Vbcr june 2013 web

Value-Based Care

in

june 2013 VOL 2 • NO 3

TM

Integrating Rheumatologists, NPs/PAs, Practice Managers & Payers www.ValueBasedRheumatology.com

Dual-Energy Computed Tomography Useful for Diagnosing Gout

Employers’ Perspective

By Rosemary Frei, MSc

R

Role of Employers in Drug Coverage Decisions for Rheumatic Diseases F. Randy Vogenberg, PhD, RPh Institute for Integrated Healthcare Co-Founder, Bentelligence

heumatoid arthritis (RA) and related maladies are part of a growing area of interest in chronic diseases among multiple-­ market stakeholders. The disease tends to hit adults of working age, often during their most productive years.

Although RA and other chronic diseases generally represent a small number of members, they also represent large expenses per member from the perspective of the healthcare services purchaser—especially employers.

There are many stakeholders in the

Montreal, Quebec—Dual-energy computed tomography (DECT) has value in gout diagnosis and management, according to a presentation at the Canadian Association of

Radiologists’ 2013 annual meeting.

DECT involves the use of 2 x-ray sources, each at a different energy level, and 2 banks of detectors 90

Continued on page 17

Use of Biologic Agents to Treat Autoimmune Inflammatory Diseases Up 29% between 2009 and 2011

By Wayne Kuznar San Diego, CA—The use of biologic agents for autoimmune inflammatory diseases has been increasing between 2009 and 2011, according to a recent analysis of utilization data from commercial health plan members, which was presented at the 2013 Academy of

Managed Care Pharmacy’s annual meeting. During that 3-year period, the overall increase of biologic drug use for autoimmune inflammatory disorders was 29.4%.

Overall, 27% of the patients who were approved by the plan to use a Continued on page 18

healthcare marketplace, including patients, managed care organizations and pharmacy providers, manufacturers, third-party payers, and purchasers of care, which include employers. The latter group represents the minority among stakeholders, yet holds the risk of paying for most of the care within commercial health plans.

For employers, the primary concerns in RA are cost and productivity. For patients, it is, of course, access to ther-

Continued on page 9

Personalized Medicine in Rheumatology™

Strong Genetic Markers Identified for Fibromyalgia

By Neil Canavan

A

study looking at families in which more than 1 member has fibromyalgia has found several strong genetic links for the disease. By examining the frequency of 341 distinct genetic markers, investigators determined that the estimated risk of fibromyalgia in siblings was

27.2% compared with just 2% in the overall population.

“The estimated sibling recurrence risk ratio…suggests a strong genetic component of fibromyalgia, [and] confirms previous reports that fibromyalgia aggregates in families,” concluded the study authors, whose findings were Continued on page 10

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

Biodegradable nanogels a promising new approach to lupus therapy New test predicts early RA

8

FDA UPDATE. . . . . . . . . . . . . . . . . 8,10 Ilaris receives new indication for juvenile idiopathic arthritis Simponi approved for ulcerative colitis

14

Rheumatology PRACTICE Management™. . . . . . . . . . . . . . . . . . .

16

Engaging patients in pain management an important strategy for rheumatology practices OSTEOARTHRITIS. . . . . . . . . . . . . .

Patellofemoral disease linked to OA impairment

17

HEALTH ECONOMICS. . . . . . . . . . 18 Infliximab dosing and use patterns in patients with RA ARTHRITIS UPDATE. . . . . . . . . . . 15 Effectiveness and costs of TNF-alpha Opioids safe, effective for RA-related pain blocker use for patients with RA FIBROMYALGIA. . . . . . . . . . . . . . . . .

Impact of pain on quality of life in patients with fibromyalgia

© Engage Healthcare Communications, LLC

For adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to methotrexate (MTX)1

Introducing XELJANZ Powerful efficacy. First in a new class.

2

Choose XELJANZ for robust efficacy as monotherapy or in combination with MTX 1-3 • XELJANZ monotherapy ACR20/50/70 response rates (month 3)1-3: - XELJANZ 5 mg twice daily: 59%†, 31%†, and 15%* - Placebo: 26%, 12%, and 6% Results of a 6-month, randomized, double-blind, controlled, multicenter monotherapy study in which 610 patients with moderate to severe active RA who had an inadequate response to a biologic or nonbiologic DMARD due to lack of efficacy or toxicity received XELJANZ 5 mg twice daily (N=241) or placebo (N=120).

At the month 3 visit, all placebo patients were advanced blindly to a second predetermined treatment of XELJANZ.

• XELJANZ in combination with DMARDs ACR20/50/70 response rates (month 6)1,2: - XELJANZ 5 mg twice daily + DMARDs: 53%†, 34%†, and 13%† - Placebo + DMARDs: 31%, 13%, and 3% Results of a 12-month, randomized, double-blind, controlled, multicenter study in which 792 patients with moderate to severe active RA who had an inadequate response to a biologic or nonbiologic DMARD due to intolerance, toxicity, or inadequate response received XELJANZ 5 mg twice daily (N=311) or placebo (N=157) added to background nonbiologic DMARD treatment. At 3 months, nonresponding placebo patients were advanced blindly to a second predetermined treatment of XELJANZ. At 6 months, all placebo patients were advanced in the same fashion.

*P<0.05 vs placebo † P<0.0001 vs placebo

INDICATION

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

• XELJANZ should not be used in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine.

References: 1. XELJANZ® (tofacitinib) Prescribing Information. New York, NY: Pfizer Inc. 2. Data on file. Pfizer Inc, New York, NY. 3. Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367(6):495-507.

Consider a change to the way you treat moderate to severe RA. IMPORTANT SAFETY INFORMATION WARNING: SERIOUS INFECTIONS AND MALIGNANCY SERIOUS INFECTIONS Patients treated with XELJANZ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

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

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

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

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

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

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with

XELJANZ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

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

SERIOUS INFECTIONS The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster and urinary tract infection. XELJANZ should not be initiated in patients with an active infection, including localized infections. Consider the risks and benefits of treatment before initiating XELJANZ in patients: • with chronic or recurrent infection; • who have been exposed to tuberculosis (TB); • with a history of a serious or an opportunistic infection; • who have lived or traveled in areas of endemic TB or mycoses; or • with underlying conditions that may predispose them to infection.

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

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

Learn more at XeljanzHCP.com

IMPORTANT SAFETY INFORMATION WARNING: SERIOUS INFECTIONS AND MALIGNANCY

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

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

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

• Invasive fungal infections, including cryptococcosis and pneumocystosis.

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

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

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

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

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

SERIOUS INFECTIONS The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster and urinary tract infection. XELJANZ should not be initiated in patients with an active infection, including localized infections. Consider the risks and benefits of treatment before initiating XELJANZ in patients: • with chronic or recurrent infection; • who have been exposed to tuberculosis (TB); • with a history of a serious or an opportunistic infection; • who have lived or traveled in areas of endemic TB or mycoses; or • with underlying conditions that may predispose them to infection.

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

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

In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one lymphoma were diagnosed in 3328 patients receiving XELJANZ with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure. Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with XELJANZ. In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high dose corticosteroids, and mycophenolic acid products, Epstein Barr Virusassociated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of 111 patients treated with cyclosporine.

TRA539315-01

© 2013 Pfizer Inc.

GASTROINTESTINAL PERFORATIONS Gastrointestinal perforations have been reported in rheumatoid arthritis clinical trials, although the role of JAK inhibition is not known. XELJANZ should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis).

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

Neutrophils Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo. Avoid initiation of XELJANZ treatment in patients with an ANC less than 1000 cells/mm3. For patients who develop a persistent ANC of 5001000 cells/mm3, interrupt XELJANZ dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with XELJANZ is not recommended. Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

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

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

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

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

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

VACCINATIONS Live vaccines should not be given concurrently with XELJANZ. Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ therapy.

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

ADVERSE REACTIONS The most common serious adverse reactions were serious infections.

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

USE IN PREGNANCY There are no adequate and well-controlled studies in pregnant women.

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

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

Printed in USA/March 2013

All rights reserved.

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

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

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

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

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

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

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

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

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

• XELJANZ should not be used in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine.

CONTRAINDICATIONS None.

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

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

XELJANZ should not be initiated in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating XELJANZ in patients: • with chronic or recurrent infection • who have been exposed to tuberculosis • with a history of a serious or an opportunistic infection • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or • with underlying conditions that may predispose them to infection.

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

Tuberculosis Patients should be evaluated and tested for latent or active infection prior to administration of XELJANZ. Anti-tuberculosis therapy should also be considered prior to administration of XELJANZ in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient.

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

Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering XELJANZ. Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with XELJANZ. The impact of XELJANZ on chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or C were excluded from clinical trials.

Malignancy and Lymphoproliferative Disorder Consider the risks and benefits of XELJANZ treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ in patients who develop a malignancy. Malignancies were observed in clinical studies of XELJANZ. In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one lymphoma were diagnosed in 3328 patients receiving XELJANZ with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure. Lymphomas and solid cancers have also been observed in the long-term extensions studies in rheumatoid arthritis patients treated with XELJANZ. In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high dose corticosteroids, and mycophenolic acid products, Epstein Barr Virus-associated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of 111 patients treated with cyclosporine.

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

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

Laboratory Parameters Lymphocytes Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean lymphocyte counts below the baseline of approximately 10% during 12 months of therapy.

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

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

Monitor lymphocyte counts at baseline and every 3 months thereafter.

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

Avoid initiation of XELJANZ treatment in patients with a low neutrophil count (i.e., ANC less than 1000 cells/mm3).

For patients who develop a persistent ANC of 500-1000 cells/mm3, interrupt XELJANZ dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with XELJANZ is not recommended.

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

Hemoglobin Avoid initiation of XELJANZ treatment in patients with a low hemoglobin level (i.e. less than 9 g/dL).

Treatment with XELJANZ should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment.

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

XELJANZ should be interrupted until this diagnosis has been excluded.

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

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

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

Vaccinations No data are available on the response to vaccination or on the secondary transmission of infection by live vaccines to patients receiving XELJANZ. Live vaccines should not be given concurrently with XELJANZ. Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ therapy.

Hepatic Impairment Treatment with XELJANZ is not recommended in patients with severe hepatic impairment.

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

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

Comparisons between placebo and XELJANZ were based on the first 3 months of exposure, and comparisons between XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily were based on the first 12 months of exposure.

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

Clinical Trial Experience The most common serious adverse reactions were serious infections.

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

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

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

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

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

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

Tuberculosis In the seven controlled trials, during the 0 to 3 months exposure, tuberculosis was not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ.

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

In the seven controlled trials, during the 0 to 12 months exposure, tuberculosis was reported in 0 patients who received 5 mg twice daily of XELJANZ and 6 patients (0.5 events per 100 patient-years) who received 10 mg twice daily

of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. Cases of disseminated tuberculosis were also reported. The median XELJANZ exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days).

cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the first 3 months of exposure in the controlled clinical trials are summarized below: • Mean LDL cholesterol increased by 15% in the XELJANZ 5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm.

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

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

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

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

The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days).

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

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

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

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

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

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

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

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

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

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

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

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

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

Lipids In the controlled clinical trials, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL

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

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

Serum Creatinine In the controlled clinical trials, dose-related elevations in serum creatinine were observed with XELJANZ treatment.

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

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

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

XELJANZ XELJANZ 5 mg 10 mg Twice Daily Twice Daily N = 1336 N = 1349 Preferred Term (%) (%) Diarrhea 4.0 2.9 Nasopharyngitis 3.8 2.8 Upper respiratory tract 4.5 3.8 infection

Placebo N = 809 (%) 2.3 2.8 3.3

Headache

4.3

3.4

2.1

Hypertension

1.6

2.3

1.1

N reflects randomized and treated patients from the seven clinical trials Other adverse reactions occurring in controlled and open-label extension studies included: Blood and lymphatic system disorders: Anemia Metabolism and nutrition disorders: Dehydration Psychiatric disorders: Insomnia Nervous system disorders: Paresthesia Respiratory, thoracic and mediastinal disorders: Dyspnea, cough, sinus congestion Gastrointestinal disorders: Abdominal pain, dyspepsia, vomiting, gastritis, nausea Hepatobiliary disorders: Hepatic steatosis Skin and subcutaneous tissue disorders: Rash, erythema, pruritus Musculoskeletal, connective tissue and bone disorders: Musculoskeletal pain, arthralgia, tendonitis, joint swelling General disorders and administration site conditions: Pyrexia, fatigue, peripheral edema DRUG INTERACTIONS Potent CYP3A4 Inhibitors Tofacitinib exposure is increased when XELJANZ is coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 (e.g., ketoconazole).

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

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

Immunosuppressive Drugs There is a risk of added immunosuppression when XELJANZ is coadministered with potent immunosuppressive drugs (e.g., azathioprine, tacrolimus, cyclosporine). Combined use of multiple-dose XELJANZ with potent immunosuppressives has not been studied in rheumatoid arthritis.

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic effects: Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. XELJANZ

TRA476916-01

should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Tofacitinib has been shown to be fetocidal and teratogenic in rats and rabbits when given at exposures 146 times and 13 times, respectively, the maximum recommended human dose (MRHD).

In a rat embryofetal developmental study, tofacitinib was teratogenic at exposure levels approximately 146 times the MRHD (on an AUC basis at oral doses of 100 mg/kg/day).

Teratogenic effects consisted of external and soft tissue malformations of anasarca, and membranous ventricular septal defects, respectively, and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day). In the rabbit embryofetal development study, tofacitinib was teratogenic at exposure levels approximately 13 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects.

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

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

Pregnancy Registry: To monitor the outcomes of pregnant women exposed to XELJANZ, a pregnancy registry has been established. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.

Nursing Mothers Tofacitinib was secreted in milk of lactating rats. It is not known whether tofacitinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from tofacitinib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug for the mother.

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

Geriatric Use Of the 3315 patients who enrolled in Studies I to V, a total of 505 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older. The frequency of serious infection among XELJANZ-treated subjects 65 years of age and older was higher than among those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.

Hepatic Impairment No dose adjustment is required in patients with mild hepatic impairment. XELJANZ dose should be reduced to 5 mg once daily in patients with moderate hepatic impairment. The safety and efficacy of XELJANZ have not been studied in patients with severe hepatic impairment or in patients with positive hepatitis B virus or hepatitis C virus serology.

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

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

There is no specific antidote for overdose with XELJANZ. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions.

Patients who develop adverse reactions should receive appropriate treatment.

This brief summary is based on XELJANZ® (tofacitinib) Prescribing Information LAB-0445-1.0 Issued: November 2012

© 2012 Pfizer Inc.

All rights reserved.

November 2012

In This Issue Value-Based Care in TM

Integrating Rheumatologists, NPs/PAs, Practice Managers & Payers

Publishing Staff Senior Vice President/Group Publisher Nicholas Englezos nick@engagehc.com Manager, Client Services Zach Ceretelle Editorial Director Dalia Buffery dalia@engagehc.com Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Senior Production Manager Lynn Hamilton Production Manager Lynn Hamilton The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattanonont Ferris Vice President of Finance Andrea Kelly Director, Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Travean Digital Programmer Michael Amundsen Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Engage Healthcare Communications, LLC 1249 South River Road, Ste 202A Cranbury, NJ 08512 Telephone: 732-992-1882 Fax: 732-992-1881

Value-Based Care in Rheumatology, ISSN applied, is published 6 times a year by Engage Healthcare Com­ munications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2013

by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Care in Rheumatology is a registered trademark of Engage Health­ care Communi­cations, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

The ideas and opinions expressed in Value-Based Care in Rheumatology do not necessarily reflect those of the editorial board, the editors, or the publisher.

Publication of an advertisement or other product mentioned in Value-Based Care in Rheumatology should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned.

Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

VOL. 2

I

NO. 3

VALUE PROPOSITIONS

ARTHRITIS UPDATE

Biodegradable nanogels a promising new approach to lupus therapy More…

Appeals of fibromyalgia-related workplace injury compensation cases Opioids safe, effective for RA-related pain More…

FDA UPDATE

Rheumatology PRACTICE

Ilaris receives new indication for juvenile idiopathic arthritis Simponi approved for ulcerative colitis

MANAGEMENT™

Engaging patients in pain management an important strategy for rheumatology practices

EMPLOYERS’ PERSPECTIVE The role of employers in drug coverage decisions for rheumatic diseases

GOUT

Personalized Medicine in Rheumatology™

HEALTH ECONOMICS

Strong genetic markers identified for fibromyalgia More…

FIBROMYALGIA Impact of quality of life in fibromyalgia More…

Dual-energy CT useful for gout diagnosis Infliximab dosing and use patterns in patients with RA Effectiveness and costs of TNF-alpha blocker use for patients with RA More…

VBCR Editorial Advisory Board Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield New York, NY Gary L. Johnson, MD, MS, MBA Regional Medical Director Humana, Inc. Madison, WI Atheer A. Kaddis, PharmD Vice President, Managed Markets Diplomat Specialty Pharmacy Swartz Creek, MI James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA Muhammad Asim Khan, MD Professor of Medicine Case Western Reserve University Cleveland, OH

John Kolstoe, MD Kolstoe Rheumatology: Musculoskeletal Medicine East Lansing, MI Assistant Clinical Professor of Medicine, Michigan State University Randall Krakauer, MD, FACP, FACR National Medical Director Medicare, Aetna Princeton, NJ Alan Menter, MD Director Baylor Psoriasis Research Center Dallas, TX Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth Murray, UT Lynn Nishida, RPh Director, Clinical Services Catamaran Center of Excellence Northwest Region Portland, OR

Gary M. Owens, MD President, Gary Owens Associates Philadelphia, PA Kim A. Papp, MD, PhD Founder and President Probity Medical Research Waterloo, Ontario, Canada Jeffrey S. Peller, MD Practicing rheumatologist Harbin Clinic/Rheumatology Rome, GA Edmund J. Pezalla, MD, MPH National Medical Director for Pharmacy Policy and Strategy Aetna, Hartford, CT Ronald van Vollenhoven, MD, PhD Associate Professor Karlinska University Hospital Solna Stockholm, Sweden F. Randy Vogenberg, RPh, PhD Principal Institute of Integrated Healthcare Greenville, SC

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

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

Permission requests to reprint all or part of any article published in this publication should be addressed to editorial@engagehc.com.

Address all editorial queries to: editorial@engagehc.com. Telephone: 732-992-1882 Fax: 732-992-1881.

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

june 2013

I

www.ValueBasedRheumatology.com

7

Value Propositions Disease Burden, Not Inefficiency in Care, Explains the Majority of Geographical Differences in Medicare Costs

A novel study offers a new explanation for the geographical differences seen in Medicare costs across the nation. Unlike the explanation offered mainly by the Dartmouth Atlas of Healthcare and other research attributing geographical variations in care to waste and inefficiency in the delivery of healthcare, “our results suggest that the portion of the geographic variation that can be explained by patient health is much greater than previously estimated, leaving less of the geographic variation potentially attributable to inefficiency,” wrote James D. Reschovsky, PhD, a senior fellow at the Center for Studying Health System Change (Washington, DC), and colleagues. Center for Studying Health System Change; May 28, 2013

Biodegradable Nanogels a Promising, Enhanced Drug Delivery Method in Lupus

A drug delivery system designed by researchers at Yale University shows promise for the treatment of lupus and other chronic autoimmune diseases.

The team used biodegradable nanoparticles to deliver low doses of drugs in an early-stage study. The use of these drug-laden nanoparticles, called nanogels, increased the median survival time of mice with lupus by 3 months. The median survival time was increased by 2 months in mice that already had severe kidney damage as a result of lupus.

“Three months of a mouse’s life is roughly equivalent to more than 8 years of a human life, so this is dramatic,” said Tarek Fahmy, Associate Professor of Biomedical Engineering at Yale University. “The potential for human benefit is clear and promising.”

Compared with conventional therapies for lupus, the nanogels improve the drug delivery to the cells and enhance drug retention in the body, allowing for the use of significantly lower drug doses. In addition, drug delivery via nanogels works without depleting white blood cells, which reduces the patient’s risk for infection.

Nanogels are made of organic materials and can circulate for longer periods of time in the body than conventional drugs because of their size and their ability to pass biological barriers. They can also be programmed to target specific cells, such as T-cells and antigen-presenting cells, thereby deactivating them and suppressing their response, which would minimize the symptoms of lupus.

The nanogels are made of materials approved by the US Food and Drug Administration and could therefore shorten the process involved in preparing them for human use. Yale News; March 1, 2013

New Test Predicts Early Disease in Patients with ACPA-Negative Arthritis

INOVA Diagnostics of San Diego, CA, has licensed a new test developed by a team of rheumatologists at Leiden University Medical Center in the Netherlands. The test measures antibodies to carbamylated protein (anti-CarP), which differs in 1 methyl group from anticitrullinated protein antibodies (ACPA) by detecting homocitrulline rather than citrulline.

The team had previously found that antibodies recognizing CarP were present in approximately 50% of patients with rheumatoid arthritis (RA), and are detected in up to 30% of patients who test negative for ACPA, with a correlation to increased joint damage.

With the new licensing agreement, the research team is optimistic that further study into anti-CarP will lead to a new understanding of the pathogenesis of RA and to new treatments. Musculoskeletal Network; February 14, 2013

Developments in Antigen-Specific Therapy for Rheumatoid Arthritis

According to Australian rheumatologist Ranjeny Thomas, MD, Professor of Rheumatology and Head of the Autoimmunity Programme at the University of Queensland Diamantina Institute, by using tolerance-inducing antigen-specific strategies and dendritic cells, the field of rheumatology is moving ever closer to developing more effective immunotherapies that may eventually achieve greater drug specificity with lower toxicity, and perhaps even the potential to develop agents that could control or even prevent rheumatoid arthritis (RA). Currently, 30% of patients with RA do not achieve sustained remission restoration of self-antigen immune tolerance with existing disease-modifying and biologic therapies, and the market for new therapies is predicted to grow to $12 billion annually by 2017.

Some of the recent key developments that Dr Thomas has reviewed include the emergence of anticitrullinated peptide antigens as a valuable biomarker in RA, targeting and injecting dendritic cells for antigen-specific tolerance, and phase 1 and phase 2 clinical trials of oral tolerization of the dnaJp1 peptide. J Musculoskelet Med; February 27, 2013

FDA Update Ilaris Receives New Indication for Juvenile Idiopathic Arthritis

The US Food and Drug Administration (FDA) approved canakinumab (Ilaris; Novartis) for the treatment of active systemic juvenile idiopathic arthritis (SJIA) in patients aged ≥2 years.

Ilaris is the first interleukin-1 beta inhibitor approved for the treatment of SJIA, and is the only agent approved for SJIA that is administered as a once-monthly subcutaneous injection.

“The efficacy of Ilaris, along with its monthly subcutaneous dosing, makes

8

it an exciting new option for children who are living with this debilitating disease,” said Daniel Lovell, MD, MPH, the Joseph E. Levinson Professor of Pediatrics at the Cincinnati Children’s Hospital Medical Center and study investigator.

The FDA’s approval of Ilaris was based on 2 pivotal phase 3 clinical trials in patients with SJIA (aged 2-19 years) that showed significant improvement in the majority of patients who received canakinumab. In the 4-week, double-blind, placebo-controlled study, 84% of the patients who

value-based CARE in Rheumatology

I

June 2013

were randomized to canakinumab achieved the primary end point of ≥30% improvement (ie, adapted pediatric American College of Rheumatology 30% response criteria [ACR30]) at day 15 compared with only 10% of the patients who received placebo.

The second study investigated the use of corticosteroids in patients receiving canakinumab. Of the 128 patients who received canakinumab 4 mg/kg up to 300 mg every 4 weeks, 62% had their corticosteroid dose tapered substantially, and 46% were able to completely discontinue the

use of corticosteroids.

The most serious side effects associated with canakinumab in the treatment of SJIA are cold symptoms, upper respiratory tract infection, pneumonia, runny nose, sore throat, urinary tract infection, gastroenteritis, stomach pain, and injection site reactions.

Ilaris is already approved for the treatment of cryopyrin-associated periodic syndromes, a rare debilitating genetic disorder, in more than 60 countries, including the European Union, the United States, Switzerland, and Japan. (May 10, 2013) Continued on page 10

VOL. 2

I

NO. 3

Employers’ Perspective

Role of Employers in Drug Coverage Decisions for Rheumatic... Continued from page 1 apies that provide optimal treatment and improved quality of life.

Purchasers want to ensure that they provide the right medication to the right patient at the right time (and price). Commercial entities that are self-funded include: • Employers (generally more than 500 employees) • Municipalities and school districts • Unions to include multiemployer plans.

These entities are involved in determining the coverage of care for patients with chronic diseases such as RA, and they play an important role in the type and delivery of care services through the choice of benefit design. Determining coverage for care is accomplished by these employers through the determination of a benefit design that is then managed by a third-­ party vendor, such as a health plan.

Reassessing the Coverage of RA Drugs Employers in particular are reassessing the role and importance that healthcare benefits represent for their employees in areas related to productivity, retention, and recruitment. For years, there has been cost shifting to employees as the cost of care increased through the recession and subsequent layoffs and reorganizations in the workplace.

Now, with the implementation of healthcare reform moving forward and a leaner workforce in place, the importance of health benefits has reemerged as a critical success factor for employers, as well as the most impor­ tant benefit to retain current employees or attract new employees to a high-productivity workplace environment.

Although the coverage options for employee benefits continue to evolve, from an insurance perspective, coverage for chronic conditions such as RA has not fundamentally changed. Even with the introduction of new biologic therapies in recent years, little has changed in the prescription drug mix.

Many plans continue to focus on older, chemical-based drugs that although less expensive, are also less advanced than some of the newer medications that are available today, thereby impacting the total cost paid by employers and the care that patients receive.

These market changes are driving shared financial risk to providers and to patients in the form of cost-sharing.

Therefore, the application of benefit management tactics such as quantity limits, prior authorization, cost-sharing (eg, copay, coinsurance, and deductibles), mandatory mail, and other stratVOL. 2

I

NO. 3

egies need to be reconsidered in the context of using new treatment technologies from an insurance risk and multiple decision-makers perspective.

F. Randy Vogenberg, PhD, RPh

for benefit design decisions.

Ideally, benefit design would reflect employers’ desire to facilitate offering valuable benefit coverage

For employers, the primary concerns in RA are cost and productivity.

Until recently, employers had little economic reason to significantly change their strategy. Now…the emerging impact of biologic agents, including those used to treat RA, on clinical treatment outcomes and economic impacts has further engaged employers in researching new options for health benefits.

Employer’s Search for New Options in Patients’ Benefits It has not always been clear to outsiders who actually controls benefit design; therefore, it is often difficult to reach decision makers to affect change, especially within self-funded entities.

Until the healthcare reform debate and the impact of the recession, employers had not felt compelled to explore more innovative and effective ways to deal with health benefits, including benefits for patients with RA. These 2 market forces have certainly had an impact on decision-making, as well as on the role that employers take on regarding health benefit strategy as it relates to the success of their business. Providers who are seeking to reach this population may now find that their messages are more likely to at least be heard.

Until recently, employers had little economic reason to significantly change their strategy. Now, in addition to other forces in the marketplace, the emerging impact of biologic agents, including those used to treat RA, on clinical treatment outcomes and economic impacts has further engaged employers in researching new options for health benefits. These options include a value-based design through existing vendors that are evolving a new services platform, as well as inhouse initiatives through onsite clinics, or a combination of such ventures.

Such changes will be done in tandem with healthcare reform mandates but not necessarily in the same way as public sector programs, as evidenced by the rollout in 2013 of private insurance exchanges. These changes are causing a shift in roles among the stakeholders, including those who are responsible

through an optimal design that is employee (ie, patient)-centric. From a patient’s perspective, health benefits should allow for the evidence-based use of all appropriate drug therapies for individualized care, with minimal restrictions. From the employers’ perspective, the question is how can healthcare benefits best align the healthcare resources for which they are paying in their plans, and how can employers influence more optimal benefit designs to achieve their desired business results.

These market changes are driving shared financial risk to providers and to patients in the form of cost-sharing.

Therefore, the application of benefit management tactics need to be reconsidered in the context of using new treatment technologies.

Plan sponsors have been seeking a value-based perspective around the total cost of care that can be easily implemented across a large variety of entities with differing yet similar business goals for healthcare coverage outcomes. Employers and value are a natural mix but, at the same time, they are heterogeneous. Recognizing these differences and similarities can hasten the adoption of innovation in benefit design by employers in collaboration with their benefit advisors as well as their vendors.

Considering that patients with RA are now routinely managed with biologic therapies, benefit innovation needs to encompass the new decision framework for clinical and economic parameters.

For example, the site of administration in the human body, as well as ownership around the site of care where clinicians practice has created confusion in current benefit administration. Such approaches have often caused key stakeholders to interact at cross-purposes because of the inadequacy of benefit design for modern healthcare coverage.

Better aligning, organizing, and encouraging a more balanced approach through benefit designs with incentives can foster better economic and clinical outcomes not only for employers as the purchasers of healthcare, but for other stakeholders with a vested interest in the same outcome measures.

More Solutions Are Needed The eventual solutions will require all of the key stakeholders to understand each other’s perspectives and develop multistakeholder-sensitive changes as part of any value-based benefit design for patients with RA. Although mandates will evolve as a result of the healthcare reform framework now in place, many clinical practice decisions and benefit design innovations are likely to occur Value-Based Decision-Making first in the commercial sector ahead of in Benefit Design any implementation action by the The trends that are emerging Centers for Medicare & Medicaid Seraround healthcare coverage are now vices or by Congress. driving value-based decision-making The speed at which change is now to encompass both clinical and eco- occurring in the private sector and as nomic performance in an employer-­ a response to commercial entity intersponsored health benefit plan. That ests can show the way to achieving approach includes the integration of the value-based benefit designs envicare processes and payment with sioned within healthcare reform. It is greater alignment across the continu- now up to the commercial marketum of care. Such an integrated ap- place to accomplish the innovation proach is necessary to achieve the op- and execution to avoid unwanted timal economic and clinical design solutions or coverage alternatives that intentions that would meet the busi- are less than desirable for employers ness goals of the entity. and for patients with RA. n june 2013

I

www.ValueBasedRheumatology.com

9

Personalized Medicine in Rheumatology

™

Strong Genetic Markers Identified for Fibromyalgia... recently published (Arnold LM, et al.

Arthritis Rheum. 2013;65:1122-1128).

Results of this work have also identified several key genetic markers for risk that suggest the potential for identifying individuals who are at high risk before disease onset, as well as for guiding discovery efforts in drug development.

The research is a crucial step forward toward the realization of personalized medicine in rheumatic diseases, and for fibromyalgia in particular, which has an enormous negative impact on patients’ quality of life, as well as a significant financial burden on the healthcare system.

Fibromyalgia is most often diagnosed in middle age. Working adults with fibromyalgia miss 17 days of work annually on average compared with only 6 days for healthy workers. The average annual direct medical costs per fibromyalgia patient are in excess of $3400.

The Fibromyalgia Family Study Previous attempts to identify fibromyalgia-susceptible genes have had limited success. For this latest study,

“The estimated sibling recurrence risk ratio…suggests a strong genetic component of fibromyalgia, [and] confirms previous reports that fibromyalgia aggregates in families.”

—Lesley M. Arnold, MD, and colleagues however, newly available DNA-sequencing technology was used to rapidly (and in a cost-effective way) com-

pare the genetic profiles of 116 families with fibromyalgia.

“To our knowledge, the present study is the first genome-wide linkage scan for fibromyalgia in a cohort of multicase families,” the investigators noted.

Despite the technology upgrade, the etiologic task was formidable; fibromyalgia is a disorder that is characterized by multiple, but not necessarily related, symptoms, including musculoskeletal pain, fatigue, sleep disturbance, depression, and, in many cases, irritable bowel syndrome. As such, it is difficult to know what to genetically look for.

Of the several specific genetic loci found in this study, the most prominent were on chromosome 17p11.2-­ ­q11.2. This region coincides with the mapped coordinates for 2 potential candidate genes for fibromyalgia: • Serotonin transporter gene, SLC6A4

Continued from page 1

• Transient receptor potential vanilloid channel 2 gene, TRPV2.

These findings strongly support some of the current treatment strategies and point the way to future drug development. Serotonin is associated with sleep regulation and depression; TRPV2 is associated with inflammation and hypersensitivity to pain.

It is already known that antidepressant medications can have a beneficial effect on patients with fibromyalgia. As for TRPV2, this target is now the subject of multiple lines of pharmacologic research.

Although the results of this study do not provide, in and of themselves, a complete picture, they do represent a significant outline of the puzzle, and they further justify the genetic approach as researchers continue to accrue increasing data from even more family member participants in the ongoing Fibromyalgia Family Study. n

Vectra DA Testing Now Available in All 50 States

T

he Vectra DA test is a multibiomarker blood test that measures disease activity in patients with rheumatoid arthritis (RA) by integrating 12 key proteins that are consistently associated with the biology of RA into a single, objective, and quantitative score to help rheumatologists make more informed treatment decisions.

In April 2013, the New York State Department of Health issued a permit to Crescendo Bioscience, a molecular diagnostic company, to provide laboratory services to physicians in New York. With this clearance, Vectra DA is now available in all 50 states.

“This is welcome news for the more than 400 rheumatologists in New York,” said Max Hamburger, MD, President of the New York State Rheu-

can help bring us closer to achieving treatment success. Vectra DA is a valuable tool that can enhance the assessment of RA disease activity to aid

rheumatologists in achieving better management of the disease,” Dr Hamburger emphasized.

Vectra DA test results are reported back within 7 to 10 days of receipt of the sample. Physicians can either receive the test results via standard mail, by fax, or through the private web portal, Vectra View.

“This is an exciting step in our continuing efforts to bring Vectra DA to more RA patients to help improve their care,” William A. Hagstrom, President and Chief Executive Offi­ cer of Crescendo Bioscience, stated.

“Since Vectra DA’s introduction in late 2010, more than 20% of the rheumatologists in the United States have successfully used it to evaluate more than 40,000 patients’ disease. We look forward to working with rheumatolo-

gists in New York and across the United States to increase access to the important information that Vectra DA provides,” he said.

“New York’s Clinical Laboratory Evaluation Program clearance is further evidence of the quality of the testing performed by Crescendo. Vectra DA can offer insight on disease activity that may not be captured by current standards of RA measurement,” said Stephen Paget, MD, FACP, FACR, Physician-in-Chief Emeritus of the Division of Rheumatology at the Hospital for Special Surgery, New York, NY. “Vectra DA brings a deep understanding of the underlying disease biology that can be utilized in the clinic and in clinical trials as we continue to develop potential new treatments for RA patients.” n

“Simponi is an important new option for patients with moderate to severe ulcerative colitis,” said Andrew E. Mulberg, MD, Deputy Director, Division of Gastroenterology and Inborn Errors Products in the FDA. “It is crucial that patients suffering from the serious and painful symptoms of ulcerative colitis have additional treatment options since patients experience the effects of the

disease and respond to treatment differently.”

The safety and efficacy of golimu­ mab for ulcerative colitis were demonstrated in 2 clinical trials. In the first study of 513 patients with moderate-to-severe ulcerative colitis, a greater proportion of patients receiving golimumab achieved a clinical response compared with those receiving placebo after 6 weeks. In the second study of

310 patients, a greater proportion of those receiving golimumab maintained their clinical response compared with those randomized to placebo through 54 weeks of therapy.

The most common adverse events with golimumab are upper respiratory infection and redness in the injection site. Patients receiving golimu­ mab are at increased risk for serious infections. (May 15, 2013) n

matology Society. “To effectively treat our patients, we need to have the most advanced technology available that

“Vectra DA is a valuable tool that can enhance the assessment of RA disease activity to aid rheumatologists in achieving better management of the disease.”

—Max Hamburger, MD

FDA Update (Continued from page 8)

Simponi Gets FDA Approval for the Treatment of Ulcerative Colitis

The FDA approved a new indication for the tumor necrosis factor inhibitor golimumab (Simponi injection; Janssen Biotech) for the treatment of adults with moderate-to-severe ulcerative colitis that is refractory to previous treatment or that requires continuous corticosteroid therapy.

10

value-based CARE in Rheumatology

I

June 2013

VOL. 2

I

NO. 3

In the fight against active, autoantibody-positive systemic lupus erythematosus (SLE) in adult patients receiving standard therapy

Add BENLYSTA to Help Make SLE More Manageable When added to standard therapy, BENLYSTA significantly reduced disease activity vs standard therapy alone at Week 521

•

BENLYSTA 10 mg/kg + standard therapy demonstrated superior efficacy vs placebo + standard therapy in reducing disease activity at Week 52 in 2 Phase III trials (Total N=1684)1-3

•

The primary endpoint was the percentage of patients meeting the SLE Responder Index (SRI) at Week 52. The SRI components measure reduction in disease activity defined as clinical improvement (SELENA-SLEDAI*) with no significant worsening in any organ system (BILAG†) and no worsening in overall patient condition (PGA‡)1 – A Phase II trial (Total N=449) did not meet the prespecified co-primary endpoints of percent change in SELENA-SLEDAI at Week 24 and

time to first flare over 52 weeks. The Phase II trial led to the selection of a targeted autoantibody-positive population in the Phase III trials (28% of the Phase II trial population was autoantibody negative at baseline)4

•

In Phase II and III clinical trials, 1458 patients with SLE have been exposed to BENLYSTA for a total of 1516 patient-years2-5

* SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus: National Assessment Version of the Systemic Lupus Erythematosus Disease Activity Index). † BILAG (British Isles Lupus Assessment Group). ‡ PGA (Physician’s Global Assessment).

Indication BENLYSTA is indicated for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy.

Limitations of Use: The efficacy of BENLYSTA has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus. BENLYSTA has not been studied in combination with other biologics or intravenous cyclophosphamide. Use of BENLYSTA is not recommended in these situations.

How supplied: BENLYSTA is available as 120 mg in a 5-mL single-use vial and 400 mg in a 20-mL single-use vial for injection, for intravenous use only.

Important Safety Information for BENLYSTA CONTRAINDICATION BENLYSTA is contraindicated in patients who have had anaphylaxis with belimumab.

WARNINGS AND PRECAUTIONS MORTALITY There were more deaths reported with BENLYSTA than with placebo during the controlled period of the clinical trials. Out of 2133 patients in 3 clinical trials, a total of 14 deaths occurred in the following groups: 3/675 in placebo, 5/673 in BENLYSTA 1 mg/kg, 0/111 in BENLYSTA 4 mg/kg, and 6/674 in BENLYSTA 10 mg/kg. No single cause of death predominated. Etiologies included infection, cardiovascular disease, and suicide.

SERIOUS INFECTIONS Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including BENLYSTA. Caution should be exercised when considering use in patients with a history of chronic infections. Patients receiving therapy for a chronic infection should not receive BENLYSTA. Consider interrupting BENLYSTA therapy in patients who develop a new infection while receiving BENLYSTA. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis.

Please see additional Important Safety Information for BENLYSTA on following page.

Please see Brief Summary of Prescribing Information for BENLYSTA on adjacent pages.

www.GSKSource.com

Important Safety Information for BENLYSTA (cont’d) WARNINGS AND PRECAUTIONS (cont’d) MALIGNANCY The impact of treatment with BENLYSTA on the development of malignancies is not known. As with other immunomodulating agents, the mechanism of action of BENLYSTA could increase the risk of malignancies.

HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS) AND INFUSION REACTIONS Hypersensitivity reactions, including anaphylaxis and death, have been reported with BENLYSTA. Delay in the onset of acute hypersensitivity reactions has been observed. Patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. Some patients received premedication; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of these reactions.

Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely. Manifestations of hypersensitivity included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea. In the event of a serious hypersensitivity reaction, discontinue BENLYSTA immediately and administer appropriate medical therapy. Infusion-associated adverse events were also reported. Serious infusion reactions included bradycardia, myalgia, headache, rash, urticaria, and hypotension.

In the event of an infusion reaction, the infusion rate may be slowed or interrupted.

Patients should be informed of the signs and symptoms of a hypersensitivity reaction and instructed to seek immediate medical care should a reaction occur.

DEPRESSION In clinical trials, psychiatric events (primarily depression, insomnia, and anxiety) were reported more frequently with BENLYSTA than with placebo. Serious psychiatric events, serious depression, and two suicides were also reported. It is unknown if BENLYSTA treatment is associated with increased risk for these events. Instruct patients to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other mood changes.

IMMUNIZATION Live vaccines should not be given for 30 days before or concurrently with BENLYSTA. BENLYSTA may interfere with the response to immunizations.

USE WITH BIOLOGIC THERAPIES OR IV CYCLOPHOSPHAMIDE BENLYSTA has not been studied in combination with other biologic therapies, including B-cell targeted therapies, or IV cyclophosphamide.

Therefore, use of BENLYSTA is not recommended in combination with these therapies.

ADVERSE REACTIONS The most commonly reported adverse reactions (≥5%) were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, and pharyngitis.

Other Important Information for BENLYSTA USE IN SPECIFIC POPULATIONS Pregnancy: Category C. BENLYSTA should be used during pregnancy only if the potential benefit outweighs the risk. Women of childbearing potential should use adequate contraception during BENLYSTA treatment and for at least 4 months after the last dose.

Pregnancy Registry: Healthcare professionals are encouraged to register patients and pregnant women are encouraged to enroll themselves by calling 1-877-681-6296.

Effect in black/African American patients: In exploratory analyses of 2 Phase III trials, response rates were lower for black patients (N=148) in the BENLYSTA group relative to black patients in the placebo group. In the Phase II trial, black patients (N=106) in the BENLYSTA group did not appear to have a different response than the rest of the study population. Although no definitive conclusions can be drawn from these analyses, caution should be used when considering BENLYSTA for black/African American patients.

References: 1. BENLYSTA [package insert]. Rockville, MD: Human Genome Sciences, Inc; 2012. 2. Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9767):721-731. 3. Furie R, Petri M, Zamani O, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011;63(12):3918-3930. 4. Wallace DJ, Stohl W, Furie RA, et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum. 2009;61(9):1168-1178. 5. Data on file, Human Genome Sciences, Inc.

Please see Brief Summary of Prescribing Information for BENLYSTA on adjacent page.

©2013 The GlaxoSmithKline Group of Companies All rights reserved. Printed in USA. BN2410R1 March 2013

BRIEF SUMMARY BENLYSTA® (belimumab) for injection, for intravenous use only.

The following is a brief summary only; see full Prescribing Information for complete product information.

INDICATIONS AND USAGE BENLYSTA® (belimumab) is indicated for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy.

Limitations of Use The efficacy of BENLYSTA has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus. BENLYSTA has not been studied in combination with other biologics or intravenous cyclophosphamide. Use of BENLYSTA is not recommended in these situations.

CONTRAINDICATIONS BENLYSTA is contraindicated in patients who have had anaphylaxis with belimumab.

WARNINGS AND PRECAUTIONS Mortality There were more deaths reported with BENLYSTA than with placebo during the controlled period of the clinical trials. Out of 2133 patients in 3 clinical trials, a total of 14 deaths occurred during the placebo-controlled, double-blind treatment periods: 3/675 (0.4%), 5/673 (0.7%), 0/111 (0%), and 6/674 (0.9%) deaths in the placebo, BENLYSTA 1 mg/kg, BENLYSTA 4 mg/kg, and BENLYSTA 10 mg/kg groups, respectively. No single cause of death predominated. Etiologies included infection, cardiovascular disease and suicide.

Serious Infections Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including BENLYSTA. Physicians should exercise caution when considering the use of BENLYSTA in patients with chronic infections. Patients receiving any therapy for chronic infection should not begin therapy with BENLYSTA. Consider interrupting BENLYSTA therapy in patients who develop a new infection while undergoing treatment with BENLYSTA and monitor these patients closely.

In the controlled clinical trials, the overall incidence of infections was 71% in patients treated with BENLYSTA compared with 67% in patients who received placebo. The most frequent infections (>5% of patients receiving BENLYSTA) were upper respiratory tract infection, urinary tract infection, nasopharyngitis, sinusitis, bronchitis, and influenza. Serious infections occurred in 6.0% of patients treated with BENLYSTA and in 5.2% of patients who received placebo. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis. Infections leading to discontinuation of treatment occurred in 0.7% of patients receiving BENLYSTA and 1.0% of patients receiving placebo. Infections resulting in death occurred in 0.3% (4/1458) of patients treated with BENLYSTA and in 0.1% (1/675) of patients receiving placebo.

Malignancy The impact of treatment with BENLYSTA on the development of malignancies is not known. In the controlled clinical trials, malignancies (including non-melanoma skin cancers) were reported in 0.4% of patients receiving BENLYSTA and 0.4% of patients receiving placebo. In the controlled clinical trials, malignancies, excluding non-melanoma skin cancers, were observed in 0.2% (3/1458) and 0.3% (2/675) of patients receiving BENLYSTA and placebo, respectively. As with other immunomodulating agents, the mechanism of action of BENLYSTA could increase the risk for the development of malignancies.

Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions, including anaphylaxis and death, have been reported in association with BENLYSTA. Delay in the onset of acute hypersensitivity reactions has been observed. Limited data suggest that patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. In the controlled clinical trials, hypersensitivity reactions (occurring on the same day of infusion) were reported in 13% (191/1458) of patients receiving BENLYSTA and 11% (76/675) of patients receiving placebo. Anaphylaxis was observed in 0.6% (9/1458) of patients receiving BENLYSTA and 0.4% (3/675) of patients receiving placebo. Manifestations included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see Warnings and Precautions]. Some patients (13%) received premedication, which may have mitigated or masked a hypersensitivity response; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of hypersensitivity reactions.

BENLYSTA should be administered by healthcare providers prepared to manage anaphylaxis. In the event of a serious reaction, administration of BENLYSTA must be discontinued immediately and appropriate medical therapy administered. Patients should be monitored during and for an appropriate period of time after administration of BENLYSTA. Patients should be informed of the signs and symptoms of a hypersensitivity reaction and instructed to seek immediate medical care should a reaction occur.

Infusion Reactions In the controlled clinical trials, adverse events associated with the infusion (occurring on the same day of the infusion) were reported in 17% (251/1458) of patients receiving BENLYSTA and 15% (99/675) of patients receiving placebo. Serious infusion reactions (excluding hypersensitivity reactions) were reported in 0.5% of patients receiving BENLYSTA and 0.4% of patients receiving placebo and included bradycardia, myalgia, headache, rash, urticaria, and hypotension. The most common infusion reactions (≥ 3% of patients receiving BENLYSTA) were headache, nausea, and skin reactions. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see Warnings and Precautions]. Some patients (13%) received premedication, which may have mitigated or masked an infusion reaction; however there is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion reactions [see Adverse Reactions].

BENLYSTA should be administered by healthcare providers prepared to manage infusion reactions. The infusion rate may be slowed or interrupted if the patient develops an infusion reaction. Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely.

Depression In the controlled clinical trials, psychiatric events were reported more frequently with BENLYSTA (16%) than with placebo (12%), related primarily to depression-related events (6.3% BENLYSTA and 4.7% placebo), insomnia (6.0% BENLYSTA and 5.3% placebo), and anxiety (3.9% BENLYSTA and 2.8% placebo). Serious psychiatric events were reported in 0.8% of patients receiving BENLYSTA (0.6% and 1.2% with 1 and 10 mg/kg, respectively) and 0.4% of patients receiving placebo. Serious depression was reported in 0.4% (6/1458) of

patients receiving BENLYSTA and 0.1% (1/675) of patients receiving placebo. Two suicides (0.1%) were reported in patients receiving BENLYSTA. The majority of patients who reported serious depression or suicidal behavior had a history of depression or other serious psychiatric disorders and most were receiving psychoactive medications. It is unknown if BENLYSTA treatment is associated with increased risk for these events.

Patients receiving BENLYSTA should be instructed to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other mood changes.

Immunization Live vaccines should not be given for 30 days before or concurrently with BENLYSTA as clinical safety has not been established.

No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving BENLYSTA or the effect of BENLYSTA on new immunizations. Because of its mechanism of action, BENLYSTA may interfere with the response to immunizations.

Concomitant Use with Other Biologic Therapies or Intravenous Cyclophosphamide BENLYSTA has not been studied in combination with other biologic therapies, including B-cell targeted therapies, or intravenous cyclophosphamide. Therefore, use of BENLYSTA is not recommended in combination with biologic therapies or intravenous cyclophosphamide.

ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials Experience The data described below reflect exposure to BENLYSTA plus standard of care compared with placebo plus standard of care in 2133 patients in 3 controlled studies. Patients received BENLYSTA at doses of 1 mg/kg (N=673), 4 mg/kg (N=111; Trial 1 only), or 10 mg/kg (N=674) or placebo (N=675) intravenously over a 1-hour period on Days 0, 14, 28, and then every 28 days. In two of the studies (Trial 1 and Trial 3), treatment was given for 48 weeks, while in the other study (Trial 2) treatment was given for 72 weeks [see Clinical Studies]. Because there was no apparent dose-related increase in the majority of adverse events observed with BENLYSTA, the safety data summarized below are presented for the 3 doses pooled, unless otherwise indicated; the adverse reaction table displays the results for the recommended dose of 10 mg/kg compared with placebo.

The population had a mean age of 39 (range 18-75), 94% were female, and 52% were Caucasian. In these trials, 93% of patients treated with BENLYSTA reported an adverse reaction compared with 92% treated with placebo.

The most common serious adverse reactions were serious infections (6.0% and 5.2% in the groups receiving BENLYSTA and placebo, respectively) [see Warnings and Precautions].

The most commonly-reported adverse reactions, occurring in ≥5% of patients in clinical trials were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, and pharyngitis.

The proportion of patients who discontinued treatment due to any adverse reaction during the controlled clinical trials was 6.2% for patients receiving BENLYSTA and 7.1% for patients receiving placebo.

The most common adverse reactions resulting in discontinuation of treatment (≥1% of patients receiving BENLYSTA or placebo) were infusion reactions (1.6% BENLYSTA and 0.9% placebo), lupus nephritis (0.7% BENLYSTA and 1.2% placebo), and infections (0.7% BENLYSTA and 1.0% placebo).

Table 1 lists adverse reactions, regardless of causality, occurring in at least 3% of patients with SLE who received BENLYSTA 10 mg/kg and at an incidence at least 1% greater than that observed with placebo in the 3 controlled studies.

Table 1. Incidence of Adverse Reactions Occurring in at Least 3% of Patients Treated With BENLYSTA 10 mg/kg Plus Standard of Care and at Least 1% More Frequently Than in Patients Receiving Placebo plus Standard of Care in 3 Controlled SLE Studies BENLYSTA 10 mg/kg Placebo + Standard of Care + Standard of Care (n = 674) (n = 675) Preferred Term % % Nausea 15 12 Diarrhea 12 9 Pyrexia 10 8 Nasopharyngitis 9 7 9 5 Bronchitis Insomnia 7 5 4 Pain in extremity 6 Depression 5 4 Migraine 5 4 Pharyngitis 5 3 Cystitis 4 3 Leukopenia 4 2 3 1 Gastroenteritis viral Immunogenicity In Trials 2 and 3, anti-belimumab antibodies were detected in 4 of 563 (0.7%) patients receiving BENLYSTA 10 mg/kg and in 27 of 559 (4.8%) patients receiving BENLYSTA 1 mg/kg. The reported frequency for the group receiving 10 mg/kg may underestimate the actual frequency due to lower assay sensitivity in the presence of high drug concentrations. Neutralizing antibodies were detected in 3 patients receiving BENLYSTA 1 mg/kg. Three patients with anti-belimumab antibodies experienced mild infusion reactions of nausea, erythematous rash, pruritus, eyelid edema, headache, and dyspnea; none of the reactions was life-threatening. The clinical relevance of the presence of anti-belimumab antibodies is not known.

The data reflect the percentage of patients whose test results were positive for antibodies to belimumab in specific assays. The observed incidence of antibody positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to belimumab with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS Formal drug interaction studies have not been performed with BENLYSTA. In clinical trials of patients with SLE, BENLYSTA was administered concomitantly with other drugs, including

corticosteroids, antimalarials, immunomodulatory and immunosuppressive agents (including azathioprine, methotrexate, and mycophenolate), angiotensin pathway antihypertensives, HMG-CoA reductase inhibitors (statins), and NSAIDs without evidence of a clinically meaningful effect of these concomitant medications on belimumab pharmacokinetics. The effect of belimumab on the pharmacokinetics of other drugs has not been evaluated [see Pharmacokinetics].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. There are no adequate and well-controlled clinical studies using BENLYSTA in pregnant women.

Immunoglobulin G (IgG) antibodies, including BENLYSTA, can cross the placenta. Because animal reproduction studies are not always predictive of human response, BENLYSTA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Women of childbearing potential should use adequate contraception during treatment with BENLYSTA and for at least 4 months after the final treatment.

Nonclinical reproductive studies have been performed in pregnant cynomolgus monkeys receiving belimumab at doses of 0, 5 and 150 mg/kg by intravenous infusion (the high dose was approximately 9 times the anticipated maximum human exposure) every 2 weeks from gestation day 20 to 150. Belimumab was shown to cross the placenta. Belimumab was not associated with direct or indirect teratogenicity under the conditions tested. Fetal deaths were observed in 14%, 24% and 15% of pregnant females in the 0, 5 and 150 mg/kg groups, respectively. Infant deaths occurred with an incidence of 0%, 8% and 5%. The cause of fetal and infant deaths is not known. The relevance of these findings to humans is not known. Other treatmentrelated findings were limited to the expected reversible reduction of B cells in both dams and infants and reversible reduction of IgM in infant monkeys. B-cell numbers recovered after the cessation of belimumab treatment by about 1 year post-partum in adult monkeys and by 3 months of age in infant monkeys. IgM levels in infants exposed to belimumab in utero recovered by 6 months of age.

Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to BENLYSTA, a pregnancy registry has been established. Healthcare professionals are encouraged to register patients and pregnant women are encouraged to enroll themselves by calling 1-877-681-6296.

Nursing Mothers It is not known whether BENLYSTA is excreted in human milk or absorbed systemically after ingestion. However, belimumab was excreted into the milk of cynomolgus monkeys.

Because maternal antibodies are excreted in human breast milk, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of breastfeeding to the infant and the importance of the drug to the mother.

Pediatric Use Safety and effectiveness of BENLYSTA have not been established in children.

Geriatric Use Clinical studies of BENLYSTA did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Use with caution in elderly patients.

Race In Trial 2 and Trial 3, response rates for the primary endpoint were lower for black subjects in the BENLYSTA group relative to black subjects in the placebo group [see Clinical Studies]. Use with caution in black/African-American patients.

OVERDOSAGE There is no clinical experience with overdosage of BENLYSTA. Two doses of up to 20 mg/kg have been given by intravenous infusion to humans with no increase in incidence or severity of adverse reactions compared with doses of 1, 4, or 10 mg/kg.

PATIENT COUNSELING INFORMATION See Medication Guide.

Advice for the Patient Patients should be given the Medication Guide for BENLYSTA and provided an opportunity to read it prior to each treatment session. It is important that the patient’s overall health be assessed at each infusion visit and any questions resulting from the patient’s reading of the Medication Guide be discussed.

Mortality: Patients should be advised that more patients receiving BENLYSTA in the main clinical trials died than did patients receiving placebo treatment [see Warnings and Precautions].

Serious Infections: Patients should be advised that BENLYSTA may decrease their ability to fight infections. Patients should be asked if they have a history of chronic infections and if they are currently on any therapy for an infection [see Warnings and Precautions]. Patients should be instructed to tell their healthcare provider if they develop signs or symptoms of an infection.

Hypersensitivity/Anaphylactic and Infusion Reactions: Educate patients on the signs and symptoms of anaphylaxis, including wheezing, difficulty breathing, peri-oral or lingual edema, and rash. Patients should be instructed to immediately tell their healthcare provider if they experience symptoms of an allergic reaction during or after the administration of BENLYSTA [see Warnings and Precautions].

Depression: Patients should be instructed to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts or other mood changes [see Warnings and Precautions].

Immunizations: Patients should be informed that they should not receive live vaccines while taking BENLYSTA. Response to vaccinations could be impaired by BENLYSTA [see Warnings and Precautions].

Pregnancy and Nursing Mothers: Patients should be informed that BENLYSTA has not been studied in pregnant women or nursing mothers so the effects of BENLYSTA on pregnant women or nursing infants are not known. Patients should be instructed to tell their healthcare provider if they are pregnant, become pregnant, or are thinking about becoming pregnant [see Use in Specific Populations].

Patients should be instructed to tell their healthcare provider if they plan to breastfeed their infant [see Use in Specific Populations].

BENLYSTA is a registered trademark of Human Genome Sciences, Inc., used under license by GlaxoSmithKline.

Manufactured by: Human Genome Sciences, Inc. Rockville, Maryland 20850 U.S. License No. 1820 Marketed by:

Human Genome Sciences, Inc. Rockville, MD 20850

GlaxoSmithKline Research Triangle Park, NC 27709

Fibromyalgia

Review of Appeals of Fibromyalgia-Related Workplace Injury Compensation Cases Sheds Light on the Medicolegal Aspects of the Disease

By Rosemary Frei, MSc Winnipeg, Manitoba—There are lessons for rheumatologists and for family physicians in how courts adjudicate cases of fibromyalgia that were alleged to have been caused by or exacerbated by workplace injury, according to a new study presented at the Canadian Pain Society’s 2013 annual meeting and was published simultaneously (Fitzcharles MA, et al.

J Rheumatol. 2013;40:323-328).

A team led by Mary-Ann Fitzcharles, MD, a rheumatologist and Associate Professor of Medicine, Division of Rheumatology, McGill University Health Centre, Montreal, Canada, reviewed 138 cases of fibromyalgia that had been examined by an appeals tribunal. They found that the tribunal members relied on outdated medical information, may not have taken previous health status into account, and that they put more credence in rheumatologists’ opinions than that of family physicians, despite the fact that family physicians have far more frequent contact with patients and are often more prepared to be their patients’ advocates.

“We have concerns about the frequent attribution of a somewhat trivial injury to the onset of a medical condition that is reportedly severe enough for persons to request disability compensation,” explained Peter Ste-Marie,

BA, LLB, a researcher at the University of Montreal and the investigator of 2 posters on this topic. “[One of the problems is that] specialists seem to be accepted as authoritative in the law rather than acknowledging the important input of the primary care physician, who should be most knowledgeable of a patient’s global health status and the impact of the alleged work-related injury.”

Of the aggravation appeals, 67% were accepted, as were 59% of the appeals of patients with new-onset fibromyalgia.

The researchers parsed information from the Workplace Safety and Insurance Appeals Tribunal website (WSIAT; www.wsiat.on.ca) on all appeals of previous negative decisions for compensation.

“With the cause of fibromyalgia still unknown in the medical and scientific fields, we wanted to understand how the legal system attributes causation of this condition to a workplace injury,” said Mr Ste-Marie.

The study included 15 cases of fibromyalgia that were allegedly aggravat-

ed by a workplace injury, and another 123 cases that were alleged to have been caused by a workplace injury.

These were heard by the WSIAT between June 2006 and December 2011.

Most (84.5%) of the appellants were women. Of the injuries, 66% were a single event, and the rest were gradual-onset injuries from repetitive work activity. Most of the injuries were acute rather than gradual and were more frequent in the upper limbs than in the lower back. They were all soft-tissue injuries without any persistent physical signs or symptoms that could explain the appellants’ continued symptoms, the researchers noted.

The average time between injury and diagnosis was 4.3 years among the cases of new-onset fibromyalgia. An average of 6 physicians’ opinions were cited in each case, with 91 (74%; N = 123) new-onset cases having been diagnosed by a rheumatologist and only 16 (13%) cases having been diagnosed by a family physician. The WSIAT sought the advice of a Workplace Safety and Insurance Board health consultant for 73 (59%) of the cases.

In 25% of the cases, previous health status was not discussed during the appeal. In 40% of the cases, reference was made to a fibromyalgia discussion paper published on the WSIAT website in February 2003 that Mr Ste-Marie

and Dr Fitzcharles note is not peer reviewed and is inadequately updated.

Of the aggravation appeals, 67% were accepted, as were 59% of the appeals of patients with new-onset fibromyalgia.

The adjudicators were more than twice likely to allow an appeal based on a rheumatologist’s evidence than that of a family physician’s. They also were relatively unlikely to rely on the number of tender points—which is congruent with current medical thinking—or on the temporality of the cases.

Dr Fitzcharles reviewed the evidence presented in each case and agreed with the tribunal decisions in 76% of the new-onset cases and in all of the aggravation cases.

“This finding is both surprising and reassuring—that even with the differences applicable to medical versus legal evaluation, agreement was generally consistent,” the researchers concluded.

Nonetheless, they also warn that “the diagnosis of fibromyalgia, a condition characterized by subjective symptoms and without an objective confirmatory test, may be used dishonestly by some persons seeking compensation benefits. In this context, physicians should be vigilant when playing a role in secondary gain situations.” n

Impact of Pain on Quality of Life in Patients with Fibromyalgia Winnipeg, Manitoba—A study on the influence of pain and catastrophizing on quality of life in patients with fibromyalgia has answered some questions and raised others.

The study was presented at the 2013 Canadian Pain Society annual meeting and involved a snapshot of correlations between scores on various health and quality-of-life measures in 229 patients with fibromyalgia who were being treated by clinicians at McGill University Health Centre in Montreal.

Of the 229, 91% were women (mean age, 48 years); of these, 35% of the patients were employed, 31% were unemployed because of fibromyalgia, and 33% were on disability.

14

“Different components of pain measurements seem to have distinct relationships with the various features of the global patient situation—that is, emotional pain associates with quality of life, sensory pain associates with physical function, and evaluative pain associates with global well-being.”

value-based CARE in Rheumatology

—Neda Faregh, PhD

I

June 2013

Lead investigator Mary-Ann Fitz­ charles, MD, a rheumatologist and Associate Professor of Medicine, Division of Rheumatology, McGill University Health Centre, and colleagues, found that emotional pain and catastrophizing predict poor quality of life; however, depression and anxiety are not the primary predictors of pain perception.

The only demographic value that correlated with poor scores on the McGill Pain Questionnaire, which measures sensory pain, was unemployment. Being on disability and having a longer duration of fibromyalgia were not associated with poor scores on the McGill Pain Questionnaire.

By contrast, “Different components

of pain measurements seem to have distinct relationships with the various features of the global patient situation—that is, emotional pain associates with quality of life, sensory pain associates with physical function, and evaluative pain associates with global well-being,” concluded coinvestigator Neda Faregh, PhD, Adjunct Professor of Psychology at Carleton University in Ottawa.

Dr Faregh added that more research is needed to verify these results and to determine their clinical implications.

It may turn out, for example, that psychological interventions targeting emotions and catastrophizing are useful adjuncts to standard pain treatments, she said.—RF n VOL. 2

I

NO. 3

Arthritis Update

Seropositive Patients with Arthritis and Inadequate Response to TNF Inhibitors May Benefit by Switching to Rituximab

By Wayne Kuznar Washington, DC—In patients with seropositive rheumatoid arthritis (RA) who have an inadequate response to a tumor necrosis factor (TNF) inhibitor, switching to rituximab (Rituxan) may be a better option than switching to another TNF inhibitor, according to data discussed by Andrea Rubbert-Roth, MD, a Rheumatologist and Senior Physician at the Klinik I für Innere Medizin at the University of Cologne, Germany.

In an observational clinical practice study, patients who had an inadequate response to a TNF inhibitor and were switched to rituximab had greater disease activity improvements and greater erythrocyte sedimentation rate (ESR) reductions compared with patients who were switched to another TNF inhibitor.

Optimal treatment strategies have not been defined for patients who have an inadequate response to, or are intolerant of, an initial TNF inhib-

itor. Dr Rubbert-Roth noted that 20% to 40% of patients with RA have an inadequate response to TNF inhibitor therapy.

“Seropositive patients discontinuing a first TNF inhibitor due to inefficacy achieved significantly better responses with rituximab compared with those receiving an alternative TNF inhibitor.”

—Andrea Rubbert-Roth, MD Switching from one TNF inhibitor to another has become a standard approach. However, recent data suggest that the response to TNF inhibitors is poorer in patients with rheumatoid factor or anticyclic citrullinated pro-

tein antibodies; these patients may benefit from switching to rituximab.

“Seropositive patients with RA achieve greater clinical responses to rituximab than seronegative patients,” Dr Rubbert-Roth said.

These data come from a prospec­ tive global cohort study known as SWITCH-RA, which included 728 patients who had completed 6 months of rituximab or an alternative TNF inhibitor after an inadequate response to an initial TNF inhibitor. Of these patients, 559 were seropositive and 169 were seronegative. The mean duration of previous TNF inhibitor therapy was similar between the 2 groups.

The primary end point was the 6-month change from baseline in the 28-joint Disease Activity Score (DAS28) with the addition of swollen and tender joint counts and level of C-reactive protein (DAS28–CRP-3).

In both groups of patients, at the time of the switch, the baseline DAS28–CRP-3 and DAS28–erythrocyte sedimentation rate (ESR)-3 standard deviation scores were higher in

See also pages 16,18

the rituximab group than in the alternative TNF inhibitor group.

At 6 months, a greater improvement was seen in DAS28–ESR-3 in seropositive patients who switched to rituximab versus patients who switched to another TNF inhibitor (1.6 vs 1.2; P = .011). No significant difference between the 2 groups was seen in the seronegative patients.

“The relative benefit of rituximab varied in seropositive patients according to the reason for interrupting the previous TNF inhibitor,” said Dr Rubbert-Roth. “Seropositive patients discontinuing a first TNF inhibitor due to inefficacy achieved significantly better responses with rituximab compared with those receiving an alternative TNF inhibitor.”

At 6 months, significantly greater decreases in the ESR were observed in seropositive patients receiving ri­ tuximab than in those receiving an alternative TNF inhibitor (–14.4 vs –7.3; P = .006); corresponding results in the seronegative patients did not reach significance. n

Learning to Live with Pain Boosts Physical Activity of Patients with Rheumatoid Arthritis

By Rosemary Frei, MSc Winnipeg, Manitoba—For the first time, a study has confirmed that acceptance of pain among patients with rheumatoid arthritis (RA) is a strong predictor of their engaging in the recommended 150 minutes or more of weekly moderate-to-vigorous physical activity for this patient population.

Pain intensity does not appear to be a significant predictor for physical activity level in these patients.

The findings of this poster were presented at the 2013 Canadian Pain Society annual meeting by investigators from the University of Saskatchewan and the University of Northern Colorado.

“The finding of pain acceptance predicting physical activity above the recommended levels for arthritis self-management helps to explain why arthritis pain is not always significantly associated with physical activity,” said lead investigator Nancy Gyurcsik, PhD, an associate professor in the College of Kinesiology at the University of Saskatchewan. “If we can ramp up people’s pain acceptance, this may be an avenue to help VOL. 2

I

NO. 3

people who have pain from their arthritis to engage in physical activity at the recommended dose for disease benefits,” she added.

“If we can ramp up people’s pain acceptance, this may be an avenue to help people who have pain from their arthritis to engage in physical activity.”

—Nancy Gyurcsik, PhD Pain acceptance is not “sucking it up,” Dr Gyurcsik said, but rather “learning to let go of attempts to control or struggle with pain, be more mindful, and pursue what is important in their lives, such as being active.”

The study is an extension of earlier published work by Dr Gyurcsik and her collaborators (J Health Psychol.

2011;16:530-539). In that study, they reported that among a group of 118 women with RA who completed 2 online surveys, women with more pain

acceptance reported lower pain intensity, more self-regulatory efficacy—in this case, the ability to overcome barriers to being active and to reach physical activity goals—and more moderate or vigorous physical activity.

Using the information from the same group of women (but for 117 rather than the 118 patients), Dr Gyurcsik and her colleagues used a hierarchical multiple regression analysis to focus on predictors of physical activity. They used a scale of pain intensity and asked the women to describe the intensity of their pain on a typical day, during a flare, not during a flare, and at the moment they were completing the survey.

The subjects also completed a Chronic Pain Acceptance Questionnaire.

Then, 14 days later, they self-reported the average weekly time they spent engaging in moderate-to-vigorous physical activity in each of the previous 2 weeks.

The women engaged in an average of 175 minutes of moderate-to-vigorous physical activity weekly. The US Department of Health and Human june 2013

I

at a glance ➤ Patients with RA who accept their pain are more likely to engage in the recommended ≥150 minutes of weekly moderate-to-vigorous physical activity than those who have not accepted their pain level ➤ Pain intensity does not appear to be a predictor of physical activity in these patients Services recommends that all adults, including patients with RA, get at least 150 minutes of moderate-to-high–­ intensity aerobic activity weekly.

The women in the study had an average pain intensity score of 5.42 (of a maximum of 10) and an average pain acceptance score of 68.52 (of a maximum of 120).

Based on their data, the researchers determined that pain intensity was not an independent predictor of physical activity, but that pain accept­ ance was. n

www.ValueBasedRheumatology.com

15

Rheumatology Practice Management

™

Engaging Patients in Pain Management an Important Strategy for Rheumatology Practices

By Phoebe Starr New Orleans, LA—An interactive, online tool shows promise in helping patients with rheumatoid arthritis (RA) self-manage their pain and could prove to be a useful adjunct to office visits for this patient population, according to a poster presented at the 2013 American Pain Society annual meeting by a team of investigators from Inflexxion, Newton, MA. They presented findings from an intervention called painACTION, an online program for the self-management of patients with pain associated with rheumatic disease.

Participants in this program had improved outcomes in pain relief, awareness about their condition, and self-management behaviors, as well as improved mood and coping skills and better quality of life compared with controls with a similar level of RA pain at baseline.

“These improvements in participants’ pain self-efficacy, pain catas­ trophizing, coping through relaxation, and quality of life indicate that painACTION can be an important element of a comprehensive disease management program for people with arthritis pain. Further research is needed to determine which subgroups can be most effectively treated

by an online intervention and to better understand why some dimensions changed after exposure to the treatment, while others did not. Pain­ ACTION may help meet the public health need for arthritis education,” according to Kimberlee J. Trudeau, PhD, of Inflexxion.

“Improvements in participants’ pain self-efficacy, pain catastrophizing, coping through relaxation, and quality of life indicate that painACTION can be an important element of a comprehensive disease management program.”

—Kimberlee J. Trudeau, PhD, and colleagues Engaging Patients with RA in Their Disease Management One in every 5 adults in the United States is affected by arthritis, and in 2000, the US Department of Health and Human Services set a goal of dis-

seminating arthritis education to more patients.

Self-management is a critical component in helping patients to learn how to identify, avoid, and manage their pain, but physicians typically do not have time to provide patient education of this nature. Internet-based programs have been shown to improve outcomes among people with back pain and migraine.

The investigators developed and tested the online, interactive self-management program for adults who suffer pain associated with osteoarthritis (OA), RA, ankylosing spondylitis, and other rheumatic conditions based on principles of Social Cognitive Theory (Bandura, 1997). The motto of the program is, painACTION “picks up where the office visit leaves off.”

The Program A total of 228 participants (mean age, approximately 50 years) were recruited via flyers and online posting. All participants had moderate-to-severe pain associated with RA, as reflected by a self-reported pain level of ≥4 in the previous week on the 0 to 10 Numerical Rating Scale. The experimental group comprised 113 patients who participat-

ed in painACTION, who were compared with 115 controls.

Approximately 68% of the participants were female, and approximately 44% were college graduates. Approximately 53% of both groups had RA, 60% had OA, and 7% had other arthritic conditions.

Participants used painACTION twice weekly for 4 weeks, followed by 5 additional monthly booster sessions.

The painACTION program included articles, lessons, and interactive tools to facilitate learning pain self-management skills.

Participants had significantly improved pain control at 1-month and 6-month follow-up, reduced pain ca­ tastrophizing at 6-month follow-up, and increased relaxation coping at 3-month follow-up. In addition, participants had improved patient perception of global change at 1-month, 3-month, and 6-month follow-up compared with controls.

By contrast, no significant differences between the groups were found in the effect of the intervention on pain awareness, the use of self-management strategies, pain level, and functioning.

More research is needed to understand these effects, the investigators said. n

Arthritis Update

Opioids Safe, Effective for RA-Related Pain New Orleans, LA—The role of opioids in the management of patients with rheumatoid arthritis (RA) is controversial. A 2011 Cochrane Review showed insufficient evidence to support the role of weak opioids in this setting for >6 weeks, or for the role of strong opioids (Whittle SL, et al. Cochrane Database Syst Rev. 2011;[11]:CD003113).

Against this background, a small study suggests that adjuvant opioids provided effective pain relief and improved physical function, with no evidence of misuse, diversion, or laboratory abnormalities in older patients with RA-associated pain. This retrospective study was presented at the 2013 American Pain Society annual meeting.

“To date, there is no reported study on the long-term outcomes of opioids used in combination with antirheumatic drugs [ARDs] in older adults.

Our study sought to evaluate the longterm efficacy and safety of adjunctive

16

opioids in older persons with pain from RA,” said lead investigator, Shirley Albano-Aluquin, MD, Rheumatologist, Penn State University College of Medicine, Hershey, PA. A total of 20 participants (aged ≥60 years) were seen from 2006 through 2012 and managed by 1 rheumatologist with geriatric training. The patients had moderate-to-severe RA pain, as reflected by a score of ≥5 on the 0 to 10 Numerical Pain Scale (NPS).

Opioids were started in patients receiving background therapy with ARDs. At baseline, 30% were receiving nonsteroidal anti-inflammatory drugs, 35% neuromodulators, 45% methotrexate, 50% corticosteroids, and 40% biologics.

Of the 20 patients, 16 were women, and the mean disease duration was approximately 10.6 years. The mean number of comorbidities was 4.8, including hypertension (85%), osteoar-

value-based CARE in Rheumatology

I

June 2013

thritis (100%), neuropathic pain (30%), stenosis (10%), and osteoporotic fracture (20%).

Five patients were treated with Schedule II short-acting morphine, oxycodone, and acetaminophen; 1 received Schedule II long-acting morphine, oxycodone or fentanyl plus Schedule III/IV hydrocodone, tramadol or codeine; 3 received Schedule II long-acting plus short-acting opioids; and 11 received Schedule III/IV opioids only. Sixteen (80%) patients received a total daily dose of 120-mg morphine equivalents or less, whereas 4 (20%) received 120-mg morphine equivalents or greater.

At early (median, 4 months) and late (median, 11 months) follow-up, 42% and 47%, respectively, achieved pain improvement of ≥30% (NPS30). NPS responders were more frequently anti-CPP positive; 78% of responders were anti-CCP positive versus 22% of

See also page 15 nonresponders. NSP30 responders also had higher baseline pain scores compared with nonresponders (median, 8.6 vs 6.2, respectively). In 56% of responders, oxycodone with or without acetaminophen was used.

On the Health Assessment Questionnaire Disability Index, improvement was seen in 27% at early assessment and in 46% at late assessment.

A ≥50% response on the RA Clinical Disease Activity Index (CDAI50) was achieved in 5% at both follow-up assessments.

Only 1 serious adverse event was reported. There was no evidence of opioid abuse.

Dr Albano-Aluquin said that these results in patients with significant comorbidities and significant arthritis-related pain and functional impairment suggest that opioids were successful at relieving pan and improving function over the long-term.—PS n VOL. 2

I

NO. 3

Osteoarthritis

Patellofemoral Disease Linked to Functional Impairment in Knee Osteoarthritis

By Wayne Kuznar

I

n patients with knee osteoarthritis (OA), moderate or severe patellofemoral (PF) OA (PFOA) that coexists with tibiofemoral (TF) OA may limit knee extension strength and range of motion, which manifests as difficulty going down stairs, found investigators at the University of Pittsburgh.

It therefore appears that “knees with more severe PF disease demonstrate features distinct from those observed in TFOA in isolation or in combination with mild PF disease,” they concluded.

The researchers’ findings were published in the April issue of Arthritis Care & Research (Hoboken) (2013;65:544-551).

Shawn Farrokhi, PT, PhD, DPT, and colleagues reviewed radiographs of the TF and PF compartments of 167 patients with knee OA. Radiographs of the painful knee in patients with unilateral symptoms and of the more painful knee in patients with bilateral involvement were analyzed. Other measures included maximum volun-

tary isometric torque output for knee extension, and knee flexion and extension range of motion.

Targeted interventions to treat the PF joint should focus on mitigating the functional deficits seen in patients with knee OA. Knee-specific information on symptoms and limitations during functional tasks was gathered using the 24item Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the 14-item Activities of Daily Living Scale (ADLS) of the Knee Outcome Survey.

Moderate or severe PFOA was associated with worse knee extension strength compared with no PFOA. Knee range of motion was also affected by the severity of PFOA. On the

WOMAC, mild PFOA was associated with 4 times more difficulty with removing socks or stockings compared with no PFOA. Difficulty in removing socks or stockings was associated with lower knee flexion range of motion after adjusting for age, sex, body mass index, and TFOA disease severity.

Patients with moderate or severe PFOA did not have an increased odds of having difficulty in removing socks or stockings, the investigators noted.

“It is plausible that patients with more severe PFOA may have developed compensatory strategies to perform this task without requiring high degrees of knee flexion,” they wrote.

“For example, to avoid pain and difficulties, patients with more severe PFOA and limited knee flexion range of motion could potentially take off their socks or stockings by flexing their hips and/or trunk instead of flexing their knees.”

On the ADLS, moderate or severe

PFOA was independently associated with greater limitations with going down stairs (adjusted odds ratio, 2.9).

Greater difficulty with going down stairs on the ADLS was significantly associated with lower knee extension strength after adjusting for age, sex, body mass index, and TFOA disease severity.

Lower extremity muscle weakness, particularly affecting the quadriceps, has been cited as a risk factor for functional impairment in patients with knee OA. Such weakness has been associated with pain severity and disability in patients with knee OA. “Quadriceps weakness may be related to disease progression over the lateral PF compartment and worsening of symptoms and functional limitations over time.”

Targeted interventions to treat the PF joint “should be considered to mitigate functional deficits present in this patient population,” they advised. n

Gout

Dual-Energy Computed Tomography Useful... degrees apart. The radiation dose is the same as for regular computed tomography. The result is 2 sets of images that can be compared to produce color-coded depictions of ligaments, tendons, bone edema, and uric acid (Figures 1 and 2).

Paul Mallinson, MBChB, a radiology fellow at Vancouver General Hospital, works on DECT in gout with Sav-

“You can look for gout in the joint or joints that you think are symptomatic, and you can also look at other joints to see if there are gout crystals even though gout hasn’t become clinically apparent in those joints yet.”

—Paul Mallinson, MBChB vas Nicolaou, MD, an assistant professor of diagnostic radiology at the University of British Columbia. DECT is noninvasive and, therefore, has advantages over the classic test, which VOL. 2

I

NO. 3

Continued from page 1

involves aspira- Figure 1. 3-D View of Knees with Urate Deposits in a Patient with Gout Figure 2. Sagittal View of the Same tion of the affected Patient in a 2-D Image joint to determine whether monosodium urate crystals and/or infection are present.

“That means the patient has to have a needle in a joint, which is a little painful and has potential complications, plus you have to limit the number of joints you test because Photo courtesy of Paul Mallinson, MBChB the patient won’t Photo courtesy of Paul Mallinson, MBChB find it acceptable to have multiple joints and you can also look at other joints to aspirated,” Dr Mallinson explained. see if there are gout crystals even areas and the calcium of the bones is Patients who are suspected to have though gout hasn’t become clinically blue (Figures 1 and 2). gout undergo DECT imaging of the apparent in those joints yet,” said Dr There can be artifacts that appear hands and wrists, followed by the el- Mallinson in explaining other advan- green on the images that are not actubows, the knees, the feet, and the an- tages of DECT. In addition, patients ally gout, but DECT users quickly kles. Previous studies have shown the can be reimaged after urate-lowering learn to differentiate these from true technique has a sensitivity ranging therapy to determine whether the gout, Dr Mallinson said. Tissues that from 84% to 100% and specificity treatment has been effective. commonly produce artifacts are the ranging from 79% to 100% (AJR Am J The images are displayed on a nails and nail beds in the feet, and Roentgenol. 2012;199:S78-S86). specialized workstation as 3-plane areas where there is thickened skin or “You can look for gout in the joint cross-sectional and 3-dimensional areas of proximate skin, such as when or joints you think are symptomatic, images. The urate is shown as green toes are pressed together. n june 2013

I

www.ValueBasedRheumatology.com

17

Health Economics

Use of Biologic Agents to Treat Autoimmune... biologic anti-inflammatory agent actually use at least 1 of these agents between 2009 to 2011. Understanding utilization patterns of biologic agents is necessary to assess opportunities for specialty pharmacy management for these agents, according to Kevin Bowen, MD, and colleagues at Prime Therapeutics in Eagan, MN. Of the approximate 2.6 million members (aged <65 years) who were continuously enrolled from 2009 through 2011, 3452 were newly initiated with a biologic drug during 2010 and 2011.

The biologic anti-inflammatory agents included in this analysis were abatacept (Orencia), adalimumab (Humira), alefacept (Amevive), ana­ kinra (Kineret), certolizumab (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade), tocilizumab (Actemra), ustekinumab (Stelara), and rituximab (Rituxan).

Over 3 years, 39,848 members had a diagnosis for which an anti-inflammatory biologic could be used, and 10,769 (27%) had a claim for ≥1 of the biologics. Some 42.5% of patients had a claim for a biologic for a diagnosis of rheumatoid arthritis (RA), 29.0% for psoriasis, 13.7% for Crohn’s disease,

3.8% for ulcerative colitis, and 11% for all other diagnoses.

agent on December 31, 2009, 77.2% (those with ulcerative colitis) to 82.0% (those with RA) were still using a biologic agent on December 31, 2011.

The mean incidence rate of any new Overall, the use of biologic biologic drug use in this analysis, by anti-inflammatory agents for diagnosis, was: autoimmune inflammatory • RA, 6.7 • Psoriasis, 4.4 diseases increased by 29.4%, • Crohn’s disease, 2.4 from 241.8 to 312.8 per • Ulcerative colitis, 0.9 100,000 members.

• Ankylosing spondylitis, 0.9 • Juvenile idiopathic arthritis, 0.3.

In this patient group, the most freOverall, the use of biologic anti-­ quent biologics used by newly initiatinflammatory agents for autoimmune ed patients with a diagnosis of RA, inflammatory diseases increased by psoriasis, Crohn’s disease, or ulcer29.4%, from 241.8 to 312.8 per 100,000 ative colitis for adalimumab, etanercept, and infliximab between 2009 members.

Of the members using a biologic and 2011 are listed in the Table.

Table F requency of Biologic Drug Use in Patients with Autoimmune Inflammatory Diseases Disease Adalimumab, % Etanercept, % Infliximab, % Rheumatoid arthritis

36.6

38.8

8.8

Psoriasis

51.4

38.7

4.6

Crohn’s disease

41.4

0.0

49.1

Ulcerative colitis

22.9

0.0

73.4

See also page 20 Continued from page 1 Overall, 27% of members who met the diagnostic criteria received a biologic anti-inflammatory agent over the 3-year study period between January 1, 2009, and the end of 2011, ranging from 6.5% of those with a diagnosis of ulcerative colitis to 59.1% with a diagnosis of ankylosing spondylitis.

The investigators note that patients recently initiating biologic and continuing therapy account for an increasing percentage of anti-inflammatory biologic drug utilization, noting that “health plans should understand that management strategies targeting choice of initial therapy may have an important impact on drug selection, but this approach will take many months to change utilization patterns.”

They further note that although health plans have a substantial cost for the increased use of biologic anti-inflammatory agents, which are known to improve outcomes, in this analysis there were 1205 members who were not receiving one of these agents; this is another reason that pharmacy management programs will need to focus on biologic anti-inflammatory agents to ensure that patients are receiving appropriate therapy. n

Infliximab Dosing and Use Patterns in the Treatment of Patients with Rheumatoid Arthritis

By Wayne Kuznar San Diego, CA—An assessment of infliximab (Remicade) use patterns for the treatment of patients with rheumatoid arthritis (RA) indicates that patients are usually maintained on the medication for longer than 2 years and that changes in dosage or dosing frequency are rare.

These patterns emerged from an examination of electronic health rec­ ords (EHRs) of patients with RA in an ambulatory care network in Sacramento, CA. The data were presented by Angela Leahy, PharmD, Clinical Outcomes Research Pharmacist, Sutter Health, at the 2013 Academy of Managed Care Pharmacy annual meeting.

A total of 125 patients with a primary diagnosis of RA were identified between January 2007 and June 2011 (the index period) who received at least 1 infusion of infliximab. Infliximab dosing and frequency were collected from the EHRs and were calculated for the

18

maintenance phase of treatment.

Dose changes were defined as an increase or decrease by ≥1 in the vials

There was little variation in the average weight-based dose over the study period.

Changes to the dosage or frequency between infusions occurred rarely.

Of the 2068 total infusions, dose increases occurred in 1.6% of the infusions and decreases occurred in 0.2% of the infusions. used. Infusion frequency changes were defined as a prescribed increase or decrease by ≥1 week compared with the previous infusion.

value-based CARE in Rheumatology

I

June 2013

The majority (82%) of the patients were female (mean age, 60 years), and 65% were taking methotrexate concomitantly. Approximately 50% of the patients were Medicare beneficiaries and 44% were commercial beneficiaries; the remaining patients were uninsured or had other insurance.

Among the entire cohort, infliximab was administered over a mean of 27.4 months at an average prescribed dose of 347.2 mg (range, 100-875 mg), corresponding to an average weightbased dose of 4.8 mg/kg (range, 2.5111.67 mg/kg). Of the infliximab recipients, 58% received a dose of >3 mg/kg to ≤5 mg/kg.

The mean weight-based dose of infliximab was within the range stated in the approved product labeling, which suggests a starting dose of 3 mg/kg at 0, 2, and 6 weeks, then every 8 weeks in conjunction with methotrexate, and dose increases up

to 10 mg/kg as often as every 4 weeks.

Among the 43 new infliximab users during the study period, the average weight-based dose was 4.3 mg/kg (range, 2.5-9.1 mg/kg).

There was little variation in the average weight-based dose over the study period. The weight-based dose increased from 4.5 mg/kg at the beginning of the index period to 5 mg/ kg at the end of the index period.

Changes to the dosage or frequency between infusions occurred rarely. Of the 2068 total infusions, dose increases occurred in 1.6% of the infusions and decreases occurred in 0.2% of the infusions. The median infusion frequency was 8 weeks (range, 2-13 weeks). The frequency was increased in 1.8% of the infusions and decreased in 1.5% of the infusions.

Infliximab dosing and infusion frequency were similar for Medicare and commercial beneficiaries. n VOL. 2

I

NO. 3

THE ENVIRONMENT OF HEALTHCARE IS CHANGING LIKE THE SURF! IS YOUR PRACTICE PREPARED? National Organization of Rheumatology Managers

Friday, September 13, 2013 and Saturday, September 14, 2013 Hyatt Regency Long Beach 200 South Pine Avenue Long Beach, CA 90802 Avoid a wipe-out by joining us for Surfing Through Rheumatology where nationally known speakers will discuss: healthcare reform, increasing leverage in payer negotiations, effective communication in your practice, and the value of social media. Breakout sessions will provide additional information on healthcare reform, dealing with specific issues when communicating with staff and patients, building culture in your practice and two exciting

lab sessions on contracting. As we move closer to the conference additional hot topics will be added to the breakout sessions.

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

Conference Registration is Now Open 2013 Dues and Early Bird Conference Registration $250 â&#x20AC;&#x153;As a physician and managing partner for our practice, NORM membership is invaluable. Both the practice manager and myself reply on the timely information on the listserv and the yearly meeting.

Every rheumatology practice in this country should participate.â&#x20AC;? Kyle Harner, MD

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

Health Economics

Effectiveness and Costs of TNF-Alpha Blocker Use for Patients with Rheumatoid Arthritis

By Kavita Nair, PhD; Vahram Ghushchyan, PhD; and Ahmad Naim, MD This is a summary of the original article published in American Health & Drug Benefits. 2013;6(2):126-136. Copyright © 2013 Engage Healthcare Communications. Used with permission. The full article is available at www.AHDBonline.com.

R

heumatoid arthritis (RA) is a chronic autoimmune disease that causes pain, stiffness, swelling, and loss of function in the joints; it occurs when the patient’s immune system attacks healthy tissue. RA is ranked among the highest of all chronic diseases for its adverse impact on health-related quality of life (QOL), limitations in physical function, increased pain and fatigue, and diminished work performance and attendance.1 Roughly 1.3 million adults in the United States have RA, representing approximately 1% of the population.2,3 Worldwide, approximately 0.5% of the adult population is affected by RA.3 Without optimal treatment, approximately 30% of patients with RA become permanently work disabled within 2 to 3 years of diagnosis.4 Predictors of poor outcomes in the initial stages of RA include a relatively low functional score early in the disease progression, lower socioeconomic status, lower education level, strong family history of the disease, and early involvement of multiple joints.4 The 2008 American College of Rheumatology (ACR) recommendation for first-line pharmacologic treatment of RA is the use of nonbiologic disease-modifying antirheumatic drugs (DMARDs), which have been found to slow the progression of joint destruction when used over the long-term.5 If patients fail to respond to nonbiologic DMARDs, the ACR’s current recommendation is to administer biologic DMARDs, or tumor necrosis factor (TNF)-alpha blockers, to patients with moderate disease activity and poor prognosis, as well as to patients with high disease activity and to patients with RA of intermediate or long duration.5 TNF-alpha blockers target specific components of the immune system, instead of broadly affecting many areas of the immune system, and they intercept TNF in the joints, potentially eliciting rapid improvement of symptoms. These medications are frequently used along with other medications for the treatment of RA. Adalimumab, etanercept, and infliximab are the primary biologic drugs (and TNF-alpha

20

blockers) recommended in the 2008 ACR guidelines.

Aggressive RA treatment with TNF-alpha blockers has been shown to help prevent long-term disability from RA, to improve QOL, and to decrease fatigue, even among patients with mild RA.6-8

The cost of untreated RA represents a significant financial burden on the US healthcare system and the economy, predominantly because of lost productivity.

The cost of untreated RA represents a significant financial burden on the US healthcare system and the economy, predominantly because of lost productivity.9,10 A US claims-based analysis of excess payer- and beneficiary-paid costs per patient with RA (compared with matched controls) reported annual excess healthcare costs of $8.4 billion, indirect costs of $10.9 billion, and total annual societal costs of $19.3 billion, including direct, indirect, and intangible costs, such as QOL deterioration.11 According to this analysis, patients incurred an estimated 28% of that burden, employers incurred 33%, the government incurred 20%, and caregivers incurred an estimated 19% of the total cost. Adding intangible costs of QOL deterioration ($10.3 billion) and premature mortality ($9.6 billion), the total annual societal costs of RA (direct, indirect, and intangible) increased to $39.2 billion.11 Benefits in terms of enhanced productivity and quality-adjusted life-years conferred by the use of TNF-­ alpha blockers have been demonstrated in several cost-effectiveness analyses.12-14 These evaluations have been based on the concept that, if treated, patients with RA will not progress to a greater disease severity—or will not progress as quickly—and thereby will avoid or defer the high costs and low utilization associated with more severe and progressed disease.15

value-based CARE in Rheumatology

I

June 2013

Study Background The Medical Expenditure Panel Survey (MEPS) database, cosponsored by the Agency for Healthcare Research and Quality and the National Center for Health Statistics, is a nationally representative survey of the US civilian noninstitutionalized population. The uniqueness of the MEPS database lies in its abundance of information, which includes patient self-reported outcomes of functioning and mental health, along with information on sociodemographics, medical utilization, cost of healthcare services, employment, missed workdays, and Short Form (SF)-12 scores.

The ability to link these many domains within the MEPS data source allowed the authors of this study to develop different severity categories for RA based on a unique algorithm created for the study.

This RA severity–ranking algorithm was based on 5 health-related outcomes (ie, SF-12 physical and mental summary scores, patient’s perceived physical and mental health status, and the number of comorbid conditions), which were used to group TNF-alpha blocker nonusers into the 3 mutually exclusive RA severity cohorts—mild, moderate, and severe RA. Patients with RA using TNF-alpha blockers were not grouped using this algorithm and were not ranked. In addition, the MEPS data provide self-reports of work loss because of illness.

The objective of the study was to use data from the MEPS for the following outcomes—healthcare expenditures, utilization, and self-reported productivity—and to compare these outcomes between patients with RA who are TNF-alpha blocker users and TNF-alpha blocker nonusers with mild, moderate, or severe RA. Outcome Measures Total annual healthcare expenditures were defined as the sum of allcause medical and pharmacy expenditures; in addition, medical and pharmacy expenditures were described separately, and were inflation-adjusted to 2010 costs.

Medical service utilization and pharmacy components included the allcause annual number of office-based

visits, outpatient visits, hospitalizations, average length of stay for hospitalizations, as well as the annual number of prescribed medications.

Productivity was estimated using multiple measures. First, the authors studied 1 full year of employment status, which they obtained from respond­­ ents’ answers to the annual MEPS. Respondents who were employed during all 3 rounds of the survey within a calendar year were assumed to be employed for a full year. Then, for those who were employed, the authors studied days (a half day or more) of work missed as a result of illness or injury; and finally, they explored the annual wage differences.

Each person in the MEPS database has a record of his/her total annual wages.

The MEPS medical conditions file in the MEPS database contains 3-digit International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes based on medical and pharmacy utilization and self-­ reporting. The authors identified patients with RA by the presence of the ICD-9 diagnosis code 714, and stratified them into 1 of 2 major groups: TNF-alpha blocker users and TNF-­ alpha blocker nonusers. Users of TNF-alpha blockers were identified on the basis of pharmacy utilization and/ or relevant intravenous therapy at office-based or outpatient visits with the ICD-9-CM diagnosis code 714.

TNF-alpha blocker nonusers were classified into 1 of 3 groups according to RA severity ranking (mild, moderate, or severe). Users of TNF-alpha blockers were not included in the severity-ranking analysis, because of the assumption that patients with the most severe form of RA were taking these medications, which is typically normative practice for this patient population.

Results A total of 1152 patients were included in the study. Approximately 5.6% of the patients (N = 65) were using TNF-alpha blockers. Of the patients with RA who were not using these drugs, 720 patients (62.50%) had mild RA, 159 (13.81%) had moderate RA, and 208 (18.05%) had severe RA. VOL. 2

I

NO. 3

Health Economics Approximately 70% to 75% of the patients in all groups were female.

The mean age ranged from 55 to 60 years across the various study cohorts. Between 80% and 90% of all patients were white, and one third of all members resided in the Midwest or the South.

average, TNF-alpha blocker users spent $2096 more in annual medical expenditures compared with TNF-alpha blocker nonusers with mild RA (the reference group).

Similarly, on average, TNF-alpha blocker users spent $2454 more in annual prescribed expenditures and $4880 more in total healthcare expenProductivity: Unemployment, Missed ditures compared with TNF-alpha blocker nonusers with mild RA. Workdays, and Annual Wages TNF-alpha blocker nonusers with The total healthcare expenditures, severe RA were approximately 5 on average, were $1864 higher for times more likely to be unemployed TNF-alpha blocker nonusers with (incidence rate ratio [IRR], 5.64; P moderate RA and $2484 higher for <.000) compared with TNF-alpha TNF-alpha blocker nonusers with blocker nonusers with mild RA. severe RA compared with TNF-alpha TNF-alpha blocker nonusers with blocker nonusers with mild RA. Anmoderate RA showed a similar trend; nual prescription expenditures were they were approximately 3 times $611 higher for TNF-alpha blocker more likely to be unemployed (IRR, nonusers with moderate RA and $698 3.19; P <.000) compared with TNF-足 higher for TNF-alpha blocker nonusalpha blocker nonusers with mild RA. ers with severe RA compared with There was no significant difference patients with mild RA, and annual between TNF-alpha blocker users and medical expenditures were $1088 nonusers with mild RA regarding the higher for TNF-alpha blocker nonuslikelihood of being employed. ers with moderate RA and $1640 highWith regard to overall missed er for TNF-alpha blocker nonusers workdays and workdays that resulted with severe RA compared with in individuals staying in bed, few dif- TNF-alpha blocker nonusers with ferences were seen among the 3 mild RA. groups when adjusting for various covariates (Table 1).

Healthcare Resource Utilization One noticeable difference was that The notable differences in medical TNF-alpha blocker nonusers with service utilization between the varimoderate RA were twice as likely to ous study groups were with regard to miss workdays by staying in bed com- all-cause emergency department vispared with TNF-足 alpha blocker non足 its, the number of hospitalizations, the users with mild RA. However, there average length of stay for a hospitalwas no significant difference between ization, and the number of prescribed TNF-alpha blocker users and nonusers medications (Table 3). with mild RA, or between TNF-alpha Significant differences with regard blocker nonusers with severe RA and to emergency department visits and those with mild RA with regard to the hospitalizations were observed between TNF-alpha blocker nonusers likelihood of missing workdays.

The unadjusted mean number of with severe RA and TNF-alpha blockmissed workdays was lowest for er nonusers with mild RA. The differTNF-alpha blocker users, ranging ences in the number of prescribed from approximately 20 days (moder- medications were significant between ate and severe RA) to 11 days (mild TNF-alpha blocker users and nonusRA), compared with all other groups. ers with mild RA, as well as between Of note, the authors were not able to TNF-alpha blocker users with severe estimate the costs associated with the RA and nonusers with mild RA. With regard to emergency departlost workdays.

With regard to significant differenc- ment visits and hospitalizations, es in wages, TNF-alpha blocker non- TNF-alpha blocker nonusers with seusers with moderate RA constituted vere RA were almost twice as likely to the only group whose mean wage was incur an emergency department visit significantly lower than that of (IRR, 1.76; P = .002) and a hospitalizaTNF-alpha blocker nonusers with tion (IRR, 2.24; P = .008) compared with nonusers with mild RA. This mild RA ($7175; P <.001). group was almost 1.5 times more likeHealthcare Expenditures ly to have a greater length of stay The incremental impact on annual (IRR, 1.65; P = .022) compared with medical expenditures, prescribed nonusers with mild RA as well. medication expenditures, and total TNF-alpha blocker users had a greater healthcare expenditures is shown in likelihood of having more prescripTable 2. All 3 categories of expendi- tion medications (IRR, 1.49; P <.001) tures were higher for TNF-alpha as were nonusers with severe RA blocker users compared with nonus- (IRR, 1.25; P = .006) and nonusers with ers with mild RA. For example, on moderate RA (IRR, 1.22; P = .012) VOL. 2

I

NO. 3

Table 1 Differences in Missed Workdays between the Study Groups Unadjusted mean (SE)

Study cohort

Incidence rate ratio

95% confidence interval P value

Missed workdays TNF-alpha blocker nonusers with mild RA

7.07

Reference group

TNF-alpha blocker nonusers with moderate RA

23.79

1.92

0.97-3.79

.060

TNF-alpha blocker nonusers with severe RA

22.67

1.99

0.35-11.37

.440

TNF-alpha blocker users

2.61

0.61

0.23-1.58

.303

Missed workdays staying in bed TNF-alpha blocker nonusers with mild RA

3.12

Reference group

TNF-alpha blocker nonusers with moderate RA

12.07

2.22

1.14-4.30

.019

TNF-alpha blocker nonusers with severe RA

4.61

1.20

0.35-4.11

.769

TNF-alpha blocker users

2.24

1.18

0.48-2.86

.719

Models were adjusted for number of chronic conditions, age, education, race, ethnicity, and type of insurance coverage.

RA indicates rheumatoid arthritis; SE, standard error; TNF, tumor necrosis factor.

Table 2 Differences in Healthcare Expenditures between the Study Groups (2009 US $) Mean P value (for Unadjusted Standard marginal mean marginal mean, $ error, $ difference, $ difference) Annual medical expenditures, excluding prescriptions TNF-alpha blocker nonusers with mild RA

5972

651

Reference group

TNF-alpha blocker nonusers with moderate RA

13,148

3597

1088

.195

TNF-alpha blocker nonusers with severe RA

17,630

2349

1640

.035

TNF-alpha blocker users

13,072

2731

2096

.027

Annual prescribed medication expenditures TNF-alpha blocker nonusers with mild RA

2301

147

Reference group

TNF-alpha blocker nonusers with moderate RA

4912

991

611

.001

TNF-alpha blocker nonusers with severe RA TNF-alpha blocker users

5645

436

698

.000

10,207

1516

2454

.000

Total annual healthcare expenditures TNF-alpha blocker nonusers with mild RA

8273

706

Reference group

TNF-alpha blocker nonusers with moderate RA

18,060

4384

1864

.037

TNF-alpha blocker nonusers with severe RA

23,275

2436

2484

.002

TNF-alpha blocker users

23,280

3449

4880

.000

Models were adjusted for number of chronic conditions, age, education, race, ethnicity, and type of insurance coverage.

RA indicates rheumatoid arthritis; TNF, tumor necrosis factor.

compared with nonusers of TNF-alpha blockers with mild RA. Discussion This study is unique in comparing how TNF-alpha blocker treatment affects patient-reported outcomes versus TNF-alpha blocker nonuse among patients with varying degrees of RA june 2013

I

severity. The outcomes examined in this study are more detailed than those observed from claims data alone and emphasize the importance of patient-reported measures in examining how drug treatment can influence key outcomes in the management of RA. To our knowledge, this is the first study to link patterns of TNF-alpha Continued on page 22

www.ValueBasedRheumatology.com

21

Health Economics

Effectiveness and Costs of TNF-Alpha Blocker... Continued from page 21 blocker treatment to patient-reported outcomes. Our results reveal that TNF-alpha blocker treatment confers increased benefit with regard to employment status and is associated with lower rates of hospitalizations and emergency department visits compared with other RA medications and compared with nonuse of TNF-­ alpha blockers in patients with moderate or severe RA. As anticipated, one of the key findings was that patients with RA who were using TNF-alpha blockers incurred the highest total healthcare, medical, and prescription expenditures compared with the other RA groups. However, despite these increased costs, the authors found that patients with severe RA who were not using TNF-alpha blockers had more emergency department visits and hospitalizations and longer hospital stays compared with the other groups.

Our results reveal that TNF-alpha blocker treatment confers increased benefit with regard to employment status and is associated with lower rates of hospitalizations and emergency department visits compared with other RA medications and compared with nonuse of TNF-­alpha blockers in patients with moderate or severe RA. Another key finding was that TNF-alpha blocker users had a greater likelihood of being employed compared with TNF-alpha blocker non­ users with moderate or severe RA. Unadjusted means also show that TNF-alpha blocker users were less likely to have missed workdays compared with the other RA groups (ie, users and nonusers), although these differences were not significant. The demonstrated positive impact of TNF-alpha blocker use on employment status may be of importance to employers and to payers alike.

Conclusion This study confirms the benefits of

22

Table 3 Differences in Healthcare Utilization between the Study Groups Unadjusted mean

95% confidence interval

P value

0.88

0.71-1.10

.274

3.57

0.88

0.71-1.09

.243

3.18

1.16

0.96-1.40

.131

1.26

0.14

Reference group

2.54

1.35

0.77

0.45-1.33

.353

2.28

0.46

0.68

0.44-1.04

.077

TNF-alpha blocker users

1.62

0.47

0.98

0.52-1.86

.962

TNF-alpha blocker nonusers with mild RA

0.23

0.03

Reference group

0.58

0.10

1.59

1.10-2.31

.014

0.89

0.11

1.76

1.24-2.52

.002

TNF-alpha blocker users

0.42

0.20

1.35

0.54-3.39

.525

TNF-alpha blocker nonusers with mild RA

0.76

0.14

Reference group

2.40

0.54

1.40

0.85-2.29

.188

Office visits, N

TNF-alpha blocker nonusers with mild RA

TNF-alpha blocker nonusers with moderate RA TNF-alpha blocker nonusers with severe RA TNF-alpha blocker users

Standard error

Incidence rate ratio

12.09

0.71

Reference group

12.83

1.13

19.55 19.63

Outpatient visits, N

TNF-alpha blocker nonusers with mild RA

TNF-alpha blocker nonusers with moderate RA TNF-alpha blocker nonusers with severe RA Emergency department visits, N

TNF-alpha blocker nonusers with moderate RA TNF-alpha blocker nonusers with severe RA Hospitalizations, N

TNF-alpha blocker nonusers with moderate RA TNF-alpha blocker nonusers with severe RA

4.15

0.99

2.24

1.24-4.04

.008

TNF-alpha blocker users

1.48

0.73

1.64

0.71-3.79

.248

TNF-alpha blocker nonusers with mild RA

0.16

0.03

Reference group

0.44

0.09

1.56

0.99-2.45

.053

0.59

0.08

1.65

1.07-2.53

.022

0.40

0.15

1.91

0.86-4.23

.112

28.98

1.35

Reference group

53.36

5.00

1.22

1.04-1.43

.012

69.77

4.90

1.25

1.07-1.46

.006

52.24

5.35

1.49

1.22-1.82

.000

Average length of stay, days TNF-alpha blocker nonusers with moderate RA TNF-alpha blocker nonusers with severe RA TNF-alpha blocker users

Prescription medications, refills included, N TNF-alpha blocker nonusers with mild RA

TNF-alpha blocker nonusers with moderate RA TNF-alpha blocker nonusers with severe RA TNF-alpha blocker users

Models were adjusted for number of chronic conditions, age, education, race, ethnicity, and type of insurance coverage.

RA indicates rheumatoid arthritis; TNF, tumor necrosis factor.

TNF-alpha blockers with regard to enhancing patients’ productivity, and illustrates the associated direct healthcare expenditures of treating this group of patients with RA, thereby providing a balanced picture of the overall costs and benefits for TNF-alpha blocker users. Employers and other payers can use this information to assess all cost components of managing this RA subgroup of TNF users to make better-informed decisions about coverage and access issues related to TNF-alpha blockers for their members. Such medication data that can demonstrate a trade-off of savings on other healthcare costs provides additional value for payers. 6 n

value-based CARE in Rheumatology

I

June 2013

References

1. Strand V, Khanna D. The impact of rheumatoid arthritis and treatment on patients’ lives. Clin Exp Rheumatol. 2010;28(3 suppl 59):S32-S40.

2. Helmick CG, Felson DT, Lawrence RC, et al, for National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58:15-25.

3. Carmona L, Cross M, Williams B, et al. Rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2010;24:733-745.

4. Rindfleisch JA, Muller D. Diagnosis and management of rheumatoid arthritis. Am Fam Physician. 2005; 72:1037-1047.

5. Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59:762-784.

6. Lindén C, Björklund A. Living with rheumatoid arthritis and experiencing everyday life with TNF-α blockers. Scand J Occup Ther. 2010;17:326-334.

7. Hoving JL, Bartelds GM, Sluiter JK, et al. Perceived work ability, quality of life, and fatigue in patients with rheumatoid arthritis after a 6-month course of TNF inhibitors: prospective intervention study and partial economic evaluation. Scand J Rheumatol. 2009; 38:246-250.

8. Bejarano V, Quinn M, Conaghan PG, et al, for Yorkshire Early Arthritis Register Consortium. Effect of the early use of the anti-tumor necrosis factor ada­

limumab on the prevention of job loss in patients with early rheumatoid arthritis. Arthritis Rheum. 2008;59: 1467-1474.

9. Filipovic I, Walker D, Forster F, Curry AS. Quantifying the economic burden of productivity loss in rheumatoid arthritis. Rheumatology (Oxford). 2011;50:1083-1090.

10. Franke LC, Ament AJ, van de Laar MA, et al.

Cost-of-illness of rheumatoid arthritis and ankylosing spondylitis. Clin Exp Rheumatol. 2009;27(4 suppl 55): S118-S123.

11. Birnbaum H, Pike C, Kaufman R, et al. Societal cost of rheumatoid arthritis patients in the US. Curr Med Res Opin. 2010;26:77-90.

12. Davies A, Cifaldi MA, Segurado OG, Weisman MH. Cost-effectiveness of sequential therapy with tumor necrosis factor antagonists in early rheumatoid arthritis. J Rheumatol. 2009;36:16-26.

13. Kobelt G, Lindgren P, Geborek P. Costs and outcomes for patients with rheumatoid arthritis treated with biological drugs in Sweden: a model based on registry data. Scand J Rheumatol. 2009;38:409-418.

14. Brennan A, Bansback N, Nixon R, et al. Modelling the cost effectiveness of TNF-alpha antagonists in the management of rheumatoid arthritis: results from the British Society for Rheumatology Biologics Registry.

Rheumatology (Oxford). 2007;46:1345-1354.

15. Benucci M, Li Gobbi F, Sabadini L, et al. The economic burden of biological therapy in rheumatoid arthritis in clinical practice: cost-effectiveness analysis of sub-cutaneous anti-TNF-alpha treatment in Italian patients. Int J Immunopathol Pharmacol. 2009;22:1147-1152.

VOL. 2

I

NO. 3

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

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

Editorial Advisory Board members provide expert commentaries and perspectives on value-based care in all rheumatic diseases and offer expert opinion on relevant topics and new developments in the field, including new and emerging drug therapies, managing patients with rheumatic diseases, practice management, as well as payers and policy issues affecting rheumatology practices.

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

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

To be considered for the Editorial Advisory Board of this exciting new publication, please complete this form.

Incomplete forms will not be considered.

Your Information _____________________________________________________________________________________ First Name

Last Name

Credentials

_____________________________________________________________________________________________________ Title Company _____________________________________________________________________________________________________ Address _______________________________________________________________________________________________________ E-mail Phone

www.ValueBasedRheumatology.com

The Rheumatology

Insights Service

Featuring

Subscribe today to the essential roadmap to navigating reimbursement in one of today’s most challenging and competitive markets  Updated a minimum of six times per year  Based on ongoing parallel surveys of 100 rheumatologists and 50 managed care decision makers  Delivers concise and insightful commentary focused on implications for current and emerging immunology brands

Subscribers receive: 1. The 2012 Rheumatology Reimbursement Report 2. Quarterly updates on key topics including biosimilars, manufacturer and sales force reimbursement effectiveness, and rheumatology practice and specialty pharmacy trends – topics tailored to meet subscribers’ key interests and strategic issues 3. Updates throughout the year driven by market and competitive events Premium subscribers also have access to customized, fast-turnaround research with members of the Reimbursement Intelligence Network, our panel of leading managed care decision makers

Contact us at info@reimbursementintelligence.com for subscription rates and information on how to subscribe, or call us at 973.805.2300.

2 Shunpike Road, 3rd Floor, Madison, NJ 07940

p: 973.805.2300

e: info@reimbursementintelligence.com

www.reimbursementintelligence.com