Value-Based Care in Rheumatology - April 2015

APRIL 2015 VOL 4 • NO 2

www.ValueBasedRheumatology.com

PRESENTATIONS FROM THE 2015 ANNUAL MEETING OF THE NORTH CAROLINA RHEUMATOLOGY ASSOCIATION

Pulmonary Arterial Hypertension Can Be Dangerous

Comprehensive Total Joint Replacement Database Will Improve Patient Outcomes Alice Goodman

T

he most comprehensive database in the United States on total hip and knee joint replacements (TJRs) and outcomes establishes benchmarks for these surgeries and offers new insights into appropriateness criteria and timing of surgeries that will enable value-based care.

Called FORCE-TJR (Function and Outcomes Research for Comparative Effectiveness in Total Joint Replacement), the database is the culmination of a 4-year, $12-million project funded by the Agency for Healthcare Research and Quality.

“Total hip and knee joint replaceContinued on page 11

CLINICAL TRIALS

P

ulmonary arterial hypertension (PAH) can have dire consequences, especially in the context of certain connective tissue

diseases (CTDs). Thus, it is important to be alert for this condition, to diagnose it accurately, and to manage it properly. That being said, Continued on page 12

Tanezumab Redux Alice Goodman

P

atients with chronic painful osteoarthritis (OA) may have a new pain killer if phase 3 clinical trials turn out to be positive. The drug in question, called tanezumab, has had a checkered history. At first, several trials showed that it was remarkably

effective in people with OA, allowing them to resume activities they had not been able to participate in. Then adverse events were reported, including joint destruction and potential effects on the nervous system. Some experts, however, thought the increase in joint

Continued on page 11

Full Clinical Trial Data Sharing Moves Closer to Reality Rosemary Frei, MSc

A

January 14, 2015, report published by the Institute of Medicine (IOM)1 walks a fine line between the competing clinical data sharing comfort zones of pharmaceutical companies, physician associations, patient groups, and other advocacy organizations.

The 249-page report lays out 4 recommendations for increased clinical

trial data sharing. These include suggesting a maximum 18-month lag between study completion and sharing of all the data—with some exceptions for trials being used to support a regulatory application—and no more than 6 months between study publication and sharing of the analytic data set. The other recommendations are for clinical trial stakeholders to “foster

Continued on page 14

INSIDE VALUE PROPOSITIONS. . . . . . . 4 PSORIATIC ARTHRITIS . . . . . 15 Cost-effectiveness Analysis for Recognizing and Treating Psoriatic Leukopenia in Patients With Arthritis Granulomatosis With Polyangiitis IN THE NEWS . . . . . . . . . . . . . . 16 RHEUMATOID ARTHRITIS.. . 15 Pregabalin Fails to Help Adolescents Mortality High, But Relatively Steady, With Fibromyalgia in Patients With Rheumatoid Arthritis Versus General Population

© 2015 Engage Healthcare Communications, LLC

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 Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Publisher Joseph Beck jbeck@the-lynx-group.com Director, Client Services Zach Ceretelle zceretelle@the-lynx-group.com Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Managing Editor Kristen Olafson kolafson@the-lynx-group.com Copyeditor Rosemary Hansen Production Manager Marie RS Borrelli

VALUE PROPOSITIONS

PSORIATIC ARTHRITIS

Cost-effectiveness Analysis for Leukopenia in Patients With Granulomatosis With Polyangiitis Health IT in a Value-Based Care Environment Cost-effectiveness of Tocilizumab in Patients With Rheumatoid Arthritis Systemic Lupus Erythematosus and Glucocorticoid Drugs: Dosage, Healthcare Utilization, and Costs

Recognizing and Treating Psoriatic Arthritis

President/CEO Brian Tyburski

RHEUMATOID ARTHRITIS

Chief Operating Officer Pam Rattananont Ferris

Mortality High, But Relatively Steady, in Patients With Rheumatoid Arthritis Versus General Population

Vice President of Finance Andrea Kelly Human Resources Jennine Leale

IN THE NEWS Pregabalin Fails to Help Adolescents With Fibromyalgia Frequency of Radiological Procedures in Rheumatoid Arthritis Obesity Compromises Drug Response in Rheumatoid Arthritis Link Between Periodontal Disease and Rheumatoid Arthritis Acetaminophen More Risky Than Assumed

Director, Strategy & Program Development John Welz Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno

VBCR Editorial Advisory Board

Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs

Howard B. Blumstein, MD Rheumatology Associates of Long Island, Smithtown, NY

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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.

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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

Engage Healthcare Communications, LLC 1249 South River Road, Ste 202A Cranbury, NJ 08512 Telephone: 732-992-1880 Fax: 732-992-1881

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Shelly P. Kafka, MD Medical Director US Medical Affairs Horsham, PA

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.

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APRIL 2015

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Value Propositions Cost-effectiveness Analysis for Leukopenia in Patients With Granulomatosis With Polyangiitis

Granulomatosis with polyangiitis (GPA) is a rare disease characterized most often by inflammation of the small blood vessels of the respiratory system, although the kidneys and other organs may also be affected.

GPA is complex, and prompt diagnosis and treatment are necessary to avoid serious complications. Approximately 90% of patients with GPA respond to treatment with a combination of corticosteroids and cyclophosphamide (CYC). The use of CYC, however, is associated with several adverse effects, including leukopenia. Currently there is no standard recommendation for monitoring white blood cell count while patients with GPA are receiving CYC therapy.

Investigators at Cleveland Clinic’s Center for Vasculitis Care and Research conducted a study to compare the cost-effectiveness of weekly versus monthly complete blood count (CBC) monitoring for surveillance of leukopenia. To evaluate weekly monitoring, the researchers used the GPA database of patients treated at Cleveland Clinic between 1992 and 2004. For the monthly arm, data from published studies were used.

Weekly CBC monitoring yielded 0.22 quality-adjusted life-years gained, a measure that reflects both the quantity and quality of life lived, and incurred $489 less in cost per patient compared with monthly monitoring. The researchers concluded that weekly CBC monitoring is cost-effective for prevention of severe leukopenia and infections in patients receiving daily CYC for severe GPA. Khasnis A. Consult QD website.

March 4, 2015.

Health IT in a Value-Based Care Environment

The Office of the National Coordinator for Health IT was established in 2004 by executive action. In 2009, Congress authorized the Meaningful Use (MU) program, which offered financial incentives for adopting electronic health records (EHR) and other information technology (IT) tools.

Although adoption has progressed, there are many unresolved issues. In preparation for an event sponsored by the Engelberg Center for Health Care Reform that addressed health IT, scholars at the Brookings Institute summarized 4 key challenges faced by many healthcare professionals as they work in an environment that is increasingly concerned with value-based care.

The authors described these key challenges: • Uniformity of requirements: The uniform approach cannot always be applied given the diversity of medical specialties • Specific, process-driven measures: MU-certified commercial EHRs limit usability by focusing on designs that meet MU requirements instead of those that would meet users needs • Failure to prioritize access to accurate, actionable information related to coverage and payment: Current MU functions do not provide broad access to needed information; this lack may result in extra costs or treatments that are delayed or denied • Gaps in practical and effective interoperability: Health plans, insurance companies, and employers often require duplicate documentation because they do not accept information in the standard EHR interoperability formats. Refocusing on practical interoperability, including an emphasis on relevant payment-related information could improve usefulness A video of the Engelberg Center program Can Forces Align to Use Health IT to Improve Care and Lower Costs? is available online at www.brookings. edu/events/2015/03/04-health-it-value-based-payment-reform. Basch P, et al. Brookings website. March 3, 2015.

Cost-effectiveness of Tocilizumab in Patients With Rheumatoid Arthritis

In an earlier study, Tanaka and colleagues found that cost-effectiveness appears to favor tocilizumab (TCZ), a humanized anti-interleukin-6 receptor monoclonal antibody, in comparison with TNF inhibitors in patients with rheumatoid arthritis (RA). (Biologics; 2014). A more recent study was designed to evaluate the cost-effectiveness of TCZ versus

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APRIL 2015

methotrexate (MTX) in patients with RA. Researchers used a Markov model­–based probabilistic simulation and data from the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) observational cohort study to measure cost-effectiveness in a real-world setting in Japan. Data were derived from records of patients with RA who were registered in the IORRA cohort study between April 2007 and April 2011.

The TCZ group (n = 104) comprised patients who used at least 1 disease-modifying antirheumatic drug and in whom TCZ treatment was initiated; the MTX group (n = 104) comprised patients in whom MTX treatment was used either for the first time or after an interruption of at least 6 months. Based on a 6-month cycle, health benefits and costs were measured over a lifetime and discounted at an annual rate of 3%. TCZ treatment had lifetime costs and quality-adjusted life years (QALYs) that were higher than those of treatment with MTX. In the TCZ group, the lifetime cumulative costs and QALYs were ¥35.4 million [$297,691.63] and 11.7 years, respectively, and in the MTX group, they were ¥23.3 million [$195,938.27] and 9.3 years, respectively. The incremental cost per QALY gained was $49,359 with TCZ, slightly lower than the cost-effectiveness threshold of $50,000 per QALY. The probability of TCZ being cost-effective was 62.2%.

The authors concluded that the simulation model using real-world data from Japan showed that tocilizumab (at a certain price) may improve treatment cost-effectiveness in patients with moderate-to-severe RA by enhancing quality-adjusted life expectancy. Tanaka E. Mod Rheumatol. Published online: February 11, 2015.

Systemic Lupus Erythematosus and Glucocorticoid Drugs: Dosage, Healthcare Utilization, and Costs

Shih-Yin Chen, PhD, and her colleagues analyzed annual healthcare utilization and costs related to the use of glucocorticoid (GC) drugs among 5 cohorts of adult patients with systemic lupus erythematosus (SLE).

A US insurance claims database covering 2007-2011 was used to identify patients having SLE as determined by ICD-9-CM diagnosis codes. Data were organized among 5 cohorts based on patients’ use of oral GC drugs during a 1-year period: non-GC users; users for <60 days; and users for ≥60 days at average daily doses of ≤7.5 mg (low dose), >7.5 mg to 15 mg (medium dose), and >15 mg (higher dose).

Among the total of 50,230 SLE patients, 52% were non-GC users; 20% used GC for <60 days; and the low-dose, medium-dose, and high-dose cohorts comprised 10%, 10%, and 8%, respectively. Incremental costs were estimated from multivariable regressions adjusting for demographic and clinical characteristics and stratified by concomitant immunosuppressant use and were calculated as the difference in total healthcare costs for the GC groups compared with those of the non-GC group.

The authors found that GC users had higher healthcare utilization than nonusers (P < .05); among those with ≥60 days of GC use, a dose-response relationship was observed. For example, the percentage of patients with inpatient stays more than doubled from low-dose users to higher-dose users (18.2% to 42.7%). GC users also incurred higher costs.

Regardless of concomitant immunosuppressant use, incremental costs were significant (all P < .01): at the medium dose, $6913 with immunosuppressant use, and $5319 without; at the higher dose, $15,019 with immunosuppressant, and $12,517 without. For the lowdose GC group using concomitant immunosuppressants costs were $1285 (P = .04); without concomitant immunosuppressants costs were $2514 (P < .01).

In addition to finding that GC use, especially at higher doses, was associated with higher healthcare utilization and costs, the authors concluded that data regarding the use of concomitant immunosuppressants suggest that therapies with GC-sparing effect may be associated with lower economic burden in SLE treatment. Chen SY, et al. Arthritis Care Res (Hoboken). Published online: March 2, 2015.

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

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

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

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

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

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

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

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

®

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

Contact a rep at ActemraHCP.com for more information

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

80

P<0.001

70

ACTEMRA MONOTHERAPY: RAPID RESPONSE AT WEEK 2

Patients (%)

60

53 40

20

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

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

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

0 BL

2

4

8

12

16

20

24

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

Time (weeks)

MTX=methotrexate.

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

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

Select Important Safety Information

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

Patients (%)

80

P=0.002

60

44 %

40

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

Please see full Prescribing Information for more information.

P<0.001

34 %

28 % 15 %

20 0 ACR50

ACR70

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

Patients (%)

80

60

40

Primary endpoint not met Non-significant P=0.19

40 %

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

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

35 %

20

0 DAS28 <2.6 DAS=disease activity score.

速

Indication

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

Important Safety Information

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

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

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

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

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

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

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

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

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

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

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

ADVERSE REACTIONS

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

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

7

5

6

8

6

Nasopharyngitis

7

6

4

6

4

Headache

7

2

6

5

3

Hypertension

6

2

4

4

3

Increased ALT

6

4

3

3

1

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

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

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

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

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

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

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

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

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

Poster THU0093.

®

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

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

WARNING: RISK OF SERIOUS INFECTIONS

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

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

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

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

The risks and benefits of treatment with ACTEMRA should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with ACTEMRA, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy [see Warnings and Precautions].

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

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

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

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

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

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

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

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

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

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

Patients at or above 100 kg weight

162 mg administered subcutaneously every week

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

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

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

WARNINGS AND PRECAUTIONS

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

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

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

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

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

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

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

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

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

Gastrointestinal Perforations

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

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

Laboratory Parameters

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Methotrexate

ACTEMRA 4 mg per kg + DMARDs

ACTEMRA 8 mg per kg + DMARDs

Placebo +

N = 288 (%)

N = 284 (%)

N = 774 (%)

N = 1582 (%)

N = 1170 (%)

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

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

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

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

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

Elevated lipids responded to lipid lowering agents.

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

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

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

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

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

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

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

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

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

ACTEMRA 8 mg per kg Monotherapy

Methotrexate

ACTEMRA 4 mg per kg + DMARDs

ACTEMRA 8 mg per kg + DMARDs

Placebo +

N = 288 (%)

N = 284 (%)

N = 774 (%)

N = 1582 (%)

N = 1170 (%)

7

5

6

8

6

7 7 6 6 3 3 2 2 2 1 1

6 2 2 4 1 2 1 2 2 2 5

4 6 4 3 2 4 4 1 3 1 2

6 5 4 3 3 3 3 3 3 2 2

4 3 3 1 2 3 1 1 2 1 1

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

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

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

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

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

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

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

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

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

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

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

DRUG INTERACTIONS

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

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

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

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

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

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

USE IN SPECIFIC POPULATIONS

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

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

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

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

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

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

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

Pediatric Use ACTEMRA by intravenous use is indicated for the treatment of pediatric patients with: • Active systemic juvenile idiopathic arthritis in patients 2 years of age and older • Active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older Safety and effectiveness of ACTEMRA in pediatric patients with conditions other than PJIA or SJIA have not been established.

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

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

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

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

OVERDOSAGE

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

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

Patients who develop adverse reactions should receive appropriate symptomatic treatment.

PATIENT COUNSELING INFORMATION

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

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

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

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

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

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

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

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

Health Economics

Comprehensive Total Joint Replacement Database… ments are…the greatest expense of the Medicare budget. The FORCE database is the first to allow independent assessment of total joint replacement effectiveness in terms of both implant performance and improvement in patient pain and physical function,” stated FORCE-TJR steering member Joan A. McGowan, PhD, in a news release dated March 23, 2015. McGowan is the director of the Division of Musculoskeletal Diseases at the NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Research findings from the database, presented at the 2015 American Academy of Orthopedic Surgery meeting in March, include the following: • Optimal timing for joint replacement can now be determined by comparing patient pain and disability scores with national benchmarks. The database shows “remarkable consistency in the level of pain and disability among TJR patients—but timing is important

and waiting too long or having surgery too early may not achieve the highest level of improvement post surgery.”

• Risk factors are accounted for so that surgeons can use the database’s risk-adjustment methods to compare their patients to national

musculoskeletal risk factors, such as multiple painful joints or low back pain, than does the Medicare population. Fortunately, these younger patients can enjoy comparable levels of pain relief from TJR and functional outcomes that can improve quality of life.

“The combination of these outcome data plus costs can be instrumental for informing value-based purchasing analysis and decisions.”

—Catherine MacLean, MD, PhD

data and adjust patient selection criteria for optimal outcomes and patient care.

• More than 40% of all TJR patients are under the age of 65, and this is the fastest-growing population for these procedures. For the first time, FORCE-TJR shows that patients under the age of 65 have more

The cohort for the database included more than 30,000 diverse TJR patients treated by a consortium of US surgeons from representative practices. FORCE-TJR includes traditional collection of data on implant-device failure and repeat surgeries, and in addition, it is the first TJR database that includes patient-reported out-

Continued from page 1

comes on measures of pain and function pre- and postsurgery, as well as readmission and infection rates, adverse events, clinical comorbidities, and other patient risk factors and demographics that may influence outcomes.

“The combination of these outcome data plus costs can be instrumental for informing value-based purchasing analysis and decisions,” stated Catherine MacLean, MD, PhD, in the news release. MacLean is with HealthCare Value Solutions and is the former staff vice president of Clinical Quality, Anthem Inc. FORCE-TJR plans to expand the enrollment of surgeons and hospitals in the database. The database not only allows access to national TJR benchmarks, but also provides real-time patient reported outcome scoring and comparative feedback from practices that will improve patient care, meet reporting requirements, allow comparison of performance among peers and institutions, and secure quality incentive payments. n

FDA Update

destruction was due to the patients’ feeling so good while taking tanezu­ mab that they were dancing and playing sports that further degraded the joints.

Beginning in 2010, the US Food and Drug Administration (FDA) halted various clinical trials of tanezumab and other drugs in its class—nerve growth factor (NGF) protein receptor blockers.

Continued from page 1

Although trials in OA were halted, trials of tanezumab and other NGF receptor blockers continued for terminal cancer pain.

On March 24, 2015, it was announced that the FDA was lifting the ban on tanezumab studies in OA after a review of nonclinical data characterizing the sympathetic nervous system response to tanezumab. Now that the

ban has been lifted, late-stage clinical trials in OA will continue.

Nearly 20% of the US population has chronic pain, and safe and effective treatment of the condition is an unmet need. NSAIDs are commonly used to mask pain but are associated with a constellation of side effects. Tanezu­ mab, a monoclonal antibody that blocks the NGF protein, represents a novel ap-

proach to chronic pain. It is estimated that the FDA approval of tanezumab would lead to sales of $100 million in the year 2020 (Cowen and Company estimate). If the drug is approved for other pain conditions, including terminal cancer pain and diabetic neuropathy, sales could be even higher.

Tanezumab is being co-developed

by Pfizer, Inc, and Eli Lilly. n

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

It is an easy process—a short phone interview and submit some photos of your center and staff.

VBCR_TakeAction22415

Tanezumab Redux

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

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Meeting Presentations

Pulmonary Arterial Hypertension…

Continued from page 1

Alice Goodman pulmonary hypertension occurring in patients with CTD is often multifactorial and difficult to manage.

At the 2015 annual meeting of the North Carolina Rheumatology Association, H. James Ford, MD, Director of the Pulmonary Hypertension Program at the University of North Carolina in Chapel Hill, reviewed the state of knowledge regarding the epidemiology, diagnosis, and management of PAH in the context of CTD, focusing on systemic sclerosis.

PAH, either idiopathic or familial, accounts for 1 to 2 cases per million per year worldwide. Anywhere from 8% to 18% of patients with systemic sclerosis and at least 5% of patients with systemic lupus develop PAH; PAH rarely occurs in patients with rheumatoid arthritis, dermatomyositis, or polymyositis.

When PAH occurs in patients with systemic sclerosis, systemic lupus, and other CTDs, the prognosis for survival is poor. “Patients with systemic sclerosis and PAH have worse outcomes and higher mortality rates in general than patients with other forms of PAH,” Ford explained.

“Evaluation and treatment of CTD-associated PAH is best done at a pulmonary hypertension referral center. Annual screening echocardiography is generally recommended for patients with scleroderma, even in the absence of cardiopulmonary

for pulmonary hypertension as well as pulmonary capillary wedge pressure ≤15 mm Hg (or left ventricular end diastolic pressure ≤15 mm Hg); pulmonary vascular resistance ≥3 Wood Units; and transpulmonary gradient (normal ≤12 mm Hg).

When PAH occurs in patients with systemic sclerosis, systemic lupus, and other CTDs, the prognosis for survival is poor.

symptoms,” he said.

Ford gave the following definitions of pulmonary hypertension and PAH. Pulmonary hypertension is a general term that describes elevated pressure in the pulmonary vascular bed, not describing the location of the lesion; the criterion for diagnosis is mean pulmonary artery pressure ≥25 mm Hg as measured by right heart catheterization. PAH, on the other hand, refers to elevated pressure in the pulmonary vasculature due to disease limited to the arteries/arterioles; diagnosis includes the criterion

Because PAH leads to progressive increase in pulmonary vasculature resistance and ultimately to right heart failure and death, it should be taken very seriously, Ford continued.

The World Health Organization (WHO) classification system groups forms of pulmonary hypertension together based on similarities in pathophysiology and response to treatment. This system was most recently updated in 2013, with 5 main groups of pulmonary hypertension—WHO 1 through WHO 5.

The differential diagnosis of PAH

is important in CTD, as there is overlap among at least 5 different entities: PAH, interstitial lung disease, pulmonary veno-occlusive disorder, myocardial involvement and systolic/diastolic dysfunction, and chronic thromboembolic disease (including antiphospholipid disease).

The US Food and Drug Administration has approved the following therapies for PAH: 7 oral drugs (bosentan, ambrisentan, macitentan, sildenafil, tadalafil, riociguat, and oral treprostinil); 2 parenteral therapies (epoprostenol, treprostinil); and 2 inhaled therapies (iloprost, treprostinil).

The rheumatologist who manages patients with systemic sclerosis and scleroderma relies on input from pulmonary function tests, echocardiography, and the catheterization lab, and ideally treatment of PAH is coordinated by the rheumatologist and the PAH treatment center.

“PAH is a niche subspecialty that usually requires referral to and comanagement with an academic or tertiary care center meeting specific criteria,” Ford noted. n

Be Alert for Hepatitis B Virus Reactivation Alice Goodman

H

epatitis B virus (HBV) reactivation is a serious and potentially lethal complication of HBV infection, and the risk is increased in patients on immunosuppressive therapy, especially anti– tumor necrosis factor (TNF) inhibitors or TNF-like antirheumatic drugs used by patients with rheumatoid arthritis (RA) and other rheumatic diseases.

This syndrome, which can occur in patients with active as well as “resolved” HBV infection, is largely preventable. Unfortunately many physicians who regularly prescribe immunosuppressive drugs are not aware of the potential for HBV reactivation.

At the 2015 annual meeting of the North Carolina Rheumatology Association, Leonard Calabrese, MD, updated attendees about HBV infection and how best to manage patients with rheumatologic disease coinfected with HBV. Calabrese is Professor of Medi-

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cine at the Cleveland Clinic Lerner College of Medicine, and R. J. Fasenmyer Chair of Clinical Immunology, Department of Rheumatic and Immunologic Disease, Cleveland Clinic, Ohio.

which can include arthralgia, arthritis, arthritis dermatitis, polyarteritis nodosa, and, less commonly, nephropathy and aplastic anemia, occur in less than 1% of HBV-infected patients.

Reactivation of HBV following immu-

Unfortunately many physicians who regularly prescribe immunosuppressive drugs are not aware of the potential for HBV reactivation.

Chronic HBV accounts for 1.25 million cases in the United States. “HBV is de-emerging as a cause of rheumatic disease, while HCV [hepatitis C virus] is increasing,” noted Calabrese.

“However, major changes in epidemiology and drug therapy make HBV reactivation a major concern.”

Extrahepatic complications of HBV,

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nosuppressive therapy is a far more worrisome complication.

“HBV reactivation can lead to severe/fatal hepatitis. This is well reported to occur in rheumatoid arthritis and other conditions with conventional or biologic therapy,” Calabrese stated.

Definitions are important: HBV re-

activation refers to abrupt, marked increases in HBV replication (HBVDNA levels), usually accompanied by elevations in serum aminotransferase levels. Reverse seroconversion refers to reappearance of hepatitis B surface antigen (HBsAg) in a person who was HBsAg negative, hepatitis B core antibody (anti-HBc) positive. Recovered hepatitis B refers to seropositivity for anti-HBc without detectable HBsAg, with or without hepatitis B surface antibody (anti-HBs). Current HBV infection refers to seropositivity for HBsAg. Drugs associated with HBV reactivation include corticosteroids, conventional chemotherapy, and injectable or infused biologic therapy (eg, anti-CD20, anti-TNF, abatacept, tocilizumab, and tofacitinib).

As HBV reactivation emerges as a major concern, various medical societies are developing guidelines. The American College of Rheumatology Continued on page 13

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Meeting Presentations

Neurological Complications of Sjögren Syndrome and Systemic Lupus Erythematosus Alice Goodman

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eurological complications of Sjögren syndrome and systemic lupus erythematosus (SLE) require a standardized diagnostic approach. Because these complications are a spectrum of both peripheral nervous system and central nervous system (CNS) manifestations, a broad differential diagnosis is necessary, explained Julius Birnbaum, MD, Associate Director of the Johns Hopkins Jerome L. Greene Sjögren’s Syndrome Center in Baltimore, Maryland.

Birnbaum reviewed the approach to these complications at the 2015 annual meeting of the North Carolina Rheumatology Association.

The “VITAMINS” mnemonic encapsulates various competing comorbidities to consider when trying to diagnose neurologic entities associated with Sjögren syndrome or SLE (Table).

“Many of the peripheral neurological complications traditionally listed in the classification criteria are sufficiently rare and should be regarded as the manifestation of a distinct and coincidental autoimmune disease,” Birnbaum told listeners.

A wide spectrum of peripheral neuropathies (PN) will occur in approximately 1% to 10% of patients with Sjögren syndrome or SLE; in SLE, approximately 40% of PN will be attributable to non-SLE causes, Birnbaum stated. By contrast, most neuropathies occurring in patients with Sjögren syndrome will be attributable to the underlying disease itself.

There are some distinctions between axonal polyneuropathies and mononeuritis multiplex occurring in these patient populations. Axonal polyneuropathies are associated with lower disease activity in both Sjögren syndrome and SLE, while mononeuritis multiplex is associated with higher disease activity. In Sjögren syndrome but not SLE, mononeuritis multiplex is associated with cryoglobulinemia (type II/III), antirheumatoid factor, and low complement 4 levels. Immunosuppressive therapy should be used to treat mononeuritis, and therapy for axonal polyneuropathies should be selected according to the background of disease activity.

Small-fiber sensory neuropathies (SFSNs) are underrecognized in both Sjögren syndrome and SLE, Birnbaum continued. SFSN (often described as burning pain) can occur even with normal results from electrodiagnostic

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studies. Therefore, further diagnostic techniques, such as punch skin biopsy, may be required. Skin biopsy studies suggest that SFSNs are as frequent as axonal neuropathies in both SLE and Sjögren syndrome.

Neuropsychiatric Manifestations Neuropsychiatric manifestations in patients with SLE can include cerebrovascular disease (5%-15%), seizures (5%-20%), cognitive impairment (up to 80%; may be present at diagnosis in 60%), and, more rarely, psychosis (5%); cognitive impairment is also documented in patients with Sjögren syndrome.

The VITAMINS mnemonic can exclude infections and other non-SLE causes of cerebrovascular disease and seizures. Small-vessel lacunar strokes occur more frequently than embolic strokes and hemorrhagic strokes. For embolic strokes, consider LiebmanSacks endocarditis, Birnbaum said.

Stringent control of “modifiable” risk factors for cerebrovascular disease is recommended. Lupus anticoagulation is more strongly associated with increased risk of thrombotic events compared with anticardiolipin or β2-glycoproteins.

If seizures occur less than 2 years into SLE, they may be associated with high extraneurological SLE disease activity, the eradication of which does not usually require prolonged antiepileptic therapy. However, seizures occurring at a later time are more likely to be associated with SLE damage, are less likely to remit, and may require ongoing antiepileptic therapy.

“Cognitive impairment in SLE patients is not a neurodegenerative disease,” Birnbaum emphasized. It is not associated with SLE disease activity, and it improves over time. “Therefore, SLE patients should be assured that they don’t have progressive dementia.

Screen for other etiologies of cognitive impairment, including depression, pain, and hypothyroidism. Depression is the most strongly associated covariate, and may emerge as a modifiable risk factor.”

If psychosis occurs, be vigilant in considering syndromes included in VITAMINS. It can be unclear whether the psychosis is due to high SLE activity or to high-dose corticosteroids used to treat SLE activity. Once extraneurological SLE activity is suppressed, it may be necessary to empir-

Table

VITAMINS Mnemonic

V — Vascular: systemic vasculitides I — Infection: HIV, hepatitis C T — Traumatic: no A — Autoimmune/inflammatory disorders: celiac disease, sarcoidosis, other rheumatic syndrome (frequently unknown) M — Metabolic disorders: diabetes and impaired glucose tolerance (need to order a 2-hour glucose tolerance test!), vitamin B12 deficiency, hypothyroidism I — Inflammatory disorders: amyloidosis, paraproteinemias, cryoglobulinemia N — Neoplastic disorders: paraneoplastic disorders S — Structural “mimics”: syringomyelia, myeloradiculopathies ically lower the dose of prednisone and see whether that has a beneficial effect, he suggested.

Demyelinating Syndromes or Multiple Sclerosis?

It is important to distinguish between CNS manifestations of Sjögren syndrome and multiple sclerosis (MS), Birnbaum continued.

“A take-home point is that most demyelinating syndromes in these patients can be clinically and radiographically distinguished from MS,” he stated.

The differential diagnosis of brain lesions in a patient with Sjögren syndrome with sensory symptoms intermittently affecting the face and extremities might include vasculitis, Lyme disease, antiphospholipid syndrome, migraine, and demyelinating disease.

Diagnostic tests should include a spi-

nal tap, MRI, spinal cord MRI, and visual evoked potential testing. Also the bathtub test is important.

Birnbaum emphasized that if the bathtub testing suggests a demyelinating syndrome, clinical correlates are necessary to make the diagnosis (ie, optic neuritis? myelitis? brainstem syndrome? cerebellar syndrome?).

“First, perform the clinical correlates to determine if there is clinical evidence of a demyelinating disease.

Second, review with a radiologist whether brain lesions satisfy the Barkhoff criteria, which are highly specific for MS versus other CNS disease and can serve as a surrogate marker for multifocal CNS dissemination,” he said. “In Sjögren syndrome, most cases of optic neuritis or myelitis will have features more consistent with neuromyelitis optica than with MS.” n

Be Alert for…

(ACR) 2012 Guidelines recommend screening high-risk patients for HBV before they receive methotrexate or leflunomide in order to mitigate the risk of HBV reactivation; testing for HBsAg is also recommended.

“All patients with a past history of HBV are at some finite risk of reactivation, regardless of presence or absence of serologic markers. The highest risk is among those with chronic HBV infection who are HBsAg positive and have high HBV-DNA viral load,” Calabrese said.

A reasonable strategy in HBV-infected patients requiring immunosuppression is to screen high-risk

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patients and to screen all patients going on immunosuppressive therapy for HBV infection, testing for the following: HBsAg, anti-HBc, and anti-HBs. Calabrese recommended following up by testing the HBV-DNA viral load in all positive cases.

He also advised preemptive therapy in all patients who are HBsAg positive and HBV-DNA positive, and careful monitoring in all isolated anti-HBc with drugs and a higher barrier to resistance. All patients who are candidates for antiviral therapy should be referred to hepatology experts, he added. n

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Clinical Trials

Full Clinical Trial Data Sharing Moves Closer… a culture in which data sharing is the expected norm,” to “mitigate the risks and enhance the benefits of sharing sensitive clinical trial data,” and to create a framework for addressing all the challenges associated with data sharing.

“While individual stakeholders can take steps to foster clinical trial data sharing, a broad range of stakeholders must act together to build an ecosystem in which responsible data sharing is expected, flourishes and continuously improves,” concluded report-committee chair Bernard Lo, MD, of the Greenwall Foundation, New York, in a summary of the report published in JAMA.2 Value-Based Care in Rheumatology contacted Richard L. Schilsky, MD, Chief Medical Officer of the American Society of Clinical Oncology (ASCO), for his view of the report. He said it responds to all of the concerns ASCO president Clifford Hudis, MD, expressed in a March 2014 comment to the report committee.3 “ASCO has long recognized that increasing the availability of clinical trial data is in the public interest. We encouraged the committee to recommend harmonizing international rules on data sharing and ensuring that the framework developed is broadly applicable to all clinical trials,” said Schilsky in an email. “We support the report’s recommendations and urge

the report’s sponsors to swiftly convene a group to begin developing the infrastructure and policies that will foster responsible data sharing.”

However, members of a group called AllTrials point out on their website4 that—other than the suggested timeframes for sharing data from trials that have been completed and/

reported, without exceptions.

GlaxoSmithKline (GSK) officials agreed to do so 2 years ago,5 and they have been true to their word. No other pharmaceutical companies have followed in GSK’s footsteps, although Johnson & Johnson last year gave data from all of its drug trials to Yale University researchers.6 Most

“The IOM report is a huge step forward for medicine….Their affirming of the value of trial registration and data sharing is a recognition that the historical moment has changed—that transparency is the new intellectual currency.”

—Trevor Butterworth

or published—there are no other hard timelines, actionable steps, or proposed penalties for noncompliance laid out by the report’s authors, which include the editor-in-chief of the New England Journal of Medicine and the chief medical officer of Johnson & Johnson.

The goal of AllTrials is to have all past and present clinical trials by both industry and nonindustry researchers registered and to have their full methods and summary results

companies are opting instead to comply with the much more lax data sharing regulations from the European Federation of Pharmaceutical Industry Associations (EFPIA) and the Pharmaceutical Research and Manufacturers of America (PhMRA).

The leaders of AllTrials know, however, that poking giants can be tricky, and hence they are opting for a softer sell.

“The IOM report is a huge step forward for medicine. And one has to

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accept that institutional change is often slow,” said Trevor Butterworth, in a conversation with Value-Based Care in Rheumatology. Butterworth heads Sense About Science USA, which is championing the AllTrials initiative in the United States. “Their affirming of the value of trial registration and data sharing is a recognition that the historical moment has changed—that transparency is the new intellectual currency. And the goal of AllTrials is to persuade all pharma companies to do what GSK did.” n References

1. Institute of Medicine (IOM) Committee on Strategies for Responsible Sharing of Clinical Trial Data. IOM website. www.iom.edu/Reports/2015/SharingClinical-Trial-Data.aspx. Published January 14, 2015.

Accessed February 2, 2015.

2. Lo B. Sharing clinical trial data: maximizing benefits, minimizing risk. JAMA. 2015;313(8):793-794.

3. ASCO comments on IOM discussion framework for clinical trial data sharing. American Society of Clinical Oncology (ASCO). www.asco.org/ascocomments-iom-discussion-framework-clinical-trialdata-sharing. Published March 26, 2014. Accessed February 2, 2015.

4. America’s Institute of Medicine says sharing data from clinical trials should “become the norm.”

AllTrials. www.alltrials.net/news/americas-insti tute-of-medicine-says-sharing-data-from-clinical-tri als-should-become-the-norm/. Published January 14, 2015. Accessed February 2, 2015.

5. GSK announces support for AllTrials campaign for clinical data transparency [news release]. London, UK. GlaxoSmithKline plc; February 2013. www.gsk.com/ en-gb/media/press-releases/2013/gsk-announc es-support-for-alltrials-campaign-for-clinical-da ta-transparency/. Accessed February 2, 2015.

6. Johnson & Johnson gives clinical trial data to researchers: a “game changer.” AllTrials. www.alltri als.net/news/johnson-johnson-gives-clinical-trial-da ta-to-researchers-a-game-changer/. Published January 30, 2014. Accessed February 2, 2015.

READER POLL

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VBCR_ReaderPoll_225915

DO YOU TALK TO PATIENTS ABOUT THE POSSIBILITY OF PARTICIPATING IN A CLINICAL TRIAL?

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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Rheumatoid Arthritis

Mortality High, But Relatively Steady, in Patients With Rheumatoid Arthritis Versus General Population Rosemary Frei, MSc

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n Ontario, Canada, study has estimated that standardized mortality rates are 41% to 51% higher in people with rheumatoid arthritis (RA) than in the general population, although the rates have been declining since 1997.1 In 1996-1997 the standardized mortality rate (SMR) among Ontario residents aged 15 years and older who had RA was 1.51, compared with those without RA. The rates were 1.50 in 2000-2001, 1.43 in 2004-2005, and 1.41 in 2008-2009; the decrease over time is not statistically significant.

“The excess mortality rate in people with RA, compared to the general population, did not significantly fall over time—survival has improved in both RA patients and the general population,” investigator Jessica Widdifield, PhD, a postdoctoral fellow at the Institute for Clinical Evaluative Sciences, Toronto, and McGill University, Montreal, said in an email to Value-Based Care in Rheumatology when queried about the mortality decline.

In an accompanying editorial, Theodore Pincus, MD, of Rush University School of Medicine, Chicago, Illinois, and 2 other experts praised the study and said that mortality is usually overlooked in rheumatology.2 They

hypothesized that payers may be more willing to reimburse providers for use of expensive rheumatology medications if the medications are shown not only to reduce patients’ symptoms and improve quality of life, but also to reduce mortality.

emailed response. “The big problem is matching need and implementation through appropriate measurement— most rheumatologists practice by intuition rather than measurement— that’s not awful, but leaves many interventions poorly managed.”

“The excess mortality rate in people with RA, compared to the general population, did not significantly fall over time— survival has improved in both RA patients and the general population.”

—Jessica Widdifield, PhD

When asked by Value-Based Care in Rheumatology whether this means that he believes biologics should be used earlier and more aggressively in people with severe RA, Pincus responded with a qualified “yes.”

“Of course biologics should be used earlier and more aggressively in patients with severe RA. But many patients who are treated with biologics donʼt need them,” noted Pincus in an

The increased rate of mortality among people with RA has been studied for many years, but there is a paucity of proof as to whether this mortality gap is closing or widening. That is why Widdifield and her colleagues studied the records from health administrative databases comprising people covered by the Ontario Health Insurance Plan and in the Ontario RA administrative database (ORAD).

They found that the proportion of people aged 15 years and older who have RA increased from 0.53% to 0.84% from 1996 to 2009. Age- and sex-standardized mortality rates among the RA population were 13/1000 people in 1996 and 9.2/1000 people in 2009. The respective rates for members of the non-RA population were 8.7/1000 and 6.0/1000.

The overall mortality rates decreased from 1996 to 2009, although the excess mortality rates (ie, SMRs) were consistently higher among females than males. When the researchers used a regression model that adjusted for changes in mortality within the overall population, they found no significant reduction in SMRs among people with RA over time. They also calculated relative excess mortality over time in RA versus non-RA individuals, in the form of mortality rate ratios and found that the mortality gap has not improved over time. n References

1. Widdifield J, Bernatsky S, Paterson JM, et al. Trends in excess mortality among patients with rheumatoid arthritis in Ontario, Canada [published online January 26, 2015]. Arthritis Care Res (Hoboken).

2. Pincus T, Gibson KA, Block JA. Mortality—the neglected outcome in rheumatic diseases? [editorial] [published online January 26, 2015]. Arthritis Care Res (Hoboken).

Psoriatic Arthritis

Recognizing and Treating Psoriatic Arthritis Alice Goodman

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he diagnosis and management of psoriatic arthritis (PsA) can be challenging. It is important to make the right diagnosis and to start treating PsA early to optimize outcomes and to reduce the social and economic burden of this disease.

“Early diagnosis and treatment [of PsA] are associated with increased chance of remission. Early sustained remission improves long-term function, health-related quality of life, work productivity, and reductions in healthcare utilization,” stated Neil Birnbaum, MD, Director, Division of Rheumatology, California Pacific

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Medical Center, and Clinical Professor of Medicine at University of California San Francisco.

Care Pharmacy.1 The symposium content was developed by Impact Education LLC.

PsA affects an estimated 750,000 people in the United States. It usually appears about 5 to 12 years after the onset of psoriasis.

Birnbaum spoke at a satellite symposium held during the 27th Annual Meeting of the Academy of Managed

PsA is a complex and disabling disease with diverse clinical presentations that can include the hands, feet, APRIL 2015

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and other joints, as well as associated psoriasis skin plaques. The disease is characterized by stiffness, pain, swelling, and tenderness of the joints and surrounding ligaments and tendons.

As distinct from rheumatoid arthritis (RA), osteoarthritis, and ankylosing spondylitis, patients with PsA typically have enthesitis, nail lesions, and psoriasis. Unlike RA, PsA is not associated with high-titer rheumatoid factor (RF), Birnbaum explained.

PsA affects an estimated 750,000 people in the United States. It usually appears about 5 to 12 years after the onset of psoriasis. The onset of PsA is Continued on page 16

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In the News Pregabalin Fails to Help Adolescents With Fibromyalgia Pregabalin (Lyrica Capsules CV; Pfizer) did not improve pain associated with fibromyalgia in adolescents aged 12 to 17 years, according to results of a phase 4 double-blind, placebo-controlled, Pfizer-sponsored, postmarketing study reported recently.

Pregabalin capsules were not significantly better than placebo in improving mean pain score.

A news release from Pfizer states that this is the first large pharmacological treatment study to be completed in this population. The study results suggest that pregabalin capsules are not a good choice for this group of patients. Pfizer conducted the study to meet US Food and Drug Administration (FDA) requirements after pregabalin was approved for fibromyalgia. Pregabalin has been FDA approved for the treatment of fibromyalgia in adults since 2007, and it has been widely used for that condition. The drug is also approved for various indications in 139 countries and regions of the world. However, a review of anecdotal experiences on the internet from patients with fibromyalgia treated with pregabalin suggests that pain relief is not universal and some patients have uncomfortable side effects.

The phase 4 trial enrolled 107 adolescents with fibromyalgia drawn from multiple centers in the United

States, Europe, and Asia. Patients were randomized to receive pregabalin capsules or placebo treatment for 15 weeks. Study medication was administered twice a day. Dosing of pregabalin was initiated at 75 mg/day and optimized over a 3-week period, adjusting for tolerability and response, to one of the following levels: 75 mg/ day, 150 mg/day, or 300 mg/day, with the best effective dose maintained for the next 12 weeks.

The treatment effect of pregabalin capsules on the mean pain score was not significantly different from that of placebo. The difference of 0.66 points represents an improvement of 1.60 points from baseline for pregabalin compared with 0.94 points for placebo (P=.121). The safety of pregabalin capsules in the adolescent population was mainly consistent with the known profile of pregabalin in adults, with the exception of nausea, which occurred more frequently in the pregabalin-treated group. The most common drug-related adverse events with pregabalin capsules were dizziness, nausea, headache, increased weight, and fatigue. Other commonly reported adverse events include constipation, euphoric mood balance disorder, increased appetite, and thinking abnormally. Pfizer press release: www. pfizer.com/news/press-release/ press-release-detail/pfizer_reports_top _line_results_from_a_phase_4_ study_evaluating_lyrica_capsules_

cv_as_a_treatment_for_adolescents_ with_fibromyalgia.

Frequency of Radiological Procedures in Rheumatoid Arthritis Although patients with rheumatoid arthritis (RA) undergo radiological evaluations, the actual use of radiological imaging in RA has not been adequately reported. A population-based study evaluated the use of radiological procedures in patients with RA compared with patients without RA. Study results indicate that radiological procedures are performed more frequently in patients with RA than in those without RA; however, overuse is not likely.

“The utilization of radiography is likely a reflection of overall disease burden,” wrote the authors. Radiological findings can help in disease diagnosis and in assessment of disease progression, and these continue to be an important part of patient management.

Some guidelines suggest that hand/ wrist radiographs be obtained every 2 years after initial diagnosis in patients with RA, but the researchers report that these were not performed with any regularity. They found that clinicians do not consistently follow suggestions regarding obtaining baseline and follow-up hand/wrist radiographs.

The study reviewed population-based cohorts from Olmsted County, Minnesota. Patients who ful-

filled American College of Rheumatology criteria for RA between 1988 and 2007 and age- and sex-mated comparator subjects were evaluated.

The study included 650 RA patients and 650 comparator subjects without RA. Mean age was 55.8 years, and 69% were female.

Radiographs were significantly more common in RA patients compared with non-RA subjects as follows: chest, upper extremity, lower extremity, spine, and hip, pelvis, or sacroiliac joints. Bone radionuclide and dual-energy x-ray absorptiometry imaging were also more common among patients with RA. The likelihood of undergoing radiological procedures was increased among RA patients with a positive rheumatoid factor, and women were more likely to undergo imaging than men.

Hand/wrist radiographs were obtained in 57% of patients within the first year of RA diagnosis, but in the subsequent 1 to 3 years following diagnosis only 42% had had radiographs, and the percentage dropped to 32% during the 3 to 5 years following diagnosis. Only about 28% had hand/wrist radiographs every 2 years, as recommended by some organizations.

No significant difference was found between the periods of 1988-1997 and 1998-2007 in the number of radiological studies performed among patients with RA. Continued on page 23

Psoriatic Arthritis

Recognizing and Treating Psoriatic Arthritis usually between 30 and 50 years of age.

About 85% of PsA patients have a previous diagnosis of psoriasis; PsA develops in up to 30% of patients with psoriasis.

Although PsA is often considered a mild disease, as many as 60% of affected patients develop joint complications, which can be severe and can compromise daily function and quality of life. Moreover, PsA poses an economic burden, with estimates of annual direct and indirect associated costs in the range of $8300 to $18,110.

Sixty percent of direct costs stem from hospitalization, and disability and lost productivity account for the majority of indirect costs.

PsA is less well recognized and characterized than some other rheumatic

16

Continued from page 15

diseases. It is frequently misdiagnosed or undiagnosed, and there is no good screening method for detecting those at highest risk for this disabling disease.

There is a need for validated treatment algorithms, standardized remission criteria, and convenient, easy-to-use treatments, Birnbaum told listeners.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) has published treatment recommendations for components of these disorders, including peripheral arthritis, skin and nail diseases, axial disease, dactylitis, and enthesitis.

Administration for the treatment of PsA: apremilast (the first novel oral treatment for this indication), secukinumab (subcutaneous), and ustekinumab (subcutaneous). These drugs have distinct mechanisms of action: apremilast is a small molecule inhibitor of phosphodiesterase 4; secukinumab selectively binds to IL-17A and inhibits its interaction with the IL-17A receptor; and ustekinumab inhibits IL-12 and IL-23 cytokines.

Three additional novel agents— brodalumab, ixekizumab, and tofacitinib—are in late-stage development for PsA.

Drugs for PsA Three new drugs have been approved by the US Food and Drug

Multidisciplinary Care Multidisciplinary care may facilitate the diagnosis of joint disease and offers

VALUE-BASED CARE IN RHEUMATOLOGY

I

APRIL 2015

a more comprehensive treatment approach for patients with psoriatic disease. Management often requires consultation with dermatologists, who may refer patients to rheumatologists.

Dermatologists should refer patients with psoriasis who develop peripheral arthritis, dactylitis, enthesitis, inflammatory low back pain, unspecified joint pain, and asymmetrical oligoarthritis. n References

1. Menter A, Birnbaum N. Assessing the clinical benefits of current and evolving therapies for the treatment of psoriatic disease in a managed care setting. Satellite symposium presented at: 27th Annual Meeting of the Academy of Managed Care Pharmacy; April 7-10, 2015; San Diego, CA. 2. Ritchlin CT, Kavanaugh A, Gladman DD, et al; Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. Treatment recommendations for psoriatic arthritis. Ann Rheum Dis. 2009;68(9):1387-1394.

VOL. 4

I

NO. 2

UPDATED RADIOGRAPHIC DATA

WHAT

DO YOUR PATIENTS WANT FROM THEIR RA TREATMENT? INDICATION â&#x20AC;˘ 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). â&#x20AC;˘ 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

In the News

Frequency of Radiological Procedures in Rheumatoid Arthritis Continued from page 16

The authors state that the role of various imaging modalities is in flux, and in the future the need for radiographs maybe be superseded by lowcost ultrasonographic joint evaluation. At present, patients with stable hand radiographs after 2 years may not need further routine radiographs of the hands. Venegas-Pont M, et al. J Clin Rheumatol. 2015;21(1):15-18.

Obesity Compromises Drug Response in Rheumatoid Arthritis Higher body mass index (BMI) in patients with rheumatoid arthritis (RA) is linked to a poorer response to a second-line biologic drug after failure of first-line treatment with a tumor necrosis factor-alpha (TNF-alpha) inhibitor, according to a study published online in Joint Bone Spine. This study adds to the body of literature showing that obesity is a risk factor for developing RA and that obese patients with RA have poorer outcomes and increased cardiovascular morbidity and mortality compared with normal-weight persons.

A team of Italian researchers at the University of Bari, Italy, led by Florenzo Iannone, MD, retrospectively analyzed data on 292 patients with RA who initiated treatment with a first TNF-alpha inhibitor after suboptimal response to 1 or more conventional disease modifying antirheumatic drugs (DMARDs). Among these patients, 66 were obese, 109 were overweight, and 117 were normal weight.

Obesity appeared to be related to the ability to continue on second-line treatment; continued treatment was observed in 39.4% of obese patients (median time 48 months) compared with 49.1% of normal-weight patients (median time 70 months), a nonsignificant difference. However, a significant difference was observed in drug discontinuation of the first anti-TNF drug favoring normal-weight patients (hazard ratio, 1.64). Obese patients were also less likely to achieve disease remission at 12 months according to the 28-joint Disease Activity Score (DAS-28).

Among 97 patients who initiated a second biologic agent (non–anti-TNF-alpha), obese patients were less able to persist on therapy compared with normal-weight patients; only 24 obese patients (43.5%) re-

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mained on therapy compared with 37 normal-weight patients (80%). Therefore, obese patients were almost 3 times more likely to discontinue drug than normal-weight patients, and only 12% of obese patients achieved disease remission based on DAS-28 versus 46% of normal-weight patients.

More research is needed on the mechanisms involved in the effect of obesity on response to different therapeutic agents for the treatment of RA. Prospective clinical trials, as well as analysis of registry data on each drug will hopefully improve understanding of this effect.

Experts agree that obesity is a modifiable risk factor, and efforts to address this should be part of clinical management of patients with RA. Iannone F, et al. Joint Bone Spine.

Published online: January 22, 2015.

Link Between Periodontal Disease and Rheumatoid Arthritis Two conditions characterized by inflammation are linked, according to researchers: periodontal disease and rheumatoid arthritis (RA). In fact, it is possible that periodontal disease may trigger the onset of RA. In a paper presented at the 93rd General Session and Exhibition of the International Association for Dental Research, Sheila Arvikar, MD, a rheumatologist at Massachusetts General Hospital, Boston, discussed research on inflammation in the mouth and joints in RA. “There has been mounting evidence of a connection between RA and periodontal disease, with an increased severity of periodontal disease in RA patients. Both are chronic inflammatory conditions that share similar pathology, but the mechanisms that connect the diseases are unclear,” Arvikar wrote in an email.

The study was conducted to understand further the significance of P gingivalis antibodies, the levels of which are elevated in RA patients, and the link between these antibodies and RA. Arvikar and her colleagues performed joint and dental examinations, determined the presence of P gingivalis antibodies, and examined inflammatory microenvironments in 23 patients with RA and 20 age-matched subjects without periodontitis/RA. Of the 23 RA patients, 15 had new onset RA and 8 had chronic RA. “The fact that two-

thirds of the patients had early RA is a rarity in these types of studies,” she wrote.

Serum P gingivalis IgG antibodies were measured by ELISA, and 23 inflammatory mediators were measured in serum, saliva, gingival crevicular fluid (GCF), and joint fluid by Luminex. All except 1 of the 23 patients received routine dental care and none was a smoker; 10 had gingivitis, and 9 had periodontitis. Despite the fact that most patients had routine dental care, a significant number (6 of 23, or 40%) had P gingivalis and all 6 had periodontitis. Also, RA patients exhibited marked inflammatory profiles in all microenvironments (serum, saliva, GCF, and joint fluid where available) even if they did not have periodontal disease.

Compared with healthy subjects, the RA patients had increased pocket depth, clinical attachment loss, bleeding on probing, and GCF volume.

The authors concluded that P gingivalis antibodies can be considered as biomarkers to help rheumatologists identify patients with periodontal disease who may benefit from treatment.

Arvikar S, et al. Presented at: 93rd General Session and Exhibition of the International Association for Dental Research.

Acetaminophen More Risky Than Assumed Paracetamol (acetaminophen in the United States) appears to have more cardiovascular, gastrointestinal (GI), and renal toxicity, as well as increased risk of mortality, than has been previously assumed, especially at high doses, according to a systematic review of the literature published online.

Paracetamol is the most widely used over-the-counter and prescription analgesic worldwide. It is currently recommended as a first-line medication by a variety of international guidelines for a wide range of acute and chronic pain. A previous study questioned the analgesic benefit of paracetamol in osteoarthritis, and the authors of the present study sought to characterize adverse events associated with use of the drug.

This review demonstrates a consistent dose-response relationship between paracetamol at standard anal-

APRIL 2015

I

gesic doses and adverse events often observed with nonsteroidal anti-inflammatory drugs (NSAIDs). This includes a dose-response relationship between paracetamol and increasing incidence of mortality and cardiovascular, GI, and renal adverse events in the general adult population, according to the authors.

They acknowledge the limitations of an observational review but state that the trends they found were “striking.” Acknowledging that every prescription decision entails balancing risks versus benefit, the authors suggest that when adequate analgesia is a priority, the risks may be acceptable to patients and physicians, but in situations in which analgesic benefit is uncertain (as in osteoarthritis), more careful consideration of paracetamol usage is required.

Prescribers need to be aware of these data showing a higher risk than that currently perceived in the clinical community, they stated.

The observational study was based on searches of Medline and Embase from inception of the databases until May 1, 2013. Of 1888 studies retrieved, 8 met the inclusion criteria, and all were cohort studies. The inclusion criteria were as follows: the study population was aged 18 years or older and the study investigated 1 or more of the adverse events of interest in people taking oral paracetamol at standard therapeutic doses of 0.5-1 g every 4-6 hours to a maximum of 4 g/day compared with nonuse.

Two studies reporting mortality compared paracetamol use with nonuse; 1 showed a dose response and found an increased relative rate of mortality from 0.95 to 1.63. Of 4 studies that looked at cardiovascular adverse events, all showed a dose response, and 1 found an increased risk ratio for all cardiovascular adverse events from 1.19 to 1.68. One study that reported GI adverse events found a dose response with increased relative rate of GI adverse events or bleeds from 1.11 to 1.49. Of 4 studies that looked at renal adverse events, 3 reported a dose response, with 1 reporting an increased odds ratio of 30% or greater decrease in glomerular filtration rate from 1.40 to 2.19. Roberts E, et al. Ann Rheum Dis. Published online: March 2, 2015. n

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