Rheumatology Practice Management June 2015 by Value-Based Cancer Care

JUNE 2015 VOL 4 • NO 3

www.ValueBasedRheumatology.com CCR CONFERENCE HIGHLIGHTS

Reinventing Disease: A Systematic Approach to Translational Rheumatology Chase Doyle

High Out-of-Pocket Cost of Biologic DMARDs Under Medicare Part D Rosemary Frei, MSc

n analysis of 2737 Medicare Part D plans’ 2013 formularies has found that mean out-ofpocket costs for biologic disease-modifying antirheumatic drugs (DMARDs) is $2712 to $2774 before reaching the “catastrophic” phase of coverage in which beneficiaries pay only 5% of

drug costs.1 Furthermore, beneficiaries with rheumatoid arthritis (RA) pay on average 29.6% coinsurance for biologic DMARD costs prior to the coverage gap. “Many Part D beneficiaries requiring biologic DMARDs will have sufficient out-of-pocket costs to reach Continued on page 13

THE Rheumatology NURSE™

heumatologists know that disease-free remission is the surest sign of long-term success— less disability, decreased morbidity

and mortality, and a greater likelihood of employment. However, fewer than 1 in 10 patients actually achieve this state. The translational Continued on page 14

Experts Make the Case for Putting Social Values Into Cost-Effectiveness Analyses Rosemary Frei, MSc

an social values be incorporated into cost-effectiveness analyses for healthcare decisions in

the United States? It may happen eventually but not in the near term, according to an expert asked by

Rheumatology Nurses Society on the Move Alice Goodman

he Rheumatology Nurses Society (RNS) recently announced some important projects. These include the publication of the Core Curriculum for Rheumatology Nursing and the Rheumatology Nurse Practice (RNP) Initiative. The Core Curriculum for Rheumatology Nursing is the first edition of a 484page hardcover textbook. The textbook was authored by a team of 26

rheumatology nurses, 5 section editors, and other experts in education, research, and publishing. The editorial board, which led this project, included Sheree C. Carter, PhD, RN; Victoria Ruffing, RN, CCRP; Cathy Patty-Resk, MSN, RN, CPNP; and Deborah Hicks, RN. The RNP Initiative has 3 programs— a peer-reviewed newsletter, a series of Google Hangout (webinar) live

Continued on page 13

INSIDE

Continued on page 12

VALUE PROPOSITIONS. . . . . . . 4 PSORIATIC ARTHRITIS . . . . . 18 Cyber Intrusion Treatment of Psoriatic Arthritis Explored by Cost-Effectiveness IN THE LITERATURE. . . . . . . . 11 LUPUS. . . . . . . . . . . . . . . . . . . . . 19 Tocilizumab Cuts Steroid Use in Treatment Outcomes and Cost Patients with Rheumatoid Arthritis Assessed for Systemic Lupus HEALTH ECONOMICS. . . . . . . 18 Erythematosus Mathematical Model Suggests ANKYLOSING SPONDYLITIS. 20 It Is Cost-Effective to Combine Switching Among TNF Agents in Bariatric Surgery and Hip Patients with Refractory Ankylosing Replacement in Morbidly Spondylitis Obese Individuals

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.

I would like to join the Editorial Advisory Board of Value-Based Care in RheumatologyTM. Fax to: 732-992-1881

To be considered for the Editorial Advisory Board of this exciting publication, please complete this form. Incomplete forms will not be considered.

Your Information _____________________________________________________________________________________ First Name

Last Name

Credentials

_____________________________________________________________________________________________________ Title Company _____________________________________________________________________________________________________ Address _______________________________________________________________________________________________________ E-mail Phone

VBCR EditBoardKsize 61014

www.ValueBasedRheumatology.com

In This Issue Value-Based Care in

Integrating Rheumatologists, NPs/PAs, Practice Managers & Payers

PUBLISHING STAFF Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com 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

VALUE PROPOSITIONS

CCR CONFERENCE HIGHLIGHTS

Cyber Intrusion Adding a Physician Assistant or Nurse Practitioner Planning for Reimbursement Preparing for ICD-10 Telemedicine in Rheumatology

Reinventing Disease: A Systematic Approach to Translational Rheumatology Microglial Modulation: The Key to Treating Neuroinflammatory Disease Biosimilars and Dose Reductions Will Reduce the Costs of Biologics Lupologists Seek “Holy Grail” of Biomarkers Psoriatic Arthritis: Treating the Totality of Disease Tendinopathy at the Molecular Level: A Translational Journey

Copyeditor Rosemary Hansen

IN THE LITERATURE

Production Manager Marie RS Borrelli

Tocilizumab Cuts Steroid Use in Patients with Rheumatoid Arthritis No Worsening of Acute Gout Attacks Treated with Allopurinol Silver Lining for Gout: Reduced Risk of Alzheimer’s Disease? Blood Test for Early Detection of Osteoarthritis on the Horizon Viscosupplementation for Knee Osteoarthritis Not Routinely Recommended

President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Director, Strategy & Program Development John Welz Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno

RHEUMATOLOGY PRACTICE MANAGEMENT Prescription Drug Cost Sharing Parsed by Panel at Pharmacoeconomics Meeting Seven Steps to Finding the Right Financial Advisor

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

VBCR Editorial Advisory Board

Creative & Design Assistants Lora LaRocca Wayne Williams Content Marketing Director Samantha Weissman

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

Web Content Manager Anthony Trevean Content Digital Manager Allison Musante

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

Digital Programmer Michael Amundsen Jr Digital Media Specialist Charles Easton IV Meeting & Events Planner Linda Mezzacappa

Sheree C. Carter, PhD, RN Assistant Clinical Professor The University of Alabama in Huntsville; President, Rheumatology Nurses Society

Project Managers Deanna Martinez Jeremy Shannon Project Coordinator Rachael Baranoski IT Manager Kashif Javaid Sales Assistant Aadam Mohamed Administrative Assistant Amanda Hedman Office Coordinator Robert Sorensen

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. EHC464-3

VOL. 4

NO. 3

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

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

Shelly Kafka, MD Medical Director, Rheumatology Medical Affairs Janssen Scientific Affairs, LLC 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, FAMCP Director, Pharmacy Services SelectHealth Murray, UT

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

Mission Statement

Value-Based Care in Rheumatology provides a forum for payers, providers, and the entire rheumatology team to consider the cost-value issues particular to rheumatology treatments. This unique focus is achieved through news coverage from major rheumatology meetings and the rheumatic diseases literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care. Contact Information: For subscription information please contact: Telephone: 732-992-1880 Fax: 732-992-1881. Permission requests to reprint all or part of any article published in this publication should be addressed to editorial@engagehc.com. Address all editorial queries to: editorial@engagehc.com. Telephone: 732-992-1880 Fax: 732-992-1881. POSTMASTER: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Care in Rheumatology, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

JUNE 2015

www.ValueBasedRheumatology.com

Value Propositions Cyber Intrusion

The government mandate to transition to electronic health records (EHRs) affects large institutions and private practitioners alike, and although the expanded use of EHRs is inevitable, it comes with significant problems. Cyber intrusion—hacking—is one of them. Each year, the number of data breaches recorded in the United States grows larger, and according to the Identity Theft Resource Center, in 2014 the “medical/healthcare” industry had more breaches than any other field. On April 8, 2014, the FBI published a “private industry notification” warning of the “likely increase [in] cyber intrusions against health care systems—to include medical devices—due to mandatory transition from paper to EHR, lax cybersecurity standards, and a higher financial payout for medical records in the black market.” (Stolen medical records are sold and then used to file fraudulent insurance claims, obtain drugs, or enable identity theft.) Every medical practice should reevaluate and strengthen its EHR security because the steps needed to rectify a data breach are wide-ranging and very expensive. As a result of the cyber intrusion threat, cyber insurance becomes another business expense that physicians must consider. Purchasing this type of insurance is usually complicated, requiring extensive research and comparisons, between companies and policies, with understanding what is covered and not covered key to making the right decisions. Sacopulos MJ. Medscape. April 30, 2015. FBI Cyber Division. PIN #: 140408-009.

Adding a Physician Assistant or Nurse Practitioner

The general media and the medical press have reported on the growing shortage of physicians, especially in fields such as rheumatology that provide care to the aging US population. The number of midlevel providers, however, continues to increase. As reported recently in The Rheumatologist, the National Commission on Certification of Physician Assistants estimates that the number of education programs for physician assistants (PAs) will grow from 180 to 250 within the next 3 years and the number of certified PAs will increase from 95,583 in 2013 to more than 125,000 by the end of 2018. The American Academy of Nurse Practitioners describes dramatic growth in the number of nurse practitioners (NPs) from 97,000 in 1999 to 171,000 in 2013, with a predicted total of 224,000 by 2025. The addition of a PA or NP may help current rheumatology practices cope with the combined problems of fewer rheumatologists and more patients. Among several advantages that Shariar Cohen-Gadol, MD, a rheumatologist in Thousand Oaks, California, finds in working with NPs and PAs are their ability, after some training in rheumatology, to fulfill specific needs in his practice as well as salary requirements lower than those of a full-time rheumatologist. According to Barbara Slusher, MSW, PA-C, assistant professor of physician assistant studies, University of Texas, Galveston, “Rheumatology is a specialty of chronic conditions, and PAs are well suited to manage and educate chronic patients.” To achieve a successful collaboration when adding an NP or PA to your rheumatology practice, consider these suggestions: check state laws thoroughly, decide on the responsibilities the NP or PA will have, let a candidate shadow you for a day or two, and introduce a newly hired provider to your patients. Caceres V. The Rheumatologist. April 1, 2015.

Planning for Reimbursement

As the era of the Medicare Access and CHIP Reauthorization Act (MACRA) begins, physicians must think about choosing 1 of 2 reimbursement systems that will go into effect in 2019: the Merit-Based Incentive Payment System (MIPS) or an alternative payment model (APM). Robert B. Doherty, senior vice president of governmental affairs and public policy for the American College of Physicians (ACP) discussed MACRA at a recent media briefing. Doherty explained that under MACRA reimbursement is stabilized and time is allowed for the transition to “value-based” payments. The program will provide annual baseline Medicare payment increases of 0.5% from July 1, 2015, through December 31, 2018. Beginning in 2019, and annually thereafter, physicians will have to participate in the MIPS program or choose an APM. Although switching from one program to the other will be permitted each year, the differences in requirements would necessitate changes in practice management.

VALUE-BASED CARE IN RHEUMATOLOGY

JUNE 2015

Of the 2 programs, the MIPS is closer to a fee-for-service model. However, reimbursement will be adjusted annually based on performance in 4 categories: clinical quality, meaningful use of health information technology, resource use, and practice improvement. Failure to meet new performance measures will result in a payment decrease. Physicians who prefer the opportunity to earn more may choose an APM and practice within an accountable care organization or advanced patient-centered medical home. There is, however, greater financial risk involved in the APM model. Nitin Damle, MD, incoming ACP president, advised physicians to begin preparing now for MACRA requirements. He said, “You really need to have electronic medical records,…team-based care, and…an office that has an efficient work flow. Otherwise, it will be very difficult…to report some of these measures…required…to get some of these payment incentives.” McKnight W. Rheumatology News Digital Network. May 1, 2015.

Preparing for ICD-10

Speakers at the annual meeting of the Healthcare Information and Management Systems Society offered advice to physicians as they prepare to implement ICD-10. According to Betty Gomez, a regulatory strategy consultant, October 1, 2015, is “just the first milestone” in the transition. She warned that along with the transition, “there are going to be unforeseen obstacles and challenges.” Physicians should reduce their backlog of denied or pending claims and be prepared with a contingency plan so that they will be able to manage any challenges that arise. A checklist could help track the completion of needed tasks, such as having a staff member or response team designated to address problems when they occur and educating staff on the use of ICD-9 codes and ICD-10 codes after the transition. She said, “You need to make sure you can continue to use both ICD-9 and ICD-10 codes, based on date of service or date of discharge.” F. Phil Cartagena, Jr, ICD-10 program manager for Partners Healthcare System in Boston, recommended that practices have a minimum of 3 months’ cash flow in reserve. It would also be beneficial to “work out agreements in which payers match or partially match physicians’ current monthly run rate during the transition,” he said. As is well known, ICD-10 has approximately 5 times as many codes as ICD-9 and will require more specific documentation. Cartagena suggested, “The more specific that you can be, the better it is, whether it matters for actually coding the record correctly, or if it’s for stratifying your patient mix or having a better understanding clinically of how the diagnoses of your patient population break down.” Gallegos A. Rheumatology News Digital Network. April 16, 2015

Telemedicine in Rheumatology

Telemedicine—first used effectively to link rural areas with specialists in urban areas by providing patient services through the use of telecommunications—is evolving. Jonathan Linkous, chief executive officer of the American Telemedicine Association, reports, “With time, the cost of both the technology and the communication services went way down, and we are just beginning to see the use of digital phones, computers and tablets in this area.” However, in diagnosing and treating rheumatology patients, touch is of great importance, and integrating telemedicine into rheumatology practice presents specific challenges. Having a specially trained RN, LPN, or medical assistant acting as “presenter” is one way to resolve this issue. The presenter can obtain typical check-in information, record vital signs, and describe physical conditions such as muscle strength, range of motion, joint tenderness, and existence of rashes. The presenter also usually operates the camera and other equipment. Costs of setting up include a telemedicine clinical cart at the patient site, available for about $30,000. The physician would need a desktop computer, about $3000; a web camera, about $100; and web-enabled telepresence software that is secure and complies with HIPAA regulations. Providing access to care by a specialist remains a primary justification for telemedicine, and rheumatologists considering adding a remote capability to their practice should first evaluate their geographic location. However, even suburban areas may become suitable for telemedicine as the expected shortage of rheumatologists develops. Ullman K. The Rheumatologist. May 15, 2015.

VOL. 4

NO. 3

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

August 2014

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

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

August April 20142014

In the Literature Tocilizumab Cuts Steroid Use in Patients with Rheumatoid Arthritis Initiation of therapy with tocilizu mab (Actemra; Genentech) enabled rapid and long-lasting reductions in corticosteroid (CS) use in patients with severe and active rheumatoid arthritis (RA) who had been on oral CS therapy for at least 3 months at baseline. CS sparing did not correlate with reduction in disease activity; therefore, tocilizumab may have positive effects (ie, CS sparing) in patients not having clinical responses. “The study showed that TCZ [tocilizumab] led to significant CS sparing during the first months of RA treatment, and that this sparing effect was observed even in non-responders, in whom the treatment could thus have major benefits despite the absence of response. Other studies are now necessary to confirm these findings and to evaluate the hypotheses put forward,” the authors wrote. They noted, “In RA patients treated with high doses of CS, clinicians’ main objective might be to reduce doses.” The multicenter, observational, retrospective study evaluated 220 patients with RA, with a mean age of 55.7 years, mean disease duration 15.9 years, and a mean disease activity score (DAS28) of 5.1, who started tocilizumab treatment at 5 centers between December 2009 and June 2011. Among these, 132 were on long-term oral CS therapy. Of these patients, 2 were excluded, leaving 130 patients in the analysis (105 women [80.8%] and 25 men; mean age of 56.7 years). Mean duration of RA was 16.3 years. RA was active in most patients (mean baseline DAS28 of 5.1). Mean CS dose was 10 mg/day (mean prednisone equivalent). Mean duration of follow-up was 21.3 weeks. Nineteen patients stopped treatment after 4 to 12 weeks for various reasons. During the study period, a significant CS-sparing effect was observed by week 24; mean daily dose of oral CS was reduced from 10 mg at baseline to 6.5 mg at week 24 (P<.0001). Along with that, mean DAS28 during the study period decreased from 5.1 to 3.0 at week 24 (P<.0001). Among 90 patients not receiving CS at baseline, 13 received CS during the study period. The only variable found to correlate with the decrease in CS dose was initial dose of the drug (r=0.82; P<.001). When these patients were added into a post hoc analysis, the early and long-lasting CS-sparing effect was observed. The study’s limitations are its open observational design and lack of a comparator group. However, the patients are those seen in “real life.” Fortunet C, et al. Rheumatology (Oxford). 2015;54(4):672-677. VOL. 4

NO. 3

No Worsening of Acute Gout Attacks Treated with Allopurinol Initiating allopurinol treatment during an acute gout attack does not worsen the attack or adversely affect resolution of the attack, according to a recent double-blind, placebocontrolled trial. Traditionally, allopurinol has not been initiated during an acute gout attack because of concern about prolonging the attack. This new study supports the 2012 American College of Rheumatology (ACR) Guidelines for Management of Gout, suggesting that urate-lowering therapy can be initiated during an acute gout attack. “Our results clearly show that the severe symptoms of gout resolved quickly in both arms of the study, and therefore our protocol captured data that included even minor residual symptoms….We are confident that if a clinically meaningful prolongation of gout were caused by the initiation of allopurinol, we would have detected it in this study,” the authors wrote. Studies suggest that only a minority of the 8 million Americans with gout are adequately treated. Annual outpatient direct costs of acute gout attacks are estimated to be as high as $1 billion. Although allopurinol has been used to treat gout for more than 30 years, many physicians believe that it and other urate-lowering drugs could worsen an acute attack. The authors note that initiation of allopurinol has the potential to reduce the number of outpatient visits and thereby the direct costs associated with gout. To address this issue, they initiated a study to compare allopurinol versus placebo during an acute attack. The 28-day study enrolled patients with crystal-proven gout if they had an acute gout attack within 72 hours of initial therapy. They were also required to have at last 1 additional criterion for urate-lowering therapy. Of 107 screened patients, 37 met enrollment criteria and were randomized to receive allopurinol or identical-looking placebo capsules. Patients were given standard prophylaxis with colchicine or nonsteroidal anti-inflammatory drugs, and allopurinol or placebo was initiated at 100 mg/day for the first 14 days; the dose was increased to 200 mg/day for the next 14 days. The study was completed by 31 patients (17 on placebo, 14 on allopurinol). Baseline disease and demographic characteristics were similar in both groups. In both intent-to-treat and completer analyses, no significant difference was observed between the 2 treatment arms for days until attack resolution: 15.4 days in the allopurinol group versus 13.4 days in the placebo group (P=.5). Secondary measures

showed similar results in pain scores and new pain. The acute gout attack resolved in all patients by study completion. Physicians correctly guessed which group the patients were randomized to 84% of the time, and patients guessed correctly 55% of the time. As expected, patients randomized to receive allopurinol had lower serum uric acid levels than did placebo patients at the end of the trial: mean serum uric acid level was 6.42 mg/dL versus 8.25 mg/dL, respectively. Allopurinol initiated at a low dose and gradually increased was well tolerated, with 1 serious adverse event reported (epistaxis requiring nasal packing in a patient on warfarin for coexisting atrial fibrillation). This is the second randomized trial to support the ACR gout guidelines recommendation that urate-lowering therapy can be started during an acute attack, provided effective management is instituted. Hill EM, et al. J Clin Rheumatol. 2015;21(3):120-125. Silver Lining for Gout: Reduced Risk of Alzheimer’s Disease? Although gout is associated with an increased risk of cardiovascular and renal disease, a population-based study suggests that gout may reduce the risk of developing Alzheimer’s disease (AD). In a large cohort of patients treated in general practice, those who developed gout had a 24% reduced risk of developing AD after adjustment for other cofactors, and this inverse risk between gout and AD was present in all subgroups. No such association was found between osteoarthritis and AD. “These findings provide the first general population-based evidence that gout is inversely associated with the risk of developing AD, supporting the purported potential neuroprotective role of uric acid,” concluded the authors. Gout is caused by hyperuricemia, which leads to the deposition of uric acid crystals in joints and ensuing inflammation. As time goes on, attacks of gout can be more frequent, longer, and more severe. Some studies have suggested that excess serum uric acid may have a neuroprotective effect on Parkinson’s disease and other neurologic conditions. The senior author of this study, Hyon K. Choi, MD, Massachusetts General Hospital in Boston, wanted to assess the potential impact of gout on developing AD in the general population. The same analysis was performed to look for associations between gout and osteoporosis as a negative control. The study was based on data from The Health Improvement Network (THIN), a computerized medical reJUNE 2015

cord database comprising 10.2 million patients drawn from 580 general practices in the United Kingdom from January 1995 to December 2013. The researchers identified 59,224 patients with gout, each of whom was matched with up to 5 persons without gout for age, sex, entry time, and body mass index (BMI) (total number, 238,805 non-gout individuals). The incidence rates of AD were compared between these 2 cohorts, excluding people with gout or dementia at baseline. There were 309 new cases of AD among patients with gout and 1942 new cases of AD in the non-gout group over a 5-year median follow-up: 1 versus 1.5 per 1000 person-years, respectively. Multivariate analysis adjusting for age, sex, BMI, socioeconomic factors, lifestyle factors, prior cardiovascular metabolic conditions, and use of cardiovascular drugs showed a similar inverse association between gout and risk of developing AD, and this association was observed among all subgroups stratified by age, sex, social deprivation index, and history of cardiovascular disease. At present, the researchers can only speculate about the potential mechanisms involved in purported neuroprotective effects of serum uric acid excess. Animal models of Parkinson’s disease and other neurologic conditions have shown neuroprotective effects, and a prospective analysis found that prior elevated serum uric acid levels (precursor of gout) were inversely associated with developing any type of dementia. Lu N, et al. Ann Rheum Dis. Published online: March 4, 2015. Blood Test for Early Detection of Osteoarthritis on the Horizon The first blood test to detect earlystage osteoarthritis (OA) appears to be in sight, according to research published online recently in Scientific Reports. The hope is that the test can identify OA before it becomes severe. The biomarker, called citrullinated protein (CP), is found in the blood. The test utilizes 3 biomarkers, including CP, anti-cyclic citrullinated peptide (CCP) antibodies, and hydroxyproline, a bone-derived substance. The test appears to be able to detect early-stage rheumatoid arthritis (RA) as well and to discriminate between OA and RA. Lead author Naila Rabbani, PhD, University of Warwick, Coventry, United Kingdom, noted that there already is an established test for early-stage RA, but there are no tests for OA. “We believe our new test will refine existing tests for early-stage RA and for the first time provide a biochemical test for early-stage OA. This remarkable and unexpected finding could facilitate

Continued on page 12

www.ValueBasedRheumatology.com

In the Literature

Blood Test for Early Detection… appropriate early-stage treatment for arthritis, maximizing the chances of success,” she stated. The authors wrote that their “diagnosis algorithm [meets] the unmet clinical need for early-stage diagnosis and typing of arthritis. Combination of [the 3 biomarkers]...gave specific and sensitive detection and discrimination of [early] OA, [early] RA, nonRA and good skeletal health.” Previous studies have shown that patients with early-stage RA have anti-CCP antibodies, but prior to the present study, this had not been shown in OA. Increased levels of CPs were seen in both early-stage OA and RA in this study. Using the algorithm of 3 biomarkers showed that anti-CCP antibodies are found in early-stage RA, whereas the absence of these antibodies characterizes early OA. This single test can potentially detect and discriminate between early-stage OA

and RA before joint destruction can occur. Ahmed U, et al. Sci Rep. Published online: March 19, 2015. Viscosupplementation for Knee Osteoarthritis Not Routinely Recommended The literature is conflicting regarding the value of intra-articular hyaluronate injections for the treatment of knee osteoarthritis (OA). Evidence to date suggests that intra-articular hyaluronate injections should not be used for the routine management of knee OA, but may have a role after a patient has not had a good response to analgesics, according to a recent review of the state-of-the-art for this type of treatment. Hyaluronate is a naturally occurring component of cartilage and synovial fluid. Exogenous intra-articular hyaluronate is available for injection, with the goal of providing and main-

Continued from page 11

taining intra-articular lubrication, which increases the viscoelastic properties of synovial fluid. This form of therapy is sometimes called “visco supplementation.” Other claims are that hyaluronate exerts anti-inflammatory, analgesic, and possibly chondroprotective effects on the articular cartilage and joint synovium. The recommended approach for management of knee OA is that physicians should emphasize a hierarchy of management as follows: first, nonpharmacologic approaches (weight loss, exercise, braces, and assistive devices); next, analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs); and last, surgery. According to the review’s author, David J. Hunter, PhD, “Too frequently, the first step [ie, non-pharmacologic approaches] is forgotten or not emphasized sufficiently, to the patients’ detriment.”

Guidelines from various organizations are contradictory regarding recommendations for intra-articular hyaluronate. The most recent Osteoarthritis Research Society International guidelines do not recommend it for either knee or multiple-joint OA, based on lack of a significant difference between the injections and placebo. The American Academy of Orthopaedic Surgeons stated that the evidence was inconclusive and a recommendation could not be made for or against intra-articular hyaluronate injections. On the other hand, the American College of Rheumatology 2012 guidelines do not advocate this strategy for initial management of knee OA, but conditionally recommend it—along with either tramadol or duloxetine—for patients who do not have a good response to acetaminophen or nonsteroidal antiinflammatory drugs. Hunter DJ. N Engl J Med. 2015;372(11):1040-1047. n

Health Economics

Experts Make the Case for Putting Social Values…

Continued from page 1

Value-Based Care in Rheumatology to comment on a presentation at the 2015 International Society for Pharmaco economics and Outcomes Research annual meeting. The National Institute for Health and Care Excellence in the United Kingdom is starting to include social values in their cost-effectiveness analyses, noted the presenters from Edmonton and Dublin. They made compelling arguments both for incorporating social values and for the complexity of doing so, even in a single-payer system. They noted that in a single-payer system there are always health services that are displaced or foregone to pay for a new technology, whereas in insurance-based systems there are services or goods that are priced out of coverage as premiums rise to pay for the new technology. “We need to decide on which value arguments are important, who determines the relative weight placed on each, and how these arguments affect the value assigned to all health services affected by a decision to adopt a new technology,” Mike Paulden, MSc, a research associate in the Faculty of Med-

icine & Dentistry, University of Alberta, Edmonton, Canada, and James O’Mahony, MA, research fellow, School of Medicine, Trinity College, Dublin, noted in their presentation. One of their main points was that

appropriate dollar threshold for the QALYs in each analysis, based on the complex social value and other parameters in each case. The variables that could or should be included in examining the cost-ef-

“We’ll probably move in that direction [including social values in the analysis] but it’ll take time because we don’t have a single-payer system.” —John FitzGerald, MD, PhD, MBA

cost-effectiveness analyses should incorporate 2 important social values. One is preference for net health improvement, meaning the expectation that a new technology with an incremental cost-effectiveness ratio below a certain threshold will yield more quality-adjusted life-years (QALYs) with its use rather than fewer, and vice versa. The second is having an

VALUE-BASED CARE IN RHEUMATOLOGY

JUNE 2015

fectiveness of any given item include disease severity, disease rarity, whether the condition is a childhood illness, the extent of innovation involved, whether it is life-saving, and treatment alternatives, according to Paulden and O’Mahony. John FitzGerald, MD, PhD, MBA, interim chief of rheumatology, and associate professor, David Geffen School of

Medicine at the University of California Los Angeles, praised the presentation and said it is “well ahead of what we’re doing here in the United States.” “We’ll probably move in that direction but it’ll take time because we don’t have a single-payer system,” said FitzGerald. “And another layer of complexity—in any country—is that there are many choices of treatment substitutes to consider. There’s also the practice of future discounting, where prices are assumed to come down over time as competition is introduced.” FitzGerald said all of these principles can be shown in examples from rheumatology. Rheumatologists are now often conducting ultrasound-guided knee injections in patients with arthritis, and there are cost-effectiveness studies that justify adding the cost of ultrasound to the cost of injections. However, the studies do not convincingly show that the marginal value from the increased accuracy and reduced pain with ultrasound guidance is worth the considerable extra cost, he said. n Reference

McCabe C, Paulden M, O’Mahony JF. Incorporating social values into cost-effectiveness analysis. Panel presentation at: ISPOR 20th International Annual Meeting; May 16-20, 2015; Philadelphia, PA.

VOL. 4

NO. 3

Health Economics

High Out-of-Pocket Cost of Biologic DMARDs…

Continued from page 1

catastrophic thresholds in total drug spending each year. Clinicians caring for individuals with RA should be aware of this and be prepared to discuss long-term affordability as well as relative efficacy of biologic DMARDs with their patients to help them make informed decisions about treatment,” noted lead investigator Jinoos Yazdany, MD, MPH, associate professor in the Division of Rheumatology, School of Medicine, University of California San Francisco, and her coauthors in their report. In January 2013, the team analyzed all 50 states’ and Washington DC’s Medicare Part D stand-alone prescription drug plans (PDPs) and Medicare Advantage PDPs (MA-PDPs). They did so using the Centers for Medicare and Medicaid Services’ Prescription Drug Plan Formulary and Pharmacy Network files. Overall, 71% of the plans covered at least 1 biologic DMARD, 95% required prior approval for the various biologic DMARDs, and 95% involved beneficiary coinsurance for them. Furthermore, 95% of the plans placed biologic DMARDs in specialty tiers. The mean percentage of coinsurance for drug costs per beneficiary was 29.6%.

The mean monthly co-payment before reaching catastrophic coverage for biologic DMARDs was $835, with the lowest being $269 for infliximab and the highest being $2993 for anakinra. The mean monthly co-payment was $24 for nonbiologic DMARDs, with the

lated the average payment by beneficiaries under a standard 2014 Part D plan for biologic DMARDs until they reached the donut hole. They found it averaged approximately $2760. This would mean that beneficiaries would reach the coverage gap by January,

“The entire policy with respect to Medicare spending on biologic DMARDs needs to be reformed to address the cost burden the program is placing on patients.” —Jinoos Yazdany, MD, MPH

highest being $114 for penicillamine. Seventy-nine percent of MA-PDPs covered biologic DMARDs compared with 69% of PDPs. However, MAPDPs also charged a higher percentage of coinsurance at 31.1% versus 29% for PDPs. Moreover, the mean co-payment was higher with MA-PDPs than PDPs, at $862 and $829, respectively. Yazdany and her team also calcu-

February, or March, depending on the biologic DMARD and the plan, and reach the catastrophic phase of coverage between January (for anakinra) and July (for infliximab), the investigators determined. “Our findings indicate that 8 years after implementation, Part D plans continue to use high cost sharing as a primary cost-control mechanism for bio-

logic DMARDs, placing a substantial financial burden on patients who require such drugs for adequate control of their RA symptoms,” they concluded. These findings complement those from another study by Yazdany and her collaborators, in which they found that Medicare beneficiaries who also receive the low-income subsidy (LIS) are more likely to receive home-administered biologic DMARDs than those who do not receive the LIS.2 Non-LIS beneficiaries had lower costs for Part B facility-administered biologics than for Part D home-administered biologics. New Affordable Care Act reforms will only slightly decrease the costs for Part D biologics for non-LIS individuals, the investigators believe. “The entire policy with respect to Medicare spending on biologic DMARDs needs to be reformed to address the cost burden the program is placing on patients,” Yazdany told Value-Based Care in Rheumatology. n References

1. Yazdany J, Dudley RA, Chen R, et al. Coverage for high cost specialty drugs for rheumatoid arthritis in Medicare Part D. Arthritis Rheumatol. 2015;67(6):1474-1480. 2. Yazdany J, Tonner C, Schmajuk G. Use and spending on biologic disease-modifying anti-rheumatic drugs for rheumatoid arthritis among U.S. Medicare beneficiaries [published online ahead of print March 16, 2015]. Arthritis Care Res. doi: 10.1002/acr.22580.

The Rheumatology Nurse

™

Rheumatology Nurses Society on the Move programs, and regional live events. The first volume of the newsletter, published March 2015, included the following topics: • Which of the current Physician Quality Reporting System (PQRS) measures are most relevant to rheumatology practices? • What is meaningful use, and why does it matter for the rheumatology community? • How have individual rheumatology practices customized their electronic health records to encourage better alignment with PQRS and other quality indicators? • How successful have rheumatology practices been in the adoption of quality standards, and what hurdles remain? The first RNP Google Hangout VOL. 4

NO. 3

took place March 18, 2015. Rheumatology nurses were encouraged to participate in this live webinar, which focused on pediatric issues in juvenile idiopathic arthritis rheumatoid factor-positive.

Continued from page 1

be posted in the free RNS Newsletter. To sign up for the newsletter, go to the website www.rnsnurse.org. Other Announcements The 8th RNS Annual Conference

The RNS has issued a position statement on administration of biologic infusions. To see the full announcement, go to www.rnsnurse.org

RNS Goes Live! In 2015 and 2016, RNS will be sponsoring live events. Dates and locations will be announced. These events will

will be held August 6-8, 2015, at the Renaissance Orlando at SeaWorld Hotel in Orlando, Florida. Prospective attendees should reserve by July 20, JUNE 2015

2015, to secure a special rate. The RNS has issued a position statement on administration of biologic infusions. To see the full announcement, go to the website. n

www.ValueBasedRheumatology.com

CCR Conference Highlights

Reinventing Disease: A Systematic Approach…

Continued from page 1

research presented at the 2015 annual Congress of Clinical Rheumatology calls for a revolution in the discovery, development, and utilization of pharmaceutical treatments. “In the pharmaceutical industry, there are unacceptably high late-failure rates,” said Iain B. McInnes, MD, PhD, professor of medicine and director of the Institute of Infection, Immunity and Inflammation at the University of Glasgow, Scotland. “Drug discovery failures are not cheap, and a late failure costs even more money. The trouble is that we’re not really getting any better. Far too few [drugs]…are translating into actual clinical benefit.” The revolution McInnes spoke of is the rejection of an antiquated system, whereby single molecules are selected and put through a ponderous, and frequently unsuccessful, discovery paradigm. As he sees it, part of the problem lies in a publication bias—“editors love the individual pathway”—and a reductionist model in science, which has instinctively driven investigators. “We can no longer afford this approach,” said McInnes. “If we continue to look for drugs this way, then we’ll never get truly transformational

alterations in the way we treat human beings with rheumatic diseases.” His answer: a systematic approach to drug discovery—capturing and integrating global sets of data from as many hierarchical levels of informa-

for working this out. While big data should lead to more knowledge and insight, if you wish to obtain life-saving answers, asking the right questions is critical. In McInnes’ opinion, these questions will come from hypothe-

“Drug discovery failures are not cheap, and a late failure costs even more money. The trouble is that we’re not really getting any better. Far too few [drugs]…are translating into actual clinical benefit.” —Iain B. McInnes, MD, PhD

tion as possible. McInnes reminded the audience that this is already happening in other fields of medicine. “The cancer doctors are miles ahead of us,” he said. “They have mathematicians working on their large-scale data sets.” One of the conundrums of so-called big data, however, is that not all information is informative, reproducible, or insightful. Nor is there a single formula

sis-generating models and the scientific property of “emergence.” “The point is, you need theories,” he said. “Looking molecule by molecule is not useful; you need to understand the behavior of groups of molecules…A systems-wide approach may reveal what an individual molecule cannot—emergent properties when considering the whole.” Learning how to navigate multilay-

ers of data in a meaningful way and building in the clinical question is very much a work in progress, but McInnes and his team remain inspired by the possibilities. They are presently collecting data from around the world, adding biology to the bioinformatics to glean insight. Or as he put it: “using existing knowledge systematically to change the future.” “The problem with a lot of science at the moment,” said McInnes, “is that we spend a lot of time and money targeting, with brilliant molecules, a therapeutic target that was never there.” Fixing this problem will require the collaboration of research scientists and clinicians alike—treating patients, contributing to trials, and generating data sets—along with the resolve to approach decisions systematically, before countless resources are squandered. “If you put all of these things together in a proper, formally structured systematic approach, then we will have a virtual cycle of discovery,” McInnes concluded. “We will still fail, of course, but we will fail less often, and if we fail, we will have understood why we failed so that we do it better next time. And that is the secret for future success.” n

Microglial Modulation: The Key to Treating Neuroinflammatory Disease Chase Doyle

icroglia may serve a protective purpose for the masses, but for those who suffer from fibromyalgia, these adaptive cells of the central nervous system are the enemy—the source of constant flu-like sickness and pain. Until recently, there has been little hope for defense. According to research presented at the 2015 annual Congress of Clinical Rheumatology, however, scientists are beginning to understand the mechanisms behind this pain, offering the promise of an effective treatment for fibromyalgia, with implications that extend far beyond this crippling disease. “I think the evidence is strongly supporting the role of microglia in fibromyalgia, chronic fatigue, major depression, and a lot of other neurological conditions and disorders,” said Jarred

Younger, PhD, associate professor in the departments of Psychology, Anesthesiology, and Rheumatology, and di-

is going to be the next huge advance in treatment when we figure out how to manipulate these microglia cells.”

”The evidence is strongly supporting the role of microglia in fibromyalgia, chronic fatigue, major depression, and a lot of other neurological conditions and disorders.” —Jarred Younger, PhD

rector of the Neuroinflammation, Pain and Fatigue Lab, at the University of Alabama at Birmingham. “I think this

VALUE-BASED CARE IN RHEUMATOLOGY

JUNE 2015

According to the National Fibromyalgia Association, an estimated 10 million people are afflicted with fibromy-

algia in the United States alone. The victims of this disease are mostly women, and prognosis is poor in terms of improvement. “It’s still a mysterious disorder,” said Younger. “We don’t have any objective test that says, ‘yes, you have this disorder.’ So, it’s frustrating for the patients, and it’s frustrating for the physicians. We just don’t have the tools to treat this effectively.” In Younger’s opinion, fibromyalgia is caused by neuroinflammation in the central nervous system, and the key to treating it is reducing the inflammatory process in the brain. None of the current US Food and Drug Administration–approved therapies, however, directly target these processes. “We’re going to have to develop and discover and employ both pharContinued on page 15

VOL. 4

NO. 3

CCR Conference Highlights

Biosimilars and Dose Reductions Will Reduce the Costs of Biologics Chase Doyle

hange comes at a price. While there is little doubt that biologics have changed the landscape of therapy in rheumatic diseases, they have also raised the costs of healthcare in the process. “If my patients are doing better, I give them the drug,” said Edward Keystone, MD, professor of medicine at the University of Toronto, Canada. “The fact is: patients perform better on biologics. I let the economics people worry about costs, but there’s no question we need less costly interventions.” One solution, proposed by Keystone at the 2015 annual Congress of Clinical Rheumatology, may seem paradoxical at first—starting patients with early rheumatoid arthritis on both methotrexate and a biologic. “Even though it costs a fortune to start both at the same time early and most payers don’t pay for it,” he said, “if you can reduce the dose or withdraw the biologic, then there’s no reason why one shouldn’t consider starting methotrexate and a biologic.” As Keystone explained, biologicfree remission is possible in 40% to 60% of patients initiating a biologic plus methotrexate in early rheumatoid arthritis. And for patients who have an inadequate response to methotrexate, although biologic-free remission is infrequent, biologic dose reduction is still possible in 60% to 80% of patients who achieve a stable low disease activity state. However, drug-free remission, which means the withdrawal of all therapies, remains unlikely for either group. “I’m personally interested in biologic-free remission,” he said. “Drug-free

remission isn’t going to happen. Maybe in early rheumatoid arthritis, but post methotrexate, it’s not happening.” Biosimilars Are Not Generics Unlike generics, biosimilars are not chemically made, and because they are manufactured living products, they cannot be fully characterized. While the ingredients are highly sim-

This notion of identity is critical for prescribers and payers alike. According to the US Food and Drug Administration, if a biosimilar is determined to be “interchangeable,” a pharmacist would be allowed to substitute the biosimilar for a prescribed biologic therapy without involving the prescribing physician. There are other concerns for clini-

In Norway and India, for example, the presence of biosimilars in the market reduced costs by more than 70%. With the exception of Norway, however, Keystone speculated that it was unlikely these savings would be passed on to consumers. “How many insurance companies when they have to pay less say, ‘we’re going to distribute wealth?’” he asked, rhetorically. “Of course [insurance companies] are going to keep the profits. They’ll make more money and it won’t be distributed any differently than it was before.” Of equal concern for Keystone was the possible impact on funding for innovative therapy, that is, diminished profits could affect Big Pharma’s investments in future drug discovery. “If prices [for drugs] go down, then profits go down,” he said, “and if profits go down, that means you don’t have the same money for creating originator products.” Despite these concerns, Keystone viewed the transition to biosimilars as inevitable, citing the planned release of 3 biosimilar products— etanercept, adalimumab, and rituximab—by Samsung Bioepis as evidence of their arrival. “In the next 10 years, biosimilars are going to take the market in many of the products we see today,” he concluded. “Biosimilars are here to stay, so get used to it.” n

“I have no idea whether biosimilars will have the same sustainability as biopharmaceuticals. That’s what we worry about most [as clinicians]. We worry about sustainability.” —Edward Keystone, MD

ilar to biopharmaceutical products already approved by a regulatory agent, they are not, in fact, the same. “Even though the amino acid structure is identical,” Keystone explained, “the carbohydrates are not the same, and this can make a difference in terms of function and sustainability, theoretically.” Perhaps it is true in theory but not yet in practice, as indicated by recent clinical data. In the 30-week PLANETRA study, biosimilars displayed nearly identical immunogenicity as biologics. The percentage of patients with antidrug antibodies was virtually the same by the end of the trial (48.4% vs 48.3%).1

cians, as well. While Keystone was convinced that biosimilars would provide the same patient support programs as the original biologics, he remained uncertain with respect to the question of sustainability. “I have no idea whether biosimilars will have the same sustainability as biopharmaceuticals,” he said. “That’s what we worry about most [as clinicians]. We worry about sustainability.” Decreasing Costs Based on economic forecasts, Keystone estimated that the availability of biosimilars could reduce the high cost of targeted therapies for patients in the United States by as much as 35%.

Reference

1. Yoo, DH. A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis. 2013;72(10):1613-1620.

Microglial Modulation: The Key to Treating…

Continued from page 14

maceutical treatments and other interventions that can get to the central nervous system and target the cells that drive the inflammation,” he said. And that means microglia, the brain’s cellular defense against invasion—fast-acting sentinels whose hypervigilance in people with fibromyalgia causes far more harm than good. In the so-called “primed state” of overexVOL. 4

NO. 3

pressed receptors, these cells are acting on a hair trigger—fine for fleeting threats, but detrimental over time. “They’re kind of like an angry drunk who’s looking for a fight,” said Younger. And, if they are activated long enough, it pushes the central nervous system to a neurodegenerative state. “There’s a lot of approaches to ma-

nipulating these microglial cells,” he said. “Probably the one with the most supporting data right now is naltrexone, but we need to work on more because it’s not going to help everybody.” As Younger explained, scientists are not locked in to any particular modalities of research. Hypotheses are still evolving alongside the quest JUNE 2015

for new drugs, and even older therapies could play a role. “We have all these anti-inflammatories, but they generally work in the peripheral nervous system,” he said. “If we could modify one of those peripheral anti-inflammatories, just to assist it to get into the central nervous system, that may be all we need.” n

www.ValueBasedRheumatology.com

CCR Conference Highlights

Lupologists Seek “Holy Grail” of Biomarkers Chase Doyle

n the rapidly evolving field of medicine, what may seem esoteric today could be standard of care tomorrow. Biomarkers, whether a simple blood test or a complicated imaging technology, inhabit this bleeding edge—a confounding space of limitation and potential, where better outcomes are only a single measurement away. According to a presentation at the 2015 annual Congress of Clinical Rheumatology, lupus needs a biomarker—stat. “Biomarkers are not esoteric,” said Susan Manzi, MD, MPH, co-director of the Allegheny Health Network’s Lupus Center of Excellence in Pittsburgh, and professor at Temple University School of Medicine in Philadelphia. “They provide a very practical application to patient care and decision making. I would love to have a test [for lupus] that provides a level of certainty in terms of susceptibility, diagnosis, disease activity, or prognosis and subsetting.” While the concept of a biomarker is simple—a physical, cellular, biochemical, molecular, or genetic measurement that indicates a normal biological process, a pathogenic process, or some kind of pharmacologic response—the path to finding one in lupus has been anything but. Easy to measure and very inexpensive, blood pressure and low-density lipoprotein (LDL) cholesterol are the greatest biomarkers in the cardiovascular world: both are indicative of

pathologic conditions (hypertension and hyperlipidemia, respectively) and both can predict bad outcomes (cardiovascular events, stroke, etc). “The holy grail in lupus is a blood pressure or LDL marker that can be that good at predicting outcomes of our diseases,” said Manzi. Unfortunately, for a heterogeneous disease like lupus, even diagnosis requires multiple tests, and accuracy is

termine whether someone has lupus or not, which leads to utilization of myriad medical resources and untold expense. The identification of patients before disease would be ideal and will, perhaps, one day be possible, with the rapid pace of gene discovery from high-throughput sequencing technology. “When you look at genome-wide scans,” said Manzi, “you can see cer-

”I would love to have a test [for lupus] that provides a level of certainty in terms of susceptibility, diagnosis, disease activity, or prognosis and subsetting.” —Susan Manzi, MD, MPH

seldom guaranteed. As Manzi explained, lupus is an outlier, the rare kind of illness that can be both underand overdiagnosed, particularly among primary care physicians. “Diagnostic accuracy was only 50% for nonrheumatologists,” she said, “and even rheumatologists only had 80% accuracy…Some people believe that we shouldn’t even call it a disease, we should call it a spectrum or a syndrome of multiple diseases within.” The point being: it is not easy to de-

tain loci much more commonly expressed in lupus than in controls…You can categorize [genes] by pathways that are relevant to lupus, whether it’s immune complex processing or signal transduction with interferon pathway, and this leads to more investigation into those pathways, not only understanding why you get lupus but also targeting therapies and developing for drug discovery.” Beyond improving diagnostic accuracy, biomarkers that help identify

what will happen to a patient, once he or she receives a diagnosis, will enable more effective treatment. “We want to be able to monitor disease activity,” she said. “A biomarker that tells us, without subjectivity, when a patient is going to get sick or that can predict flares would be incredibly useful.” According to Manzi, autoantibody status already plays a role in the diagnosis and clinical subsetting of lupus, but it is not sufficient to stand alone; other measures are needed. Cellbound compliment activation products could provide a portfolio of biomarkers for diagnosis, monitoring, and subsetting, and proinflammatory high-density lipoprotein (HDL) may represent a biomarker for cardiovascular disease in lupus. There is also imaging in the form of carotid ultrasound to aid in predicting cardiovascular disease in high-risk patients. In the end, however, it could be a combination of all the above—and other, heretofore unknown indicators—that provide lupologists with the “grail” they desperately seek. Manzi imagines these biomarkers will likely require a panel of tests that can be compiled into indices. “It’s going to be hard work,” she concluded, “but if we can identify people before they develop disease, intervene early, or better prognosticate so we can aggressively treat for any organ we think our patients are at risk for, it will definitely be worth it.” n

Psoriatic Arthritis: Treating the Totality of Disease Chase Doyle

he power of technology is driving breakthroughs in medicine with advances in genomics, proteomics, metabolomics, and informatics, to name just a few. But heterogeneous conditions like psoriatic arthritis require more than just technology—they demand a holistic approach to therapy, with careful consideration and treatment of the totality of disease. At the 2015 annual Congress of Clinical Rheumatology, Iain B. McInnes, MD, PhD, professor of medicine and director of the Institute of Infection, Immunity and Inflamma-

tion at the University of Glasgow, Scotland, said, “I love the fact that we are simplifying our therapeutic ap-

about each tissue compartment, including metabolic and psychological [components]. If we take all of those

Heterogenous conditions demand a holistic approach to therapy, with careful consideration and treatment of the totality of disease.

proach with the aid of algorithms, but psoriatic arthritis needs to give us pause for thought. I’d like us to think

VALUE-BASED CARE IN RHEUMATOLOGY

JUNE 2015

together, we will offer truly holistic care that really will make a difference for our patients.”

In his own words, psoriatic arthritis is a “dreadful diagnosis.” Although pathologic features of this condition include synovitis, enthesitis, osteitis, and skin and nail diseases, there are other functional deficits too. Patients suffer from vascular and metabolic syndromes, and according to McInnes, it is undoubtedly a psychoneurologic disorder. There is also the issue of outcome heterogeneity. Dermatologists, for example, give psoriasis the same name when it is phenotypically different. All of this, he said, “really reflects the fact we don’t know how to measure Continued on page 17

VOL. 4

NO. 3

CCR Conference Highlights

Psoriatic Arthritis: Treating the Totality…

Continued from page 16

the totality of the disease very well.” Part of this totality is a psychoneurologic component. A recent imaging study of 12 patients with psoriatic arthritis (excluding those with depression) revealed dysregulation of hippocampal chemical function. “These patients are depressed, not because of swollen joints or skin problems,” said McInnes, “but because the disease involves the brain. There’s a molecular component of the disorder.” Conflation with rheumatoid arthritis is also a problem. Despite differences in physiology, genetics, therapeutic response, gender response, and a host of other factors, psoriatic arthritis is

often treated as the same condition. “The big problem for us is that we’ve treated rheumatoid and psoriatic arthritis the same,” said McInnes. “We have to treat them as their own diseases. Psoriatic arthritis must move away from the dogma of rheumatoid and live in its own space.” Understanding our evolutionary history may help. As McInnes sees it, the complex interrelation of human metabolic and immune systems is an adaptive measure—a byproduct of our hunter-gatherer past—which is why dysregulation of the immune system often leads to some form of metabolic syndrome.

“The immune system uses different immune phenotypes in different parts of the body,” he explained. “Airway responses are different from skin responses, [which] are different from oral responses, [which] are different from intra-organ responses, and there’s a good reason for that—the immune system evolved to deal with the context as well as the nature of the insult.” Given the variance of phenotypic response, McInnes is skeptical of unified outcome measures, which might overlook key differences, especially for new therapeutic interventions. “What a tragedy,” he said, “if you gave a new intervention that cleared

the skin but missed a holistic outcome measure because you needed to have joints better, as well.” Finally, McInnes stressed the risks associated with vascular disease in people with psoriatic arthritis, encouraging his fellow rheumatologists to take the lead in reducing morbidity and mortality. “If we were actually to change comorbid risk, we’ll save lives, and we’ll do it very quickly,” he concluded. “The patients’ challenge is the totality of the disease, so we need to find ways of working together, whether it’s rheumatologists, dermatologists, or primary care physicians.” n

Tendinopathy at the Molecular Level: A Translational Journey Chase Doyle

espite early and aggressive intervention, remission rates remain low for rheumatology patients; damage is often progressive, morbidity and mortality are significant, and socioeconomic decline is an ongoing concern. The challenges facing translational scientists are vast, but the journey to understand one disorder at the molecular level could provide valuable insights for the future. “Forty percent of musculoskeletal consults are actually related to tendinopathy,” said Iain B. McInnes, MD, PhD, professor of medicine and director of the Institute of Infection, Immunity and Inflammation at the University of Glasgow, Scotland. “So we decided to ‘molecularize’ tendon disease...If you knew how to tell a tendon not to go from type I to type III collagen, you would end up with stronger repairs and break the cycle of damage that’s created.” As McInnes explained at the 2015 annual Congress of Clinical Rheumatology, early changes in the human tendon cause the body to make a value judgment that results in the rapid production of collagen. Because type I collagen, which is very strong, cannot be quickly produced, the body makes type III collagen instead.

VOL. 4

NO. 3

“It’s like pitching a tent and constructing a building around the tent,” said McInnes. “Type III collagen is fast, but it’s not very strong, so you get an early repair that’s not useful very long. If you continue to work that tendon, a vicious cycle of damage is created.” The first step to breaking this cycle was biopsying a torn or partially ruptured tendon in arthroscopic repair. Although this step has been performed numerous times over the

full of mast cells, neutrophils, monocytes, and T cells. “Early tendinopathy is a bona fide inflammatory disease,” said McInnes, “every bit as inflamed as a lot of synovitis.” Pathogenesis-Led Discovery While basic scientists might be tasked with pursuing single pathways, McInnes and his team “follow the disease” in a pathogenesis-driven

The journey to understand one disorder at the molecular level could provide valuable insights for the future.

years, what McInnes and his team did next has not: they biopsied the opposite tendon as well. “Because this tendon has come under mechanical stress but has not yet shown any sign of damage, it is therefore the earliest sequence of events that leads to pathology. No one has ever looked at that before,” he said. The first surprise? It turns out that early tendon disease is very different from established tendon disease. It is an acutely inflammatory lesion

approach to discovery. “I’m a translational biologist,” he said. “I don’t have the luxury of going after pathways just because they’re there.” Thus, the most important questions for his team were: (1) What is the sequence of events that lead to improper healing in the tendon; and (2) If you target the relevant tissue, does it make a difference? What they discovered, using mouse models to mimic early tendon damage, was a molecule called interleukin

JUNE 2015

33 (IL-33), which was functionally and temporally related to type III collagen production. In other words, neutralizing IL-33 regulated the levels of type III collagen. In a complicated process involving microRNA delivery vehicles, researchers were able to “switch off” the production of type III collagen and revert back to type I for healthy, strong, and rapid tendon repairs. Future Implications Could tennis players inject themselves with monoclonal antibodies before a match one day to stave off inflammation? Given the constant microprocessing and microtearing of tissues, the notion might not be as farfetched as it sounds. “I’m not sure I would do it in everyone before they play tennis,” said McInnes, “but for those people who have a tendency of developing tendinopathy, then absolutely—there might well be prophylactic normaltendon modulation.” For now, McInnes and his team are betting on horses. “We have clinical trials beginning with racehorses now,” he concluded. “Twenty-five percent of racehorses actually develop career-threatening tendinopathy, so we’re seeing if we can change that first.” n

www.ValueBasedRheumatology.com

Health Economics

Mathematical Model Suggests It Is Cost-Effective to Combine Bariatric Surgery and Hip Replacement in Morbidly Obese Individuals Rosemary Frei, MSc

n analysis of a theoretical cohort of patients using a mathematical model suggests that it is cost-effective for morbidly obese individuals to have bariatric surgery prior to total hip arthroplasty (THA), compared with having hip-replacement surgery alone. Emily Dodwell, MD, assistant professor of orthopedic surgery, Weill Cornell Medical College, New York, and her colleagues presented the results at the American Academy of Orthopaedic Surgery’s 2015 annual meeting. Previous studies showed that hip osteoarthritis is 2 to 4 times more common in people who are obese, and that hip-osteoarthritis patients who are obese are 3 times more likely to need THA, than those who are not obese. Based on this, Dodwell’s team created a “state-transition Markov model” using data from real

patients. It simulated a theoretical flow of 100,000 morbidly obese patients either through primary THA with persisting obesity, or through

The assumptions in the model included that patients had a body mass index of at least 35 kg/m2 and had end-stage hip osteoarthritis and there-

“Performing bariatric surgery before [total hip arthroplasty] appears to be cost-effective in the current state of what we believe in the US is the societal willingness to pay for QALYs.” —Emily Dodwell, MD

bariatric surgery followed by THA after losing excess weight. The model also took into account the probabilities of needing repeat surgery and other patient parameters.

fore were primary THA candidates. The model yielded a cost of $55,795/ patient for THA alone and $75,207/ patient for bariatric surgery followed by THA. They also found there were

13.94 additional quality-adjusted lifeyears (QALYs) associated with THA alone and 15.11 QALYs associated with combining bariatric surgery and THA. By dividing the cost difference of $19,412 by the QALY difference of 1.17, the team arrived at an incremental cost-effectiveness ratio (ICER) of $16,591/QALY. In addition, they performed a tornado analysis, which is a form of sensitivity analysis, and found this also favored combined surgery over THA alone. “Performing bariatric surgery before THA appears to be cost-effective in the current state of what we believe in the US is the societal willingness to pay for QALYs,” Dodwell said. n Reference

Southren DL, McLawhorn AS, Figgie MP, et al. Cost-effectiveness of bariatric surgery prior to total hip arthroplasty in morbidly obese patients. Poster presented at: American Academy of Orthopaedic Surgery 2015 Annual Meeting; March 24-28, 2015; Las Vegas, NV. Abstract P078.

Psoriatic Arthritis

Treatment of Psoriatic Arthritis Explored by Cost-Effectiveness Caroline Helwick

ccording to a network meta-analysis and cost-perresponder (CPR) analysis presented at the recent Academy of Managed Care Pharmacy annual meeting, adalimumab was the most cost-effective biologic for the treatment of psoriatic arthritis (PsA) in terms of incremental CPR for 2 clinical efficacy measurements and at 2 time points, weeks 12 and 24. Keith Betts, PhD, of the Analysis Group Inc, Boston, Massachusetts, determined the CPR for drugs used in treating PsA: the tumor necrosis factor-α (TNF-α) inhibitors adalimumab, certolizumab, etanercept, golimumab, and infliximab; the interleukin 12/23 inhibitor ustekinumab; and the oral phosphodiesterase (PDE4) inhibitor apremilast. “Reliable evidence about the compar-

ative effectiveness of these therapies is needed to inform clinical and economic decisions regarding their use,” the authors suggested on their poster. They identified 16 publications that included the clinical efficacy measures of ACR20 and PASI75, and determined the relative probability of achieving these measures with each drug (at approved doses) at weeks 12 and 24. They also calculated the number needed to treat (NNT) and compared cost per incremental ACR20 and PASI75 responder. In terms of relative effectiveness on the PASI75 at week 12, the NNTs were significantly lower for adalimumab and infliximab, compared to apremilast, which held true for week 24, with golimumab also significantly lower. For ACR20, adalimumab,

VALUE-BASED CARE IN RHEUMATOLOGY

JUNE 2015

etanercept, infliximab, and golimu mab had significantly lower NNTs relative to apremilast and ustekin umab 90 mg at week 12. At week 24, adalimumab and golimumab had significantly lower NNTs relative to apremilast and ustekinumab 45 mg. The incremental costs per ACR20 responder at week 24 were found to be quite low for 4 drugs: adalimumab ($36,496), golimumab ($39,928), etanercept ($48,439), and infliximab ($48,577). Higher costs were observed with apremilast ($59,526), certolizumab ($65,777), ustekinumab 45 mg ($117,164), and ustekinumab 90 mg ($188,879). Importantly, the authors noted that adalimumab, infliximab, and golimumab were consistently associated with lower CPR for treating both joint and skin symptoms related to

PsA. “In the treatment of PsA, the goal of therapy is to have improvements in both skin and joint symptoms,” they stated. Etanercept was only associated with lower CPR for treating joint symptoms related to PsA, and certolizumab, ustekinumab, and apremilast were not associated with lower CPR for treating either skin or joint problems related to PsA, their study found. n Disclosure: The study was funded by AbbVie, Inc. Reference

Betts K, Griffith J, Reichmann W, et al. Network meta-analysis and cost per responder of tumor necrosis factor, interleukin, and phosphodiesterase inhibitors in the treatment of psoriatic arthritis. Poster presented at: Academy of Managed Care Pharmacy 27th Annual Meeting & Expo; April 7-10, 2015; San Diego, CA.

VOL. 4

NO. 3

Lupus

Treatment Outcomes and Cost Assessed for Systemic Lupus Erythematosus Caroline Helwick

espite the high direct medical costs of treating systemic lupus erythematosus (SLE), opportunities exist for improving SLE treatment rates, treatment appropriateness, and referral to specialists, according to research presented at the Academy of Managed Care Pharmacy annual meeting. “These changes may result in better clinical and economic outcomes for patients with SLE,” Hong Kan, PhD, of GlaxoSmithKline, suggested on the study poster. Treatment options for SLE include corticosteroids, immunosuppressants, and biologics, each of which has a unique risk-benefit profile that should be considered by prescribing physicians. This retrospective observational study sought to identify treatment patterns in newly diagnosed SLE patients and their associated clinical and economic outcomes. The investigators followed the

treatment of an incident SLE cohort (N=1611) for 4 years, using the Truven MarketScan commercial claims database. The analysis included 5 SLE

ciated with better clinical and economic outcomes, compared with treatment by primary care providers… [and] corticosteroid monothera-

Treatment options for SLE include corticosteroids, immunosuppressants, and biologics.

therapies: corticosteroids, hydroxychloroquine, azathioprine, mycophenolate mofetil, and methotrexate. Clinical outcomes included number and severity of flares, as well as number of hospitalizations, emergency department visits, and office and out patient visits. Economic outcomes included the total costs of hospitalizations, emergency department visits, office and outpatient visits, prescription drugs, and medical care. “Treatment by specialists was asso-

py was associated with the worst clinical and economic outcomes of all the treatment clusters,” Kan and colleagues indicated on their poster. The study’s key findings were these: • SLE treatments did not change substantially over the 4-year period in this newly diagnosed cohort • Minimal treatment was the most common approach to managing these patients (42.8%) • The greatest persistent and nonpersistent uses of the drugs were

for hydroxychloroquine monotherapy (34.0%), corticosteroid monotherapy (11.2%), and the combination of these (7.8%) • Clinical and economic outcomes were poorest with corticosteroid monotherapy • Corticosteroid monotherapy outcomes may improve with the addition of hydroxychloroquine and/ or immunosuppressive agents • Compared with the minimally treated cluster, hydroxychloroquine monotherapy had similar or better outcomes • A large proportion of SLE care is provided by non-specialists (45%), despite the potential benefits of involving specialists n Reference

Kan H, Nagar S, Patel J, et al. Longitudinal treatment patterns and associated outcomes in patients newly diagnosed with systemic lupus erythematosus (SLE) in the US. Poster presented at: Academy of Managed Care Pharmacy 27th Annual Meeting & Expo; April 7-10, 2015; San Diego, CA.

Ankylosing Spondylitis

Ankylosing Spondylitis Treatment Costs Assessed Caroline Helwick

n a study reported at the Academy of Managed Care Pharmacy annual meeting, adalimumab was found to have the lowest incremental cost per responder (CPR) and to be cost-saving, compared with the next most cost-effective option, etanercept, among the biologics approved by the US Food and Drug Administration (FDA) for treating ankylosing spondylitis (AS). “Taking costs into account, adalimumab was found to be the most cost-effective biologic treatment…,” Keith Betts, PhD, of the Analysis Group Inc, Boston, Massachusetts, and colleagues, noted on their poster. Biologic therapies, specifically the tumor necrosis factor-α (TNF-α) inhibitors, confer immediate, significant, and sustained improvements for almost all clinical symptoms of

VOL. 4

NO. 3

AS, but there have been few headto-head comparisons of their efficacy and costs. The current study was a CPR analysis of the FDA-approved biologics for treating active AS, based on data from 13 randomized clinical trials evaluating the drugs in their approved doses versus placebo. The drugs included adalimu mab, etanercept, certolizumab, golim umab, and infliximab. Betts and his team determined the relative probability of achieving response at week 12 according to ASAS 20 (improvement ≥20% or ≥10-unit reduction in at least 3 of 4 domains, without worsening in the fourth domain). They also determined ASAS40 response (≥40% improvement). Treatment costs were calculated based on wholesale acquisition costs. The incremental CPR was calculated by multi-

Table ASAS20 Response: TNF Inhibitor Versus Placebo TNF Inhibitor

NNT

CPR (2014 USD)

Etanercept

2.96

$23,991

Adalimumab

2.81

Golimumab

3.09

Infliximab

2.29

Certolizumab

4.40

plying the incremental drug cost by the number needed to treat (NNT). The investigators found no statistical differences between the biologic treatments in terms of ASAS20 response. Numerically, infliximab had the highest estimated ASAS20 (71%), followed by adalimumab (63%), etanercept (61%), golimumab (60%), and certolizumab (50%). ASAS40 response was also not statistically differJUNE 2015

$21,067

$25,102 $25,616

$48,715

ent between the treatments: infliximab (51%), adalimumab (49%), etanercept (41%), golimumab (39%), and certolizumab (35%). However, the network meta-analysis for the estimated ASAS20 NNT and incremental cost per ASAS20 responder numerically favored adalimumab, whose incremental cost ($21,067) was $2924 lower than the next lowest, etanercept. The costs and Continued on page 20

www.ValueBasedRheumatology.com

Ankylosing Spondylitis

Switching Among TNF Agents in Patients with Refractory Ankylosing Spondylitis Rosemary Frei, MSc

n analysis of data from 337 people with treatment-refractory ankylosing spondylitis (AS) indicated 88.1% received only one line of anti–tumor necrosis factor-α (anti-TNF-α) therapy while the remaining 11.9% switched to one or more anti-TNF-α agents. The results were presented at the 2015 annual meeting of the International Society for Pharmacoeconomics and Outcomes Research. Value-Based Care in Rheumatology asked lead investigator Jacqueline Palmer, PharmD, whether she was surprised by any of the results. “In a structurally progressive disease like AS, it is surprising to see a [relatively] high number of patients discontinue use of biologic treatments, which could have implications for the long term,” noted Palmer, associate director, Health Economic & Outcomes Research, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey. “In addition, patients

[who had only] one line (first) of biologic treatment had the highest medical costs. Further study is needed, but this could be due to severity of symptoms at the onset of treatment.”

care Supplemental and Coordination of Benefits Database. Two hundred and ninety-seven patients did not switch from one anti-TNF-α therapy to another. Among

“In a structurally progressive disease like AS, it is surprising to see a [relatively] high number of patients discontinue use of biologic treatments.” —Jacqueline Palmer, PharmD

Palmer’s team used data gathered between January 1, 2005, and September 30, 2013, from Truven Health’s MarketScan Commercial Claims and Encounters Database and the Medi-

those patients, 217 (73.1%) discontinued the biologic during a 3-year follow-up and 80 (26.9%) remained on the original biologic. Another 30 of the 337 patients (8.9%) received a

second biologic and 10 (3%) also received a third. Overall, the most commonly used biologics were etanercept (41.5% of patients), adalimumab (40.9%), infliximab (12.2%), and golimumab (5.3%). Etanercept was also the most commonly used first-line biologic among patients who switched to another agent (62.5% of 40) while adalimumab was the most popular biologic among patients who were not switchers (43.4% of 297). Medical costs totaled $354 for nonswitchers. The respective totals were $225 for people who received 2 lines of anti-TNF-α medications and $112 for those who received 3 or more lines. Total pharmacy drug costs were similar in all 3 groups, non-switchers at $1899, 2 lines $1955, and 3 lines $1890. n Reference

Palmer J, Liao M, Herrera V, et al. Modification of biologic therapy in patients with ankylosing spondylitis. In: Proceedings from the ISPOR 20th International Annual Meeting; May 16-20, 2015; Philadelphia, PA. Abstract PMS19.

Rheumatoid Arthritis

Biologic Therapy Discontinuation in RA Rosemary Frei, MSc

here is an association between discontinuation of biologic therapy in patients with rheumatoid arthritis (RA) and using a lower number of disease-modifying antirheumatic drugs (DMARDs) or

not using concomitant methotrexate. A Canadian team funded by AbbVie Corporation used a database of approximately 22,800 patients with inflammatory disease in Quebec. They focused on 623 adults who had been

Ankylosing Spondylitis… Continued from page 19 NNT versus placebo per ASAS20 responder are shown in the Table. Irrespective of costs, infliximab was found to require the lowest NNT to achieve ASAS20 or ASAS40 response, the authors noted. “We conducted 3 sensitivity analyses to evaluate the robustness of the outcomes and found consistent results,” they indicated on the poster. n

Disclosure: The study was funded by AbbVie, Inc. Reference

Betts K, Griffith J, Mittal M, et al. Indirect treatment comparison of adalimumab, etanercept, certolizumab, golimumab, and infliximab for the treatment of ankylosing spondylitis. Poster presented at: Academy of Managed Care Pharmacy 27th Annual Meeting & Expo; April 7-10, 2015; San Diego, CA.

VALUE-BASED CARE IN RHEUMATOLOGY

JUNE 2015

diagnosed with RA and had been treated with at least one biologic since 2003. Their average age was 53.2 years and 77.1% were women. Furthermore, average disease duration was 7.7 years. Two hundred and thirty-three patients (37%) had stopped their first biologic treatment after 6 months, while 326 (52%), 405 (65%), and 438 (70%) had done so after 12, 24, and 36 months, respectively. The patients’ average time on their first biologic agent was 1.7 years. The investigators constructed Cox proportional hazard models that showed working part time was associated with a 57% higher probability of biologic discontinuation over the complete treatment duration compared with working full time, with a hazard ratio (HR) of 1.57. Annual incomes of either $20,000 to $39,999 or $80,000 to $99,999 were both associated with a higher probability of biologic discontinuation than earning less than $20,000,

with HRs of 1.35 and 2.16, respectively. The 2 factors the researchers found to be associated with a lower probability of biologic discontinuation were use of a higher number of DMARDs (HR=0.89) and the concomitant use of methotrexate (HR=0.80). “AbbVie is interested in the topic of treatment adherence, as we are committed to improving the treatment experience for people living with chronic diseases. We hope that by better understanding the factors associated with lower adherence and treatment discontinuation, we can improve patient outcomes,” according to a statement sent to Value-Based Care in Rheumatology by Scott C. Brun, MD, Vice President, Pharmaceutical Development, AbbVie, Saint-Laurent, Quebec. n Reference

Choquette D, Laliberté M-C, Desjardins O, et al. Biologic discontinuation in rheumatoid arthritis: experience from Canadian clinics. In: Proceedings from the ISPOR 20th International Annual Meeting; May 16-20, 2015; Philadelphia, PA. Abstract PMS60.

VOL. 4

NO. 3

Rheumatology Practice Management

™

Prescription Drug Cost Sharing Parsed by Panel at Pharmacoeconomics Meeting Rosemary Frei, MSc The goal is to lower use of expensive drugs when it is therapeutically appropriate, she told Rheumatology Practice Management. Elise Gould, PhD, senior economist and health policy research director,

”The Affordable Care Act did not ambitiously take on what we might call the middlemen, the third-party payers— it kept them front and center in the marketplace.” —Elise Gould, PhD

ticipated in a session on prescription cost shifting from payers to patients at the recent annual meeting of the International Society for Pharmacoeconomics and Outcomes Research. Elizabeth Hargrave, MPA, principal research scientist, Health Care Research Department, NORC at the University of Chicago, outlined the evolution of government- and private-insurance health plans over the past decade. Deductibles have gone up, there are more drug tiers, cost sharing is now common, prior authorization has increased, and there is greater use of preferred pharmacy networks. While there are some differences between the trends in employer-sponsored plans compared with Part D plans, such as dramatic increases in deductibles in the former compared with the latter, noted Hargrave, the overall thrust has been to put more of patients’ skin in the game.

Economic Policy Institute, Washington, DC, made the argument that the “more skin in the game” approach is misguided. She said cost sharing is a poorly targeted cost-containment device that can lead to medically and economically inefficient decisions. She cited highly publicized previous research showing higher cost can have unintended consequences such as reduced drug compliance and less use of preventive services. Patients end up being the losers, she said, while insurance companies improve their bottom lines. “For sure, the Affordable Care Act did not ambitiously take on what we might call the middlemen, the third-party payers—it kept them front and center in the marketplace,” she said in a telephone interview with Rheumatology Practice Management. “What was supposed to restrain insurance companies was the medical

loss ratio. But insurance companies, if they’re going to get a share of the total spending, they’re not incentivized to have the total spending go down.” Mark Fendrick, MD, professor of internal medicine, University of Michigan Health System, Ann Arbor, presented what he believes is a middle path, value-based insurance design (VBID), which moves away from the “one size fits all” cost sharing. Use of VBID in high-deductible health plans creates “smarter deductibles,” with the cost-sharing level based on clinical benefit rather than the acquisition price of the service or product, he explained to attendees. Therefore high-value services would have no more than modest cost sharing. “There are very, very, very, very few healthcare-reform ideas that have as broad-based support as VBID does,” he

Rheumatology’s board of directors, for a comment. “America is built and embedded in a capitalist economy where insurance and pharmaceutical companies do not have to lower their profits to meet the healthcare cuts. Instead, profits go up for these companies, and hassle and cost go up for patients—without explanation or recourse in the vast majority of cases. Simultaneously, providers are reimbursed less or inadequately to cover the cost of delivering quality care,” said King. “When we try to reconcile these 2 competing values, the stakeholders are left with a total lack of transparency on where the money is being spent to add to the value of healthcare. I favor a solution where the costs of procedures and treatments are contained and agree with the notion of VBID,

”Stakeholders are left with a total lack of transparency on where the money is being spent to add to the value of healthcare.” —Charles King, MD

said in a telephone interview. “That’s because it makes sense, it’s easy to explain, and no one’s against value.” Rheumatology Practice Management asked Charles King, MD, senior clinical rheumatologist, North Mississippi Health Services, Tupelo, and a member of the American College of

where cost is kept to a minimum for high-value services and goods.” n Reference

Hargrave E, Gould E. Should the name of the game be more “skin in the game?” The scope and consequence of Rx cost shifting from payers to patients. Panel presentation at: ISPOR 20th International Annual Meeting; May 16-20, 2015; Philadelphia, PA.

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

ow can the high cost of healthcare be spread among all stakeholders to produce the biggest patient-care bang for the buck? That is the question thousands of experts are fixated on, including several who par-

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

VOL. 4

NO. 3

JUNE 2015

www.ValueBasedRheumatology.com

Rheumatology Practice Management

™

Seven Steps to Finding the Right Financial Advisor W. Ben Utley, CFP, and Lawrence B. Keller, CFP, CLU, ChFC, RHU, LUTCF

W. Ben Utley

Lawrence

s a physician with substantial income (or income potential), you will most likely be contacted by a number of individuals offering various types of financial products and services throughout your career. If you are in the market for an advisor, you will want to know the qualifications and experience level of each one you are considering. Unlike medicine, which has a standardized path that physicians must take to gain the education, training, and experience necessary to obtain board certification, the insurance and financial services industry does not. While advisors must pass certain tests to earn a license in securities or insurance, for the most part, anyone can call himself or herself a financial advisor. Credentials and Certifications Finding the right financial advisor to help you build your financial future can be as challenging as choosing the right doctor to care for your health, so it is important to look for several key credentials. Following is a brief summary of some of the most recognizable designations or certifications that you might see among financial service professionals and what it takes to earn them. Certified Public Accountant (CPA): CPAs provide you with advice on tax matters and help you prepare and submit your income tax returns to the Internal Revenue Service. To be a CPA, candidates must pass a 14-hour computer-based test with 4 sections: auditing and attestation; financial accounting and reporting; regulation; and business environment and concepts. There are also work experience requirements that must be met. Not all accountants are CPAs. CPAs must meet stringent continuing education requirements and are regulated by states as well as their profession’s code of ethics.

Personal Financial Specialist (CPA/PFS): A PFS is a CPA who has demonstrated both knowledge and significant practical experience in the area of personal financial planning. Only CPAs who are members of the American Institute of Certified Public Accountants can earn this designation. Certified Financial PlanB. Keller ner (CFP): The CFP certification is one of the most recognized and prestigious credentials in the financial services industry. CFPs have completed a series of courses in investments, insurance, income taxes, estate, and retirement planning. They have also passed a comprehensive 10-hour certification exam. Additionally, CFPs must have at least 3 years of planning experience and meet stringent continuing

also have at least 3 years of professional experience. Chartered Financial Analyst (CFA): CFAs have expertise in investing and portfolio management. They have passed 3 exams based on investment principles, applied financial analysis, and investment management. Each exam is approximately 6 hours in length. Additionally, CFAs must have at least 3 years of experience in the investment decision-making process. Generally, the CFA designation is recognized as the definitive standard for measuring competence and integrity in the fields of portfolio management and investment analysis. The Steps Financial planning takes the guesswork out of managing your finances and helps you understand the implications of each financial decision you make. Everyone has different goals, so it is important to have a unique plan

Whereas most licenses require an advisor to pay a fee and pass an exam,…certifications usually require a higher level of commitment and dedication.

education requirements as well as have a bachelor’s degree. While an estimated 700,000 people currently call themselves financial planners, only 1 in 10 holds the CFP designation. If you need help with more than 1 issue in your financial life or if you are targeting long-term goals like retirement or college, make sure a CFP is on your list. Chartered Financial Consultant (ChFC) : ChFCs have credentials similar to CFPs. ChFCs have completed a series of courses and exams covering financial, insurance, and estate planning subjects. The ChFC program provides financial planners and others in the financial services industry with in-depth knowledge of the skills needed to perform comprehensive financial planning for their clients. Chartered Life Underwriter (CLU) : CLUs are insurance agents who have completed comprehensive educational courses and demonstrated expertise in different areas of estate and insurance planning. This designation is specifically designed to enhance the knowledge of people employed in the life insurance industry. CLUs must

VALUE-BASED CARE IN RHEUMATOLOGY

JUNE 2015

that works for you and your financial situation, both now and in the future. The following 7 steps will help you find an advisor who understands and meets your unique goals and needs

Make a Well-Founded List of Prospective Advisors Begin your research by conducting an internet search using the terms “physician financial advisor” or “physician financial planner.” Look for signs of expertise such as published articles, a book, or maybe even a blog. A search outside of your community means you increase the odds of finding the best-qualified advice for the price you may pay. A search inside of your state means that the advisors you find are more likely to understand your financial environment, including your state’s tax laws, economy, job market, unique investment opportunities, and other factors that may impact the success of your financial plan. If you are concerned about the advisor’s location, keep in mind that today many financial advisors work with clients by telephone, email, and video conference on a regular basis.

Next, it is important to search a few specific organizations. CFP Board (www.cfp.net) is a nonprofit organization acting in the public interest by fostering professional standards in personal financial planning through its setting and enforcement of the education, examination, experience, ethics, and other requirements for CFP certification. The National Association of Personal Financial Advisors (www.napfa.org) is the country’s leading professional association of fee-only financial advisors. Finally, the Financial Planning Association (www.plannersearch.org) is the largest membership organization for CFP professionals in the United States and also includes members who support the financial planning process. To round out your list of prospective advisors, ask your colleagues, your accountant, and your attorney who they recommend. Ask them why they believe this advisor is the best one for you. If their reason sounds valid, add the advisor to your list.

Select for Quality Every prospective financial advisor on your list should have at least 1 real credential. Beware of generic pseudocredentials like financial advisor, financial consultant, and wealth manager. These titles merely signify that an advisor is in the business and may hold a license. Whereas most licenses require an advisor to pay a fee and pass an exam, these may be easily acquired with a minimal commitment of time and effort. In contrast, certifications usually require a higher level of commitment and dedication. Formal training, rigorous examination, continuing education, years of experience, and oversight by a board or governing body are part of attaining and keeping a certificate, so certification is an outward indicator of the quality of advice you may receive. Narrow your list by crossing advisors off your list if they do not have at least 1 of the previously listed credentials.

Do Your Homework Learn more about the advisors who remain on your list. Visit their websites, and search for answers to questions such as the following: • How long have you been in business? • What type of clients do you work with? • What services do you provide? VOL. 4

NO. 3

Rheumatology Practice Management

™

• What is your specialty? • What is your approach to financial planning?

Conduct an Interview Every advisor on your newly trimmed list warrants a preliminary phone call. This is an interview, and you are the interviewer, not the interviewee, so make sure that you get the answers you need. First and foremost, ask the candidate how he or she is paid. Planners can be paid in several ways: through fees, commissions, or a combination of both. Your financial planner should clearly state how he or she will be paid for the services to be provided. Although there is no single method of paying for financial services that is inherently better than another, you will nevertheless want to consider, and discuss with your planner, how the method of compensation could affect the advice you receive or the way you work with the advisor. You and your financial planner should discuss these issues, including any conflicts of interest that may be created by the method of compensation. Then ask whether the advisor has ever been publicly disciplined for any unlawful or unethical actions in his or her professional career. Several government and professional regulatory organizations, such as the Financial Industry Regulatory Authority, your state insurance and securities departments,

and the CFP Board keep records on the disciplinary history of financial planners and advisors. If a CFP professional violates any of the CFP Board’s standards, he is subject to disciplinary action up to permanent revocation of certification. Ask which organizations the planner is regulated by and contact these groups to conduct a background check. You can also visit http://broker check.finra.org. Make appointments to visit advisors who remain on your list after this screening round.

Speak with at Least 3 Prospective Advisors Now you are ready to make the biggest mistake that most people make when selecting an advisor: engaging the very first advisor you meet. While this may solve your immediate problem, it may lead to less-than-stellar results over the long haul. Why? Almost all advisors hold up well during the first interview. They have been interviewed hundreds of times and are ready to sign you up today. Resist the temptation to sign up for services at the first meeting. Instead, collect information and get a feel for how you and the advisor might work together over the longer haul.

Consider What You Have Learned Think about your interview

with each advisor. Ask yourself these last few questions before making your final decision: • How well did each financial advisor listen to me? The hallmark of a good relationship with your financial advisor will be your ability to communicate your needs. This means that he or she must do an excellent job of listening to you in order to understand how he or she can help. • How clearly did each financial advisor express himself or herself? Even if you receive the very best financial advice from your new advisor, you might not follow the advice unless you fully understand it. Consider whether the advisor “speaks your language.” • What promises did each financial advisor make? Consider how each advisor attempted to win you as a client. The best advisors attempt to set clear, realistic expectations about your work with them during the very first meeting. They know the foundation for a great, long-term advisor–client relationship is their ability to make promises and deliver on them.

Select a Financial Advisor Who Suits You When you finally decide which advisor to hire, you may realize something that good financial advisors al-

ready know: the financial advisor you choose may be a lot like you. People have a natural tendency to trust others who are much like themselves, so the advisor you choose will likely share your interests, your outlook, and even some of the same financial goals you hold. Summary No matter which financial advisor you choose, make sure the one thing that you have in common is an uncompromised interest in your financial health. Start your search for a competent financial advisor today and begin enjoying better financial health tomorrow. n W. Ben Utley, CFP, is the lead advisor with Physician Family Financial Advisors, a fee-only financial planning firm helping doctors throughout the United States to save for college and invest for retirement. He can be reached at 541463-0899 or by email to ben@physician family.com. Lawrence B. Keller, CFP, CLU, ChFC, RHU, LUTCF, is the founder of Physician Financial Services, a New York– based firm specializing in income protection and wealth accumulation strategies for physicians. He can be reached at 516677-6211 or by email to Lkeller@physi cianfinancialservices.com with comments or questions.

A forum for members of the rheumatology team to have a discussion on the day-to-day operations of running a business. The goal is to share ideas and best practices, and provide a resource to ultimately help run a more efficient practice and improve patient care.

JOIN OUR LinkedIn GROUP TODAY

www.RheumatologyPracticeManagement.com RPM LinkedIn_51914

VOL. 4

NO. 3

FOR OFFICE ADMINISTRATORS, RHEUMATOLOGISTS, PHYSICIAN ASSISTANTS, AND NURSE PRACTITIONERS JUNE 2015 I www.ValueBasedRheumatology.com

ENHANCED USER-FRIENDLY WEBSITE

NOW AVAILABLE!

Added Features:

Archives Resources Article Submission e-Newsletter Registration More News VBCR_WebKsize_53014