VBCR August 2014 Vol 3, No 4

august 2014 VOL 3 • NO 4

www.ValueBasedRheumatology.com

The Needs of the Patient Come First at Mayo Clinic

A Conversation with Eric L. Matteson, MD, Chair, Division of Rheumatology, Mayo Clinic, Rochester, MN

VBCR Perspective

Rheumatologists Responsible for Vaccination in Immunocompromised Patients

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

I

n 2013, the National Vaccine Advisory Committee (NVAC) updated its Standards for Adult Immunization Practice.1 The new standards, recognizing the dismal rate of adult vaccination in the United States, emphasized the role of all providers to

assess immunization status and recommend needed vaccines.

“Every health care provider, in all settings, has a fundamental responsibility to ensure that all patients are up-to-date with respect to recommended immunizations,” according Continued on page 13

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n a recent interview, Eric L. Matteson, MD, Chair of the Division of Rheumatology at Mayo Clinic, Rochester, MN, and Professor of

Medicine, discussed the Division of Rheumatology. The staff consists of 18 rheumatologists, including 2 pediatric rheumatologists or joint pediContinued on page 15

the Rheumatology nurse™

Clinical Research: 1 Hat or 2?

By Sheree C. Carter, PhD, RN Dr Carter is Assistant Clinical Professor, The University of Alabama in Huntsville; and President, Rheumatology Nurses Society (RNS)

T

here is a growing need for dedicated healthcare providers from rheumatology private practice to step into the role of researcher and participate in clinical

trials to evaluate treatment regimens and therapies.

In addition, there is a widening gap in the rheumatology nursing literature and a great need exists for

Continued on page 19

Biosimilars Make Headway in Rheumatoid Arthritis

By Phoebe Starr Paris, France—Rheumatologists, patients, and payers in the United States are eager to determine whether biosimilars of expensive biologic therapies for rheumatoid arthritis (RA) and other rheumatic conditions will pass the hurdles of testing for approval by the US FDA regulatory agencies. At the recent 2014 European League Against Rheumatism (EULAR) Con-

Continued on page 9

inside VALUE PROPOSITIONS. . . . . . . . . . .

Increasing Utilization of TKA Affects Lifetime Medical Costs

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HEALTH ECONOMICS. . . . . . . . . . . . . 7 Value-Based Pricing Benefits Patients, Pharmaceutical Companies Alike RHEUMATOID ARTHRITIS . . . . . . 9 Safety of Tofacitinib Stable Over Time JUVENILE IDIOPATHIC ARTHRITIS. . . . . . . . . . . . . . . . . . . . . . . . 13 Reassuring Long-Term Safety for Biologics in Children with JIA © 2014 Engage Healthcare Communications, LLC

gress, 2 separate randomized, double-blind, phase 3 trials showed progress.

The trials found that biosimilars of etanercept and infliximab are equivalent to their reference compounds.

These studies are important steps toward establishing true equivalence, but questions remain.

Although some biosimilars are ap-

RHEUMATOLOGY UPDATE. . . . 14 Combined Rheumatology-Dermatology Clinic Benefits Specialists, Patients Personalized Medicine in Rheumatology™. . . . . . . . . . . . . . . . . . . . 18 Advances in Genotyping Pinpoints to Genetic Determinant PSORIATIC ARTHRITIS. . . . . . . . . 20 Risk Factors to Consider in Patients with New-Onset Psoriatic Arthritis LUPUS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Childhood SLE Is an Independent Predictor of Low Employment Rates

NOW

APPROVED!

First oral treatment FDA-approved for adults with active psoriatic arthritis Please see Important Safety Information on the adjacent page.

INDICATION Otezla® (apremilast) is indicated for the treatment of adult patients with active psoriatic arthritis.

IMPORTANT SAFETY INFORMATION Otezla is contraindicated in patients with hypersensitivity to apremilast or to components in its formulation.

Depression was reported by patients taking Otezla, including serious depression. Some patients discontinued treatment due to depression.

Weigh the risks and benefits of treatment with Otezla for patients with a history of depression and/or suicidal thoughts/behavior, and in patients who develop such symptoms while on Otezla.

Weight loss was reported in patients taking Otezla. Monitor body weight regularly.

Concomitant use of Otezla with CYP450 enzyme inducers (eg, rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended.

The most common adverse reactions (≥5%) in clinical trials, and those most frequently leading to treatment discontinuation, were diarrhea, nausea, and headache.

Otezla is Pregnancy Category C; it has not been studied in pregnant women. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. Caution should be exercised when Otezla is administered to a nursing woman.

Otezla dosage should be reduced in patients with severe renal impairment (creatinine clearance less than 30 mL/min); for details, see Dosage and Administration, Section 2, in the Full Prescribing Information.

Please see Brief Summary of Full Prescribing Information on the following page.

Get the latest news at www.otezla.com

Otezla® is a registered trademark of Celgene Corporation. © 2014 Celgene Corporation 05/14 USII-APR130013g

Rx Only OTEZLA® (apremilast) tablets, for oral use The following is a Brief Summary of the Prescribing Information; see Full Prescribing Information for complete product information.

INDICATIONS AND USAGE OTEZLA® (apremilast) is indicated for the treatment of adult patients with active psoriatic arthritis.

CONTRAINDICATIONS OTEZLA is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients in the formulation [see Adverse Reactions (6.1)].

WARNINGS AND PRECAUTIONS Depression: Treatment with OTEZLA is associated with an increase in adverse reactions of depression. During the 0 to 16 weeks placebo-controlled period of the 3 controlled clinical trials, 1.0% (10/998) of patients treated with OTEZLA reported depression or depressed mood compared to 0.8% (4/495) treated with placebo. During the clinical trials, 0.3% (4/1441) of patients treated with OTEZLA discontinued treatment due to depression or depressed mood compared with none in placebo treated patients (0/495). Depression was reported as serious in 0.2% (3/1441) of patients exposed to OTEZLA, compared to none in placebo treated patients (0/495). Instances of suicidal ideation and behavior have been observed in 0.2% (3/1441) of patients while receiving OTEZLA, compared to none in placebo treated patients (0/495). In the clinical trials, two patients who received placebo committed suicide compared to none in OTEZLA treated patients. Before using OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior prescribers should carefully weigh the risks and benefits of treatment with OTEZLA in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with OTEZLA if such events occur.

Weight Decrease: During the controlled period of the studies, weight decrease between 5-10% of body weight was reported in 10% (49/497) of patients treated with OTEZLA 30 mg twice daily compared to 3.3% (16/495) treated with placebo [see Adverse Reactions (6.1)]. Patients treated with OTEZLA should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of OTEZLA should be considered.

Drug Interactions: Co-administration of strong cytochrome P450 enzyme inducer, rifampin, resulted in a reduction of systemic exposure of apremilast, which may result in a loss of efficacy of OTEZLA. Therefore, the use of cytochrome P450 enzyme inducers (e.g. rifampin, phenobarbital, carbamazepine, phenytoin) with OTEZLA is not recommended. [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

ADVERSE REACTIONS Clinical Trials Experience in Psoriatic Arthritis: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The majority of the most common adverse reactions presented in Table 2 occurred within the first two weeks of treatment and tended to resolve over time with continued dosing. Diarrhea, headache, and nausea were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for patients taking OTEZLA were nausea (1.8%), diarrhea (1.8%), and headache (1.2%). The proportion of patients with psoriatic arthritis who discontinued treatment due to any adverse reaction was 4.6% for patients taking OTEZLA 30 mg twice daily and 1.2% for placebo-treated patients.

Table 2: Adverse Reactions Reported in ≥ 2% of Patients on OTEZLA 30 mg Twice Daily and ≥ 1% Than That Observed in Patients on Placebo For Up To Day 112 ( Week 16) Placebo

Preferred Term

OTEZLA 30 mg BID

Day 1 to 5 Day 6 to Day 112 Day 1 to 5 Day 6 to Day 112 (N=495) (N=490) (N=497) (N=493) n (%)c n (%) n (%) n (%)

Diarrhea a

6 (1.2)

8 (1.6)

46 (9.3)

38 (7.7)

Nauseaa

7 (1.4)

15 (3.1)

37 (7.4)

44 (8.9)

Headachea

9 (1.8)

11 (2.2)

24 (4.8)

29 (5.9)

Upper respiratory tract infectionb

3 (0.6)

9 (1.8)

3 (0.6)

19 (3.9)

Vomitinga

2 (0.4)

2 (0.4)

4 (0.8)

16 (3.2)

Nasopharyngitisb

1 (0.2)

8 (1.6)

1 (0.2)

13 (2.6)

Abdominal pain upperb

0 (0.0)

1 (0.2)

3 (0.6)

10 (2.0)

a

Of the reported gastrointestinal adverse reactions, 1 subject experienced a serious adverse reaction of nausea and vomiting in OTEZLA 30 mg twice daily; 1 subject treated with OTEZLA 20 mg twice daily experienced a serious adverse reaction of diarrhea; 1 patient treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction of headache. b Of the reported adverse drug reactions none were serious. c n (%) indicates number of patients and percent.

Other adverse reactions reported in patients on OTEZLA were hypersensitivity, weight decrease, frequent bowel movement, gastroesophageal reflux disease, dyspepsia, decreased appetite*, migraine, cough, and rash. *1 patient treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction.

DRUG INTERACTIONS Strong CYP 450 Inducers: Apremilast exposure is decreased when OTEZLA is co-administered with strong CYP450 inducers (such as rifampin) and may result in loss of efficacy [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C : OTEZLA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to OTEZLA during pregnancy.

Information about the registry can be obtained by calling 1-877-311-8972.

Nursing Mothers: It is not known whether OTEZLA or its metabolites are present in human milk. Because many drugs are present in human milk, caution should be exercised when OTEZLA is administered to a nursing woman. Pediatric use: The safety and effectiveness of OTEZLA in pediatric patients less than 18 years of age have not been established. Geriatric use: Of the 1493 patients who enrolled in Studies PsA-1, PsA-2, and PsA-3 a total of 146 psoriatic arthritis patients were 65 years of age and older, including 19 patients 75 years and older. No overall differences were observed in the safety profile of elderly patients ≥ 65 years of age and younger adult patients < 65 years of age in the clinical studies. Renal Impairment: OTEZLA pharmacokinetics were not characterized in subjects with mild (creatinine clearance of 60-89 mL per minute estimated by the Cockroft– Gault equation) or moderate (creatinine clearance of 30-59 mL per minute estimated by the Cockroft–Gault equation) renal impairment. The dose of OTEZLA should be reduced to 30 mg once daily in patients with severe renal impairment (creatinine clearance of less than 30 mL per minute estimated by the Cockroft– Gault equation) [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. Hepatic Impairment: Apremilast pharmacokinetics were characterized in subjects with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment. No dose adjustment is necessary in these patients.

OVERDOSAGE In case of overdose, patients should seek immediate medical help. Patients should be managed by symptomatic and supportive care should there be an overdose.

Manufactured for: Celgene Corporation, Summit, NJ 07901 OTEZLA® is a registered trademarks of Celgene Corporation.

Pat. www.celgene.com ©2014 Celgene Corporation, All Rights Reserved.

OTZPBS.001 03/14

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

Publishing Staff Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Director, Client Services Zach Ceretelle zceretelle@the-lynx-group.com Editorial Directors Dalia Buffery dbuffery@the-lynx-group.com Frederique H. Evans, MBS fevans@the-lynx-group.com Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Senior Production Manager Lynn Hamilton Production Manager Melissa Lawlor The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Associate Director, Content Strategy & Development John Welz Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede

TM

VALUE PROPOSITIONS

OSTEOPOROSIS

Cost-savings of biologics vary based on definition of remission in RA More…

Better adherence seen in weekly versus daily regimens in patients with osteoporosis

HEALTH ECONOMICS

Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Manager Jini Gopalaswamy Project Coordinators Mike Kodada Deanna Martinez IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski Administrative Coordinator Stephanie Ramadan Office Coordinator Robert Sorensen Engage Healthcare Communications, LLC 1249 South River Road, Ste 202A Cranbury, NJ 08512 Telephone: 732-992-1882 Fax: 732-992-1881

Value-Based Care in Rheumatology, ISSN (applied), is published 6 times a year by Engage Healthcare Com­ munications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2014 by Engage Health­ care Communications, LLC. All rights reserved. Value-Based Care in Rheumatology is a trademark of Engage Health­care Communi­cations, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including pho­ tocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Print­ ed in the United States of America.

The ideas and opinions expressed in Value-Based Care in Rheumatology do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an adver­ tisement or other product mentioned in Value-Based Care in Rheumatology should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

FDA UPDATE

RHEUMATOID ARTHRITIS

FDA approves first generic celecoxib

Safety of tofacitinib stable over time More…

PSORIATIC ARTHRITIS Risk factors to consider in patients with new-onset psoriatic arthritis

JUVENILE IDIOPATHIC ARTHRITIS Reassuring long-term safety for biologics in children with JIA

LUPUS

RHEUMATOLOGY UPDATE

Childhood SLE is an independent predictor of low employment rates More…

Combined rheumatology-dermatology clinic benefits specialists and patients

GOUT Febuxostat versus allopurinol postmarketing study to be conducted in Europe

VBCR Editorial Advisory Board

Creative & Design Assistant Lora LaRocca

Web Content Managers David Maldonado Anthony Trevean

Advances in genotyping pinpoints to genetic determinant

Value-based pricing benefits patients, pharmaceutical companies alike More…

Director, Creative & Design Robyn Jacobs

Director, Digital Media Anthony Romano

Personalized Medicine in Rheumatology™

Howard B. Blumstein, MD Rheumatology Associates of Long Island, Smithtown, NY Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield New York, NY Sheree C. Carter, PhD, RN Assistant Clinical Professor The University of Alabama in Huntsville; President, Rheumatology Nurses Society Gary R. Feldman, MD, FACR Private Practice, Pacific Rheumatology, Los Angeles, CA Gary L. Johnson, MD, MS, MBA Regional Medical Director Humana, Inc, Madison, WI Atheer A. Kaddis, PharmD Vice President, Managed Markets Diplomat Specialty Pharmacy Swartz Creek, MI Shelly P. Kafka, MD, FACR Rheumatologist, Mountain State Rheumatology, Medical Director, Mountain State Clinical Research Clarksburg, WV Clinical Assistant Professor West Virginia University School of Medicine, Morgantown, WV

Lynn Nishida, RPh Director, Clinical Services Catamaran Center of Excellence Northwest Region, Portland, OR

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

Gary M. Owens, MD President, Gary Owens Associates Philadelphia, PA

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

Kim A. Papp, MD, PhD Founder and President Probity Medical Research Waterloo, Ontario, Canada

John Kolstoe, MD Kolstoe Rheumatology Musculoskeletal Medicine East Lansing, MI Randall Krakauer, MD, FACP, FACR National Medical Director Medicare, Aetna, Princeton, NJ Joel M. Kremer, MD Pfaff Family Professor of Medicine Albany Medical College Director of Research, Center for Rheumatology, Albany, NY Alan Menter, MD Director, Baylor Psoriasis Research Center Dallas, TX Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Murray, UT

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 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: 732-992-1882 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.

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www.ValueBasedRheumatology.com

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Value Propositions Coaching Program Cost-Effective in Patients with Early RA

In a 1-year coaching program, patients with early rheumatoid arthritis (RA) who underwent physical activity intervention had an improved clinical effect in health status with higher costs. Costs were estimated retrospectively and cost-effectiveness was derived from the intervention cost per patient in relation to a change in health status, measured by the EuroQol global visual analog scale (EQ-VAS), and activity limitation, measured by the health assessment questionnaire (HAQ).

The cost per patient was approximately $957, and the total cost for the 1-year program was almost $9000. The difference in the total societal cost between the intervention group and the control group was estimated at $775 per patient. The incremental cost-effectiveness ratio for a 1-point improvement in EQ-VAS was estimated to be approximately $155. An additional 15.5-point improvement was noted in EQ-VAS, and a 0.13point improvement was noted on the HAQ for the same cost gain when intervention was offered to more affected patients. Although the intervention was not cost-effective from a general population perspective, the investigators noted, the intervention was cost-effective in a subgroup of patients who were more affected by RA compared with less affected patients.

To optimize cost-effectiveness, physical activity intervention programs should be targeted toward individuals who are largely affected by their RA. Brodin N, et al. Disabil Rehabil. 2014 July 14 (Epub ahead of print)

Economic Impact of Psoriasis on Patients

Treatment for psoriasis may result in high monetary costs, as well as time-related costs. Using a multidimensional perspective, researchers examined the economic burden incurred by patients with psoriasis. The majority of healthcare costs for patients with psoriasis were travel costs and lost time, they found. Other accumulated costs included visit charges and copayments.

The investigators enrolled 232 Finnish patients with psoriasis or psoriatic arthritis who visited a clinic during a 1-year period from October 1, 2009, to September 30, 2010. Overall, 199 patients with psoriasis and 33 patients with psoriatic arthritis were enrolled. Data were collected through patient questionnaires, medical records, and reimbursement of Finland data from the Social Insurance Institution. Item costs were collected from patients based on the actual costs charged, and all-time costs were collected using the Human Capital Approach method.

Patients receiving traditional systemic medications or phototherapy incurred higher total costs compared with patients who did not receive these treatments. The travel costs and travel-time costs contributed to more than 60% of the cost of phototherapy. In addition, skin care was time-consuming and was noted as a significant burden to patients. Hospital visits accounted for most visit costs, and a small percentage of these visits was associated with primary care visits. These costs should be taken into consideration in future pharmacoeconomic studies when evaluating costs of treatments for psoriasis, the authors concluded. Mustonen A, et al. Dermatol Ther (Heidelb). 2014;4:115-124

Biologics Effective, Lead to Cost-Savings in RA

In a retrospective study, investigators used a claim-based algorithm to estimate the cost per patient of biologics in patients with moderate-tosevere rheumatoid arthritis (RA).

A total of 15,251 commercially insured patients with RA aged 18 to 36 years were included in the study. The patients were administered biologics, including abatacept, adalimumab, etanercept, golimumab, or infliximab between 2007 and 2010. Effectiveness was defined as having high adherence, no biologic dose increase, no biologic switching, no new nonbiologic disease-modifying antirheumatic drug, no increased or new oral glucocorticoid use, and no more than 1 glucocorticoid injection. For each biologic agent, cost per effectively treated patient was defined as total

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drug cost and administration cost divided by the number of effectively treated patients.

The algorithm showed that within the first year, treatment was effective in 30% of patients taking etanercept, 30% of patients taking adalimumab, 20% of patients taking infliximab, 27% of patients taking abatacept, and 29% of patients taking golimumab. In addition, effectiveness was similar for all the biologics, except for infliximab, the authors observed.

The 1-year biologic cost per effectively treated patient was $49,952 for etanercept, $50,189 for golimumab, $52,858 for adalimumab, $71,866 for abatacept, and $104,333 for infliximab. Subcutaneous biologic agents had a lower cost per effectively treated patient within the 1-year period than intravenous biologics. Curtis JR, et al. Clin Ther. 2014;36:996-1004

Cost-Savings of Biologics Vary Based on Definition of Remission in RA

Investigators assessed the variation of cost-savings when different definitions of remission were applied to patients with rheumatoid arthritis (RA). The highest estimate for savings was noted in patients achieving Simplified Disease Activity Index (SDAI) remission and the least was noted in patients achieving Clinical Disease Activity Index (CDAI) remission.

For the purpose of this study, remission definitions included the 2011 American College of Rheumatology/European League Against Rheumatism Boolean-based definition, SDAI â&#x2030;¤3.3, CDAI â&#x2030;¤2.8, and Disease Activity Score-28 (DAS28) â&#x2030;¤2.6. A total of 1086 patients were enrolled in this study. The annual cost was estimated based on physician billing claims, outpatient visits, and hospitalizations. Using each definition of remission, researchers compared cost-savings in patients who had a continuous 1-year remission with patients who did not have a continuous 1-year remission.

The sustained remission rates were 16.1% for DAS28, 8.8% for Boolean, 5.5% for CDAI, and 4.2% for SDAI. The annual cost-savings per patient achieving remission were $1928 for SDAI, $1676 for DAS28, and $1259 for Boolean. The annual cost-savings per patient for CDAI was not significant at $423. Future pharmacoeconomic studies should consider all remission definitions in order to accurately assess treatment. Barnabe C, et al. J Rheumatol. 2014;41:1600-1606

Increasing Utilization of Total Knee Arthroplasty Affects Lifetime Medical Costs

Researchers estimated the total lifetime cost in relation to total knee arthroplasty (TKA) in patients with symptomatic knee osteoarthritis (OA).

Direct medical costs in 2013 were obtained from the Medicare reimbursement schedules and Red Book Online. Time costs were derived from published literature and from the US Bureau of Labor Statistics. The Osteoarthritis Policy Model was used to estimate the total lifetime costs and TKA utilization in patients with symptomatic knee OA. Data for TKA utilization were retrieved from the Multicenter Osteoarthritis Study and calibrated to Healthcare Cost and Utilization Project data.

For patients diagnosed with knee OA, the average discounted (3% per year) lifetime costs were $140,300. The direct medical costs were $129,600, of which $12,400 (10%) were attributed to knee OA over 28 years. Patients with OA spend 13 years on average waiting for TKA after failing nonsurgical treatment. According to current TKA eligibility criteria, 54% of patients with knee OA underwent TKA during their lifetimes. When TKA eligibility was limited to K-L 3 or 4, the discounted lifetime direct medical costs were $12,400; when TKA eligibility was expanded to include OA with less structural damage, lifetime medical costs increased to $16,000. Overall, nonsurgical treatment for knee OA is not very effective and is low in cost; extending TKA indications increases costs, prompting the need for more effective nonsurgical treatment options. Losina E, et al. Arthritis Care Res (Hoboken). 2014 July 21 (Epub ahead of print)

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Health Economics

Reduced Medical Expenditures with Tofacitinib in Patients with Inadequate Response to Other RA Therapies

By Lianne Bennett Tampa, FL—Post-hoc analyses of the phase 3 trials, ORAL Standard and ORAL Step, revealed that tofacitinib––a novel oral Janus kinase inhibitor––and adalimumab led to lower monthly medical expenditures (MMEs) compared with placebo in patients with moderate-to-severe rheumatoid arthritis (RA) who did not respond to either methotrexate or tumor necrosis factor (TNF) inhibitors, according to investigators Regina Rendas-Baum, MS, scientist at QualityMetric, and colleagues.

The Oral Standard Trial The ORAL Standard was a 12-month trial that compared the safety and efficacy of tofacitinib 5 mg or 10 mg twice daily, adalimumab 40 mg every 2 weeks, or placebo in patients receiving methotrexate but not responding to treatment. The ORAL Step, a 6-month trial, compared the safety and efficacy of tofacitinib 5 mg or 10 mg twice daily with placebo in patients receiving methotrexate with inadequate response to TNF inhibitors.

In these post-hoc analyses––performed for the first 3 months of treat-

ment in each trial––the investigators used the 12-Item Short-Form Health Survey (SF-12) v2 to translate physical component summary (PCS) scores and mental component summary

tients themselves,” Ms Rendas-Baum told Value-Based Care in Rheumatology.

“It is sometimes hard to interpret treatment-related changes captured by patient-reported-outcome mea-

“Analyses indicated that patients treated with tofacitinib are likely to have significant reductions in medical expenditures.”

—Regina Rendas-Baum, MS, and colleagues

(MCS) scores into predicted medical expenditures and assess whether treatment with tofacitinib or adalimumab reduced MME compared with placebo.

“We wanted to translate treatment-related effects captured in the SF-36 [36-Item Short-Form Health Survey] v2 into outcomes that are easily understood and relevant to payers, clinicians, employers and also to pa-

sures, such as the SF-36v2, and this type of analysis provides important information about what those treatment-related changes may actually mean beyond their numerical value.”

Because of the high correlation between SF-36v2 and SF-12v2, the algorithm based on SF-12v2 was applied to the PCS and MCS scores that were obtained using the SF-36v2, according to Ms Rendas-Baum.

Long-Term Benefits In the nonresponders included in the ORAL Standard trial, results showed that by the third month, there was a 25%, 23%, and 24% reduction in MME with tofacitinib 5 mg, tofacitinib 10 mg, and adalimumab, respectively, compared with a 13% reduction in MME with placebo.

Substantial reductions in MME were also observed with tofacitinib in the ORAL Step trial for patients with inadequate response to TNF inhibitors. Significant reduction in MME with tofacitinib was evident by 2 weeks. By the third month, there was >20% reduction in MME compared with a 9% reduction in MME with placebo.

“Analyses indicated that patients treated with tofacitinib are likely to have significant reductions in medical expenditures,” Ms Rendas-Baum stated when asked about the longterm implications of the study results. “Rheumatoid arthritis will continue to worsen if left untreated so the relative gains for these patients should be greater in the long-term.” n

Value-Based Pricing Benefits Patients, Pharmaceutical Companies Alike

By Rosemary Frei, MSc Montreal, QC—What is the impact of value-based pricing across indications on medical practices and their pa-

at a glance ➤ Value-based pricing across all indications will be implement in the United Kingdom this fall ➤ The approach has the potential to benefit both patients and pharmaceutical companies ➤ The use of biologics, as well as other factors, may bring added pressure to implement value-based pricing in rheumatology

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tients? That question is on the minds of healthcare professionals in all areas of medicine, including rheumatology.

However, the answer to this question will not be known for some time to come, according to presenters at the International Society for Pharmacoeconomics and Outcomes Research 2014 Annual Meeting.

Model Coming to the United Kingdom The Director of the Office of Health Economics in London, United Kingdom, Adrian Towse, MA, MPhil, moderated the session on value-based pricing across indications. He said that this approach, which will be implemented in the United Kingdom this fall, has the potential to benefit

both patients and pharmaceutical companies. However, in practice, there are likely to be some wrinkles, noted Dr Towse.

“Companies may not develop small-population, high-value follow-on indications if they cannot get a high price without losing their existing higher-volume but lower-value indication,” Dr Towse explained. In addition, patients and payers will only benefit if “there are large differences in value between indications … and more patient groups get access [to the medication].”

Jeffrey Hoch, PhD, Director of Pharmacoeconomics Research Centre, Cancer Care Ontario, Toronto, agreed that many forces are put into play when considering value-based pricing august 2014

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across indications. It comes down to whether the price should reflect what the payer is able to pay, willing to pay or perceives is the value, or what the payers and pharmaceutical company negotiate.

“These health reimbursement decisions are often very, very political,” he told Value-Based Care in Rheumatology. They are also a function of the overall objective, he added. “Do you want to spur innovation? Or do you want to have the simplest possible bureaucratic decision? Or more bureaucracy but more flexibility [in setting prices]?”

Agreement Among Key Stakeholder Lacking In a separate interview, Daniel SolContinued on page 8

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Health Economics

Economic Outcomes Data on Adherence Lacking in Rheumatology Cost-adherence programs needed

By Phoebe Starr Paris, France—Nonadherence to medications is widespread in rheumatologic diseases, but the literature is sparse as to how this impacts healthcare outcomes and costs, according to speakers at the 2014 European League Against Rheumatism Congress.

Nonadherence Linked to Morbidity, Mortality “Nonadherence is vastly underestimated in rheumatology,” according to Axel Hueber, MD, PhD, University of Erlangen, Germany, told listeners.

“The consequences of nonadherence [in general] are dramatic and include increased morbidity and mortality, with costs in the billions.”

at a glance ➤ Patient factors, physician factors, and therapy affect nonadherence ➤ Rheumatologists should discuss preferences with patients and set goals for treatment ➤ Cost-adherence programs are lacking in the field of rheumatology

Factors affecting nonadherence fall into 3 categories: patient factors, physician factors, and therapy itself such as complexity and high doses. The physician–patient relationship can make or break adherence. Patient factors include age, emotional factors, belief systems, and money.

“Money can be a big problem if the patient is not insured, inadequately insured, or can’t afford to pay for biologics,” he stated.

Dr Hueber emphasized the importance of physician–patient interactions in improving adherence. “The physician needs to discuss preferences with the patient to find out what he or she wants. The patient may not like injections, so in that case we can recommend infusion. We need to set goals with the patient, and the healthcare system has to back up the doctor,” Dr Hueber added.

Costs and Outcomes Data Another speaker addressed a knowledge gap regarding adherence and healthcare outcomes and costs.

“We are lacking the data we would want to assess these areas,” said Maria Suarez-Almazor, MD, MD Anderson Cancer Center, Houston, TX. Some studies show rates of adherence to rheumatoid arthritis medica-

tions of approximately 60%. These studies also show under- and overdosing of disease-modifying antirheumatic drugs and prednisone, she noted. In all studies, nonadherent patients did worse.

“Money can be a big problem if the patient is not insured, inadequately insured, or can’t afford to pay for biologics.”

—Axel Hueber, MD, PhD

In 1 study of approximately 18,000 patients with gout, <50% were adherent. Among those who were adherent, approximately 50% reached target uric acid levels of <6 mg/dL compared with only 25% of nonadherent patients.

Nonadherence to gout medications leads to exacerbation of hyperuricemia, and this in turn can lead to more flares. “We can speculate that low adherence would increase uric acid and thus costs of treating the disease. No studies have been done in this area,”

Value-Based Pricing Benefits Patients... omon, MD, MPH, Chief, Section of Clinical Sciences, Division of Rheumatology, and Division of Pharmacoepidemiology, and Co-Director, Center for Patient Centered Comparative Effectiveness Research, Brigham and Women’s Hospital, and Professor of Medicine, Harvard Medical School, Boston, commented on the value-based pricing in rheumatology.

“There are a lot of people working on it who are smart and are writing editorials on it, but I’m not sure that there’s a lot of agreement between payers, manufacturers, patient groups and payer groups on how to assess value,” said Dr Solomon. “So it won’t be put into practice for the near term—I don’t see it being an immedi-

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“I’m not sure that there’s a lot of agreement between payers, manufacturers, patient groups and payer groups on how to assess value.”

—Daniel Solomon, MD, MPH

ate issue in rheumatology. [However,] if the patient-centered medical home becomes the dominant model in the

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according to Dr Suarez-Almazor.

Studies of osteoporosis show an adherence rate of 24% at 2 years, and nonadherent patients have a 70% increased risk of fracture (Curtis JR, et al. J Bone Miner Res. 2008;23:1435-1441). The costs of fractures are high, but so are the costs of osteoporosis drugs, making cost-effectiveness questionable, Dr Suarez-Almazor continued. If the adverse events associated with bisphosphonates are factored into costs (ie, paradoxical trochanter fraction), this further compromises an estimation of true cost-effectiveness.

Studies in osteoporosis suggest that nonadherence increases the rate of hip and other fractures, and fracture costs are in excess of $2.5 million. On the other hand, she explained, some studies suggest that the direct costs of the drug and the number needed to treat to avoid 1 fracture may be too high to meet the threshold of costeffectiveness.

“We don’t have any cost–adherence programs in rheumatology,” she concluded. “We need to fill this knowledge gap.…Extrapolating from other diseases like hypertension suggests that nonadherence increases disease activity and direct medical costs. For higher levels of disease activity, there are higher costs.” n

next 3 to five years people will say, ‘Yes, we have to tackle expensive biologic drugs.’ Rheumatology has a lot

of expensive biologics. So people are trying to understand what these agents’ value is.”

The issue may also be forced to the forefront if an agent outside of rheumatology, such as lipid-lowering agents proprotein convertase subtilisin/kexin type 9 inhibitors, prove to be safe and effective, according to Dr Solomon.

“Then the genie will be out of the bottle, and it will add tremendous financial pressure to implement value-based pricing. Payers will push the producers of these drugs and providers writing the prescriptions to demonstrate the value that these agents provide over existing lipid-lowering drugs.” n VOL. 3

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Health Economics

Costs of Musculoskeletal Conditions Strain Healthcare Budgets

By Phoebe Starr Paris, France—Musculoskeletal conditions (MSKCs), which consist of approximately 150 different diseases, are the main driver of healthcare costs, according to a Dutch study presented at the 2014 European League Against Rheumatism (EULAR) Congress.

MSKCs were the single most costly of any chronic health condition (direct and indirect costs), including migraine, cancer, respiratory, skin, mental, and bowel conditions. The presence of MSKCs led to the steepest increase in costs in patients with additional comorbidities.

Data Applicable in United States Even though this was a Dutch study, these data are generalizable to other Western countries, including the United States, according to Gerd Burmester, MD, President of EULAR, and Professor of Medicine, Department of Rheumatology and Clinical Immunology at the Charité University Hospital, Free University and Humboldt University of Berlin, Germany.

This was further validated by the lead author of the study, Antje van der Zee-Neuen, MD, Maastricht University, the Netherlands, who agreed that the study results are applicable to Europe and the United States.

“It is clear that the cost of delivering

care to patients with musculoskeletal conditions is considerably higher than for those with other diseases. The implication of our study is that policymakers should pay attention to these findings by prioritizing MSKCs in their healthcare budgets,” she stated.

“It is clear that the cost of delivering care to patients with musculoskeletal conditions is considerably higher than for those with other diseases.”

—Antje van der Zee-Neuen, MD

Awareness Needed Among Physicians, Policymakers The results of this study were based on a cross-sectional household survey of 8904 randomly selected Dutch individuals 18 years old and older who completed a questionnaire on sociodemographic and lifestyle factors; self-reported, physician-diagnosed diseases; and self-reported healthcare costs over the last 3 months.

Twenty-nine percent of the study population reported 1 morbidity; 8.5%

had an MSKC condition as a single condition. More than 1 disease was reported in 19% of respondents, and MSKC was 1 of those comorbidities in 20%. MSKC was reported in 6.1% of individuals with 2 comorbidities, and 5.6% with >2 comorbidities. Each additional morbidity led to a steep increase in costs; costs were highest when MSKC was present.

“Costs for an individual with 2 conditions—neither of which was MSKC—were twice as high as costs for a healthy person,” Dr van der ZeeNeuen explained. “But if one of the individual’s 2 diseases was musculoskeletal, healthcare costs were 3 times higher.”

Reference prices from the Dutch manual for pharmacoeconomic healthcare evaluations 2010, which were adjusted for inflation, were used to estimate total healthcare costs for 3 months per individual with and without MSKC as a single condition and for an individual with comorbidities with and without MSKC. The average healthcare cost for a healthy individual for 3 months was estimated at approximately $233, $444 for men with MSKC as a single morbidity and $654 for women. The addition of MSKC to 2 comorbidities increased 3-month costs by about $250

at a glance ➤ MSKCs are the single most costly of any chronic health condition, including both direct and indirect costs ➤ The cross-sectional survey consisted of 8904 randomly selected Dutch individuals 18 years old and older who completed a questionnaire on several factors, including sociodemographic and lifestyle ➤ Cross-talk among rheumatologists, family physicians, and other specialists is needed to provide optimal treatment and reduce associated costs compared with those same comorbidities without MSKC. Dr van der Zee-Neuen said she hopes this study raises the awareness of physicians and policymakers about the high costs of treating patients with MSKCs, and that it generates crosstalk among rheumatologists, family physicians, and other specialists who treat patients with these diseases to provide optimal treatments and reduce associated costs. n

Rheumatoid Arthritis

Biosimilars Make Headway... proved in Canada, Europe, India, and Asia, they have not yet been approved in the United States. Expectations are high, and it is assumed that biosimilars will be much less expensive, but they still have to be shown to be cost-effective, according to Maya Buch, MD, from the University of Leeds, United Kingdom. Rheumatologists will need to have full confidence that biosimilars are equivalent to the reference compounds before they prescribe them to patients, she added. That will depend on what the studies show.

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comparable, according to presenting author Sang-Cheol Bae, MD, Hanyang University Hospital for Rheumatic Diseases in Seoul, South Korea.

“As more biosimilars become available, it is critical that patients, healthcare providers, and regulators can have confidence in the safety and efficacy of these compounds,” Dr Bae stated.

Overall, 294 patients with active RA were randomized to receive 25 mg of HD203 (n = 147) or 25 mg of etanercept (n = 147), in combination with methotrexate subcutaneously twice a week for 48 weeks. The primary end point was the proportion of patients who achieved at least a 20% response according to American College of Rheumatology 20% (ACR20) criteria for improvement by week 24. Both groups achieved simi-

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lar results for the primary end point: 82.48% for HD203 compared with 81.36% for etanercept.

Results were also similar on the ACR20 at week 12 and week 48, Dr Bae continued, but HD203 achieved numerical superiority—not statistically significant—compared with etanercept for achieving at least a 50% response on ACR50 at weeks 24 and 48.

The rate of treatment-emergent adverse events was 76.87% for HD203 compared with 78.08% for etanercept.

There were no unexpected adverse events and few patients developed antidrug antibodies.

In a second phase 3 trial, investigators found that BOW015, a biosimilar of infliximab, had comparable efficacy and safety to the biosimilar of inflixaugust 2014

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imab. The investigators randomized 189 patients with active RA on stable doses of methotrexate to either BOW015 or infliximab. This study is distinct from other studies of biosimilars conducted thus far in that efficacy was evaluated at different time points leading up to the primary end point for ACR20 response at week 16, explained presenting author Jonathan Kay, MD, University of Massachusetts Memorial Medical Center, Worcester. The percentages of responders at weeks 0, 2, 6, and 14, leading up to the primary end point were comparable for BOW015 and infliximab.

“This provides particularly convincing evidence that these compounds are therapeutically equivalent,” according to Dr Kay. n

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Rheumatoid Arthritis

Safety of Tofacitinib Stable Over Time

By Phoebe Starr Paris, France—Long-term safety data of tofacitinib were reassuring, demonstrating no new safety concerns in patients with rheumatoid arthritis (RA) exposed to the drug for as long as 4 years. The pattern of adverse events remained stable over time, according to an integrated safety analysis presented at the 2014 European League Against Rheumatism Congress.

The median duration of exposure to the drug was 2.4 years at data cutoff; 555 patients had taken the drug for 4 years. Presenting investigator Jeffrey Curtis, MD, University of Alabama at Birmingham, said safety data up to this point were reassuring.

“Long-term follow-up will continue, and additional observational experience and pharmacovigilance activities will further characterize the safety of tofacitinib in patients with rheumatoid arthritis,” he noted.

The integrated safety analysis was based on a total of 5671 patients enrolled in 6 phase 2 trials, 6 phase 3 studies, and 2 ongoing long-term extension studies. All patients with RA enrolled in these studies had not responded to conventional or bio­logic disease-modifying antirheumatic ­ drugs.

As of April 2013—the cutoff date

for the integrated safety analysis— exposure to tofacitinib was 12,664 patient-years. The rate of treatment discontinuations from adverse events was 16.3%.

was 4.22 per 100 patient-years (95% CI, 3.87-4.61); in patients with up to 6 months of tofacitinib exposure, the rate of herpes zoster was 4.20 per 100 patient-years (95% CI, 3.47-5.07); and

“Long-term follow-up will continue, and additional observational experience and pharmacovigilance activities will further characterize the safety of tofacitinib in patients with rheumatoid arthritis.”

—Jeffrey Curtis, MD

Specific Adverse Events Serious infections were reported at the rate of 2.57 per 100 patient-years in patients treated with tofacitinib for up to 6 months (95% confidence interval [CI], 2.02-3.27) and 1.89 per 100 patient-years for those remaining on the drug for more than 42 months (95% CI, 1.16-3.09). Most of the serious infections were pneumonias, Dr Curtis noted.

The incidence rate of herpes zoster

the rate was 2.11 per 100 patient-years for those receiving treatment for more than 42 months (95% CI, 1.29-3.44).

More than 90% of zoster cases were benign, Dr Curtis added.

Other serious infections had lower rates of occurrence. The incidence rate of opportunistic infections, for example, was 0.25 per 100 patient-years (95% CI, 0.18-0.36), and the rate of tuberculosis was 0.21 per 100 patient-years (95% CI, 0.14-0.30).

Malignancy rates were similar to those reported in the general US population from the Surveillance, Epidemiology, and End Results (SEER) program and to those reported in patients with RA treated with anti– tumor necrosis factor-α agents, Dr Curtis continued. The rate of malignancy excluding nonmelanoma skin cancer was 0.85 per 100 patient-years (95% CI, 0.70-1.02). Among patients with less than 6 months of exposure to tofacitinib, the rate of malignancy was 0.70 per 100 patient-years (95% CI, 0.44-1.11), compared with patients who were exposed to the drug for more than 42 months and had a rate of malignancy of 1.04 (95% CI, 0.54-2).

The overall rate of lymphoma and lymphoproliferative disorders was 0.06 per 100 patient-years (95% CI, 0.03-0.13), 0.04 per 100 patient-years for those with less than 6 months of exposure (95% CI, 0.01-0.28), and 0.12 per 100 patient-years among those with more than 42 months of exposure (95% CI, 0.02-0.82).

Fewer than 1 in 100 patients experienced a major cardiovascular adverse event. One death was report­ed in this study, which was due to appendicitis. n

Multibiomarker Disease Activity Blood Test Leads to Improved Functional Status Test also reduces cost in patients with rheumatoid arthritis

By Lianne Bennett Tampa, FL—Current disease assessment measures for rheumatoid arthritis (RA) are not optimal and have several limitations, including subjective and variable assessment of disease activity, limited predictive ability to capture structural joint damage, and presence of confounding comorbidities. However, the multibiomarker disease activity (MBDA) blood test is an emerging tool used to objectively measure disease activity in patients with RA. MBDA improves functional status and reduces costs in patients with RA, according to a study presented at the Academy of Managed Care Pharmacy 26th Annual Meeting.

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at a glance “Future analyses should incorporate data from further studies on MBDA’s long-term effects on outcomes and costs, as well as impacts on other aspects of patient management.”

—Kaleb Michaud, PhD, and colleagues

Quantifying the Blood Test Using the Health Assessment Ques­tionnaire (HAQ) to assess physical function, quality-adjusted lifeyears (QALYs), and costs over 10 years to third-party payers and employers in the United States, Kaleb Michaud, PhD, Codirector at the National Data Bank for Rheumatic Dis-

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eases, and colleagues sought to quantify the effects of the MBDA blood test compared with the current clinical practice on outcomes in patients with RA. Baseline HAQ data for patients with established RA were derived from the National Data Bank for Rheumatic Diseases, and baseline

➤ Subjective and variable assessment of disease activity are some of the several limitations of disease assessment measures is one of several in RA ➤ Results from the MBDA test suggest that changes in antirheumatic treatment regimens are recommended for patients with early and established RA with RA HAQ data for patients with early RA were derived from the GO-BEFORE (Golimumab Before Employing

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Time to Get on TRACK and RACE to Excellence Together!

o National O r ganizat ion of R heumatolo g y Mana gers Racing to Rheumatology Excellence Friday, September 12, 2014 and Saturday, September 13, 2014 Increase your odds of “being in the winner’s circle” by joining us for the 2014 NORM Conference where nationally known speakers will help NORM members race on the fast track rather than the sloppy track.

Presentations and breakouts on topics such as MU2, OSHA, Customer Service, Physician and Team Engagement, and Financial Management of your practice will help your practice win the race. The conference will end with a presentation on Understanding the Impact of ICD-10 and an ICD-10 workshop stocked with take-aways for your practice. This year NORM has added 6 product theatres offering attendees the opportunity to be hands-on with some products.

NORM membership also provides access to the NORM listserv and education portal. The listserv allows NORM members to seek answers to their practice and nationwide issues from members across the country.

The educational portal provides access to training and informational presentations as well as sample documents.

Conference Registration is Now Open | 2014 Dues and Conference Registration $250

For more information contact NORM at info@normgroup.org or visit our website www.normgroup.org

“Of all the practice management resources out there, none are as relevant and as valuable to me as my NORM membership. With benefits like the member listserv and an affordable annual conference, the NORM group provides a forum for mentorship, education, professional feedback, cutting edge ideas and inspiration.” Jay Salliotte

Diamond Level Corporate Member - Janssen Biotech, Inc

Platinum Level Corporate Member - Celgene Corp

Rheumatoid Arthritis

Medication Adherence in RA Linked to Lower Rates of Hospital Admissions Fewer emergency department visits seen

By Sosie Coco

at a glance ➤ Patients with RA who were adherent to their medication had significantly lower hospital admission rates compared with patients who were nonadherent ➤ Adherence to medication was also significantly associated with lower ER visits than nonadherence ➤ Medication adherence has a meaningful and measurable impact on health outcomes

al Meeting indicated that nonadherent patients had more hospital admissions and emergency department visits than patients who were adherent to their RA medications. In addition, hospital admission rates decreased as adherence rates increased, the investigators found.

A Retrospective CaseComparison Analysis As part of an analysis of a large national retail pharmacy chain database of patients with RA taking biologics, Bobby Clark, PhD, MSPharm, MHA, MS, MA, Walgreens, Deerfield, IL, and colleagues evaluated the relationship between adherence and clinical outcomes.

Using a retrospective case-comparison design, the investigators examined hospital admissions per 1000 patients as well as emergency department visits per 1000 patients. The case cohort study consisted of patients who were adherent to their medication regimen, with a medication possession ratio (MPR) ≥80%.

Patients in the comparison cohort

were not adherent to their RA medications (MPR <80%) and were extracted from the national benchmark medical and pharmacy claims database. The 1-to-1 propensity score– matching system yielded 512 matched pairs. The covariates included in the analysis were age, sex, risk score, socioeconomic status, standard industrial classification code, comorbidities, and premedication gap.

“This analysis supports the contention that medication adherence has a meaningful and measurable impact on health outcomes.”

—Bobby Clark, PhD, MSPharm, MHA, MS, MA

Medication Adherence Has a Measurable Impact In 1 year, patients who were adherent to medication had 139 hospital

Multibiomarker Disease Activity Blood Test...

Methotrexate as the First-Line Option in the Treatment of Rheumatoid Arthritis of Early Onset) study. Based on results from the MBDA test, changes to the treatment regimens for antirheumatic drugs were recommended to patients with early and established RA. The relationships between HAQ score and RA-related medical costs and quality of life were extracted from regression models of the National Data Bank for Rheumatic Diseases data.

After the treatment regimens were modified and implemented, the investigators assessed differences in pre- and post-MBDA outcomes, including HAQ, QALYs, drug costs, other direct costs, and work productivity costs.

Cost-Savings Linked to MBDA Test Following the MBDA test results, 30% of patients were prescribed an

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additional drug or a higher dose of the antirheumatic drug, and 9% of patients were prescribed a reduction in therapy intensity.

Results from the analysis showed that in the first year of using the MBDA test, the patients’ HAQ scores were estimated to be lower by 0.09 units on average. Over the 10-year period, QALYs increased by 0.08 units. Furthermore, there was an increase of $1909 in direct medical costs but a savings of $2069 in productivity

READER POLL

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admissions per 1000 patients, and patients who were nonadherent had 273 admissions per 1000 patients. In addition, adherent patients had 258 emergency department visits per 1000 patients, compared with nonadherent patients who had 324 emergency department visits per 1000 patients. Patients with MPR <39% had 362 admissions per 1000 hospital admissions, patients with MPR ranging from 40% to 79% had 265 admissions per 1000 hospital admissions, and patients with MPR ≥80% had 139 admissions per 1000 hospital ad­ missions, demonstrating that as adherence rates increased, hospital admission rates decreased, according to the investigators.

Patients with RA who were adherent to their RA medications had significantly lower hospital admissions and lower emergency department visits than nonadherent patients.

“This analysis supports the contention that medication adherence has a meaningful and measurable impact on health outcomes,” Dr Clark and colleagues reported. n

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costs, resulting in a net cost-savings of $160.

In patients with early RA, the use of the MBDA test was associated with cost-savings because of “efficiencies of earlier evaluation and management,” the investigators observed.

However, for patients with established RA, the cost per QALY gained was $31,923. Overall, the MBDA test yielded to cost-savings from a combined payer and employer perspective; excluding the employer perspec-

tive, the use of the MBDA test cost $25,102 per QALY gained. The probability of being cost-effective at a willingness-to-pay threshold of $50,000 was 89%.

“Future analyses should incorporate data from further studies on MBDA’s long-term effects on outcomes and costs, as well as impacts on other aspects of patient management (eg, imaging procedures, and patient adherence),” Dr Michaud and colleagues noted. n

DO YOU USE BLOOD TESTS TO £ Yes MEASURE DISEASE ACTIVITY IN RA? £ No

VBCR_ReaderPoll081414

Tampa, FL—There have been considerable advances in the treatment of patients with rheumatoid arthritis (RA), including new biologic agents.

Although research supports the safety and efficacy of these medications, the effectiveness of biologics is often limited by patient adherence.

Data presented at the Academy of Managed Care Pharmacy 26th Annu-

Send us feedback about how you manage your patients and submit your vote to this poll online. Results will be published in print in the upcoming issue.

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VBCR Perspective

Rheumatologists Responsible for... to the standards. Patients trust their rheumatologists. As the NVAC put it, “data show that…patients are more likely to get vaccinated when vaccines are recommended by trusted healthcare professionals.”

Use and Access to Vaccines Many of the patients who rheumatologists see are or will be immunocompromised by the use of immunosuppressive drugs, including corti­ costeroids, methotrexate, and tumor necrosis factor antagonists.2 All vaccines are effective and safe when given at least 4 weeks before these drugs are started, and inactivated vaccines are safe and somewhat effective even after these immunosuppressants have been started. Whether rheumatologists administer the vaccine themselves or are part of a group of physicians who administer vaccines, it is incumbent on rheumatologists to ensure that their patients are appropriately vaccinated.

A rheumatologist whose group

does not provide vaccinations should have patient referral relationships that allow the rheumatologist to refer the patient to a vaccine provider. The rheumatologist should provide the patient with the names of the needed vaccines, explanation of their importance, a prescription for the vaccine if needed, and contact information for the vaccine provider. The rheumatologist should follow up with the patient at the next visit to monitor and document vaccine use and should convey the information to the patient’s primary care provider, if he or she is not also the vaccine provider.

Reducing Disease Burden Specifically, what vaccines should the rheumatologist recommend to an adult patient on immunosuppressants?3 Pneumococcal conjugate vaccine (PCV13) is indicated in immunocompromised patients with rheumatic disease. If your patient has had neither PCV13 nor pneumococcal polysaccharide (PPSV23), PCV13 should be given

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first, and PPSV23 given at least 8 weeks later. If the patient has already had PPSV23, the PCV13 should be given at least 1 year after the PPSV23 dose.

PPSV23 is also indicated in this patient population. Up to 2 doses at least 5 years apart before 65 years of age should be given, and a dose after age 65 years at least 5 years after the last dose is also indicated.

Influenza, tetanus/diphtheria/pertussis, hepatitis B, and other vaccinations are also indicated for immunocompromised patients with rheumatic diseases. The inactivated influenza vaccine is indicated annually. Tetanus/diphtheria/pertussis is indicated every 5 years to 10 years. If the patient has not already had the complete series, then hepatitis B vaccine is indicated.

The American College of Rheumatology has endorsed and is promoting several quality indicators, including whether a patient has been screened for tuberculosis before a first course of therapy using a biologic disease-mod-

ifying antirheumatic drug.4 I would support a quality indicator that checks whether a patient has been fully vaccinated before a first course of immunosuppressive therapy.

Vaccination preventable diseases remain an important cause of illness, hospitalization, and death. Let’s all do what we can to reduce the burden of these diseases on our patients. n Dr Breidbart is Chief Medical Officer, Empire BlueCross BlueShield, New York, NY. The opinions in this editorial are the author's and do not necessarily reflect those of Empire BlueCross BlueShield.

References

1. National Vaccine Advisory Committee. Recommendations from the National Vaccine Advisory Committee: Standards for Adult Immunization Practice. Public Health Rep. 2014;129:115-123.

2. Rahier JF, Moutschen M, Van Gompel A, et al.

Vaccinations in patients with immune-mediated inflammatory diseases. Rheumatology (Oxford). 2010;49: 1815-1827.

3. Rubin LG, Levin MG, Ljungman P, et al. 2013 IDSA Clinical Practice Guideline for Vaccination of the Immunocompromised Host. Clin Infect Dis. 2013;20:1-57.

4. American College of Rheumatology. Rheumatoid Arthritis Quality Indicators. www.rheumatology.org/ Practice/Clinical/Quality/Rheumatoid_Arthritis_ Quality_Indicators/. Accessed July 22, 2014.

Juvenile Idiopathic Arthritis

Reassuring Long-Term Safety for Biologics in Children with Juvenile Idiopathic Arthritis

By Phoebe Starr Paris, France—Biologics are a welcome advance for the treatment of patients with rheumatoid arthritis.

They appear to be safe in adults, but there is always heightened concern when it comes to the effects of immunosuppressants and biologics in children. Two studies presented at the 2014 European League Against Rheumatism Congress provide reassuring long-term data on the safety of etanercept and adalimumab compared with methotrexate (MTX) in children with polyarticular juvenile idiopathic arthritis (JIA).

Biologics are typically reserved for moderate to severe JIA. The disease itself carries a risk of serious infection, and serious infections are a major concern with immunosuppressants and biologics.

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when MTX was combined with either of the 2 biologics; overall, the safety was reassuring, according to lead investigator Gerd Horneff, MD, Asklepios Children’s Hospital, Sankt Augustin, Germany.

Ideally, he said, the use of biologics will achieve good control of JIA, so children can have limited exposure to these drugs.

He presented a multivariate analysis of 3350 children with JIA and a total of 5929 exposure-years who were part of the prospective observational JIA biologic registry (BiKeR).

The only 2 factors that were strongly associated with risk of infection were disease activity level and combination therapy.

The number of serious infections was 28, which translates to a rate of 4.7 per 1000 person-years. Etanercept and adalimumab significantly increased the infection risk compared with MTX (etanercept + MTX, P = .001; adalimumab + MTX, P = .022).

Treatment with corticosteroids also

contributed to risk of infection.

The risk of serious infection increased by 12% for every increase in class on the 10-joint Juvenile Arthritis Disease Activity Score (JADAS). A score of 1.2 on the JADAS during exposure to biologics was significantly associated with risk of infection versus MTX (P <.001).

“Surprisingly, the disease activity itself is of value,” Dr Horneff noted in a follow-up interview with ValueBased Care in Rheumatology. These findings suggest that lowering disease activity will not only improve patients’ lives but also may lower the risk of infection. A separate study presented at the same session focused on the long-term overall safety of adalimumab or etanercept compared with MTX in children with JIA. According to presenter Jens Klotsche, PhD, German Rheumatism Research Centre, Berlin, this is the most comprehensive long-term safety study to date of etanercept and adalimumab in children. august 2014

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He noted that published data on the safety of biologics in children with JIA are limited by small numbers of years of exposure in most recent studies and lack of a biologic-naïve control group.

The study was based on data from 2263 patients who participated in the prospective BiKeR and juvenile arthritis MTX/biologics long-term observation (JuMBO) registries with 4500 patient-years of exposure for etanercept, 500 patient-years of exposure for adalimumab, and 2900 patient-years of exposure to MTX. Overall, 75 serious adverse events (SAEs) occurred in MTX-treated patients at a rate of 2.6 per 100 person-years; 199 SAEs in the etanercept-treated group at a rate of 4.5 per 100 person-years; and 23 SAEs in those taking adalimumab at a rate of 4.6 per 100 patient-years.

No significant difference was observed between patients exposed to either of the 2 biologics versus MTX. n

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Rheumatology Update

Combined Rheumatology-Dermatology Clinic Benefits Specialists and Patients

By Rosemary Frei, MSc Toronto, ON—A rheumatology-dermatology clinic that is open 1 day a week in Vancouver, BC, is helping to build a bridge between the 2 disciplines, in a similar way that rheumatology-ophthalmology clinics function.

A Symbiotic Relationship The Dermatology and Rheumatology Treatment (DART) clinic has been open for 3 years. The attending rheumatologist, Kam Shojania, MD, head of rheumatology at the University of British Columbia, told Value-Based Care in Rheumatology that because of the constant dialogue with dermatologists, he has “learned an amazing amount of dermatology—which translates into better care for my patients.”

“It’s a symbiotic relationship—the dermatologists help us make the local diagnosis, and we look at the rest of the body and make the diagnosis and medication recommendation,” Dr Shojania explained. “And we also help manage the biologic treatment and the side effects including infection risks.”

For example, he now can tell whether a facial rash is simply rosacea or a malar rash in a patient with lupus.

Cutaneous lupus is the third most common dermatologic condition seen in the busy clinic, and systemic lupus erythematosus (SLE) is the most common rheumatologic condition, according to a review of cases from July 2011 to June 2013. The chart review was presented in e-poster form at the Canadian Dermatology Association 89th Annual Conference. It was conducted by dermatology resident Michael Samycia, MD, and dermatologist Collette McCourt, MD, who was a rheumatology/dermatology fellow.

A Breakdown of the Patient Population There were a total of 30 different rheumatologic diagnoses in the 320 patients seen in that period of time.

Rheumatoid arthritis and psoriatic arthritis were the second- and thirdmost common diagnoses, respectively. Moreover, there were 43 different dermatologic diagnoses dictated by dermatitis and psoriasis.

Dr Shojania—together with attending dermatologist Sheila Au, MD, head of dermatology at Providence Health Care, Vancouver, and a re-

volving roster of rheumatology and dermatology residents and fellows— sees a wide range of dermatologic conditions in rheumatology patients

“As a dermatologist, I have really come to respect and value the thought process that lies behind the diagnosis of inflammatory diseases like rheumatoid arthritis and connective tissue disease.”

—Sheila Au, MD

and vice versa. Not only do patients with SLE present with cutaneous lupus (29% of patients with SLE); they also have dermatitis (16%), acne (14%), and alopecia (12%). Dermatitis

is also relatively common in patients with psoriatic arthritis (10%), although psoriasis is the most common dermatologic diagnosis in these patients (76%).

In addition, common dermatologic conditions found in patients with rheumatoid arthritis are erythema nodosum (24%) and rheumatoid nodule (16%). Conversely, patients with dermatitis have been diagnosed with rheumatoid arthritis (20%), SLE (15%), and undifferentiated connective tissue disorder (10%), while patients with alopecia have been diagnosed with SLE (33%) and rheumatoid arthritis (24%).

The DART team is altering educational seminars for rheumatology and dermatology trainees based on the review’s findings. For example, rheumatology residents are now being taught to diagnose and treat alopecia.

“As a dermatologist, I have really come to respect and value the thought process that lies behind the diagnosis of inflammatory diseases like rheumatoid arthritis and connective tissue disease,” said Dr Au, “because rheumatologists are the experts in these conditions.” n

Osteoarthritis

MiRNA Biomarkers Identified for Osteoarthritis Severity

By Phoebe Starr Paris, France—Three biomarkers have been identified that may be used to determine disease severity in osteo­

at a glance ➤ Three biomarkers—miR 454, miR 885-5p, and miR let-7e— may predict the development of severe OA in patients with early disease ➤ Older age and higher body mass index were 2 factors significantly associated with the need for joint replacement ➤ Ongoing studies are planned to establish the clinical utility of these markers

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arthritis (OA), according to data presented at the 2014 European League Against Rheumatism (EULAR) Congress. The miRNAs—miR 454, miR 885-5p, and miR let-7e—may predict the development of severe OA in patients with early disease.

If validated in future studies, these specific miRNAs could play a role in decision-making for treatment of early OA, targeting aggressive treatment for patients who need it the most.

“Ours is the first study to identify these biomarkers for people at risk of severe OA in a large population-based cohort. Results suggest that for the first time, we will be able to predict the severity before the disease starts to impact patients’ lives,” said Christian Beyer, MD, from the University of

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Erlangen-Nuremberg, Germany. “We will be able to take preventive action early on to decrease the impact of disease on patients’ lives and the socioeconomic burden of the disease.”

“Results suggest that for the first time we will be able to predict the severity before the disease starts to impact patients’ lives.”

—Christian Beyer, MD

Predicting Disease Severity The study was based on an analysis of serum samples from 816 patients

with OA who were part of the Bruneck cohort and who were followed from 1995 to 2010. The need for hip or knee joint replacement surgery was used as the outcome that correlated with disease severity.

During the 15-year follow-up period, 67 patients underwent at least 1 hip or knee replacement surgery for severe OA. Factors that were significantly correlated with the need for a joint replacement include older age (P = .053) and higher body mass in­ dex (P = .002), compared with patients who did not undergo surgery.

Identifying miRNA Signatures Identifying miRNAs in existing blood samples of the patient population was a 2-step process.

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Rheumatology Center Profile

The Needs of the Patient... atric-adult rheumatologists. It also includes several mid-level providers, including nurse practitioners, physician assistants, and nurses.

The practice in Rochester is divided into subspecialty clinics, including inflammatory arthritis, connective tissue diseases, vasculitis, and inflammatory muscle disease. In addition, the Division of Rheumatology includes a joint clinic with orthopedics and physical medicine, and rehabilitation for the assessment and management of regional musculoskeletal pain comprising nonoperative rotator cuff problems, as well as knee and hip problems. Mayo Clinic also includes a vasculitis center as well as a cardiology rheumatology clinic shared with the division for cardiovascular diseases.

“We have personnel who work in this clinic to assess patients who have vasculitis together with our cardiology colleagues,” Dr Matteson explained. “Then we have another joint clinic with cardiology that is called the Cardio-Rheumatology Clinic.” That clinic is dedicated to the evaluation of patients with systemic rheumatic diseases to determine their cardiovascular risk factors, because patients with rheumatic diseases have higher heart disease risk.

In addition to the clinical aspect of the practice, Mayo Clinic also comprises research laboratories currently focusing on the immunogenetics of rheumatic diseases and immunogenetics of drug metabolism of drugs that we use for treating rheumatic diseases. Mayo Clinic Rheumatology also uses resources of the Rochester Epidemiology Project to understand

Continued from page 1

the epidemiology of rheumatic diseases and how this impacts clinical needs and treatment approaches.

What is the approach to care at Mayo Clinic?

Eric L. Matteson (ELM): As a general principle, our approach to care is integrative. We have integrated clinics in several areas in orthopedics, physical medicine, cardiovascular diseases, and vasculitis that are unique.

We work very closely in the management of chronic pain, which is a major issue for patients with rheumatic diseases. With our pain rehabilitation center—we have a fibromyalgia center as well, a fibromyalgia clinic— that is part of the integrated approach to the management of our patients with rheumatic diseases.

The approach to the patients that distinguishes Mayo Clinic is that we are truly an integrated practice. That means we have a single record for all of our patients. We have combined clinics and easy access to all of the services and providers that are required for patients with rheumatic diseases.

I think if I were to describe in 1 phrase the approach to the patient that we pursue here in the division, it is the approach that we value at Mayo Clinic, and that is that our fundamental principle is that the needs of our patients come first. That is the ethos of the Mayo Clinic, and of our division, and that is what makes Mayo Clinic unique.

How does this approach to care translate to better outcomes?

ELM: What we have been able to identify in rheumatoid arthritis, for

MiRNA Biomarkers Identified... Continued from page 14 Approximately 374 miRNAs were tested and a panel of 12 candidate miRNAs was identified. A Cox regression analysis further identified 3 miRNAs associated with the need for hip or knee replacement surgery: miR 454, miR 885-5p, and miR let-7e. Dr Beyer said the strongest predictor of joint replacement surgery among these 3 biomarkers was let-7e.

The signature of miRNA in individuals with OA was then compared with controls to validate that the signature was specific to OA. Validating the Data This was a single-center study, and the findings need to be validated in a larger population. Ongoing studies VOL. 3

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are planned to establish the clinical utility of these markers. According to EULAR Scientific Program Chair Ulf Müller-Ladner, MD, these small mi­ RNAs hold great promise for predicting OA severity. MiRNAs are already being used as biomarkers in cancer, diabetes, and cardiovascular disease.

They have attractive properties for testing, because they can persist, are stable under different temperatures and conditions, and can be measured in the blood, Dr Müller-Ladner added.

If these findings are validated, then the information can be used to counsel patients about how to manage their OA more aggressively if the markers are present and less aggressively if not, according to the investigators. n

example, is that over the years since we have been following patients systematically through the Rochester Epidemiology Project since 1955, we were the first to show that this integrated management of patients with rheumatoid arthritis has led to an improvement of patients’ life expectancy and a decrease in the need for ortho-

“Some of the major opportunities that we have are in the field of individualized medicine.”

—Eric L. Matteson, MD

pedic surgeries, because of better disease management.

We also have—because we work very closely with our orthopedic colleagues—been able to have better outcomes from orthopedic surgeries, as well; for example, very low complication and infection rates following a joint orthoclastic surgery.

Those are just a couple of examples of very concrete improvements in the outcomes of patients who have rheumatic diseases as a result of how we approach our patients.

What advice would you give to physicians when referring a patient to Mayo Clinic?

ELM: We value very highly the relationships that we have with physicians across the country and actually all around the world. The principal advice that we give to physicians considering referring patients is to have a clear question for us that they would like to ask us to address and to resolve.

We ask them to provide as much information about the patients as they can. The physicians who refer patients to us have high standards themselves.

They have, very often, done very thorough evaluations of the patients, but still the diagnosis and management questions are open. august 2014

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Providing us with as complete information as possible about the patients is extremely helpful to setting up the evaluation here, to have it be efficient and timely and also as helpful to them as possible.

What is the biggest challenge you are facing in the profession?

ELM: Without a doubt, the biggest challenge that we have in rheumatology is access. It is access to medications and access to rheumatologists.

We, as a field, are seeing that the number of people in rheumatology or going into rheumatology has been fairly stagnant in the last several years.

Rheumatologists, as a group, are pretty senior. I think the average age of a rheumatologist is around 55 or so these days.

Patient access to rheumatologists is becoming a major issue. Access to services like medications is a major issue.

That access is limited by cost. That is a major issue now that patients and physicians have. Access to effective medications is limited by the insurance plans and cost of the drugs and access to procedures that are helpful in assessing patients. Access to advanced imaging procedures, in particular, are becoming a real problem.

How has the specialty changed since you first joined the profession?

ELM: I have been in rheumatology for 28 years. In that time, there has been a dramatic improvement in the outcomes of patients who have rheumatic diseases driven by better understanding of the disease process, better medications, and the more rational and scientific application of those medications.

Globally, we are seeing less joint damage in patients with rheumatoid arthritis. In the field of vasculitis, for example, patients now live longer and better than they have in the past because of better diagnosis and better approaches to the management.

I think that those are some things that have happened that have been very positive. That has also driven a lot of enthusiasm for rheumatology for the field in general because we are able to be effective in treating our patients now much more than in the past.

What advice would you give to a rheumatologist just starting out?

ELM: I think that, most importantly, it is to not only have a good understanding of the diseases, but also a good understanding of the business of medicine and the business of rheumaContinued on page 16

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Osteoporosis

Better Adherence Seen with Weekly versus Daily Regimens in Patients with Osteoporosis

By Rosemary Frei, MSc Montreal, QC—Researchers analyzed studies of patient adherence to daily and weekly medications to evaluate the impact of dosing frequency on medication adherence. Osteoporosis was the condition selected by the investigators because there are many

daily and weekly medications available for this indication. Their results showed that patients on weekly regimens are 90% more likely to be adherent than those on daily regimens.

“Weekly dosing is more convenient for patients and that is likely why they have a greater propensity to stick to weekly therapy.”

at a glance ➤ Patients taking an osteoporosis medication with once-weekly dosing had 12% more days on which they were taking the medication ➤ Odds ratio for adherence was 1.90 on average for onceweekly versus once-daily dosing ➤ Patients on once-weekly osteoporosis medication were more likely to be adherent to their medication than patients on once-daily dosing

house Station, NJ. Dr Mavros, who presented the results in a presentation at the International Society for Pharmacoeconomics and Outcomes Research 19th Annual

—Panagiotis Mavros, PhD

“Weekly dosing is more convenient for patients and that is likely why they have a greater propensity to stick to weekly therapy,” said lead investigator Panagiotis Mavros, PhD, Executive Director, Outcomes Research, and Lead, Medical Data Analytics, Merck & Co, Inc, White-

International Meeting, explained that the systematic review and meta-analysis included studies in the English language published between January 2002 and August 2013. They focused on 7 studies that measured the medication possession ratio in patients with osteoporosis; none of the articles

included were crossover studies.

On average, patients taking an osteoporosis medication with onceweekly dosing had 12% more days on which they were taking the medication. This held true when they removed the data from 1 study that appeared to have erroneous data on record with extremely narrow confidence intervals. However, there was significant heterogeneity in the studies with respect to this measure. “We have to interpret this result with caution,” acknowledged Dr Mavros.

The researchers also found that the odds ratio for adherence was 1.90 on average for once-weekly versus once-daily dosing. There was a low level of heterogeneity between studies in this measure. “We trust this result even more,” concluded Dr Mavros.

“We can say with confidence that patients on once-weekly osteoporosis medication were 90% more likely to be adherent to their medication than those on once-daily dosing.” n

Rheumatology Center Profile

The Needs of the Patient... tology. That is very important and it is still not adequately taught.

In the end, I would have to say though, that the most impor­tant advice I can give is advice that a very famous physician—William Osler— already gave more than 100 years ago that still applies today. A rheumatologist starting out should care more for his or her individual patient than the special features of the disease. The patient comes first.

What key opportunities lie ahead in the field?

ELM: Some of the major opportunities that we have are in the field of individualized medicine. By that, I mean developing and using biomarkers that will help us to understand the prognosis of all the rheumatic diseases.

This applies to all of the systemic rheumatic diseases that we deal with, and biomarkers that will help us to understand which drug therapies will be the best. By “the best,” I mean both

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Continued from page 15

in terms of how well they work for an individual patient and choosing the right drug, as well as understanding which drugs are actually going to be problems and should be avoided. I think that those are major opportunities that we have.

“A rheumatologist starting out should care more for his or her individual patient than the special features of the disease.”

—Eric L. Matteson, MD

We are going to continue to see advances in understanding of the pathobiology of these diseases, and I am looking forward to translating those discoveries into benefits for patients.

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I also think that a key area of opportunity in rheumatology is in regenerative medicine. We know that a lot of our diseases are very destructive to not only joints, but other internal organs. Being able to restore function of joints beyond joint replacement and doing so in a biologic way, for example, restoring lung function or kidney function in patients who have had damage from rheumatic diseases, is a major opportunity.

To that point, at Mayo Clinic, we collaborate with our colleagues in our Center for Regenerative Medicine, Center for Individualized Medicine, and Center for the Science of Health Care Delivery, to improve outcomes in our patients.

How have patients with rheumatologic conditions been affected by the implementation of the Affordable Care Act? ELM: In general, I think that it has improved access. We are seeing patients

now that we would not have seen before, because they didn’t have the means to be seen.

A change that is not so favorable, it appears that the cost of medications for patients is increasing. This is mainly reflected in higher premiums now.

The good news seems to be that more people are becoming insured, but the bad news is that the insurance rates are becoming so high that it’s still very much a concern for patients, particularly patients who are working. I think that there are a lot of ongoing challenges with that.

“In my view the excellence of the clinical care that we have here at Mayo Clinic, we can attribute to lots of things,” Dr Matteson concluded.

“But in the end it's the people here, their commitment to the patients that matter the most, the way that our organization is set up to provide care in this integrated fashion.” n VOL. 3

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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.

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Mission Statement Value-Based Care in RheumatologyTM provides a forum for providers, payers, and the entire rheumatology team to consider the cost-value issues particular to rheumatology treatments.

This unique focus is achieved through news coverage from major rheumatology meetings and the rheumatic diseases literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care.

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Personalized Medicine in Rheumatology

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Advances in Genotyping Pinpoints to Genetic Determinant Valine 11 on the HLA-DRB1 gene may be an indicator of radiographic damage in RA

By Phoebe Starr Paris, France—Progress in genotyping patients with rheumatoid arthritis (RA) suggests that the amino acid valine at position 11 of the HLADRB1 gene appears to be the strongest independent genetic determinant of radiographic damage in this disease.

In addition, positions 71 and 74 on the HLA-DRB1 gene were independent predictors of radiographic damage. All 3 positions together were strongly associated with disease severity, treatment outcomes, and mortality in a study presented at the 2014 Euro­ pean League Against Rheumatism (EULAR) Congress.

Although the study is preliminary, the authors are enthusiastic about the promise of this research. “This major advance in genetics might allow stratification of RA patients at the onset of disease to identify those at risk of joint damage and early death, and also those who are more likely to respond to anti-TNF [tumor necrosis factor] biological therapy,” stated lead author Sebastien Viatte, MD, Arthritis Research UK Centre for Genetics and Genomics, Manchester.

Genotype Has a Strong Influence in the Epidemiology of RA The exact cause of RA is unknown.

Environmental factors contribute to approximately 30% of disease susceptibility, and genetic factors contribute to the remainder. The geographic distribution of the prevalence of RA can provide some genetic indi-

cations, according to Dr Viatte.

For example, in most countries the prevalence of RA ranges from 0.5% to 1%, but in Native Americans the prevalence is higher, whereas it is very low in populations in China and Japan.

“This major advance in genetics might allow stratification of RA patients at the onset of disease to identify those at risk of joint damage and early death, and also those who are more likely to respond to anti-TNF biological therapy.”

colleagues adds to the growing body of evidence for position 11, implicating positions 71 and 74.

The study was based on patients from 3 multicenter prospective cohort studies: the Norfolk Arthritis Register, the Early Rheumatoid Arthritis Study, and a cohort from 57 centers in the United Kingdom totaling 1691 patients with 2811 x-rays, 421 patients with 3758 x-rays, and 1846 patients with treatment response, respectively.

These cohorts were used to assess whether HLA-DRB1 positions 11, 71, and 74 could predict radiologic outcome, anti-TNF response, and mortality in patients with RA. ImmunoChip array was used to perform the human leukocyte antigen (HLA) typing.

at a glance ➤ Amino acid valine at position 11 of the HLA-DRB1 gene may be the strongest independent genetic determinant of radiographic damage in RA ➤ Positions 71 and 74 on the HLA-DRB1 gene were independent predictors of radiographic damage ➤ Altogether, positions 11, 71, and 74 were strongly associated with disease severity, treatment outcomes, and mortality

“This supports the strong influence of genotype on the epidemiology of RA,” Dr Viatte stated.

It has previously been shown that a group of alleles on the HLA-DRB1 gene (ie, shared epitope) accounted for the strongest susceptibility to RA. A group of researchers then found that position 11 outside this epitope was a stronger predictor than the shared epitope. The multicenter study presented at EULAR by Dr Viatte and

On the Way to Tailoring Therapy The findings were replicated in all 3 cohorts. Fifty-two percent of all patients carried the HLA-DRB1 haplotype. The 3 positions were strongly associated with disease outcome, and the hierarchy of these 3 positions was correlated with disease susceptibility.

These 3 positions were also predictors of good treatment response from antiTNF therapy and predicted both allcause and cardiovascular mortality.

“If these susceptibility markers can predict disease severity, treatment response, and mortality, this will allow us to tailor therapy so that every patient gets the right treatment,” Dr Viatte noted.

EULAR President Gerd Burmester,

MD, said that, at present, the findings of the study by Dr Viatte and colleagues are not clinically applicable. If future studies validate this work, then risk stratification of patients will be possible based on the genetic polymorphisms within the HLA gene.

“This is a first step toward classification of patients into different categories based on genetic predisposition to identify those at risk of disease progression and early death,” Dr Bur­ mester said.

“The study needs to be replicated in independent cohorts, and we may need more markers to add to this. But I would expect to see genotyping in the clinical arena within 5 to 10 years,” Dr Burmester said. “Cancer is way ahead of us, but rheumatology is on its way.” n

capsules in 50-mg, 100-mg, 200-mg, and 400-mg strengths, and has 180day exclusivity on the 100-mg, 200mg, and 400-mg products. Mylan Pharmaceuticals Inc received approval to market 50-mg celecoxib capsules.

Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID). All NSAIDs have a boxed warning in their prescribing information to alert healthcare professionals and patients about the risk of

heart attack or stroke that can lead to death. This chance increases for people with heart disease or risk factors for heart disease, such as high blood pressure, or taking NSAIDs for long periods of time. The boxed warning also highlights the risk of serious, potential life-threatening gastrointestinal bleeding that has been associated with the use of NSAIDs. In the clinical trials for celecoxib,

the most commonly reported adverse reactions in patients taking the drug for arthritis were abdominal pain, diarrhea, dyspepsia, flatulence, peripheral edema, accidental injury, dizziness, pharyngitis, rhinitis, swollen nasal passages, sinusitis, upper respiratory tract infection, and rash.

Information about the availability of generic celecoxib can be obtained from the companies. n

—Sebastien Viatte, MD

FDA Update FDA Approves First Generic Celecoxib

The first generic versions of Celebrex (celecoxib) capsules, a treatment for patients with rheumatoid arthritis, osteoarthritis, acute pain, and other conditions, have been approved by the FDA, according to a press release by the agency.

Teva Pharmaceutical Industries received approval to market celecoxib

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The Rheumatology Nurse

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Clinical Research...

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healthcare practitioners to produce and publish studies for rheumatology nurses on the best practices of patient care. However, funding obstacles, finding passionate mentors, as well as the lack of scientifically exciting and rigorous environments, are frequently heralded as barriers for researchers in private practice.

The pathway for practitioner/scientist in private practice requires protected research time, passionate mentors, and loyal advocacy. It is equally and vitally important for nurses to step into the role of researcher/investigator to develop strategies and evaluate outcomes of care, and to create, inform, and evaluate evidence-based practice in rheumatology.

maintaining an office or infusion room clinical practice along with the conduction of clinical trials. Dedicated staff, protected time, and a large clinical base of patients from which to obtain potential volunteers is the very basis for success.

Creating the Right Environment The 2010 Institute of Medicine Future of Nursing report1 and research

by Benner and colleagues2 strongly advise academic nursing programs to encourage faculty to require students to follow-through on the care of their patients by examining patient outcomes. In addition, student nurses must be able to comfortably access the literature, be able to discern relevant research, and critically evaluate patient population-based evidence for care of their patients before and after their clinical assignments.

The passion for research and scholarly evaluation skills must be fostered in nursing school so it can nurture and grow in clinical practice. Nurses should be expected to acquire and consummate practice research skills, if for no other reason than to advance the art and science of nursing.

There is benefit to private practice performing clinical research studies if properly planned, supported, and maintained. In an article published in the Journal of Medical Practice Management, Christine Pierre suggested that private practices considering the clinical research arena should primarily determine if they have a sufficient patient population base to recruit from, as well as adequate space for protocol materials, to perform any laboratory aspects of the clinical trials, and space for pharmaceutical monitors to visit, and for work related to the evaluation of a trial.3

Realizing it is not ideal in all cases to have dedicated staff for clinical trials, nurses in particular must be cognizant of wearing 2 hats. Nurses have the trust of the patient and must maintain a balance when working between clinical and investigator/researcher responsibilities. They should be able to differentiate between the nursepatient and researcher-participant relationship.

Nurse researchers must be aware of power relationships that affect the decision of patients whether to participate in a research trial.4 Nurses in researcher roles must be cognizant of the possibility that study participants may have unexpressed concerns.

Think of these concerns as an exacer-

Points to Consider In addition, personnel responsible for clinical trials should be completely dedicated to that service. Ideally, they should not require a dual role in

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misconception. The nurse must make clear to the patient that the right to refuse to participate in a research study is always an option at any point during the study and carries no adverse consequences or ill feelings and will not affect care in any way.

Share your ideas, knowledge, and triumphs. Also share the failures, so that others do not repeat the mistakes.

—Sheree C. Carter, PhD, RN

It is important that the nurse pre­sents the duality of role concretely to the patient to eliminate therapeutic misconception. bation of therapeutic misconception.

When the nurse functions in the role of a healthcare provider as well as a principal investigator, the patient may misunderstand this dual role. For example, the patient may confuse the preexisting trusting relationship with the nurse as a healthcare provider and be fearful of losing that relationship when approached by that same nurse in a researcher role.

It is important that the nurse pre­ sents the duality of role concretely to the patient to eliminate therapeutic

Following a Code of Practice Nursing practice is primarily dedicated to patient care and is governed by a distinct code of ethics by the American Nurses Association. Rheumatology nurses follow a newly designed Scope and Standards of Practice for Rheumatology Nurses.5 The US Food and Drug Administration Guidance on Investigator Responsibilities relates to patient protection, safety concerns, and ethical standards found in the Code of Ethics for Nurses.6 Clinical trial research also follows many distinct codes and documents such as the Belmont Report and Code of Federal Regulations, 21 Part 50.7 Nurses in research must critically adjust to the guidance and codes involved, and maintain the ethics and safety of the nursing profession when assuming a dual role in practice.

In an academic setting, there has been an increase in strategies for fostering research and evidence-based nursing practice in the clinical setting.

Nurse researchers must be adequately prepared through formal education in nursing research. Benner and colleagues1 suggest that research is a skill set that all nurses must come to realize. More rheumatology clinical nurses are needed to embrace a researcher role, not only for clinical trial research, but also for the sake of evidence-based practice.

Sadly, there is little research in the literature to support evidence-based practice in rheumatology nursing.

Nurses in private practice can address many practical issues within nursing research with the expectations that conclusions derived from their studies can be applied to infusion suites and other practices. Share your ideas,

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knowledge, and triumphs. Share equally the failures so that others do not repeat the mistakes. In rheumatology nursing today, there is a tendency for care and practice decisions to be based on experience, recalling outcomes from previous trial-and-effort situations with patients. Providing nursing research conducted in an ethical and scientific manner, specifically for rheumatology nursing practice, provides validation to the profession.

Participation in clinical trials may add prestige to your practice. It can increase networking with other investigators to compare and contrast treatment modalities. The personal reward for an investigator is the knowledge that participation in a clinical trial can add to the body of the science of medicine. Equally important is the advancement of nursing knowledge and an impact on demonstrating how the profession cares specifically for rheumatology patients. If you have the luxury of 1 hat as a researcher, you are fortunate. If you must wear 2 hats, make sure you are very clear to your patients which hat you are wearing in your different encounters. Wear only 1 hat at a time by focusing on priorities. Diligence and attention to the care of the patient comes first, and in some cases may override the research role. n Dr Carter is Assistant Clinical Professor, The University of Alabama in Huntsville; and President, Rheumatology Nurses Society (RNS).

References

1. Institute of Medicine of the National Academies.

The Future of Nursing: Leading Change, Advancing Health. www.iom.edu/Reports/2010/The-Future-ofNursing-Leading-Change-Advancing-Health.aspx.

Published October 5, 2010. Accessed August 11, 2014.

2. Benner PE, Sutphen M, Leonard V, Day L. Educating Nurses: A Call for Radical Transformation. 1st ed. San Francisco, CA: Jossey-Bass; 2010.

3. Pierre C. Physician to investigator: clinical practice to clinical research—ethical, operational, and financial considerations. J Med Pract Manage. 2008;24:9-12.

4. Judkins-Cohn TM, Kielwasser-Withrow K, Owen M, Ward J. Ethical principles of informed consent: Exploring nurses’ dual role of care provider and researcher. J Contin Educ Nurs. 2014;45:35-42.

5. Rheumatology Nursing: Scope and Standards of Practice. American Nurses Association, Rheumatology Nurses Society. Published 2013.

6. Guidance for Industry: Investigator responsibilities, protecting the rights, safety, and welfare of study subjects. US Department of Health & Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, Center for Devices and Radiological Health. www.fda.gov/downloads/ Drugs/.../Guidances/UCM187772.pdf. Published October 2009. Accessed August 11, 2014.

7. US Department of Health, Education, and Welfare.

The Belmont Report. www.hhs.gov/ohrp/humansubjects/guidance/belmont.html. Published April 18, 1979. Accessed August 11, 2014.

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Psoriatic Arthritis

Risk Factors to Consider in Patients with New-Onset Psoriatic Arthritis

By Rosemary Frei, MSc Toronto, ON—The results of a study on new-onset psoriatic arthritis (PsA) underline the importance of attention to warning signs in order to achieve early referral of patients to rheumatologists. The study showed that the

risk for PsA, which is a relatively common condition, is highest in individuals with a higher Psoriasis Area and Severity Index (PASI) score, nail involvement, and a higher body mass index (BMI).

at a glance ➤ The risk of PsA is highest in individuals with a higher PASI score, nail involvement, and a higher BMI ➤ Patients in the PsA and nonPsA groups had similar characteristics, including percentage of men, median age at diagnosis, and percentage of patients who ever smoked ➤ Members of the PsA group had a significantly higher median most recent PASI score compared with those without PsA

for management of their joint disease,” Cheryl Rosen, MD, told ValueBased Care in Rheumatology at the Canadian Dermatology Association’s 89th Annual Conference where she presented the results.

“People with pain in their joints who also have psoriasis and nail disease, and a higher BMI—these are patients that dermatologists should consider referring to rheumatologists for management of their joint disease.”

—Cheryl Rosen, MD

“People with pain in their joints who also have psoriasis and nail disease, and a higher BMI—these are patients that dermatologists should consider referring to rheumatologists

Dr Rosen, Head of the Division of Dermatology at the University Health Network, Toronto, ON, collaborated with principal investigator Dafna Gladman, MD, Director of the

University Health Network’s Psoriatic Arthritis Program, and other researchers on the large Toronto Psoriasis Cohort. The analysis focused on the 40 patients who developed PsA since the cohort was established in 2006. The investigators matched these 40 patients with new-onset PsA to 1:2 with other cohort members who had a similar duration of psoriasis but had not developed PsA. The PsA and non-PsA groups had similar characteristics, including percentage of men, median age at diagnosis, percentage of patients who ever smoked, and proportion who had ever used disease-modifying antirheumatic drugs or biologics.

However, members of the PsA group had a significantly higher median most recent PASI score compared with patients without PsA (4 vs 3.5, respectively; P = .02). Patients with PsA were also more likely to have nail involvement than patients without PsA (72.5% vs 53.8%, respectively; P <.0001), and have a higher median BMI (29.7 vs 27.1 kg/m2, respectively). n

Lupus

Stopping Immunotherapy in Patients with Lupus

By Phoebe Starr Paris, France—A study presented at the 2014 European League Against Rheumatism (EULAR) Congress reports that a sizable proportion of selected patients with lupus can stop therapy without triggering new disease flares for up to 5 years.

Candidates able to cease therapy are those in clinical remission for at least 1 year with low disease activity and on very low or no doses of steroids. The study results emphasize that tapering of immunosuppressant therapy should be gradual.

This is good news because there are no guidelines on how or when to stop immunotherapy, said EULAR Scientific Chair Ulf Müller-Ladner, MD, who commented on this study. “The key messages are that we can stop but we have to be careful. Not every patient can stop. We have to know who the candidates are,” he stated. “They

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should be closely monitored after they stop.”

Study author Zahi Touma, MD, University of Toronto, Canada, said, “In the absence of guidelines, the deci-

“In the absence of guidelines, the decision to stop immunotherapy is up to the individual physician.”

—Zahi Touma, MD

sion to stop immunotherapy is up to the individual physician. Immunosuppressive agents are very important in the management of lupus, but they do have side effects that patients would like to avoid. The study tries to

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fill the gap in knowledge about how and when to stop, and results confirm that stopping immunosuppressants is possible in a selected group of patients.”

Of 99 clinically stable patients with lupus who were able to stop treatment successfully, 74% had no disease flares within 2 years of discontinuing either azathioprine, methotrexate, or mycophenolate mofetil; 50% had no flares within 3 years and remained stable for up to 5 years, avoiding the adverse effects associated with long-term immunosuppressant treatment.

The study population was drawn from a registry of 1678 patients with lupus at the Toronto Lupus Clinic; 973 patients were prescribed an immunosuppressant between 1970 and 2012. Of these, 179 patients had tapering attempts and 99 patients (56%) were able

to stop therapy. Of the 99 patients who stopped, 25 patients flared within 2 years (30% flare rate), 46% flared within 3 years, and 51% flared by 5 years.

There were 3 time points for data collection per patient: initiation of tapering (ie, the first visit when there was at least a 25% decrease in immunosuppressant dose); date of immunosuppressant discontinuation; and end of study (ie, the date of flare or last clinical visit after discontinuation of the immunosuppressant).

The 179 patients included in the study had their dose of immunosuppressant therapy tapered by at least 25%, were in clinical remission based on no activity in the Systemic Lupus Erythematosus Disease Activity Index, and were taking <7.5 mg prednisone daily. Mean age at tapering was 40.4 years, and mean disease duration was 11.4 years. n VOL. 3

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Lupus

Childhood SLE Is an Independent Predictor of Low Employment Rates

By Lianne Bennett

A

dults with childhood systemic lupus erythematosus (cSLE) are significantly less likely to be employed than adults with adult-onset SLE (aSLE), according to a large, prospective, longitudinal study

by Erica F. Lawson, MD, Department of Pediatrics, Division of Rheumatology, University of California, San Francisco, and colleagues.

Evaluating Education, Employment Using data from 929 patients with SLE who participated in telephone interviews between 2002 and 2010 as part of the Lupus Outcomes Study—

at a glance ➤ Demographic and socio­ economic characteristics, as well as several other factors, including SLE disease activity and medications, were evaluated as part of the survey ➤ Patients with cSLE were more likely to have completed a bachelor’s degree compared with patients with aSLE ➤ Additional vocational training and workplace support is warranted so patients with cSLE can succeed in the working world

an ongoing longitudinal survey of patients with SLE in the United States—the investigators sought to compare educational and vocational outcomes among adults with cSLE and adults with aSLE. The survey questions pertained to demographic and socioeconomic characteristics, SLE disease activity, medications, general health, mental health, cognition, employment, health­ care use, and health insurance coverage. The primary outcome measures were completion of a 4-year college degree and employment status, and the primary predictor variable was cSLE, which was defined as patients diagnosed before 18 years of age.

Other predictor variables for employment included disease duration, disease activity, renal damage, and physical function.

At baseline, patients in the analysis were aged between 18 years and 60 years; patients with cSLE were younger overall than patients with aSLE. Patients with cSLE also had longer mean disease duration, were more affected by renal disease, and had lower baseline disease activity compared with patients with aSLE. In addition, patients with cSLE were more likely to have completed a bachelor’s degree compared with patients with aSLE; the difference was not significant. However, other factors, including age, sex, and geographic location, were significant predictors of

education attainment. For example, women patients and nonwhite patients were significantly less likely to have completed a bachelor’s degree. In addition, younger patients and patients living in the northeastern United States were significantly more likely to have completed a bachelor’s degree.

“Individuals with cSLE are less likely to enter the workforce due to complications of their illness, whereas individuals who were successfully employed prior to onset of SLE are more likely to return to the workforce.”

—Erica F. Lawson, MD, and colleagues

Disease Complications May Affect Employment Status A longitudinal multivariate analysis showed that patients with cSLE were significantly less likely to be employed compared with patients with aSLE (odds ratio, 0.62; 95% confidence interval, 0.42-0.91). Furthermore, investigators found that patients with cSLE were significantly less likely to be continuously employed than those with aSLE. Other factors associated

with low employment and low continuous employment included baseline physical function and disease activity, history of dialysis and need for dialysis during the follow-up period, and female sex.

To exclude the possibility that the low employment rate was due largely to patients still completing school, those who are already retired, and the recent economic recession, the investigators removed these factors from their analysis. Even after controlling for these confounders, cSLE remained an independent predictor of employment status.

The authors proposed several theories to explain the low employment rate in adults with cSLE, such as complications of the disease. “It is possible that individuals with cSLE are less likely to enter the workforce due to complications of their illness, whereas individuals who were successfully employed prior to onset of SLE are more likely to return to the workforce,” noted Dr Lawson and colleagues. In addition, the authors added that the workplace may not be flexible enough to provide timeoff during disease flares.

The authors agreed that although patients with cSLE may receive adequate educational support, additional vocational training and workplace support is warranted so that these patients can also succeed in the working world. n

In the Literature

Bone Mineral Density Should Be Checked in All Hypogonadal Men

By Rosemary Frei, MSc

A

recent retrospective study of 114 patients with hypogonadism has led to the conclusion that men with this condition should be screened with dual-energy x-ray absorptiometry (DEXA) for low bone mineral density (BMD). Almost half of the men who participated in this study with testosterone levels below 300 ng/dL were found in the retrospective chart review to have either osteopenia or osteoporosis.1

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Hypogonadism has long been recognized as a risk factor for osteoporosis and osteopenia. However, there has been very little investigation of the strength of this association and of what factors are the strongest predictors of low BMD. Presented at the American Society of Andrology’s 2014 Annual Meeting, the study examined BMD scans on

patients with clinical hypogonadism.

Participants presented with clinical symptoms as well as biochemical deaugust 2014

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ficiencies. Hypogonadism among the older adult male population is expected to increase in coming years; the mean ± standard deviation age of the cohort in this study was 48.3 ± 13.7 years.1,2 “Even though the Endocrine Society’s 2010 guidelines state that hypogonadal men should get DEXA scans only when they have severe testosterone deficiency—that is, below 150 ng/dL—we found you still have just Continued on page 22

www.ValueBasedRheumatology.com

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Gout

Febuxostat versus Allopurinol Postmarketing Study to Be Conducted in Europe

By Lianne Bennett

G

out affects 1% to 2% of adults in Western countries and 2.5% of adults in the United Kingdom. Compared with the general population, patients with gout have increased cardiovascular morbidity and mortality, and researchers largely attribute this increased risk to urate levels. According to the European League Against Rheumatism (EULAR) guidelines for the management of gout, urate-lowering therapy should be used to treat patients with recurrent acute flares, arthropathy, tophi, or radiographic changes of gout.

Allopurinol and febuxostat, both xanthine oxidase inhibitors, are uratelowering therapies indicated for the management of gout. A phase 3 clinical trial showed that febuxostat was superior to allopurinol in achieving and maintaining EULAR-recommended target urate levels (<357 μmol/L). However, phase 3 longterm extension studies of febuxostat indicated that there was a higher rate of cardiovascular events with febuxostat than with allopurinol.

A prospective, randomized, openlabel, blinded, end point, postmarketing study known as FAST (Febuxostat

versus Allopurinol Streamlined Trial) will be conducted in the United Kingdom and in Denmark to evaluate the cardiovascular safety of febuxostat compared with allopurinol in patients with gout (MacDonald TM, et al. BMJ Open. 2014;4:e005354). Lead author Thomas M. MacDonald, MD, Medicines Monitoring Unit, Ninewells Hospital, University of Dundee, United Kingdom, and colleagues stated that “When completed, FAST will help to establish the cardiovascular safety of febuxostat and allopurinol in a population with high cardiovascular risk.”

Patient Recruitment and Treatment The study investigators are planning to recruit a total of 5706 patients, with 2853 patients in each treatment arm. The recruited patients must be aged ≥60 years, prescribed allopurinol for gout, and with at least 1 additional cardiovascular risk factor. The patients will be randomized to allopurinol or febuxostat and followed for an average of 3 years.

Patients will receive febuxostat 80 mg daily; the dose will be increased to 120 mg daily if the serum urate level is >357 μmol/L at a 2-week check. Be-

cause febuxostat is a more potent urate-lowering therapy than allopurinol, an allopurinol lead-in phase, prior to treatment randomization, will determine the dose of allopurinol at randomization. If the serum urate level is above the EULAR-recommended tar-

“When completed, FAST will help to establish the cardiovascular safety of febuxostat and allopurinol in a population with high cardiovascular risk.”

—Thomas M. MacDonald, MD, and colleagues

get level, the allopurinol daily dose will be increased by 100 mg, and rechecked after 2 weeks, until the target level is achieved. All patients will have an allopurinol washout period of at least 7 days before and after randomization.

Adjustment of treatment dosages may be necessary because of efficacy and tolerability concerns. All dosage

adjustments and any adverse reactions will be recorded in web-based electronic clinical report form.

Study End Points and Analysis The primary end point is the first occurrence (after randomization) of Antiplatelet Trialists’ Collaboration (APTC) events, including hospitalization for nonfatal myocardial infarction, nonfatal stroke, or death because of a cardiovascular event. The secondary end points include all-cause mortality, hospitalization for heart failure, and others.

The first analysis will assess non­ inferiority of the primary end point based on the per-protocol population and on the intent-to-treat population.

A total of 456 APTC events are required to demonstrate noninferiority between febuxostat and allopurinol. If noninferiority is demonstrated (ie, upper limit of the 95% confidence interval for the hazard ratio is <1.3 for the per-protocol analysis), a superiority analysis on the intent-to-treat population will follow. In addition, a sensitivity analysis will be performed by censoring patient follow-up at 90 days beyond the per-protocol period or end of study. n

In the Literature

Bone Mineral Density Should Be Checked... as much of a chance of having hypogonadism below 300 ng/dL, and no levels below this are predictive of having worse BMD,” Igor Sorokin, MD, third year urology resident at the Albany Medical College and lead author of a poster presentation on the results. “The study confirms that any male coming to your clinic with hypogonadism should get a baseline DEXA regardless of previous treatment.”3 Hypogonadism is associated with a number of comorbidities; symptoms include reduced libido/erectile dysfunction, reduced muscle mass and strength, increased adiposity, and depressed mood and fatigue. It has also long been recognized as a risk factor for osteoporosis and osteo-

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penia. However, there has been very little investigation of the strength of this association and of what factors are the strongest predictors of low BMD.1,2 Andrew McCullough, MD, surgery professor, Division of Urology, Albany Medical College, led the team who reviewed the records of 114 consecutive patients who were being treated for hypogonadism between February 2011 and September 2013 at the Men’s Health Center. Hypogonadism is defined as the presence of both symptoms and serum testosterone levels of <300 ng/dL. The subjects had all undergone BMD assessment.1 Forty-four (38.6%) of the men had been found on DEXA screening to have osteopenia and 9 (7.9%) had os-

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teoporosis. Their mean testosterone level at diagnosis was 183 ng/dL. The researchers found lower total and mean testosterone were not significantly associated with lower BMD, nor were longer duration of hypogonadism or higher serum estradiol levels.1 Former or current smoking was associated with a higher prevalence of osteopenia and osteoporosis: 57% of people with osteopenia were former or current smokers, whereas 43% were never-smokers, and the respective numbers for subjects with osteoporosis were 78% and 22%.

The team did not find a correlation between total testosterone levels and t-scores of the spine, hip, or femoral neck. They did find higher total tes-

Continued from page 21

tosterone levels in men who had previously received testosterone treatment than in those who had not received such treatment, but previous testosterone treatment was not associated with higher BMD.1 n References

1. Sorokin I, et al. Prevalence of bone density deficiencies in men presenting for hypogonadism treatment: do we need to worry? American Society of Andrology’s 39th Annual Meeting, April 4-8, 2014, Atlanta. Poster 69.

2. Dandona P, Rosenberg MT. A practical guide to male hypogonadism in the primary care setting. Int J Clin Pract. 2010;64:682-696.

3. The Endocrine Society’s Clinical Guidelines.

Testosterone therapy in adult men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. 2010. http://www.endocrine.org/~/ media/endosociety/Files/Publications/Clinical%20 Practice%20Guidelines/FINAL-Androgens-in-MenStandalone.pdf. Accessed May 6, 2014.

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

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

To learn more about SLE, visit

www.TalkSLE.com

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

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

Rheumatology (Oxford). 2012;51(3):491-498. ©2014 GSK group of companies.

All rights reserved. Printed in USA. BN2671R0 April 2014