vbcr february vol 2, no 1

VALUE PROPOSITIONS . . . . . . . . . . 7New Medicare rules will save providers $676 million annually

HEALTH ECONOMICS . . . . . . . . . . . . 8Cost-effectiveness helps differentiate drug classes for acute gout treatment

SCLERODERMA . . . . . . . . . . . . . . . . . .11Prophylactic use of ACE inhibitors may not be advisable

Rheumatology PRACTICEMANAgEMENT™ . . . . . . . . . . . . . . . . . . 12Exercise program cost-effective for arthritic knee pain

PERSONALIzED MEDICINE in Rheumatology™ . . . . . . . . . . . . . . . . . . . 14New genetic loci potential targets for novel therapies for gout

OSTEOPOROSIS . . . . . . . . . . . . . . . . .15Odanacatib effective in women with osteoporosis uncontrolled with alendronate

DRUg UPDATE . . . . . . . . . . . . . . . . . .16Tofacitinib: a new treatment option for patients with RA

www.ValueBasedRheumatology.com

february 2013 VOL 2 • NO 1Value-Based

Care in RheumatologyfrOm the pubLishers Of AmericAn HeAltH & drug benefits®

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© 2013 Engage Healthcare Communications, LLC

i n s i d e

Washington, DC—Medicare benefi-ciaries who have a low-income sub-sidy are more likely to have access to rheumatoid arthritis (RA) biolog-

ic therapy through their Part D drug benefit than those who face the Medicare coverage gap (also known as the “donut hole”), according to

High Out-of-Pocket Cost of Biologic DMARDs for Medicare Patients with RAAccess to a rheumatologist key to appropriate drug therapy By Phoebe Starr

Continued on page 8

Continued on page 4

Washington, DC—Sjögren’s syn-drome has been understudied and is not well understood, but an interna-tional collaboration has produced new classification criteria for this au-toimmune disease, and experts are working on guidelines for the man-agement of this condition. These ef-forts were discussed at the 2012 meet-ing of the American College of Rheumatology (ACR).

The New CriteriaNew criteria for the classification of

Sjögren’s syndrome proposed by the ACR were developed by an interna-tional group called the Sjögren’s Syn-drome International Collaborative Clinical Alliance (SICCA) and were based on 1362 participants who were enrolled in the SICCA registry. The proposed classification considers that Sjögren’s syndrome is a multisystem autoimmune disease that should in-volve multidisciplinary treatment in rheumatology, ophthalmology, and oral medicine.

Continued on page 11

Progress in Classifying and Managing Sjögren’s SyndromeACR’s proposed new criteria the basis for this development By Phoebe Starr

Year in Review, Part 2By Wayne Kuznar

Washington, DC—In the previous issue of Value-Based Care in Rheuma-tology, clinical publications of impact from the peer-reviewed literature from late 2011 and 2012 were select-ed for review by David A. Isenberg, MD, FRCP, FAMS, Arthritis Research Campaign’s Diamond Jubilee Profes-

sor of Rheumatology, University Col-lege London, and presented at the 2012 meeting of the American College of Rheumatology.

This second article focuses on Dr Isenberg’s selections in translational medicine, as well as a category he called “quirky reports.”

Washington, DC—Although differ-ences in the effectiveness between different drug classes used in acute gout treatment are small, some treat-ments offer more value, said Kimber-ly Reiter, MD, of Presbyterian Medi-cal Group, Albuquerque, NM, at the 2012 meeting of the American College of Rheumatology (ACR).

The recent ACR guidelines for the treatment of acute and chronic gouty arthritis indicate that corticosteroids,

colchicine (Colcrys), and nonsteroidal anti-inflammatory drugs (NSAIDs) are appropriate first-line therapies for acute gout. However, according to Dr Reiter, the guidelines do not “go far enough” in ranking the classes of drugs for the treatment of acute gout, nor do they incorporate costs.

She presented the findings from a study that compared the drug classes used to treat acute gout flares in terms

Cost-Effectiveness Helps to Differentiate Drug Classes for Acute gout TreatmentBy Wayne Kuznar

Continued on page 8

References:1. COLCRYS (colchicine, USP) full prescribing information, June 2012. 2. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population:

the National Health and Nutrition Examination Survey 2007-2008. Arthritis Rheum. 2011;63:3136-3141.

COLCRYS is a trademark of Takeda Pharmaceuticals U.S.A., Inc., registered with the U.S. Patent and Trademark Offi ce and used under license by Takeda Pharmaceuticals America, Inc. ©2013 Takeda Pharmaceuticals U.S.A., Inc. 44004 03/13

Important Safety Information

• COLCRYS is contraindicated in patients with renal or hepatic impairment who are currently prescribed P-gp inhibitors or strong inhibitors of CYP3A4. In these patients, life-threatening and fatal colchicine toxicity has been reported with colchicine taken in therapeutic doses. Dose adjustments of COLCRYS may be required when co-administered with P-gp or CYP3A4 inhibitors in patients with normal renal and hepatic function.

• Fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine. Keep COLCRYS out of the reach of children.

• Blood dyscrasias such as myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia have been reported in patients taking colchicine at therapeutic doses.

Colcrys_44004_4Pg_Jrnl100896_P01Takeda2/21/13 GM

Please see brief summary of completePrescribing Information on the following pages.

If your patients are experiencing gout fl ares, consider COLCRYS (colchicine, USP)Low-dose COLCRYS is indicated to treat acute attacks of gout, a common form of arthritis.1,2

Indications COLCRYS (colchicine, USP) 0.6 mg tablets are indicated in adults for the prophylaxis of gout flares and treatment of acute gout flares when taken at the first sign of a flare.

COLCRYS is not an analgesic medication and should not be used to treat pain from other causes.

• Colchicine-induced neuromuscular toxicity and rhabdomyolysis have been reported with chronic treatment in therapeutic doses, especially when colchicine is prescribed in combination with other drugs known to cause this effect. Patients with renal dysfunction and elderly patients, even those with normal renal and hepatic function, are at increased risk.

• Monitor for toxicity and if present consider temporary interruption or discontinuation of colchicine.

• The most common adverse reactions in clinical trials were diarrhea (23%) and pharyngolaryngeal pain (3%).

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4 value-based CaRe in Rheumatology I febRuaRy 2013 vol. 2 I no. 1

Rheumatology Update

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATIONCOLCRYS (colchicine, USP) tablets for Oral use

INDICATIONS AND USAGEGout FlaresCOLCRYS (colchicine, USP) tablets are indicated in adults for prophylaxis and the treatment of acute gout flares.

Prophylaxis of Gout Flares: COLCRYS is indicated for prophylaxis of gout flares. Treatment of Gout Flares:COLCRYS tablets are indicated for treatment of acute gout flares when taken at the first sign of a flare.

Familial Mediterranean fever (FMF)COLCRYS (colchicine, USP) tablets are indicated in adults and children 4 years or older for treatment of familial Mediterranean fever (FMF).COLCRYS is not an analgesic medication and should not be used to treat pain from other causes.CONTRAINDICATIONSPatients with renal or hepatic impairment should not be given COLCRYS in conjunction with P-gp or strong CYP3A4 inhibitors (this includes all protease inhibitors, except fosamprenavir). In these patients, life-threatening and fatal colchicine toxicity has been reported with colchicine taken in therapeutic doses.WARNINGS AND PRECAUTIONSFatal OverdoseFatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine [see OVERDOSAGE]. COLCRYS should be kept out of the reach of children.Blood DyscrasiasMyelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia have been reported with colchicine used in therapeutic doses.Drug InteractionsColchicine is a P-gp and CYP3A4 substrate. Life-threatening and fatal drug interactions have been reported in patients treated with colchicine given with P-gp and strong CYP3A4 inhibitors. If treatment with a P-gp or strong CYP3A4 inhibitor is required in patients with normal renal and hepatic function, the patient’s dose of colchicine may need to be reduced or interrupted [see DRUG INTERACTIONS]. Use of COLCRYS in conjunction with P-gp or strong CYP3A4 inhibitors (this includes all protease inhibitors, except fosamprenavir) is contraindicated in patients with renal or hepatic impairment [see CONTRAINDICATIONS].Neuromuscular ToxicityColchicine-induced neuromuscular toxicity and rhabdomyolysis have been reported with chronic treatment in therapeutic doses. Patients with renal dysfunction and elderly patients, even those with normal renal and hepatic function, are at increased risk. Concomitant use of atorvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, gemfibrozil, fenofibrate, fenofibric acid, or benzafibrate (themselves associated with myotoxicity) or cyclosporine with COLCRYS may potentiate the development of myopathy [see DRUG INTERACTIONS]. Once colchicine is stopped, the symptoms generally resolve within 1 week to several months.ADVERSE REACTIONSProphylaxis of Gout Flares:The most commonly reported adverse reaction in clinical trials of colchicine for the prophylaxis of gout was diarrhea.Treatment of Gout Flares:The most common adverse reactions reported in the clinical trial with COLCRYS for treatment of gout flares were diarrhea (23%) and pharyngolaryngealpain (3%). FMF:Gastrointestinal tract adverse effects are the most frequent side effects in patients initiating COLCRYS, usually presenting within 24 hours, and occurring in up to 20% of patients given therapeutic doses. Typical symptoms include cramping, nausea, diarrhea, abdominal pain, and vomiting. These events should be viewed as dose-limiting if severe as they can herald the onset of more significant toxicity.Clinical Trials Experience in Gout Because clinical studies are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug, and may not predict the rates observed in a broader patient population in clinical practice. In a randomized, double-blind, placebo-controlled trial in patients with a gout flare, gastrointestinal adverse reactions occurred in 26% of patients using

the recommended dose (1.8 mg over 1 hour) of COLCRYS compared to 77% of patients taking a non-recommended high-dose (4.8 mg over 6 hours) of colchicine and 20% of patients taking placebo. Diarrhea was the most commonly reported drug-related gastrointestinal adverse event. As shown in Table 3, diarrhea is associated with COLCRYS treatment. Diarrhea was more likely to occur in patients taking the high-dose regimen than the low-dose regimen. Severe diarrhea occurred in 19% and vomiting occurred in 17% of patients taking the non-recommended high-dose colchicine regimen but did not occur in the recommended low-dose COLCRYS regimen.

Table 3Number (%) of Patients with at Least One Drug-Related Treatment

Emergent Adverse Events with an Incidence of ≥ 2% of Patients in Any Treatment Group

MedDRA System Organ ClassMedDRA Preferred Term

COLCRYS Dose Placebo(N=59)n (%)

High (N=52)n (%)

Low (N=74)n (%)

Number of Patients with at Least One Drug-Related TEAE

40 (77) 27 (37) 16 (27)

Gastrointestinal Disorders 40 (77) 19 (26) 12 (20)

Diarrhea 40 (77) 17 (23) 8 (14)

Nausea 9 (17) 3 (4) 3 (5)

Vomiting 9 (17) 0 0

Abdominal Discomfort 0 0 2 (3)

General Disorders and Administration Site Conditions

4 (8) 1 (1) 1 (2)

Fatigue 2 (4) 1 (1) 1 (2)

Metabolic andNutrition Disorders

0 3 (4) 2 (3)

Gout 0 3 (4) 1 (2)

Nervous System Disorders 1 (2) 1 (1.4) 2 (3)

Headache 1 (2) 1 (1) 2 (3)

Respiratory Thoracic Mediastinal Disorders

1 (2) 2 (3) 0

Pharyngolaryngeal Pain 1 (2) 2 (3) 0

Postmarketing ExperienceSerious toxic manifestations associated with colchicine include myelosuppression, disseminated intravascular coagulation, and injury to cells in the renal, hepatic, circulatory, and central nervous systems.These most often occur with excessive accumulation or overdosage[see OVERDOSAGE].The following adverse reactions have been reported with colchicine. These have been generally reversible upon temporarily interrupting treatment or lowering the dose of colchicine.

Neurological: sensory motor neuropathyDermatological: alopecia, maculopapular rash, purpura, rashDigestive: abdominal cramping, abdominal pain, diarrhea, lactose intolerance, nausea, vomiting Hematological: leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, aplastic anemiaHepatobiliary: elevated AST, elevated ALTMusculoskeletal: myopathy, elevated CPK, myotonia, muscle weakness, muscle pain, rhabdomyolysisReproductive: azoospermia, oligospermia

DRUG INTERACTIONSCOLCRYS (colchicine) is a substrate of the efflux transporter P-glycoprotein (P-gp). Of the cytochrome P450 enzymes tested, CYP3A4 was mainly involved in the metabolism of colchicine. If COLCRYS is administered with drugs that inhibit P-gp, most of which also inhibit CYP3A4, increased concentrations of colchicine are likely. Fatal drug interactions have been reported.Physicians should ensure that patients are suitable candidates for treatment with COLCRYS and remain alert for signs and symptoms of toxicities related to increased colchicine exposure as a result of a drug interaction. Signs and symptoms of COLCRYS toxicity should be evaluated promptly and, if toxicity is suspected, COLCRYS should be discontinued immediately.


Year in Review... Continued from page 1

Translational MedicineIn a study of 55 serologically active,

clinically quiescent patients with sys-temic lupus erythematous (SLE) and 110 SLE controls matched for age, sex, disease duration, and damage score, patients with prolonged, serologically active, clinically quiescent SLE ac-crued less damage over a decade than

the SLE controls (Steiman AJ, et al. Arthritis Care Res [Hoboken]. 2012;64: 511-518.)

Therefore, management by active surveillance without the use of steroids or immunosuppressive agents is opti-mal. “In other words, treat the patient, don’t treat the result,” said Dr Isenberg.

Muro and colleagues (Rheumatology

[Oxford]. 2012;51:800-804) studied an-tibodies against the melanoma differ-entiation-associated gene 5 (MDA5), which is a marker for dermatomyosi-tis. These antibodies are especially associated with progressive intersti-tial lung disease. The researchers es-tablished enzyme-linked immuno-sorbent assay to measure anti-MDA5

in 11 patients who were followed for 3 months to 16 years. At the stage of clinical remission, the anti-MDA5 an-tibodies disappeared in 9 of the pa-tients, which suggests that anti-MDA5 antibodies may be useful for monitor-ing disease activity in interstitial lung disease that is complicated by amyop-athic dermatomyositis.

In a study known as ESPOIR, patients who had at least 2 swollen joints for >6 weeks but <6 months had the serum levels of various cytokines measured (Gottenberg JE, et al. Ann Rheum Dis. 2012;71:1243-1248). At the 1-year follow-up, 578 of the patients had developed rheumatoid arthritis (RA), and 132 were deemed to have undifferentiated arthritis. On univar-iate analysis, only interleukin (IL)-6 and IL-21 distinguished RA. On mul-

tivariate analysis, IL-6 and anticyclic citrullinated protein were linked to radiographic erosions.

Nielsen and colleagues (BMJ. 2012; 345:e5244) assessed the levels of rheu-matoid factor in 9712 individuals who were part of the Copenhagen City Heart Study and followed them for up to 28 years. Using multivariate adjust-ed hazard ratios for RA development, they found that the highest abso-lute risk of RA (32%) was observed

in women aged 50 to 69 years who smoked and had a rheumatoid factor >100 IU/mL.

Mammen and colleagues suggest-ed in a recent study that there may be a mechanistic link between statin exposure, increased anti–hydroxy-methylglutaryl- coenzyme A reduc-tase (anti-HMGCR) expression, and the possible presentation of HMG-CR-derived peptides by DRB1*11:01 (Mammen AL, et al. Arthritis Care Res [Hoboken]. 2012; 64:1233-1237). Human

leukocyte antigen (HLA) links to statin myopathy were assessed in 20 Cauca-sian patients and 487 Caucasian con-trols, and 8 black patients and 167 black controls. In the Caucasian pa-tients, HLA and DR11, DQA5, and DQB7 were strongly associated. In blacks, only DR11 was linked to HLA. High-resolution mapping helped to establish that the best overall link with anti-HMGCR myopathy was to DRB1*11:01.

Quirky ReportsIn a Finnish town in which tap

water was contaminated with feces in November 2007, gastrointestinal symptoms, especially diarrhea and blood in the feces, predicted joint complaints (Laine J, et al. Rheumatology [Oxford]. 2012;51:513-518). Joint symp-toms occurred in 13.9% of the respon-dents living in the area with fecal-con-taminated tap water and in 4.3% of the respondents living in areas with uncontaminated water.

Milman and Smith (Arthritis Care Res [Hoboken]. 2011;63:1195-1202) de-scribed 8 patients with cocaine-relat-ed cutaneous vasculopathy. Three patients stopped using cocaine and their skin problems improved, but problems were chronic and persistent in the 4 patients who continued to use it, 2 of whom died.

The ability of tumor necrosis factor (TNF)-alpha inhibitors to prevent the development of diabetes mellitus in 1587 patients with RA was explored in a retrospective study (Antohe JL, et al. Arthritis Care Res [Hoboken]. 2012;64:215-221). Only 3% of the patients who re-ceived TNF-alpha inhibitors devel-oped diabetes compared with 7% of the patients who had not received TNF-alpha inhibitors, indicating that the use of TNF-alpha inhibitors may offer the additional benefit of reducing the risk of diabetes in patients with RA.

Testicular function is normal over-all in primary antiphospholipid syn-drome (PAPS) despite morphofunc-tional penile abnormalities, as was found in a cross-sectional study (Ra-belo-Júnior CN, et al. Lupus. 2012;21: 251-256) of 12 male patients with PAPS and 20 controls who were as-sessed with testicular ultrasound and other urologic studies. n

5 vol. 2 I no. 1 febRuaRy 2013 I www.valuebasedRheumatology.com

Rheumatology Update

Table 4 provides recommendations as a result of other potentially significant drug interactions. Table 1 provides recommendations for strong and moderate CYP3A4 inhibitors and P-gp inhibitors.

Table 4Other Potentially Significant Drug Interactions

Concomitant Drug Class or Food

Noted or anticipated Outcome

Clinical Comment

HMG-Co A Reductase Inhibitors:atorvastatin, fl uvastatin,lovastatin, pravastatin, simvastatin

Pharmacokinetic and/orpharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality)

Weigh the potential benefi ts and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.

Other Lipid Lowering Drugs:fi brates, gemfi brozil

Digitalis Glycosides:digoxin

P-gp substrate; rhabdomyolysis has been reported

USE IN SPECIFIC POPULATIONS PregnancyPregnancy Category CThere are no adequate and well-controlled studies with colchicine in pregnant women. Colchicine crosses the human placenta. While not studied in the treatment of gout flares, data from a limited number of published studies found no evidence of an increased risk of miscarriage, stillbirth, or teratogenic effects among pregnant women using colchicine to treat familial Mediterranean fever (FMF). Although animal reproductive and developmental studies were not conducted with COLCRYS, published animal reproduction and development studies indicate that colchicine causes embryofetal toxicity, teratogenicity, and altered postnatal development at exposures within or above the clinical therapeutic range. COLCRYS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Labor and DeliveryThe effect of colchicine on labor and delivery is unknown.Nursing MothersColchicine is excreted into human milk. Limited information suggests that exclusively breast-fed infants receive less than 10 percent of the maternal weight-adjusted dose. While there are no published reports of adverse effects in breast-feeding infants of mothers taking colchicine, colchicine can affect gastrointestinal cell renewal and permeability. Caution should be exercised and breast-feeding infants should be observed for adverse effects when COLCRYS is administered to a nursing woman.Pediatric UseThe safety and efficacy of colchicine in children of all ages with FMF has been evaluated in uncontrolled studies. There does not appear to be an adverse effect on growth in children with FMF treated long-term with colchicine. Gout is rare in pediatric patients, safety and effectiveness of colchicine in pediatric patients has not been established.Geriatric UseClinical studies with colchicine for prophylaxis and treatment of gout flares and for treatment of FMF did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient with gout should be cautious, reflecting the greater frequency of decreased renal function, concomitant disease, or other drug therapy.Renal Impairment Colchicine is significantly excreted in urine in healthy subjects. Clearance of colchicine is decreased in patients with impaired renal function. Total body clearance of colchicine was reduced by 75% in patients with end-stage renal disease undergoing dialysis.Prophylaxis of Gout Flares: For prophylaxis of gout flares in patients with mild (estimated creatinine clearance Clcr 50 – 80 mL/min) to moderate (Clcr 30 – 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, the starting dose should be0.3 mg per day and any increase in dose should be done with close monitoring. For the prophylaxis of gout flares in patients undergoing dialysis, the starting doses should be 0.3 mg given twice a week with close monitoring. Treatment of Gout Flares:For treatment of gout flares in patients with mild (Clcr 50 – 80 mL/min) to moderate (Clcr 30 – 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored

closely for adverse effects of COLCRYS. However, in patients with severe impairment, while the dose does not need to be adjusted for the treatment of gout flares, a treatment course should be repeated no more than once every2 weeks. For patients with gout flares requiring repeated courses consideration should be given to alternate therapy. For patients undergoing dialysis, the total recommended dose for the treatment of gout flares should be reduced to a single dose of 0.6 mg (1 tablet). For these patients, the treatment course should not be repeated more than once every 2 weeks. FMFAlthough, pharmacokinetics of colchicine in patients with mild(Clcr 50 – 80 mL/min) and moderate (Clcr 30 – 50 mL/min) renal impairment is not known, these patients should be monitored closely for adverse effects of colchicine. Dose reduction may be necessary. In patients with severe renal failure (Clcr less than 30 mL/minute) and end-stage renal disease requiring dialysis, COLCRYS may be started at the dose of 0.3 mg/day. Any increase in dose should be done with adequate monitoring of the patient for adverse effects of COLCRYS.Hepatic ImpairmentThe clearance of colchicine may be significantly reduced and plasmahalf-life prolonged in patients with chronic hepatic impairment, compared to healthy subjects.Prophylaxis of Gout Flares: For prophylaxis of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. Dose reduction should be considered for the prophylaxis of gout flares in patients with severe hepatic impairment.Treatment of Gout Flares: For treatment of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended COLCRYS dose is not required, but patients should be monitored closely for adverse effects of COLCRYS. However, for the treatment of gout flares in patients with severe impairment while the dose does not need to be adjusted, the treatment course should be repeated no more than once every 2 weeks. For these patients, requiring repeated courses for the treatment of gout flares, consideration should be given to alternate therapy. FMFIn patients with severe hepatic disease, dose reduction should be considered with careful monitoring.OVERDOSAGEThe exact dose of colchicine that produces significant toxicity is unknown. Fatalities have occurred after ingestion of a dose as low as 7 mg over a 4-day period, while other patients have survived after ingesting more than 60 mg. A review of 150 patients who overdosed on colchicine found that those who ingested less than 0.5 mg/kg survived and tended to have milder toxicities, such as gastrointestinal symptoms, whereas those who took 0.5 to 0.8 mg/kghad more severe reactions, such as myelosuppression. There was100% mortality in those who ingested more than 0.8 mg/kg.The first stage of acute colchicine toxicity typically begins within 24 hours of ingestion and includes gastrointestinal symptoms, such as abdominal pain, nausea, vomiting, diarrhea, and significant fluid loss, leading to volume depletion. Peripheral leukocytosis may also be seen. Life-threatening complications occur during the second stage, which occurs 24 to 72 hoursafter drug administration, attributed to multi-organ failure and its consequences. Death is usually a result of respiratory depression and cardiovascular collapse. If the patient survives, recovery of multi-organ injury may be accompanied by rebound leukocytosis and alopecia starting about 1 week after the initial ingestion.Treatment of colchicine poisoning should begin with gastric lavage and measures to prevent shock. Otherwise, treatment is symptomatic and supportive. No specific antidote is known. Colchicine is not effectively removed by dialysis.COLCRYS is a trademark of Takeda Pharmaceuticals U.S.A., Inc., registered with the U.S. Patent and Trademark Office and used under license byTakeda Pharmaceuticals America, Inc.All trademarks are the property of their respective owners.Distributed by:Takeda Pharmaceuticals America, Inc.Deerfield, IL 6001542901-Brf. Rev 01, June 2012For more detailed information, see the complete prescribing information for COLCRYS (colchicine, USP) tablets at Colcrys.com or contact Takeda Pharmaceuticals America, Inc. at 1-877-825-3327. L-ECH-0612-2


David A. Isenberg, MD, FRCP, FAMS


In This Issue

Value-Based CareinRheumatology

FROM THE PUBLISHERS OF AMERICAN HEALTH & DRUG BENEFITS®

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PublisherNicholas [email protected]

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Mission StatementValue-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 rheuma-tology meetings and the rheumatic diseases literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care.

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Value-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 © 2013 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Care in Rheumatology is a registered trademark of Engage Health care Communi cations, 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 photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

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VBCR Editorial Advisory Board

RHEUMATOLOgY UPDATEYear in review, part 2: from the ACR 2012

meeting

VALUE PROPOSITIONSNew Medicare rules will save providers

$676 million annuallyPotential new target for lupus therapy

discoveredMore…

HEALTH ECONOMICSHigh out-of-pocket cost of biologic DMARDs

for Medicare patients with RA Cost-effectiveness helps to differentiate drug

classes for acute gout treatment

ARTHRITIS UPDATEStep-down strategy feasible for patients

with RA who achieve remissionEscalated dose of tocilizumab safe and

effective for patients with RA

More…

SJÖgREN’S SYNDROMEProgress in classifying and managing

Sjögren’s syndrome

SCLERODERMAProphylactic use of ACE inhibitors in patients

with scleroderma may not be advisable

Rheumatology PRACTICEMANAgEMENT™

Program integrating exercise and self-management more cost-effective than outpatient physiotherapy for arthritic knee pain

PERSONALIzED MEDICINE in Rheumatology™

New genetic loci uncovered, potential targets for novel therapies for patients with gout

IN THE LITERATURELow-cost walking program improves outcomes

for patients with knee OACell-mediated immunity impaired in patients

with fibromyalgia

More…

OSTEOPOROSISOdanacatib effective in women with osteoporosis

uncontrolled with alendronate

DRUg UPDATETofacitinib: a new treatment option for RA

Kim A. Papp, MD, PhDFounder and PresidentProbity Medical ResearchWaterloo, Ontario, Canada

Edmund J. Pezalla, MD, MPHNational Medical Director for Pharmacy Policy and StrategyAetnaHartford, CT

Ronald van Vollenhoven, MD, PhDAssociate ProfessorKarlinska University Hospital SolnaStockholm, Sweden

F. Randy Vogenberg, RPh, PhDPrincipalInstitute of Integrated HealthcareSharon, MA

Randall Krakauer, MD, FACP, FACRNational Medical DirectorMedicare, AetnaPrinceton, NJ

Alan Menter, MDDirectorBaylor Psoriasis Research CenterDallas, TX

Matthew Mitchell, PharmD, MBA Manager, Pharmacy ServicesSelectHealthMurray, UT

Lynn Nishida, RPhDirector, Clinical ServicesCatamaran Center of ExcellenceNorthwest RegionPortland, OR

gary M. Owens, MDPresidentGary Owens AssociatesPhiladelphia, PA

Scott Breidbart, MD Chief Medical OfficerEmpire BlueCross BlueShieldNew York, NY

gary L. Johnson, MD, MS, MBARegional Medical DirectorHumana, Inc.Madison, WI

Atheer A. Kaddis, PharmDVice President, Managed MarketsDiplomat Specialty PharmacySwartz Creek, MI

James T. Kenney, Jr, RPh, MBA Pharmacy Operations ManagerHarvard Pilgrim Health CareWellesley, MA

Muhammad Asim Khan, MDProfessor of MedicineCase Western Reserve UniversityCleveland, OH


Value Propositions

New Medicare Rules Will Save Providers $676 Million Annually

Removing Medicare regulations that are deemed unnecessary or un-justifiably burdensome on providers and hospitals would save nearly $676 million annually, and $3.4 billion over 5 years, through a rule pro-posed by the Centers for Medicare & Medicaid Services (CMS) in support of President Obama’s call on federal agencies to modify and streamline regulations on business.

“We are committed to cutting the red tape for healthcare facilities, in-cluding rural providers,” said the US Department of Health and Human Services (HHS) Secretary Kathleen Sebelius. “By eliminating outdated or overly burdensome requirements, hospitals and healthcare profession-als can focus on treating patients.”

Many of the rule’s provisions streamline the standards healthcare pro-viders must meet to participate in Medicare and Medicaid, without jeop-ardizing patient safety. The proposed rule would:• Help small critical access hospitals and rural clinics, by eliminating

the requirement that a physician must be on site every 2 weeks, al-lowing physicians to provide care via telemedicine and other means that can reduce costs without sacrificing quality of care

• Save hospital resources by permitting registered dietitians to order patient diets without the supervision of a physician, to free up physi-cians’ time

• Eliminate unnecessary requirements that ambulatory surgical centers must meet to provide radiologic services

• Permit trained nuclear medicine technicians in hospitals to prepare radiopharmaceuticals, without a supervising physician/pharmacist, particularly during off-hours

• Eliminate a redundant data submission requirement for transplant centers, while maintaining strong federal oversight.These rules are in addition to the rules CMS issued in May 2012 to

reduce burdensome regulations for hospitals and providers, which are saving nearly $1.1 billion in the first year. Department of Health and Human Services; February 4, 2013

HHS Allocates $1.9 Million to Establish Telehealth Programs for Underserved Populations

The HHS has allocated $1.9 million for new telehealth regional re-source centers to serve rural and medically underserved populations. Qualified regional centers will each receive a $325,000 grant through the Telehealth Resource Center Grant Program. These funds are targeted for healthcare organizations and healthcare networks that are establishing medical services programs via telemedicine to reach patients at rural and medically underserved areas of the country. Funding will be avail-able through 2015, and those qualified for the funding will have to pro-vide technical training and support for healthcare providers. The goal is to reach a large population of patients through telemedicine, as well as support research into the best ways to promote telehealth services and resource centers to meet the needs of those living in remote and/or rural areas. www.mHIMSS.org; January 3, 2013

Early Occupational Therapy Improves Hand Function in Patients with Osteoarthritis

Referring patients with osteoarthritis to an occupational therapist early in the disease can improve hand function. In addition to pain manage-ment, occupational therapy goals include resting the joint through splint immobilization and teaching patients how to modify their activities so that the joints are protected. Occupational therapists use a variety of modalities, such as moist heat packs, ice packs, and paraffin baths, to relieve discomfort and strengthening and range-of-motion exercises to help patients manage their daily tasks without causing pain or further stress on the affected joints.

In addition, occupational therapists often use splints to stabilize the affected joints during activity, as well as to rest the joints during periods of inactivity, when the splint can help decrease pain and swelling. Refer-ring a patient with osteoarthritis to an occupational therapist improves the likelihood that the proper splint or splints will be used, and that the splints are properly fitted to give the patient the maximum benefit. Huber L, Palmer E. Ebesco Publishing; June 2012

Novel Small Molecule May Help Promote Cartilage Repair

In very early-stage research, scientists at the Genomics Institute of the Novartis Research Foundation have discovered a small molecule, called kartogenin, that, in a mouse model, promoted increases in the number of chondrocytes and matrix proteins, as well as hyaline articular cartilage restoration. This finding may have positive implications for cartilage repair and symptom relief in patients with osteoarthritis.

Kartogenin was identified using an image-based screen of primary human bone marrow multipotent mesenchymal stem cells, and it was subsequently evaluated on articular chondrocytes, where it was found to promote the formation of the mesenchymal stem cells and be chondro-protective. Johnson K, et al. Science; May 2012

Potential New Target for Lupus Therapy Discovered

A research team at the Scripps Research Institute has found that block-ing a specific pathway that prevents key events in lupus from occurring could lead to the development of new therapy for autoimmune diseases.

In a study of laboratory mice with lupus, the lack of molecule SLC15A4, which resides inside immune cells and possesses signaling properties, may be linked to a more slowly developing process of autoimmunity. Com-pared with healthy laboratory mice, the mice with lupus suffered less dam-age to their immune systems when expression of SLC15A4 was inhibited.

The researchers are confident that SLC15A4 is a potential new target for lupus therapy; this could eventually lead to the development of a drug capable of inhibiting lupus and other autoimmune diseases by tar-geting and suppressing only the immune cells that are directly responsi-ble for lupus, and do so without affecting the rest of the immune system. Proceedings of the National Academy of Sciences (online); February 4, 2013


of costs and effectiveness, using a decision-analytic model approach. The investigators considered NSAIDs (selective COX-2 inhibitor and non-selective NSAIDs), colchicine, cortico-steroids (single intramuscular dose), and a canakinumab-like biologic ther-apy. Canakinumab (Ilaris) is not ap-proved by the US Food and Drug Administration for the treatment of acute gouty arthritis.

This 8-week ambulatory care study considered men with uncomplicated acute gouty arthritis and no contrain-dications to the included therapies. The treatment period was 3 days. Ef-fectiveness was measured by the daily probability of response to treat-ment, an increase in usefulness as a result of decreased pain, and utility decrements for adverse events (AEs).

Highest Response with BiologicsThe highest (93%) probability of

cumulative response (after 3 days of therapy) was seen in the biologic group, Dr Reiter reported.

Among the nonbiologics, colchicine was the most efficacious (82.5%), fol-lowed by NSAIDs (nonselective, 76%; selective COX-2 inhibitor, 73%). Ste-roids were the least efficacious (65%).

Adverse EventsFor total cumulative AEs, colchicine

had the highest (52.7%) AE probabili-ty and the COX-2 inhibitor the lowest

rate (20.8%); similarly, for cumulative mild AEs, colchicine had the highest rate (52.2%) and the COX-2 selective inhibitor had the lowest rate (15.6%).

For cumulative moderate AEs, col-chicine and steroids had very low rates (0.65% and 0.35%, respectively), with the highest rate (8.3%) seen in the nonselective NSAIDs.

Cumulative serious AEs were “very improbable” for colchicine and steroids (0.0066% and 0.0035%, re-spectively), but the highest serious AE rate was seen in the biologic group (0.95%).

The cumulative discontinuation rate because of AEs was highest for the nonselective NSAIDs (8.9%) and lowest for colchicine (0.66%).

Overall Effectiveness and CostsThe smallest benefit was seen in the

steroid group—0.8 quality-adjusted life-days (QALDs) compared with no treatment for flare. Colchicine provid-ed an incremental QALDs of 2.1 com-pared with steroids. The biologic

drug was most effective, providing an additional 0.184 QALDs compared with colchicine.

“While the biologic drug was the most effective, because of the high costs of the drug and the rare serious AEs, it came out to be quite a bit more incrementally in costs, at $60,088 per QALD, or $22.9 million per quali-ty-adjusted life-year,” Dr Reiter said.

In a sensitivity analysis, flare dura-tion was important. For untreated flares that lasted <2.8 days, nonselec-tive NSAIDs no longer dominated and had the most favorable incremen-tal cost-effectiveness ratio. For flares lasting >3.5 days, the NSAIDs (both nonselective NSAIDs and selective COX-2 inhibitors) dominated.

Dr Reiter concluded that colchicine provides reasonable value for the money in treating an acute gout flare compared with an intramuscular cor-ticosteroid. Furthermore, “the poten-tial health benefits of long-acting bio-logics are not commensurate with high costs,” she said. n

Cost-Effectiveness Helps to Differentiate Drug Classes... Continued from cover

“While the biologic drug was the most effective, because of the high costs of the drug and the rare serious adverse events, it came out to be quite a bit more incrementally in costs, at $60,088 per QALD, or $22.9 million per quality-adjusted life-year.”

—Kimberly Reiter, MD

Health Economics

Continued on page 9

results of a study reported by Jinoos Yazdany, MD, Assistant Professor at the University of California, San Fran-cisco, at the 2012 meeting of the Amer-ican College of Rheumatology (ACR). A second study by Dr Yazdany and colleagues showed that older and poorer patients with RA face reduced

access to appropriate care provided by a rheumatologist.

Medicare Part D provides prescrip-tion drug benefits to older and dis-abled Americans, and the program now includes many of the biologic therapies used to treat RA. However, Medicare beneficiaries pay a deduct-ible, then 25% coinsurance up to an initial limit of $2930. Then, they face the donut hole until their total out-of-pocket (OOP) expenses reach $4700. After that figure is reached, they pay 5%, $2.50 for generic drugs and $6.30 for brand-name drugs.

Biologic versus Nonbiologic DMARD Costs

The first study compared the drug utilization and OOP costs for biologic and nonbiologic disease-modifying antirheumatic drugs (DMARDs) for 2 groups of patients who were enrolled in Medicare Part D who were sub-ject to a coverage gap and low-in-come patients who were not subject to cost-sharing. The study population was a random sample of 5808 Medi-care beneficiaries aged ≥65 years who had claims for Medicare Part D pre-scription drugs and 1414 beneficiaries with a low-income subsidy.

Overall, 679 (12%) were classified as DMARD users and 5129 (88%) were

classified as nonbiologic DMARD users. Of these, 1414 (24%) received a low-income subsidy: 44% of the bio-logic DMARD users versus 22% of the nonbiologic users.

For the low-income subsidy group, the OOP annual costs for biologics and nonbiologics were low ($26 and $11, respectively), with little variation over the benefit phases. The nonsubsidized OOP costs for biologics and nonbi-

ologics were $3009 and $85, respec-tively. Across the benefit phases, larg-er variations in OOP costs were for biologics (from $21 to $1805) com-pared with nonbiologics (from $21 to $75), with the highest costs occurring during the coverage gap phase.

“This study suggests that the cov-erage gap may prevent patients with RA who face substantial cost-sharing from accessing biologics through Part D. There are no generic equivalents of biologics, and 100% of patients with RA will reach the donut hole. How-ever, low-income patients receive a subsidy to fill the donut hole, and they are not exposed to cost-sharing for Part D. We compared the popula-tion that faced the donut hole with the population that received a low- income subsidy,” stated Dr Yazdany.

Dr Yazdany noted that the Afford-able Care Act will eliminate the donut hole by 2020; however, Part D will shift the coinsurance levels so that patients will be responsible for 25% of their drug costs until they reach the “catastrophic” level of $4000 an-nually. “Our analysis suggests that patients will fare about the same as they did with the donut hole. We will still have a problem. We have to fig-ure out how to pay for these expen-sive drugs,” she noted.

High Out-of-Pocket Cost of Biologic DMARDs... Continued from cover

“Access to a rheumatologist was the single strongest predictor of DMARD use. Medicare recipients who did not see a rheumatologist were more likely to be treated with steroids alone, which is not recommended therapy. This study suggests that it is important to track the use of DMARDs as a performance measure in Medicare recipients.”

—Jinoos Yazdany, MD

➤ Nonsubsidized OOP costs for Medicare patients with RA are $3009 for biologic DMARDs and $85 for nonbiologic DMARDs

➤ A full 100% of Medicare beneficiaries with RA will reach the donut hole, which can result in $2930 to $4700 in OOP expenses in 1 year

➤ The Affordable Care Act will eliminate the donut hole by 2020, but patients will then pay 25% of their drug costs

➤ Access to a rheumatologist is the strongest predictor of appropriate DMARD use

➤ Medicare patients with RA who do not see a rheumatologist are likely to receive a steroid instead of a DMARD

at a glance


Washington, DC—Tapering the doses of anti–tumor necrosis factor (TNF) drugs can be done successfully in some patients with rheumatoid arthritis (RA) who achieve remission. A step-down strategy was possible in >80% of pa-tients without significant increases in disease activity or functional impair-ment, although relapses occurred more frequently than in those who remained using a full regimen, said Bruno Fau-trel, MD, PhD, a professor at the Uni-versity of Paris Medical Center, at the 2012 meeting of the American College of Rheumatology.

Dr Fautrel and his colleagues con-ducted an 18-month equivalence ran-domized controlled PROBE (Prospec-tive Open Blinded Endpoint) trial in 137 established patients with RA who received etanercept (Enbrel) or ada-limumab (Humira) and were in stable remission by the 28-joint Disease Activ-ity Score (DAS28) criteria (DAS28 ≤2.6).

“A lot of effort has been dedicated to the development of new treatments for RA, leading to a substantial in-crease in RA costs. Nowadays, remis-sion is achievable and treatment ta-pering needs to be considered and assessed,” said Dr Fautrel.

The goal of the study was to com-

pare the impact of a step-down strat-egy based on the progressive spacing of anti-TNF injections with a strategy

that maintained the therapy at full doses at the approved time intervals. The study was powered to demon-strate noninferiority of the step-down arm.

All of the patients were using etanercept or adalimumab for 1 year, as monotherapy or in combination with other agents. The patients were permitted to take ≤5 mg of predni-sone daily. The mean duration of RA

was 9.5 years, and the mean DAS28 was 1.8. The mean number of previ-ous disease-modifying antirheumatic drugs taken per patient was 2.7. Eighty-eight percent of the patients had erosive disease.

In the step-down group, the time between the 2 injections was expand-ed by 50% every 3 months up to a complete stop by the fourth interval. If DAS28 remission was not main-tained, the full regimen was reestab-lished. The primary end point was disease activity based on DAS28 mea-sures performed every 3 months for 18 months.

After 18 months, 82% of the pa-tients in the step-down arm were able to space out or stop their anti-TNF injections, without significant increas-es in either disease activity on the DAS28 or in functional impairment. Another 15% of the patients were able to stop therapy completely, and 67% were able to taper off their medica-tion. The remaining 18% of the pa-tients were unable to taper their treat-ment and remained at the initial injection interval.

“However, we failed to demon-strate the equivalence between the 2 strategies [P = .6] and, due to the step-

down strategy, a relapse occurred more frequently in the step-down than in the full regimen arm—81% versus 56%,” said Dr Fautrel. “Al-though we failed to demonstrate the equivalence between the 2 strategies, the spacing strategy did not result in a significant increase in disease activ-ity or functional impairment.”

The impact of the spacing strategy on x-ray structural damage is current-ly being analyzed. n

Step-Down Strategy Is Feasible in Many Patients with Rheumatoid Arthritis Who Achieve Remission By Wayne Kuznar

at a glance➤ After 18 months, 67% of the

patients in the step-down arm were able to taper off their anti-TNF injections

➤ Another 15% of the patients were able to stop therapy completely

➤ Tapering or stopping therapy completely did not result in significant increases in disease activity or in functional impairment

➤ The remaining 18% of the patients were unable to taper their treatment

“A lot of effort has been dedicated to the development of new treatments for RA, leading to a substantial increase in RA costs. Nowadays, remission is achievable and treatment tapering needs to be considered and assessed.”

—Bruno Fautrel, MD, PhD

Arthritis Update

Access to a Rheumatologist Is Crucial

A second study showed that Medi-care beneficiaries without access to a rheumatologist were more likely to be treated with suboptimal therapy.

“Access to a rheumatologist was the single strongest predictor of DMARD use. Medicare recipients who did not see a rheumatologist were more like-ly to be treated with steroids alone, which is not recommended therapy. This study suggests that it is important to track the use of DMARDs as a per-formance measure in Medicare recipi-ents,” Dr Yazdany stated.

To look at the patterns of care, the investigators tracked the use of DMARDs, which is recommended by the ACR guidelines, and steroid ther-apy in a random sample of Medicare fee-for-service beneficiaries with RA. Of these, 7974 patients with RA were treated with a DMARD, and among those who did not receive a DMARD, 824 received ≥6 months of steroids as the sole therapy for their RA.

Compared with those who received a DMARD, those in the steroid-alone group were more likely to be older (17% were aged ≥85 years, 7% were 74-79 years) and to have low incomes (13% had low income vs 9% in other income groups).

The strongest predictor of steroid utilization as the sole treatment for RA was access to a rheumatologist; only 6% of the patients with RA who saw a rheumatologist received steroids alone compared with 16% of those who saw other providers. In addition, the rates of in-patient admissions and comorbidities were higher in the patients who received steroids alone.

“Patients with multiple risk fac-tors—that is, low income, older age, and no contact with a rheumatolo-gist—fared worse in terms of receiv-ing recommended treatment,” Dr Yazdany said. “This information may be useful to payers and health sys-tems seeking to improve performance on quality measures for RA.” n

High Out-of-Pocket Cost... Continued from page 8 Escalated Dose of Tocilizumab Safe and Effective for Patients with RABy Phoebe Starr

Atlanta, GA—Escalating the dose of tocilizumab (Actemra) is safe and im-proves the core symptoms of rheuma-toid arthritis (RA) in patients who have had a suboptimal response to tocili-zumab 4 mg/kg plus a disease-modi-fying antirheumatic drug (DMARD).

Doubling the dose of tocilizumab from 4 mg/kg to 8 mg/kg at or after week 8 improved the measures of dis-ease activity and maintained a stable safety profile in a subanalysis of the ACT-STAR trial that was reported at the 2012 meeting of the American Col-lege of Rheumatology (ACR).

Michael E. Weinblatt, MD, Co-director of Clinical Rheumatology and Associate Director of the Cen-ter for Arthritis and Joint Diseases at Brigham and Women’s Hospital, Boston, MA, and colleagues indicat-

ed that dose escalation of tocilizumab was safe and effective in patients who failed to meet the ACR 20% criteria for improvement (ACR20) with the lower dose.

ACT-STAR was a phase 3b, 24- week, open-label, multicenter evalu-ation of tocilizumab in patients with active RA who had inadequate clini-cal response or safety and/or tolera-bility issues on previous DMARD therapy. The patients who did not achieve ≥20% improvement in the tender joint count and the swollen joint count were titrated to the higher tocilizu mab dose.

Dose titration was done at or after week 8. A total of 68 of the 363 pa-tients randomly assigned to receive tocilizumab 4 mg/kg plus a DMARD were titrated to 8 mg/kg (plus a



Arthritis Update

Washington, DC—A reduction in hospital admissions coincides with an increase in annual prescriptions for anti–tumor necrosis factor (TNF) agents in patients with rheumatoid ar-thritis (RA), likely resulting in signifi-cant cost-savings, according to a new analysis. A separate analysis shows that biologic agents are possibly pre-venting premature death in this pa-tient population. Both analyses were presented at the 2012 meeting of the American College of Rheumatology.

Oliver M. FitzGerald, MD, a Profes-sor in the Department of Rheumatolo-gy at St. Vincent’s University Hospital in Dublin, Ireland, and his colleagues used a national database to examine the hospitalization records from 1995 to 2010 of patients admitted with a diagnosis of RA. They also recorded national prescription data from 2000 to 2010 for anti-TNF use.

The in-patient records of 57,774 patients with RA were reviewed. The annual number of anti-TNF prescrip-tions written increased by 156% from 2000 to 2010. This increase correlated with a decrease in in-patient days as-sociated with RA, corresponding to a 13% reduction in hospital admissions for any reason, from 49,000 annual-

ly before 2002 to 31,000 in 2010. The fewer hospital days likely contribut-ed to savings of approximately €16 million annually, said Dr FitzGerald.

The researchers also found a 47% reduction in total musculoskeletal surgical procedures from 2002 to 2010, from an average of approxi-mately 500 procedures annually in the prebiologic era to just more than 200 in the more recent years, a 10% yearly decrease. This decrease in musculoskeletal surgical procedures was significantly associated with an increased use of anti-TNF drugs. The reduction in hip replacement surgery was 47%, and the reduction in total knee replacement was 53%. There also were significant reductions in

hand and wrist surgery, with signif-icant correlations to increases in anti- TNF prescribing.

The rates of foot and ankle surger-ies remained approximately the same between the 2 eras.

“These data do suggest that anti- TNF prescribing is certainly one of the factors that have led to improved outcomes in our patients with RA,” said Dr FitzGerald. “We’re not saying that it’s the only reason that patient outcomes have improved. Addition-al factors that could have improved patient outcomes include an increase in rheumatology consults, improved use of nonbiologic disease-modify-ing treatments (ie, methotrexate), and treat-to-target strategies.”

RA Mortality Reduction in CanadaA separate analysis using data from

the Canadian Ministry of Health showed an association between the use of biologic agents and a reduced risk of premature mortality in patients with RA.

Patients with RA who received treatment between January 1996 and March 2006 were extracted from the database; follow-up continued until March 2010. The 2156 patients who were receiving biologics were matched for age, gender, and calen-dar year with patients who had never

used a biologic drug. The analysis controlled for differences in disease severity and other factors between groups. The control subjects had re-ceived at least 3 other disease-modi-fying antirheumatic drugs.

A total of 247 deaths occurred in the biologic therapy group during the follow-up period, compared with 326 in the control group, corresponding to a 25% reduction among the patients who were treated with biologic agents, reported Diane Lacaille, MD, MHSc, FRCPC, lead investigator of the study and Senior Research Scientist at the Arthritis Research Centre of Canada, Vancouver, British Columbia.

“We find the same results whether we look at all biologics or only anti- TNFs, but in the sample, the majority of the patients [>90%] had received an anti-TNF,” Dr Lacaille said. n

“These data do suggest that anti-TNF prescribing is certainly one of the factors that has led to improved outcomes in our patients with RA.”

—Oliver M. FitzGerald, MD

Escalated Dose of Tocilizumab Safe... Continued from page 9

at a glance➤ The annual anti-TNF drug

prescriptions written in Irish hospitals increased by 156% from 2000 to 2010

➤ The increase correlated with a decrease in hospitalized days for RA, from 49,000 annually before 2002 to 31,000 in 2010

➤ This decrease likely contributed to savings of approximately €16 million annually

➤ The number of anti-TNF drug prescriptions written between 2000 and 2010 also corresponded with reductions in hip and total knee replacement surgeries by 47% and 53%, respectively

DMARD) after week 8, 142 patients were titrated to the higher dose at week 8, and 152 patients remained at the lower tocilizumab dose.

Among the patients who received an escalated dose of tocilizum-ab after week 8, 58.8% achieved the ACR20 response at week 24, 36.8% achieved at least an ACR50 response, and 11.8% achieved at least an ACR70 response. At base-line, the mean 28-joint Disease Activ-ity Score (DAS28) was 5.76; at week 8, the DAS28 decreased to 4.45; at week 16, the DAS28 decreased to 4.20; and at week 24, the DAS28 decreased to 3.77.

In patients who were titrated to the higher tocilizumab dose after week 8 (at the discretion of their physicians), the proportion who achieved ACR50 and ACR70 increased, but the pro-portion achieving ACR20 responses remained stable.

In patients who were titrated at week 8, the ACR20, ACR50, and

ACR70 responses were seen in 30.3%, 12.0%, and 3.5%, respective-ly, at week 24. The mean DAS28 level decreased from 5.69 at baseline to 5.39 at week 8, to 4.32 at week 16, and to 4.17 at week 24 in this group.

From week 8 to week 24, the re-searchers observed improved marked mean changes in DAS28-C- reactive protein (CRP) in those who were titrated at week 8, and only modest reductions in CRP in those who were titrated after week 8.

Serious infections were the most common adverse events in the sub-group analysis of ACT-STAR both before and after the dose titrations. No patients who were titrated after week 8, and 3 patients of the 142 (2.1%) who were titrated at week 8 experienced serious infections.

Adverse events for the titrated patients were slightly higher, but, overall, were consistent with the main results of the previously pub-lished ACT-STAR trial. n

“We find the same results whether we look at all biologics or only anti-TNFs, but in the sample, the majority of the patients had received an anti-TNF.”—Diane Lacaille, MD, MHSc, FRCPC

The clinical burden of rheumatoid arthritis (RA) and other rheumatic diseases is significant and is expect-ed to increase. Correspondingly, the cost of treating this patient popula-tion is ever-growing.

According to the Centers for Dis-ease Control and Prevention, current national data indicate that: ➤ An estimated 50 million US adults

have been told by a physician that they have some form of RA, gout, lupus, or fibromyalgia

➤ In 2007-2009, 50% of Americans aged ≥65 years reported an RA diagnosis

➤ By 2030, an estimated 67 million Americans aged >18 years are pro-jected to be diagnosed with RA

➤ The annual direct medical cost of treating RA in the United States is $10.9 billion, with an average of $5700 per patient

➤ The associated annual indirect cost is $8.4 billion

➤ Of the combined $19.3 billion total annual cost associated with RA, 33% is the cost to employers, 28% is the cost to patients, 20% is the cost to the federal gov-ernment, and 19% is the cost to providers. n

The Clinical and Economic Burden of Arthritis

Anti-TNF Drugs for Rheumatoid Arthritis Are Reducing Morbidity and Mortality By Wayne Kuznar

Washington, DC––The 1-year mortal-ity rate for patients with scleroderma who were taking angiotensin-convert-ing enzyme (ACE) inhibitors at the time they developed a renal crisis was twice that of patients with scleroderma who had not been taking these drugs, according to a study reported at the 2012 meeting of the American College of Rheumatology.

Based on an adjusted analysis, the patients who had previously taken ACE inhibitors showed a 1.56 hazard ratio (HR) for death at 1 year (95% confidence interval [CI], 0.70-3.47) after a renal crisis compared with patients who had not used ACE inhib-itors before a renal crisis. However, an analysis adjusted for baseline predni-sone use revealed that the risk of death 1 year after a renal crisis was more than double in prednisone users who were exposed to ACE inhibitors (HR, 2.42; 95% CI, 1.02-5.75; P = .046) compared with nonusers.

“This study suggests that ACE in-hibitors should be used with great

caution in patients with scleroderma, particularly early in the disease, when the risk of renal crisis is greatest,” stat-ed lead author Marie Hudson, MD, Assistant Professor in the Department of Medicine, McGill University, Mon-treal, Canada.

Renal crisis is a potentially fatal complication of scleroderma. It typi-cally manifests fairly early in the course of the disease and presents with rapid development of malignant hypertension. The effectiveness of ACE inhibitors to treat renal crisis has

spurred keen interest in their potential value as a prophylaxis, but opinions vary on this issue. According to Dr Hudson, “Some would argue that there is no clear physiologic rationale for this, because most patients are not hyperreninemic prior to the onset of their crisis.”

To help resolve this question, data were collected through a prospective, web-based survey of approximately 600 clinicians who treat patients with scleroderma. The clinicians were que-ried every 2 weeks to determine if they had diagnosed a patient with renal crisis in the previous 2 weeks. For each “yes” response, a follow-up questionnaire was sent to obtain infor-mation on the patient’s demograph-ics, disease characteristics, and use of ACE inhibitors.

The primary outcome measure was death or dialysis 1 year after the onset of renal crisis.

Of the 88 cases (mean age, 52 years) of renal crisis reported in the survey, 18 patients had previously received

ACE inhibitors and 59 patients had not. Most of the patients had diffuse cutaneous disease. Regardless of ACE

Prophylactic Use of ACE Inhibitors in Patients with Scleroderma May Not Be AdvisableBy Phoebe Starr

at a glance➤ The hazard ratio for death in

patients with scleroderma who had taken ACE inhibitors was 1.56 at 1 year

➤ The risk of death 1 year after a renal crisis was more than double in prednisone users who were exposed to ACE inhibitors

➤ Renal crisis is a potentially fatal complication of scleroderma, typically manifesting early in the disease with rapid development of malignant hypertension

➤ These results are further evidence that ACE inhibitors as prophylaxis may worsen outcomes in patients with scleroderma

“ACE inhibitors should be used with great caution in patients with scleroderma, particularly early in the disease, when the risk of renal crisis is greatest.”

—Marie Hudson, MD


Sjögren’s Syndrome

Rheumatologists are supposed to be experts in the diagnosis and man-agement of Sjögren’s syndrome, ex-plained Lindsey A. Criswell, MD, MPH, Chief of the Division of Rheu-matology at the University of Califor-nia, San Francisco, and coauthor of the new ACR criteria. “Yet the under- attention it has received in terms of research has been a major problem for patients with Sjögren’s syndrome.”

Dr Criswell commented that the new criteria, which are based on data from the SICCA registry, will address this gap by enabling improved re-search into the etiology, genetics, and therapy of this autoimmune disease. These criteria are stringent enough to be used as entry criteria for clinical trials of new biologic immunomodu-lating agents.

Over the past 4 decades, a variety of approaches to diagnosing or clas-sifying patients with Sjögren’s syn-drome have been proposed. Howev-er, none has been endorsed by the ACR or the European League Against Rheumatism, and there has been no consensus on the approach to classifi-

cation, Dr Criswell stated.The new criteria encompass the 3

main components of the syndrome: • Dryness and other effects in the eyes• Dryness and other effects in the

mouth• Systemic manifestations.

The proposed classification is based on objective test results, and patients must meet 2 of the 3 following objec-tive features to be classified with Sjögren’s syndrome: 1. A positive serum anti-SSA and/or

anti-SSB result, or a positive rheu-matoid factor and antinuclear anti-body titer >1:320

2. An ocular staining score >33. The presence of focal lymphocyt-

ic sialadenitis with a focus score >1 focus/4 mm2 in labial salivary gland biopsy samples.The authors of the proposed clas-

sification criteria said that previ-ous diagnoses of certain conditions would be considered exclusions for participation in trials because of over-lapping clinical criteria, including his-tory of head-and-neck radiation treat-ment, hepatitis C infection, AIDS,

sarcoidosis, amyloidosis, graft-ver-sus-host disease, and immunoglobu-lin G4–related disease.

The proposed Sjögren’s criteria do away with the distinction between primary and secondary forms of the disease, considering this distinction to be most likely obsolete. “It seems of little use and risks potential confusion to distinguish in a given patient one autoimmune disease and secondary to another. Accordingly, the diagnosis should be given to all who fulfill these criteria while diagnosing any concur-

rent organ-specific or multiorgan au-tomimmune diseases, without distin-guishing as primary and secondary,” the authors of the criteria wrote.

Guideline DevelopmentGuidelines for the management of

Sjögren’s syndrome are currently being developed under the umbrella of the Sjögren’s Syndrome Founda-tion, said Steven E. Carsons, MD, Chief of the Division of Rheumatolo-gy, Clinical Immunology, and Aller-gy at Winthrop-University Hospital, Mineola, New York.

The committee developing the guidelines is addressing 3 main issues:• Which treatments are beneficial for

the treatment of inflammatory joint disease associated with Sjögren’s syndrome?

• What is the appropriate manage-ment of fatigue?

• What is the role of oral and biologic disease-modifying antirheumatic drugs for the SICCA syndrome components of Sjögren’s syndrome?“These areas represent a significant

unmet need,” Dr Carsons said. n

Progress in Classifying and Managing Sjögren’s... Continued from cover

Scleroderma

“Rheumatologists are supposed to be experts in the diagnosis and management of Sjögren’s syndrome….Yet the under-attention it has received in terms of research has been a major problem for patients.”

—Lindsey A. Criswell, MD, MPH



Rheumatology Practice Management™

Program Integrating Exercise and Self-Management More Cost-Effective than Outpatient Physiotherapy for Arthritic Knee PainBy Wayne Kuznar

Washington, DC—A rehabilitation program that integrates exercise and self-management, called the Enabling Self-Management and Coping of Ar-thritic Knee Pain through Exercise (ES-CAPE-knee pain), is more cost-effec-tive than outpatient physiotherapy in the management of patients with knee pain, said Michael V. Hurley, PhD, Professor of Rehabilitation Sciences, St. George’s University of London, and Kingston University, London, United Kingdom, at the 2012 American Col-lege of Rheumatology meeting.

The personal and socioeconomic consequences of chronic knee pain are increasing with the aging of soci-ety. Evidence-based guidelines rec-ommend exercise and self-manage-ment interventions as core treatments. These are usually delivered separate-

ly, but their benefits may be en-hanced by integrating physical and educational approaches. “The prob-lem is that the integrated rehabilita-tion programs are long, complex, and expensive, and, therefore, they have limited clinical applications,” he said.

The ESCAPE-Knee Pain Program

The ESCAPE-knee pain program integrates patient education, self- management, and coping strategies with a challenging exercise regimen. The integrated program changes pa-tients’ health beliefs and behaviors, “and they learn that they can control their symptoms and alter the course of their condition,” said Dr Hurley.

The ESCAPE-knee pain program produced short-term improvements in pain and physical function com-pared with usual primary care, but sustaining these improvements is problematic. In addition, the pro-gram is untried in the community, where it is most likely to be delivered. The study evaluated the feasibility of delivering ESCAPE-knee pain in a community setting, and compared its

clinical effectiveness and costs with outpatient physiotherapy.

A total of 64 patients with chronic knee pain were randomized to outpa-tient physiotherapy or to the ESCAPE-knee pain program in a local adult education community center in Lon-don. “Our inclusion criteria were kept very broad, because we wanted to capture the representative population who were knocking on their general practitioners’ doors,” Dr Hurley said.

The primary outcome was physi-cal function assessed using the West-ern Ontario and McMaster Universi-ties Osteoarthritis Index (WOMAC). Secondary outcomes included pain, objective functional performance, anxiety, depression, exercise-related health beliefs, exercise self-efficacy, and healthcare utilization. All out-comes were assessed at baseline and 12 months after completion of the interventions (the primary end point).

The patients who were randomized to outpatient physiotherapy followed usual clinical practice and were asked to record the number of sessions and treatment modalities in which they participated. They were allowed a 30- to 45-minute initial assessment and up to 10 treatment sessions.

The ESCAPE-knee pain program involves 2 sessions weekly for 5 weeks. A psychosocial intervention was pro-vided for the first 15 to 20 minutes of each session that involved an infor-mal group discussion to improve the patients’ understanding of their con-dition; cognitive restructuring; simple pain control techniques; reassurance about what they should and should not be doing; specific goal-setting; and self-management.

The next 40 to 45 minutes consisted of an individualized progressive exercise regimen devised by a physio-therapist to improve strength, bal-ance, coordination, and functional performance. After the 10 sessions, the patients were discharged with a home exercise program. Four months after completing the program, they were offered a 1-hour review session to reinforce the key messages and to review the exercises.

Of the 64 patients randomized, 8 from each group withdrew by the end of year 1.

ResultsWOMAC function improved simi-

larly in both groups, and the improve-ment was sustained to 12 months. There were no differences between the groups in the secondary clinical outcomes of pain, function, anxiety, and depression, “except beliefs and self-efficacy, which improved more in the people who had undergone ESCAPE, and were sustained at 12 months,” said Dr Hurley.

The intervention “costs about half as much as outpatient physiothera-py,” he added. Specifically:• Outpatient physiotherapy costs

£130 per person• Healthcare utilization costs of

physiotherapy for 1 year were £583• The ESCAPE-knee pain program

costs £64 per person• Healthcare utilization costs were

£320 in the program. “It was largely because people

didn’t seem to be accessing second-ary care,” Dr Hurley said. The group therapy with the ESCAPE-knee pain program also minimized costs. n

at a glance➤ A program that integrates

exercise and self-management is more cost-effective than outpatient physiotherapy for patients with knee pain

➤ The ESCAPE-knee pain program involves 2 sessions weekly for 5 weeks

➤ Informal group discussion focused on improving patients’ understanding of their condition, self-management, and specific goal-setting

➤ This approach costs about half as much as outpatient physiotherapy, because of reduced secondary care

The integrated program changes patients’ health beliefs and behaviors, “and they learn that they can control their symptoms and alter the course of their condition.”

—Michael V. Hurley, PhD

inhibitor use before the onset of renal crisis, the patients were well matched for markers of disease severity, ane-mia, cardiovascular events, and large joint contractures. The median disease duration was 1.5 years.

Exposure to prednisone emerged as an important difference between the groups. Patients who had taken ACE inhibitors before the onset of renal cri-sis also had twice the daily dose of prednisone compared with those pa-

tients who did not take ACE inhibitors (18 mg vs 9 mg daily; P = .03). Before adjusting for the baseline prednisone dose, the risk of death was almost twice in the exposed group compared with the patients who did not receive ACE inhibitors before the onset of renal crisis, but the result was not sig-nificant (HR, 1.88; 95% CI, 0.82-4.3).

Within the first year of the onset of renal crisis, the event rate was 61%; 36% of the patients died, and 25% of

them remained on dialysis. The researchers carried out a post

hoc analysis to look for possible con-founding by indication (ie, hyperten-sion or hypertension related to renal disease). Although the mean blood pressure levels in the prednisone-ex-posed group were higher than in the unexposed group (139/85 mm Hg and 124/75 mm Hg, respectively), the risk of death remained about twice as high (HR, 2.17; 95% CI, 0.88-5.33) in the ex-

posed group, even after adjusting for differences in blood pressure levels.

The current study provides more ev-idence that the use of ACE inhibitors as prophylaxis in patients with scleroder-ma may be, at the very least, question-able, and perhaps even dangerous. This position is also supported by ret-rospective data that have recently emerged, indicating worse outcomes in patients who received ACE inhibi-tors before a renal crisis. n

Prophylactic Use of ACE Inhibitors... Continued from page 11

AVBCCKsize20413

CONFERENCE CO-CHAIRS

May 2-5, 2013 • Westin Diplomat • Hollywood, Florida

Craig K. Deligdish, MDHematologist/OncologistOncology Resource Networks

Gary M. Owens, MDPresidentGary Owens Associates

Burt Zweigenhaft, BSPresident and CEOOncoMed

THURSDAY, MAY 2, 20138:00 am - 5:00 pm Registration

FRIDAY, MAY 3, 20137:00 am - 8:00 am Simultaneous Symposia/Product Theaters

8:15 am - 9:15 am Session 1: Welcome, Introductions, and Opening RemarksConference Co-Chairs - Craig K. Deligdish, MD; Gary M. Owens, MD; Burt Zweigenhaft, BS

9:15 am - 10:15 am Keynote Address

10:15 am - 10:30 am Break

10:30 am - 11:45 am Session 2: Trends in Treatment Decision-Making: Pathways and Stakeholder CollaborationsMarcus Neubauer, MD; Michael Kolodziej, MD

12:00 pm - 1:00 pm Exclusive Lunch Symposium/Product Theater

1:15 pm - 2:00 pm Session 3: Cost of Cure: When, How, and How Much?John Fox, MD; John Hennessy

2:00 pm - 2:45 pm Session 4: Where Is Oncology Care Headed in the Future?Jayson Slotnick, JD, MPH (Moderator); Barbara L. McAneny, MD

2:45 pm - 3:30 pm Session 5: What Will the Cancer Delivery System Look Like in 2015?Ted Okon; John D. Sprandio, MD

3:30 pm - 3:45 pm Break

3:45 pm - 4:30 pm Session 6: Employers and Oncology CareF. Randy Vogenberg, PhD, RPh (Moderator); Bridget Eber, PharmD; Patricia Goldsmith; Darin Hinderman

4:30 pm - 5:15 pm Session 7: Advanced Care Directives: Palliative Care, Hospice, Ethics J. Russell Hoverman, MD, PhD; Thomas Smith, MD, FACP, FASCO

5:15 pm - 5:45 pm Summary/Wrap-Up of Day 1

6:00 pm - 8:00 pm Cocktail Reception in the Exhibit Hall

SATURDAY, MAY 4, 20137:00 am - 8:00 am Simultaneous Symposia/Product Theaters

8:15 am - 8:30 am Opening Remarks

8:30 am - 9:15 am Session 8: The Role of Government in the Future of Oncology CareJayson Slotnick, JD, MPH

9:15 am - 10:00 am Session 9: Medicaid: A Healthcare Delivery System ReviewMatthew Brow

10:00 am - 10:15 am Break

10:15 am - 11:00 am Session 10: Payer, Government, and Industry Insights: Balancing Cost and QualityKip Piper

11:00 am - 11:45 am Session 11: National Coalition for Cancer Survivorship: Medication Nonadherence IssuesPat McKercher; Lillie Shockney, RN, BS, MAS


1:15 pm - 3:00 pm Session 12: Meet the Experts Networking Roundtable Session

3:00 pm - 3:45 pm Session 13: Personalized Medicine, Companion Diagnostics, Molecular Profiling,Genome Sequencing—The Impact on Cost, Treatment, and the Value PropositionMark S. Boguski, MD, PhD; Gary Palmer, MD, JD, MBA, MPH



SUNDAY, MAY 5, 20137:00 am - 8:00 am Simultaneous Symposia/Product Theaters


8:30 am - 9:15 am Session 14: Cancer Rehabilitation: The Next Frontier in Survivorship CareJulie Silver, MD

9:15 am - 10:00 am Session 15: Current and Future Considerations for the Oncology Practice ManagerDawn Holcombe, MBA, FACMPE, ACHE; Leonard Natelson

10:00 am - 10:15 am Break

10:15 am - 11:00 am Session 16: Access to Drugs—Shortages, BiosimilarsDouglas Burgoyne, PharmD; James T. Kenney, Jr., RPh, MBA

11:00 am - 11:45 am Session 17: Perspectives from Oncology Group Practices—Successes, Issues, and ChallengesThomas Marsland, MD; David Eagle, MD

11:45 am - 12:00 pm Summary and Conclusion of Conference*Agenda is subject to change.

PROGRAM OVERVIEWFollowing on the success of our Second Annual Conference, AVBCC will be comingto Hollywood, Florida, on May 2-5, 2013. We continue to be guided by the expertise ofleaders in these fields providing at tendees with a thorough understanding of the evo-lution of the value equation as it relates to cancer therapies. Our goal is to be able toassist them in implementing, improving, and sustaining their organizations and institu-tions, while improving access for patients and ultimately quality patient care.

TARGET AUDIENCEThis conference is intended for medical oncologists, practice managers/administrators,and managed care professionals. Stakeholders in a position to impact cancer patientcare, such as advanced practice nurses, pharmacists, and medical directors, are alsoinvited to join this exciting forum.

SPONSORSThis activity is jointly sponsored by the Florida Society of Clinical Oncology, MedicalLearning Institute Inc, Association for Value-Based Cancer Care, Inc., Center of Excel-lence Media, LLC, and Core Principle Solutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENTGrant requests are currently being reviewed by numerous supporters. Support will beacknowledged prior to the start of the educational activities.

REGISTERED NURSE DESIGNATIONMedical Learning Institute Inc. Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 17.25 contact hours.

REGISTERED PHARMACY DESIGNATIONThe Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Comple-tion of this knowledge-based activity provides for 17.25 contact hours (1.725 CEUs)

of continuing pharmacy education credit. The Universal Activity Number for this activityis (To be determined).

PHYSICIAN CREDIT DESIGNATIONThe Medical Learning Institute Inc designates this live activity for a maximum of 17.25AMA PRA Category 1 Credits™. Physicians should claim only the credit commensuratewith the extent of their participation in the activity. This activity has been planned andimplemented in accordance with the Essential Areas and policies of the AccreditationCouncil for Continuing Medical Education through the joint sponsorship of the MedicalLearning Institute Inc and the Center of Excellence Media, LLC. The Medical LearningInstitute Inc is accredited by the Accreditation Council for Continuing Medical Educa-tion to provide continuing medical education for physicians.

DESIGNATION OF CREDIT STATEMENTS

LEARNING OBJECTIVESUpon completion of this activity, the participant will be able to:• Discuss the current trends and challenges facing all stakeholders in optimizing value

in cancer care delivery.• Define the barriers associated with cost, quality, and access as they relate to health-

care reform and what solutions are currently being considered.• Compare and contrast the different approaches/tools providers and payers are

utilizing to manage and deliver care collaboratively.• Examine the current trends in personalized care and companion diagnostics.• Analyze the patient issues around cost, quality, and access to care.

$375.00 until March 15, 2013$425.00 after March 15, 2013

Influencing the Patient-Impact Factor

THIRD ANNUALAssociation for Value-Based

Cancer Care Conference

www.regonline.com/avbcc2013REGISTER TODAY AT

AGENDA*

This activity is jointly sponsored by the Florida Society of Clinical Oncology,

Medical Learning Institute Inc, Association forValue-Based Cancer Care, Inc.,

Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

CONFERENCE REGISTRATION

AVBCC2013Ksize13013_AVBCC 2/4/13 12:44 PM Page 1

AVBCCKsize20413

CONFERENCE CO-CHAIRS

May 2-5, 2013 • Westin Diplomat • Hollywood, Florida

Craig K. Deligdish, MDHematologist/OncologistOncology Resource Networks

Gary M. Owens, MDPresidentGary Owens Associates

Burt Zweigenhaft, BSPresident and CEOOncoMed

THURSDAY, MAY 2, 20138:00 am - 5:00 pm Registration

FRIDAY, MAY 3, 20137:00 am - 8:00 am Simultaneous Symposia/Product Theaters

8:15 am - 9:15 am Session 1: Welcome, Introductions, and Opening RemarksConference Co-Chairs - Craig K. Deligdish, MD; Gary M. Owens, MD; Burt Zweigenhaft, BS

9:15 am - 10:15 am Keynote Address

10:15 am - 10:30 am Break

10:30 am - 11:45 am Session 2: Trends in Treatment Decision-Making: Pathways and Stakeholder CollaborationsMarcus Neubauer, MD; Michael Kolodziej, MD


1:15 pm - 2:00 pm Session 3: Cost of Cure: When, How, and How Much?John Fox, MD; John Hennessy

2:00 pm - 2:45 pm Session 4: Where Is Oncology Care Headed in the Future?Jayson Slotnick, JD, MPH (Moderator); Barbara L. McAneny, MD

2:45 pm - 3:30 pm Session 5: What Will the Cancer Delivery System Look Like in 2015?Ted Okon; John D. Sprandio, MD

3:30 pm - 3:45 pm Break

3:45 pm - 4:30 pm Session 6: Employers and Oncology CareF. Randy Vogenberg, PhD, RPh (Moderator); Bridget Eber, PharmD; Patricia Goldsmith; Darin Hinderman

4:30 pm - 5:15 pm Session 7: Advanced Care Directives: Palliative Care, Hospice, Ethics J. Russell Hoverman, MD, PhD; Thomas Smith, MD, FACP, FASCO



SATURDAY, MAY 4, 20137:00 am - 8:00 am Simultaneous Symposia/Product Theaters


8:30 am - 9:15 am Session 8: The Role of Government in the Future of Oncology CareJayson Slotnick, JD, MPH

9:15 am - 10:00 am Session 9: Medicaid: A Healthcare Delivery System ReviewMatthew Brow

10:00 am - 10:15 am Break

10:15 am - 11:00 am Session 10: Payer, Government, and Industry Insights: Balancing Cost and QualityKip Piper

11:00 am - 11:45 am Session 11: National Coalition for Cancer Survivorship: Medication Nonadherence IssuesPat McKercher; Lillie Shockney, RN, BS, MAS


1:15 pm - 3:00 pm Session 12: Meet the Experts Networking Roundtable Session

3:00 pm - 3:45 pm Session 13: Personalized Medicine, Companion Diagnostics, Molecular Profiling,Genome Sequencing—The Impact on Cost, Treatment, and the Value PropositionMark S. Boguski, MD, PhD; Gary Palmer, MD, JD, MBA, MPH



SUNDAY, MAY 5, 20137:00 am - 8:00 am Simultaneous Symposia/Product Theaters


8:30 am - 9:15 am Session 14: Cancer Rehabilitation: The Next Frontier in Survivorship CareJulie Silver, MD

9:15 am - 10:00 am Session 15: Current and Future Considerations for the Oncology Practice ManagerDawn Holcombe, MBA, FACMPE, ACHE; Leonard Natelson

10:00 am - 10:15 am Break

10:15 am - 11:00 am Session 16: Access to Drugs—Shortages, BiosimilarsDouglas Burgoyne, PharmD; James T. Kenney, Jr., RPh, MBA

11:00 am - 11:45 am Session 17: Perspectives from Oncology Group Practices—Successes, Issues, and ChallengesThomas Marsland, MD; David Eagle, MD

11:45 am - 12:00 pm Summary and Conclusion of Conference*Agenda is subject to change.

PROGRAM OVERVIEWFollowing on the success of our Second Annual Conference, AVBCC will be comingto Hollywood, Florida, on May 2-5, 2013. We continue to be guided by the expertise ofleaders in these fields providing at tendees with a thorough understanding of the evo-lution of the value equation as it relates to cancer therapies. Our goal is to be able toassist them in implementing, improving, and sustaining their organizations and institu-tions, while improving access for patients and ultimately quality patient care.

TARGET AUDIENCEThis conference is intended for medical oncologists, practice managers/administrators,and managed care professionals. Stakeholders in a position to impact cancer patientcare, such as advanced practice nurses, pharmacists, and medical directors, are alsoinvited to join this exciting forum.

SPONSORSThis activity is jointly sponsored by the Florida Society of Clinical Oncology, MedicalLearning Institute Inc, Association for Value-Based Cancer Care, Inc., Center of Excel-lence Media, LLC, and Core Principle Solutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENTGrant requests are currently being reviewed by numerous supporters. Support will beacknowledged prior to the start of the educational activities.

REGISTERED NURSE DESIGNATIONMedical Learning Institute Inc. Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 17.25 contact hours.

REGISTERED PHARMACY DESIGNATIONThe Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Comple-tion of this knowledge-based activity provides for 17.25 contact hours (1.725 CEUs)

of continuing pharmacy education credit. The Universal Activity Number for this activityis (To be determined).

PHYSICIAN CREDIT DESIGNATIONThe Medical Learning Institute Inc designates this live activity for a maximum of 17.25AMA PRA Category 1 Credits™. Physicians should claim only the credit commensuratewith the extent of their participation in the activity. This activity has been planned andimplemented in accordance with the Essential Areas and policies of the AccreditationCouncil for Continuing Medical Education through the joint sponsorship of the MedicalLearning Institute Inc and the Center of Excellence Media, LLC. The Medical LearningInstitute Inc is accredited by the Accreditation Council for Continuing Medical Educa-tion to provide continuing medical education for physicians.

DESIGNATION OF CREDIT STATEMENTS

LEARNING OBJECTIVESUpon completion of this activity, the participant will be able to:• Discuss the current trends and challenges facing all stakeholders in optimizing value

in cancer care delivery.• Define the barriers associated with cost, quality, and access as they relate to health-

care reform and what solutions are currently being considered.• Compare and contrast the different approaches/tools providers and payers are

utilizing to manage and deliver care collaboratively.• Examine the current trends in personalized care and companion diagnostics.• Analyze the patient issues around cost, quality, and access to care.

$375.00 until March 15, 2013$425.00 after March 15, 2013

Influencing the Patient-Impact Factor

THIRD ANNUALAssociation for Value-Based

Cancer Care Conference

www.regonline.com/avbcc2013REGISTER TODAY AT

AGENDA*

This activity is jointly sponsored by the Florida Society of Clinical Oncology,

Medical Learning Institute Inc, Association forValue-Based Cancer Care, Inc.,

Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

CONFERENCE REGISTRATION

AVBCC2013Ksize13013_AVBCC 2/4/13 12:44 PM Page 1


A detailed genetic analysis of more than 140,000 people of European ancestry has led to

the discovery of 18 previously un-characterized genetic loci that are associated with serum urate concen-trations and could eventually be used as drug targets for the develop-ment of new therapies for patients with gout (Köttgen A, et al. Nat Genet. 2013;45:145-154).

“A first step toward the design of novel therapies is to understand how these genes exert their effect on a mo-lecular level. Functional studies are an important next step, but can take years to deliver insights. So we ex-pect that there will be no immediate translation into novel therapies, but that our study will stimulate research in this area,” said lead investigator Anna Köttgen, MD, MPH, Freiburg University Clinic, Germany, and Ad-junct Assistant Professor, Depart-ment of Epidemiology, Johns Hop-kins Bloomberg School of Public Health, Baltimore.

The team of more than 250 investi-gators who are involved in the Global Urate Genetics Consortium combined genomewide data from 110,347 peo-ple in 48 studies with measured serum urate concentrations, and from 69,374 individuals who had taken part in studies of gout. The research took about 2.5 years, with many more years of study leading up to the col-laborative analyses.

The researchers had information from each subject on approximately 2.5 million single-nucleotide poly-morphisms (SNPs) or single-nucleo-tide DNA-sequence variants. Of these SNPs, 2201 were found to be associat-ed to some extent with serum urate concentration.

Further analyses revealed that SNPs in 26 different genomic re-gions—only 10 of which were previ-ously described—are of genomewide significance, meaning that their effect on gene products significantly influ-ences the cascade of events that affect serum urate concentration. The team

replicated these findings in 32,813 new study subjects.

Two of these genetic loci—dubbed SLC2A9 and ABCG2—had the great-est impact on serum urate concentra-tions. Altogether, the newly charac-terized and previously described loci account for 7% of the overall variance in serum urate concentrations.

Many of the genes in which the SNPs are located are responsible for urate transport, but several of the newly described SNPs are located in genes that may be connected with metabolic control of serum urate pro-duction and excretion.

The group also used sophisticated methods to discover 2 more loci that had not been previously described as being associated with serum urate concentrations. This brought the total of newly described loci to 18.

The researchers also found that the SNPs they characterized are associat-ed with variation in the serum urate concentrations in people of non-Euro-pean background.

The team conducted previous anal-yses that showed a positive correla-tion between the effect of SNPs on serum urate concentration and an increased likelihood of developing gout, as well as an increased risk of gout with the more urate-increasing variants that are found in individual carries. n

New genetic Loci Uncovered, Potential Targets for Novel Therapies for Patients with goutDiscovery of 18 new genetic regions involved in gout reinforces role for targeted treatments for this disease By Rosemary Frei, MSc

“A first step toward the design of novel therapies is to understand how these genes exert their effect on a molecular level. Functional studies are an important next step, but can take years to deliver insights.”

—Anna Köttgen, MD, MPH

Personalized Medicine in Rheumatology™

IN THE LITERATURE

Low-Cost Walking Program Improves Outcomes for Patients with Knee OA

Patients with osteoarthritis (OA) tend to become sedentary as their dis-ease progresses, although physical activity has been shown to improve symptoms and quality of life (QOL). A prolonged lack of physical activity can further increase the risk for chron-ic diseases in this patient population. A new study compared the clinical and QOL benefits of a low-cost, com-munity-based walking program and a walking program that also involved behavioral or an educational program for patients with knee OA (Brosseau L, et al. BMC Public Health. 2012;12:1073).

This single-blind controlled trial ran-domized 222 patients with mild- to-moderate knee OA into 3 groups —a community-based walking pro-gram combined with behavioral inter-vention and education, a supervised community-based walking pro gram combined with education only, and a self-directed control group with education only.

The Arthritis Impact Measurement

Scale 2 (AIMS2) and the Short Form 36 (SF-36) questionnaires were used to evaluate QOL measures (ie, disease ac-tivity, pain, and depression). Function-al status was measured using the West-ern Ontario and McMaster Universities Osteoarthritis Index (WOMAC).

All 3 groups demonstrated im-provements in QOL measures and in clinical function status at the end of the 12-month intervention phase and the 18-month follow-up phase of the study. Only a few significant differ-ences were found among the 3 groups in QOL and in clinical function out-comes based on the AIMS or the SF-36 measures. The self-directed control group showed significant improve-ment compared with the other 2 groups in physical functioning (P = .01) and in the pain index (P = .03).

At 12 months, no significant differ-ences were seen on the total WOMAC scores. At 18 months, the self-directed control group demonstrated the low-est mean pain scores at 23.50 com-pared with 23.60 for the walking-only group and 26.16 for the walking plus behavioral intervention group (a non-

significant difference); the only signif-icant difference among the 3 groups in total WOMAC score favored the walking-only group (P = .019).

These results suggest that behavior-al intervention and patient education have less of an impact on the clinical outcomes and QOL of patients with knee OA than does the participation in a walking program.

Cell-Mediated Immunity Impaired in Patients with Fibromyalgia

Fibromyalgia (FM) is common in patients with other autoimmune dis-orders, but its etiology is not com-pletely understood. In the past, FM was considered an inflammatory rheumatologic disorder. Recent re-search has centered on the role of the immune system in the pathogenesis of this disorder, as highlighted in a new study that investigated whether cyto-kine production by immune cells is altered in patients with FM (Behm FG, et al. BMC Clin Pathol. 2012;12:25).

The investigators compared the re-sponses to the mitogenic activators

PHA or PMA of stimulated plasma and peripheral blood mononuclear cells (PBMCs) from 110 patients with FM and from 91 healthy controls.

A comparison of the concentrations of 8 cytokines, including several inter-leukins and proteins, showed no signif-icant differences between the 2 groups.

The investigators then cultured samples of PBMCs from the 2 groups. The samples were cultured alone and with the mitogenic activators PHA or PMA. An immunoassay analysis showed that the cytokine levels of the stimulated PBMCs were significantly increased compared with the matched, nonstimulated PBMC cultures from the healthy controls.

By contrast, when comparing the samples from the patients with FM, the concentrations of most of the 8 cytokines were significantly lower (P values from P <.001 to P = .007) in the stimulated PBMCs compared with the nonstimulated samples, suggesting a lack of cytokine response to the pres-ence of these mitogenic activators in this patient population.

This reduction in cytokine respons-Continued on page 15


Osteoporosis

Washington, DC—Odanacatib, an investigational agent, was effective in building bone mass in women with postmenopausal osteoporosis who did not respond to 3 years of treatment with alendronate (Fosa-max). Odanacatib treatment signifi-cantly improved bone mineral den-sity (BMD) at the femoral neck, hip, trochanter, and lumbar spine com-pared with placebo in this group of women, and it had acceptable safety and tolerability.

The results of this phase 3 clinical trial were presented during the 2012 meeting of the American College of Rheumatology. The study was halt-ed prematurely by an independent data and safety monitoring commit-tee because of the robust effectiveness of odanacatib versus placebo.

Impressive Results“Odanacatib inhibits bone resorp-

tion while maintaining bone forma-tion, unlike bisphosphonates that reduce bone resorption and bone for-mation,” stated lead author Roland Chapurlat, MD, Hôpital Edouard Herriot, Lyon, France. “The treatment was safe and well tolerated, with no evidence of excess bone formation or abnormal stress fracture.”

The goal of the study was to deter-mine if odanacatib would be effective in women who had previously re-ceived alendronate for postmeno-pausal osteoporosis. This randomized, double-blind, placebo-controlled, 24- month trial was conducted at 42 sites in 12 countries and included 246 women aged ≥60 years (mean age, 71.3 years) with osteoporosis. The pa-tients were randomized to receive odanacatib 50 mg once weekly or pla-cebo. All of the patients received vita-min D and calcium supplementation.

Baseline demographic and disease characteristics were similar between the 2 treatment arms. Most women were Caucasian, 73.7% had a histo-ry of any fracture, and 68.3% had sustained a postmenopausal fracture.

The patients had taken alendronate for a mean of 5.5 years, and ≥50% had used that drug for 3 to 5 years.

Dr Chapurlat noted that, typically, patients using alendronate over the long-term continue to have a residual effect on bone turnover, even after they stop treatment. This effect prob-ably accounted for an approximately 6-month lag until the effect of the novel agent became evident.

Odanacatib was significantly supe-rior to placebo in building BMD at the femoral neck (the primary end point) and the hip. After 24 months of treatment, a 2.67% difference in femoral neck BMD was observed in favor of odanacatib (P <.001). Total hip BMD had a 2.7% difference favor-ing odanacatib (P <.001). For both end points, the effect of odanacatib was not seen until about 6 months after treatment was initiated, presumably because of the residual effect of alen-dronate, Dr Chapurlat noted.

At 24 months, BMD was signifi-cantly improved at the trochanter

(3.18% difference vs placebo) and the lumbar spine (2.57% difference vs placebo; P <.001 for both com-parisons). At 24 months, odanacat-ib significantly reduced the markers of bone resorption and significantly increased markers of bone formation compared with placebo (P <.001 and P = .011, respectively).

The rate of discontinuation because of adverse events (AEs) was 9% in the odanacatib group versus 3% in the placebo group. No significant differ-ences in AEs were observed between the 2 treatment arms.

Although the study was not de-signed to assess fracture as the pri-mary end point, the fracture rate was 4.9% in the odanacatib group versus 13.2% for placebo. The results of an ongoing phase 3 clinical trial that is investigating the effect of odanacatib on bone fractures in 16,000 women are expected next year.

Cost ConsiderationsFinancial analysts forecast odana-

catib as a blockbuster drug if it is ap-proved by the US Food and Drug Ad ministration, which is poised to replace alendronate, but some rheu-matologists believe that this will not happen soon. The consensus is that bisphosphonates are quite inexpen-sive, very effective, and have a long track record. The challenge is to de-termine the optimal length of treat-ment to avoid the rare cases of atypi-cal fracture that are reported with bisphosphonates. n

“Odanacatib inhibits bone resorption while maintaining bone formation, unlike bisphosphonates that reduce bone resorption and bone formation.”

—Roland Chapurlat, MD

at a glance➤ The investigational agent

odanacatib showed impressive results in a phase 3 clinical trial in postmenopausal women with osteoporosis

➤ At 24 months, BMD was significantly improved at the trochanter (a 3.18% difference vs placebo) and the lumbar spine (a 2.57% difference vs placebo)

➤ Odanacatib significantly reduced bone resorption markers and increased bone formation markers

➤ The study was halted prematurely by an independent monitoring committee as a result of the robust effectiveness of odanacatib versus placebo

Odanacatib Effective in Women with Osteoporosis Uncontrolled with Alendronate By Phoebe Starr

IN THE LITERATURE

es indicates that cell-mediated immu-nity is impaired in patients with FM, which may help to explain the etiolo-gy of this condition. The lower anti-in-flammatory/higher proinflammatory cytokine patterns that were identified in the patients with FM compared with the controls may also explain the overlap in diagnoses of chronic pain and depression in these patients.

Low Disease Activity in Patients with RA Sustained with Low-Dose Etanercept

Treatment effects in moderately active rheumatoid arthritis (RA) have not been well studied, although re-mission and low disease activity are

as clinically relevant in this patient population as they are in patients with higher disease activity. The PRESERVE trial investigated wheth-er low doses or complete withdrawal of etanercept in patients with moder-ately active RA would help to slow or stop joint destruction and reduce disability in this patient population (Smolen JS, et al. Lancet. Epub Janu-ary 16, 2013).

In this randomized controlled trial, 834 patients (aged 18-70 years) with moderately active RA despite treat-ment with methotrexate were enrolled at 80 international centers. All patients received 15 mg to 25 mg of methotrex-ate every week for ≥8 weeks.

During a 36-week open-label peri-od, the patients received etanercept 50 mg plus methotrexate every week. To be eligible for the double-blind period of 52 weeks, the patients had to have achieved sustained low dis-ease activity as measured by a mean disease activity score in 28 joints (DAS28) of ≤3.2 by week 36. The 604 patients who were eligible to ad-vance to the next phase were ran-domized to 1 of 3 groups—etaner-cept 50 mg plus methotrexate, etanercept 25 mg plus methotrexate, or placebo plus methotrexate. The primary end point was the propor-tion of patients in the etanercept 50- mg group or the placebo group with

low disease activity at week 88. The conditional end point was the pro-portion of patients in the etanercept 25-mg group who achieved low dis-ease activity.

At week 88, 166 of 201 patients who received ≥1 dose of etanercept 50 mg had low disease activity com-pared with 159 of 201 patients who received etanercept 25 mg and 84 of 197 patients who received a placebo.

The withdrawal of etanercept in the patients who had achieved sustained low disease activity caused the wors-ening of symptoms despite the use of methotrexate, but the dose reduction to 25 mg was able to maintain low disease activity for up to 88 weeks. n

Continued from page 14


Tofacitinib: A New Treatment Option for Patients with Rheumatoid ArthritisBy Alice Goodman, Medical Writer

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation

of the joints and surrounding tissues. The cause is unknown, but some evi-dence suggests that infection, genet-ics, and hormone changes may be associated with RA.1 Approximately 1.3 million Americans are estimated to have RA.2

Although RA can occur at any age, the peak age of onset is between 30 and 55 years.1,2 RA affects women 2 to 3 times more than men.1,3

The symptoms of RA usually occur bilaterally, with wrists, fingers, knees, feet, and ankles being the most com-mon sites of disease. RA typically has a slow onset that is characterized by minor joint pain and swelling, stiffness, and fatigue. Over time, the affected joints may develop a restrict-ed range of motion and the joints may become deformed.1

Other symptoms of RA can include chest pain when taking a breath; dry eyes and mouth; burning, itching, and discharge of the eyes; nodules under the skin; numbness, tingling, or burning of the hands and feet; and difficulty sleeping.1

The Economic Burden of RARA is associated with a significant

economic burden, including function-al impairment and work disability.4 A significantly higher percentage of patients with RA report work disabili-ty compared with the general popula-tion; 66% of patients with RA lose an average of 39 working days each year.5 The costs to the US economy in terms of work-related disability can amount to billions of dollars annually.6

Functional disability is the most significant predictor of premature mortality and work disability in pa-tients with RA.4 An estimated 25% of patients with RA experience a reduc-tion in their income.7

In 2000, the estimated average an-nual medical cost associated with RA was $5720 per patient, of which inpa-tient cost was the largest component.8 This amount is likely to be much high-er in 2013. In terms of indirect costs, one study estimated an annual work-place cost of $16,335 per employee with RA; the indirect costs included reduced productivity, absenteeism or disability, and job turnover.9

A Complex DiagnosisOne review suggested that genes

may account for up to 60% of the risk of developing RA.4 Susceptibil-ity genes include HLA-DRB1, with a strong link to the presence of anti-cyclic citrullinated peptide (anti-CCP) antibodies.

No single test is available to con-firm the diagnosis of RA, but most patients with RA will have some abnormal results on different tests.1 However, test results will be normal for some patients. Two helpful tests are the rheumatoid factor test and the anti-CCP antibody test, but at least 30% of patients with RA have nega-tive results on these 2 tests.1,4

Other tests that can lend supportive evidence for the diagnosis of RA include a complete blood count, C-re-active protein (CRP), erythrocyte sedi-mentation rate (ESR), joint ultrasound or magnetic resonance imaging, joint x-rays, and synovial fluid analysis.1

The Approach to TreatmentOnce the diagnosis of RA is strong-

ly suspected or confirmed, the disease usually requires lifelong treatment, which can include medications, phys-ical therapy, exercise, education, and possibly surgery. Evidence suggests that early, aggressive treatment of RA can delay joint destruction.1

Nonbiologic DrugsThe first line of treatment for RA

typically entails a nonbiologic dis-ease-modifying antirheumatic drug (DMARD), most often methotrexate. Other nonbiologic DMARDs include leflunomide and chloroquine. Anti- inflammatory drugs are also used, including aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen.1

Although these drugs are effec-tive at relieving symptoms, they have associated side effects. DMARDs require frequent blood tests for mon-itoring, and long-term use of NSAIDs can cause irritation of the gastrointes-tinal tract leading to ulcers and bleed-ing, and, depending on the NSAID used, possibly heart problems. The selective NSAID celecoxib, although effective for pain relief, carries a Boxed Warning about heart disease and stroke.1

Antimalarial medications are some-times used in combination with metho-trexate, but these drugs have a slow onset of action. Corticosteroids are effective at reducing joint swelling and inflammation, but it is advisable

to take them at low doses and for short periods because of the potential for long-term side effects.1

Biologic DrugsOver the past decade or so, biologic

DMARDs that target the immune sys-tem have become available, and these agents can be extremely effective. Biologics are typically reserved for patients with a suboptimal response to nonbiologic DMARDs or other drugs, and they are typically given subcutaneously or intravenously.1

Although biologic agents are effec-tive in treating RA, they carry the risk of serious bacterial, fungal, or viral infection, secondary leukemia and lymphoma, and psoriasis.1 Monitoring is necessary because of these risks.1

Surgery, ExerciseOccasionally, surgery may be used

to correct severely damaged joints.1 The types of surgery include removal of the joint lining (synovectomy), or total joint replacement of the knee, hip, ankle, shoulder, or other joints for extreme cases of RA. Physical thera-py and exercise are recommended to delay the loss of joint function and to maintain muscle strength and range of motion.1 Patients with RA should have a balanced diet that includes foods rich in omega-3 fatty acids.1

TofacitinibThe most recently approved bio-

logic agent for the treatment of RA is the Janus kinase (JAK) inhibitor tofa-citinib (Xeljanz). Tofacitinib is the first oral biologic agent for RA to become available in more than 20 years.10 The US Food and Drug Adminis-tration (FDA) approved tofacitinib in November 2012 for the treatment of adults with moderate-to-severe active RA who have had an inade-quate response to, or are intolerant of, methotrexate. The approval of tofaci-tinib was granted as monotherapy or in combination with methotrexate or other nonbiologic DMARDs.

Mechanism of ActionTofacitinib is an oral JAK inhibitor

with a novel mechanism of action, targeting JAK1 and JAK3, as well as JAK2. Unlike other biologics that target extracellular molecules, such as proinflammatory cytokines, tofac-itinib targets the intracellular signal-ing pathways that operate as hubs in the inflammatory cytokine network.10

DosingThe recommended dose of tofaci-

tinib is 5 mg twice daily.11 The drug should be taken orally without food. The dosage should be reduced to 5 mg once daily for patients with moderate or severe renal insufficien-cy, patients with moderate hepatic impairment, those receiving potent inhibitors of the cytochrome (CY) P3A4 enzyme, and patients receiving 1 or more concomitant medications that result in moderate inhibition of CYP3A4 and in potent inhibition of CYP2C19.11

Clinical Trial ProgramThe clinical development program

for tofacitinib included 2 dose-rang-ing trials and 5 confirmatory trials. The 2 dose-ranging trials showed that the 10-mg and 15-mg doses achieved a similar American College of Rheu-matology 20% criteria for improve-ment (ACR20) response in patients with active RA.

In all 7 trials, the patients who received tofacitinib demonstrated improvement in clinical response and in physical functioning compared with patients who received placebo.11

Confirmatory TrialsStudy I was a 6-month monother-

apy trial that included 610 patients with moderate-to-severe active RA whose disease had an inadequate response to a nonbiologic or a bio-logic DMARD. The patients received tofacitinib 5 mg or 10 mg twice daily, or a placebo. At month 3, all of the patients in the placebo group were randomized in a blinded fashion to tofacitinib 5 mg or 10 mg twice daily. The primary end points at month 3 were the percentage of patients who achieved an ACR20 response, chang-es in the Health Assessment Ques-tionnaire-Disability Index (HAQ-DI), and a 28-joint Disease Activity Score (DAS28)-4(ESR) <2.6.11

Study II was a 12-month trial that enrolled 792 patients with moder-ate-to-severe active RA and an inad-equate response to a nonbiologic DMARD. The patients received tofa-citinib 5 mg or 10 mg twice daily or a placebo added to background DMARD therapy that did not include potent immunosuppressive treat-ment. At month 3, the patients who had an inadequate response were advanced to blinded treatment with tofacitinib 5 mg or 10 mg twice daily.

Drug Update


Drug Update

At the end of month 6, all place-bo-receiving patients were advanced to their second predetermined treat-ment with tofacitinib 5 mg or 10 mg twice daily in a blinded fashion. The primary end points were the pro-portion of patients who achieved an ACR20 response at month 6, changes in HAQ-DI at month 3, and a DAS28-4(ESR) <2.6 at month 6.11

Study III was a 12-month trial of 717 patients with moderate-to-severe active RA and an inadequate response to methotrexate. Patients were treated with tofacitinib 5 mg or 10 mg twice daily, adalimumab 40 mg subcutane-ously every other week, or placebo added to background methotrexate. The placebo-receiving patients were advanced to their second predeter-mined treatment as in Study II. The primary end points were the pro-portion of patients who achieved an ACR20 response at month 6, chang-es in the HAQ-DI at month 3, and a DAS28-4(ESR) <2.6 at month 6.11

Study IV is an ongoing 2-year trial with a planned analysis at 1 year that enrolled 797 patients with moder-ate-to-severe active RA and an inade-quate response to methotrexate. The patients were treated with tofacitinib 5 mg or 10 mg twice daily or with pla-cebo added to background metho-trexate. The placebo-receiving patients were advanced to their second pre-determined treatment as in Study II. The primary end points were the pro-portion of patients who achieved an ACR20 response at month 6, a mean change from baseline in the van der Heijde–modified total Sharp Score at month 6, changes in the HAQ-DI at month 3, and a DAS28-4(ESR) <2.6 at month 6.

Study V was a 6-month trial that enrolled 399 patients with moderate- to-severe active RA and an inade-quate response to at least 1 approved tumor necrosis factor (TNF)-inhibit-ing biologic agent. The patients were treated with tofacitinib 5 mg or 10 mg twice daily or placebo in addition to a background methotrexate. At month 3, all of the patients in the placebo group were randomized in a blinded fashion to tofacitinib 5 mg or 10 mg twice daily. The primary end points at month 3 were the percentage of pa-tients who achieved an ACR30 re-sponse, changes in the HAQ-DI, and a DAS28-4(ESR) <2.6.

Clinical ResponseAll 5 trials had similar ACR20,

ACR50, and ACR70 results at months 3 and 6, in that tofacitinib 5 mg or 10 mg twice daily achieved higher response rates versus placebo, with or without background DMARD treat-ment. Higher ACR20 responses were

observed within 2 weeks for tofaci-tinib compared with placebo. In the 12-month trials, the ACR responses to tofacitinib were consistent at months 6 and 12.11

In Studies I and IV, the ACR20 responses to tofacitinib at month 3 ranged from 55% to 65% versus approximately 26% with placebo. The month 6 ACR20 responses ranged from 50% to 70% with tofacitinib, compared with 25% with placebo. In Study V (ie, the inadequate respond-ers to TNF inhibitors), the month 3 ACR20 responses ranged from 41% to 48% on tofacitinib versus 24% with placebo; the month 6 ACR20 respons-es ranged from 51% to 54% with tofacitinib, and was not available for placebo (Table 1).

In Study IV, more patients in the 2 tofacitinib arms plus methotrexate achieved a low level of disease activity as measured by a DAS28-4(ESR) <2.6 at 6 months compared with metho-trexate alone: 6% for tofacitinib 5 mg twice daily, 13% for tofacitinib 10 mg twice daily, and 1% for placebo.

In addition, looking at the separate components of the ACR responses at month 3 (ie, number of tender and/or swollen joints, pain, patient global assessment, HAQ-DI, physician glob-al assessment, and CRP levels), simi-lar results were seen in all 5 studies for patients receiving tofacitinib ver-sus placebo (Table 2).

In all 5 studies, the tofacitinib-treat-ed patients demonstrated greater improvement in physical functioning as measured by changes in HAQ-DI versus placebo at month 3, 6, and 12.11

Safety ProfileOverall, the use of tofacitinib was

associated with an increased risk of serious infections including oppor-tunistic infections, tuberculosis, can-cers, and lymphoma. In clinical trials,

serious infections were the most com-mon serious adverse event (AE). The percentage of patients who discontin-ued treatment because of any AE in months 0 to 3 was 4% for tofacitinib and 3% for placebo.11

No cases of tuberculosis were reported in months 0 to 3 in any patients enrolled in the clinical tri-als. However, during months 0 to 12, tuberculosis was reported in 0 patients in the 5-mg twice-daily group and 6 patients in the 10-mg twice-

daily group. Cases of disseminated tuberculosis were also reported.

From months 0 to 3 in the 7 con-trolled clinical trials, no patient in the placebo group reported malignancy, and 2 patients taking tofacitinib report-ed malignancy (excluding nonmelano-ma skin cancer). During months 0 to 12, malignancies occurred in 5 patients in the 5-mg twice-daily group and 7 patients in the 10-mg twice-daily group. The most common types of malignancies observed over 12 months


Table 1 Tofacitinib versus Placebo: Proportion of Patients with an ACR Response, by Study

Study I: Monotherapy in nonbiologic or biologic DMARD

inadequate respondersa

Study IV: MTX inadequate

respondersb

Study V: TNF inhibitor inadequate respondersc

Placebo(N = 122)

Tofacitinib 5 mg twice daily(N = 243)

Tofacitinib 10 mg twice daily(N = 245)

Placebo + MTX(N = 160)

Tofacitinib 5 mg twice daily + MTX(N = 321)


Placebo + MTX(N = 132)



ACR20Month 3Month 6

26%NAd

59%69%

65%70%

27%25%

55%50%

67%62%

24%NAd

41%51%

48%54%

aInadequate response to at least 1 DMARD (biologic or nonbiologic) because of a lack of efficacy or toxicity.bInadequate response to MTX defined as the presence of sufficient residual disease activity to meet study entry criteria.cInadequate response to at least 1 TNF inhibitor because of a lack of efficacy and/or intolerance.dNot applicable (NA); data for placebo treatment are not available beyond 3 months in Studies I and V because of placebo advancement.ACR indicates American College of Rheumatology; DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; TNF, tumor necrosis factor.Adapted from Reference 11.

Table 2 Components of ACR Response at 3 Months: Study IV

Tofacitinib 5 mg twice daily + MTX

(N = 321)

Tofacitinib 10 mg twice daily+ MTX

(N = 316)

Placebo + MTX

(N = 160)Component (mean)a

Baseline

Month 3a

Baseline

Month 3a

Baseline

Month 3a

Number of tender joints (0-68)

24(14)

13(14)

23(15)

10(12)

23(13)

18(14)

Number of swollen joints (0-66)

14(8)

6(8)

14(8)

6(7)

14(9)

10(9)

Painb 58(23)

34(23)

58(24)

29(22)

55(24)

47(24)

Patient global assessment

58(24)

35(23)

57(23)

29(20)

54(23)

47(24)

Disability index (HAQ-DI)c

1.41(0.68)

0.99(0.65)

1.40(0.66)

0.84(0.64)

1.32(0.67)

1.19(0.68)

Physician global assessmentb

59(16)

30(19)

58(17)

24(17)

56(18)

43(22)

CRP (mg/L) 15.3(19.0)

7.1(19.1)

17.1(26.9)

4.4(8.6)

13.7(14.9)

14.6(18.7)

aData shown are mean (standard deviation) at month 3.bVisual analog scale: 0 = best, 100 = worst.cHealth Assessment Questionnaire-Disability Index (HAQ-DI): 0 = best, 3 = worst; 20 questions; categories, dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.CRP indicates C-reactive protein; MTX, methotrexate. Adapted from Reference 11.

of exposure to tofaci tinib, and in the long-term extension studies, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma, and malignant melanoma.

Abnormal laboratory tests includ-ed lymphocytes, neutrophils, liver enzyme tests, lipids, and serum cre-atinine. Other AEs occurring in at least 2% of the patients were diar-rhea, nasopharyngitis, upper respi-ratory tract infection, headache, and hypertension.

There are no adequate or well-con-trolled studies in pregnant women. Risks to the fetus and the patient ver-sus the benefits of treating a pregnant woman should be determined.11

Warnings and ContraindicationsTofacitinib carries a Boxed Warning

for serious infections and ma lig nancy.11

Pneumonia, cellulitis, herpes zos-ter, and urinary tract infections were among the serious infections reported with tofacitinib. Opportunistic infec-tions include tuberculosis and other mycobacterial infections, Cryptococcus, esophageal candidiasis, pneumocyto-sis, multidermatomal herpes zoster, cytomegalovirus, and BK virus. Some serious infections presented as dis-seminated rather than localized dis-eases, and patients with disseminated infections were often taking concomi-tant immunomodulating agents.

Patients taking tofacitinib should be monitored for infection, and treatment should be interrupted if a serious infection develops. Patients should also be evaluated and tested for latent or active tuberculosis before initiation of treatment with tofacitinib. Viral reactivation can also occur.

Other warnings and precautions are listed in the package insert.11

ConclusionTofacitinib is the most recently

FDA-approved oral biologic agent for the treatment of RA. A JAK inhib-itor that targets JAK1, JAK2, and JAK3, tofacitinib can be used as a monotherapy or in combination with methotrexate or with other nonbio-logic DMARDs in adults with mod-erate-to-severe RA who have had an inadequate response to methotrexate. Patients who received tofacitinib in 7 clinical trials demonstrated improve-ment in clinical response and physical functioning compared with patients who received placebo. n

References1. National Library of Medicine, National Institutes of Health. Rheumatoid arthritis. www.ncbi.nlm.nih.gov/

pubmedhealth/PMH0001467/. Accessed February 1, 2013.2. Helmick CG, Felson DT, Lawrence RC, et al. Nation-al Arthritis Data Workgroup. Estimates of the preva-lence of arthritis and other rheumatic conditions in the United States. Part 1. Arthritis Rheum. 2008;58:15-25.3. Lawrence RC, Helmick CG, Arnett FC, et al. Estimates of the prevalence of arthritis and select-ed musculoskeletal disorders in the United States. Arthritis Rheum. 1998;41:778-779.4. Epidemiology, genetics and economic burden of rheumatoid arthritis. In: Luqmani R, Pincus T, Boers M, eds. ORL Rheumatoid Arthritis. New York, NY: Oxford University Press; 2010.5. Burton W, Morrison A, Maclean R, Ruderman E. Systematic review of studies of productivity loss due to rheumatoid arthritis. Occup Med (Lond). 2006;56:18-27. 6. Zhang W, Anis AH. The economic burden of rheumatoid arthritis: beyond health care costs. Clin Rheumatol. 2011;30(suppl 1):S25-S32. 7. Albers JM, Kuper HH, van Riel PL, et al. Socio-economic consequences of rheumatoid arthritis in the first years of the disease. Rheumatology (Oxford). 1999;38:423-430.8. Cooper NJ. Economic burden of rheumatoid arthritis: a systematic review. Rheumatology (Oxford). 2000;39:28-33.9. Birnbaum H, Pike C, Kaufman R, Cifaldi M. Employer model of workplace impacts of anti-TNF therapy for rheumatoid arthritis. J Occup Environ Med. 2009;5:1167-1176.10. Data on file. Tofacitinib: A Novel JAK Inhibitor. New York, NY: Pfizer; 2012. 11. Xeljanz [package insert]. New York, NY: Pfizer; 2012. http://dailymed.nlm.nih.gov/dailymed/drug Info.cfm?id=81354. Accessed February 1, 2013.


Drug Update

Tofacitinib: A New Treatment Option... Continued from page 17

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