual Scientific Meeting; February 4-7, 2015; Quebec City, Quebec. Abstract 61.

2. Solomon DH, Love TJ, Canning C, et al. The risk of diabetes among patients with rheumatoid arthritis, psoriatic arthritis, and psoriasis. Ann Rheum Dis. 2010;69(12):2114-2117.

3. Solomon DH, Massarotti E, Garg R, et al. Association between disease-modifying antirheumatic drugs and diabetes risk in patients with rheumatoid arthritis and psoriasis. JAMA. 2011;305(24):2525-2531.

4. Jiang P, Li H, Li X. Diabetes mellitus risk factors in rheumatoid arthritis: a systematic review [published online December 22, 2014]. Clin Exp Rheumatol.

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Gout

Use of Colchicine Reviewed York. This includes providing the most appropriate starting dose and adjustments.

“Based on recent pharmacokinetic studies, colchicine use for acute gout is shown to be as effective at a dose of

Continued from page 1

as a number of antiretrovirals and azole antifungals. Of particular concern is coadministration of clarithromycin, owing to the relatively common use of that agent.”

Colchicine was approved by the US

“Colchicine dosing, whether acute or chronic, needs to be adjusted for renal function as well as the coadministration of moderate to strong CYP3A4 inhibitors and/or P-glycoprotein inhibitors...”

—Michael Pillinger, MD

1.2 mg followed by 0.6 mg 1 hour later, as compared to the previously used regimen of 0.6 mg hourly, but with side effects equivalent to [those associated with] placebo,” Pillinger told Value-Based Care in Rheumatology in summarizing one of the key messages from the article.

He also noted that “colchicine dosing, whether acute or chronic, needs to be adjusted for renal function as well as the coadministration of moderate to strong CYP3A4 inhibitors and/or P-glycoprotein inhibitors such

Food and Drug Administration (FDA) in 2009 for acute gout and Mediterranean fever, and is considered to be first-line treatment for those conditions as well as for the prophylaxis of gout. The agent also is used for patients with pseudogout, pericarditis, Behcet disease, and neutrophilic dermatoses. Moreover, the medication now has been shown in clinical trials to help prevent or treat some cardiovascular diseases, noted Pillinger and his coauthors.

Colchicine is largely metabolized

by CYP3A4 and P-glycoprotein in the liver. The pathways constitute the nexus of colchicine’s interactions with a number of other drugs, ranging from clarithromycin and fluoxetine to azole antifungals and nondihydropyridine calcium channel blockers, and from cyclosporine to a number of statins. Moreover, colchicine’s plasma concentration and hence toxicity risk increase significantly with age because of a reduction in total body clearance. For some older patients, starting with half the usual dose and titrating up as needed may be a reasonable strategy, according to Pillinger.

He and his colleagues note that the FDA originally included but later withdrew approval for intravenous colchicine because of the risk of lethal overdose—even at intravenous doses of 0.5 mg/kg, colchicine is very toxic.

The Acute Gout Flare Receiving Colchicine Evaluation (AGREE) trial indicated that 1.2 mg followed 1 hour later by 0.6 mg has similar efficacy and fewer adverse events compared with 1.2 mg followed by 0.6 mg every hour for 6 hours for a maximum of 4.8 mg.2 This led to the FDA’s approval of the lower dose for acute gout. The American College of Rheumatology echoes this recommendation.

In summary, colchicine is beneficial

for: • Prophylaxis and acute treatment of calcium pyrophosphate crystal arthritis (pseudogout) • Familial Mediterranean fever— “Doses as high as 1.8 mg daily in divided doses are recommended, and even when colchicines does not adequately control the attacks it usually prevents the development of amyloid renal disease,” said Pillinger • Several types of vasculitis including Behcet disease • Neutrophilic dermatoses • Pericarditis including initial attacks of acute pericarditis.

According to the review article, there also is some evidence that colchicine may prevent or be used to treat stable coronary artery disease, acute coronary syndromes, and postoperative atrial fibrillation.

“Ongoing research will further elucidate the mechanism of action and therapeutic utility of this historic medicine,” concluded Pillinger and his coauthors. n References

1. Slobodnick A, Shah B, Pillinger MH, et al. Colchicine: old and new [published online Dec 12, 2014]. Am J Med. 2. Terkeltaub RA, Furst DE, Bennett K, et al. High versus low dosing of oral colchicine for early acute gout flare: twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum. 2010;62(4):1060-1068

FDA Update

Secukinumab Approved for Psoriasis

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n January 21, 2015, the US Food and Drug Administration (FDA) approved secukinumab (Cosentyx; Novartis Pharmaceuticals Corporation) for the treatment of adults who have moderate to severe plaque psoriasis and who are candidates for systemic therapy and/or phototherapy. Plaque psoriasis is the most common form of psoriasis, often beginning in people between 15 and 35 years of age. Patients develop scales that are thick and red with flaky, silver-white patches.

Secukinumab is an antibody that

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binds to interleukin-17A (IL-17A), a protein that is involved in inflammation. Secukinumab prevents IL-17A from binding to its receptor, inhibiting its ability to trigger the inflammatory response that has a role in the development of plaque psoriasis.

Amy Egan, MD, MPH, deputy director of the Office of Drug Evaluation III in the Center for Drug Evaluation and Research, said in an FDA press release that “Plaque psoriasis can cause significant skin irritation and discomfort for patients, so it is important to have a variety of treatment options available to patients.”

The safety and effectiveness of secukinumab were evaluated in 4 clinical trials. A total of 2403 patients with plaque psoriasis participated in the trials—all participants were candidates for systemic therapy or phototherapy. The results of the trials showed that the patients who received secukinumab achieved a greater clinical response than the patients who were given placebo. Clinical response was assessed by scoring the extent, nature, and severity of psoriatic changes of the skin.

Secukinumab is administered as a subcutaneous injection.

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The most common adverse events associated with secukinumab include diarrhea and upper respiratory infections. The FDA approval indicated that the Medication Guide inform patients that secukinumab is a medication that affects the immune system, which may increase the risk of infections (in the clinical trials, there was a higher rate of infection in patients treated with secukinumab compared to those who were given placebo).

Information about secukinumab can be obtained from the FDA and from the company. n

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