VBCR August 2013

august 2013 VOL 2 • NO 4

www.ValueBasedRheumatology.com

EULAR Updates Its Arthritis Guidelines, Focusing on Treatment Priorities, Overtreatment Biologics now seen safer than previously thought

By Phoebe Starr

the Rheumatology nurse™

Nurse-Led RA Programs Can Improve Patient Management Successful interventions provided by rheumatology nurses

By Alice Goodman

EULAR - Madrid

June 2013

Madrid, Spain—The 2013 European League Against Rheumatism (EULAR) guidelines for rheumatoid arthritis (RA) were released for the first time at the 2013 EULAR

annual meeting by Josef S. Smolen, MD, Head, Department of Internal Medicine III, Medical University of Vienna, and Head, Second Medical Department, Hietzing Hospital, Vi-

Madrid, Spain—Two companion studies reported at the 2013 annual meeting of the European League Against Rheumatism (EULAR) show that nurse-led programs can improve the management of patients with rheumatoid arthritis (RA). Physician extender programs such as these can potentially be resource-saving and cost-saving.

The studies evaluated 2 programs led by nurses—a screening program

for comorbidities in patients with RA, who are known to have a high number of concurrent health problems; and a self-assessment program for measuring disease activity according to the 28-joint Disease Activity Score (DAS28).

Screening Program and Self-Assessment Program The first analysis showed that nurse-led screening resulted in more

Continued on page 10

Personalized Medicine in Rheumatology™

New Biomarkers and Biomarker Panels Show Promise for Diagnosing and Monitoring Rapid Response with Brodalumab in Patients with Lupus Continued on page 9

the Treatment of Psoriatic Arthritis A new treatment strategy with a novel IL-17 receptor inhibitor

By Phoebe Starr Madrid, Spain—Data from a phase 2 trial for a novel interleukin (IL)-17 inhibitor, called brodalumab, suggest that it may become a new option for the treatment of psoriatic arthritis. Brodalumab was effective in re-

ducing the signs and symptoms of psoriatic arthritis at week 12, and responses were further improved at week 24.

Previous studies have shown that brodalumab achieves rapid improveContinued on page 19

By Rosemary Frei, MSc There are finally some bright prospects in the search for accurate tools to diagnose patients with systemic lupus erythematosus (SLE) and to monitor

Continued on page 18

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

First standards for rheumatology nurses issued Biomarker 14-3-3η for arthritis FDA UPDATE. . . . . . . . . . . . . . . . . . . . . .

Simponi approved for rheumatoid arthritis

8 8

EULAR ANNUAL MEETING . . . . . 9 Head-to-head comparison of 2 biologics Response faster with biologics than conventional DMARDs

© 2013 Engage Healthcare Communications, LLC

the effects of treatment on the disease, according to the authors of a recent review article (Liu CC, et al. Biomarkers in systemic lupus erythematosus:

HEALTH ECONOMICS. . . . . . . . . . 14 AMPLE: comparing cost-effectiveness of 2 biologics

IN THE LITERATURE . . . . . 14,16 Vitamin D confers modest benefit in lupus TNF inhibitors sustain remission in AS LUPUS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 New diagnostic algorithm for lupus ARTHRITIS UPDATE. . . . . . . . . . . 20 Depression predicts early retirement DRUG UPDATE. . . . . . . . . . . . . . . . . . 21 Ilaris indicated for systemic juvenile idiopathic arthritis CONTINUING EDUCATION. . . 23 Expert perspectives in rheumatology

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

XELJANZ—First in a new class2 Powerful efficacy.

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.

TRA561006-01

© 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/May 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

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 Melissa Lawlor 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.

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VALUE PROPOSITIONS

LUPUS

First standards for rheumatology nurses issued Biomarker 14-3-3η for arthritis diagnosis More…

New diagnostic algorithm for lupus More…

FDA UPDATE

Personalized Medicine in Rheumatology™

Simponi approved for rheumatoid arthritis

New biomarkers for lupus

THE Rheumatology NURSE™

PSORIATIC ARTHRITIS

Nurse-led RA programs improve outcomes

EULAR ANNUAL MEETING

Rapid response seen with brodalumab More…

ARTHRITIS UPDATE

EULAR updates its RA guidelines More…

Depression predicts early retirement More…

HEALTH ECONOMICS

DRUG UPDATE

AMPLE: comparing cost-effectiveness of 2 biologics

Ilaris indicated for systemic juvenile idiopathic arthritis

IN THE LITERATURE

CONTINUING EDUCATION

TNF inhibitors sustain remission in AS More…

Expert perspectives in rheumatology

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.

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

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Value Propositions ANA and Rheumatology Nurses Society Issue First Standards for Rheumatology Nurses

The American Nurses Association (ANA) together with the Rheumatology Nurses Society issued a new guide to contemporary rheumatology nursing titled “Rheumatology Nursing,” which follows the establishment last year of rheumatology nursing as a new nursing specialty.

Victoria Ruffing, RN, CCRP, Cofounder and President of Rheumatology Nurses Society, said, “This achievement advances and validates the role of the professional rheumatology nurse. Moreover, this accomplishment substantiates the nurse as an integral part of the health care team in the treatment and care of individuals with rheumatic diseases.”

This new guide contains up-to-date information on rheumatology nursing practice for registered nurses and advanced practice registered nurses who are practicing or wish to practice in this new specialty. This guide defines the level of nursing practice and professional performance needed by rheumatology nurses in all rheumatology practice settings.

American Nurses Association; August 1, 2013

Biomarker 14-3-3η Can Help the Diagnosis of Arthritis, Detect Disease Activity

Early diagnosis of rheumatoid arthritis (RA) is particularly important for initiating early treatment and preventing joint damage in patients with RA. Researchers have recently discovered that the 14-3-3η protein can detect early inflammatory processes indicative of RA. “14-3-3η is a protein involved in many intracellular functions from cell proliferation to regulating the intracellular communication networks that are involved in various inflammatory processes relevant to rheumatoid arthritis,” according to Walter P. Maksymowych, MD, Consultant Rheumatologist and Professor of Medicine, University of Alberta, Canada.

At the recent European League Against Rheumatism (EULAR) annual meeting, Dr Maksymowych and colleagues presented data from several trials that involved the use of 14-3-3η as a supplemental test for the diagnosis of RA or to determine the response to RA therapy.

Elevated levels of 14-3-3η in blood have been associated with more severe disease activity. In patients undergoing anti–tumor necrosis factor (TNF) therapy, low titers of this biomarker may suggest a good response to therapy, according to Dr Maksymowych.

The researchers presented data from 112 patients with early and established RA who had undergone the biomarker test. An analysis of serum 14-3-3η in their blood samples confirmed the presence of RA in these

patients, even in patients whose C-reactive protein levels were low. The RAPPORT trial included 75 patients with established RA who were using anti-TNF therapy. A serum 14-3-3η analysis at week 15 showed that the 20% of patients who achieved a good response to therapy had 0.72 ng/mL median serum 14-3-3η levels at baseline compared with 2.52 ng/mL for those who did not respond as well to therapy. EULAR, June 12-15, 2013; Madrid

Biomarker β2MG Found in Saliva May Help the Diagnosis of Sjögren Syndrome

Elevated levels of the biomarker β2 microglobulin (β2MG), a polypeptide found in saliva and serum, combined with sodium may be a new way to diagnose patients with Sjögren syndrome, according to a new study from Japan. Previous evidence has shown that β2MG in blood is a marker for disease activity in patients with Sjögren syndrome. In this new study, patients with primary or secondary Sjögren syndrome had significantly higher levels of salivary β2MG than healthy controls. The cut-off levels that differentiate between patients with this condition and healthy individuals are 2.3 mg/L for β2MG and 23 mEq/L for sodium. Asashima H, et al. Clin Exp Rheumatol. 2013 Jun 26 (Epub ahead of print)

Azathioprine Safe for Pregnant Women with Inactive Lupus Nephritis

Results of a new study reported at EULAR 2013 indicate that replacing mycophenolate mofetil with the immunosuppressant drug azathioprine 6 weeks before conception in women with inactive lupus nephritis is safe and does not increase their risk for renal flares. Mycophenolate mofetil is often used in this patient population during pregnancy to protect the fetus.

The study involved 54 women who had inactive lupus and quiescent lupus nephritis and who were considering pregnancy. Overall, 31 women received azathioprine and 23 received a tapered dose of mycophenolate mofetil; those in the latter group were switched to azathioprine if no renal or extra-adrenal flare was detected. Of the 48 women who became pregnant, 1 woman in each of the 2 groups had renal flare after delivery, which was successfully treated with steroids. Renal function did not worsen in any of the patients during the mean 31 months of follow-up postpartum.

EULAR, June 12-15, 2013; Madrid

FDA Update Simponi Aria Receives FDA Approval for Rheumatoid Arthritis

The US Food and Drug Administration (FDA) approved a new indication for golimumab (Simponi Aria for infusion; Janssen Biotech) for the treatment of adult patients with moderate-to-severe rheumatoid arthritis (RA) to be used in combination with methotrexate. Only 2 months earlier, the FDA approved golimumab injection for the treatment of patients with ulcerative colitis.

This is the first FDA approval of a fully human anti–tumor necrosis factor (TNF) therapy for infusion. The

8

approval was based on findings from the phase 3 clinical trial known as GO-FURTHER (Golimumab, an AntiTNF-alpha Monoclonal Antibody, Administered Intravenously, in Subjects with Active Rheumatoid Arthritis Despite Methotrexate Therapy).

The study included 592 patients with moderate-to-severe active RA who had at least 6 tender and 6 swollen joints, as well as elevated C-reactive protein levels, and who had been receiving background methotrexate for ≥3 months.

At week 14, 30% of the patients receiving golimumab plus methotrexate achieved at least a 50% improvement

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in American College of Rheumatology (ACR) response criteria (ACR50) compared with 9% of the patients receiving placebo plus methotrexate (95% confidence interval, 15.3-27.2).

Significant improvements in ACR20 were seen as early as week 2: 33% of patients achieved an ACR20 response after 1 infusion of golimumab versus 12% of patients receiving placebo.

Golimumab is administered as an intravenous dose of 2 mg/kg at weeks 0 and 4 and then every 8 weeks. The drug is infused over a 30-minute period.

In the GO-FURTHER trial, golimumab significantly improved the signs

and symptoms of RA by week 24 “and inhibited the progression of structural damage in patients with moderate to severe RA at week 24 and 52,” said Sergio Schwartzman, MD, Director, Inflammatory Arthritis Center, Hospital for Special Surgery, and Associate Professor, Weill Cornell Medical College, New York, NY. This approval “offers rheumatologists a new anti-TNF infusible treatment for patients who demonstrate an inadequate response to methotrexate; having treatment options remains critical for us to continue to meet the needs of our patients,” Dr Schwartzman added. (July 18, 2013) VOL. 2

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EULAR Annual Meeting

AMPLE: Head-to-Head Comparison of Adalimumab and Abatacept Shows Similar Efficacy, Safety

By Phoebe Starr Madrid, Spain—The first randomized, controlled, head-to-head comparison of 2 anti–tumor necrosis factor (TNF) agents showed similar efficacy and safety for adalimumab (Humira) and for abatacept (Orencia) in the treatment of patients with rheumatoid arthritis (RA). As a result of the AMPLE (Abatacept Versus Ada­ limumab Comparison in BiologicNaive RA Subjects with Background Methotrexate) trial, rheumatologists can be comfortable prescribing either drug to patients with RA, experts say.

“The robust data set demonstrates that subcutaneous abatacept and adalimumab are equally efficacious in clinical, functional, and radiographic outcomes in moderate-to-severe RA. This helps clinicians make an informed choice of a biologic agent when an incomplete response to methotrexate occurs. The study is a great leap forward, showing that another treatment is as effective as adalimumab,” said lead investigator Michael H. Schiff, MD, Clinical Professor of Medicine, Rheumatology Division, University of Colorado School of Medicine, Denver, who

presented these results at the 2013 European League Against Rheumatism (EULAR) annual meeting.

A subanalysis of the cost-effectiveness of these drugs was also presented at the meeting (see article on page 14).

AMPLE is a phase 3b randomized, investigator-blinded study of 646 biologic-naïve patients with active RA

“The robust data set demonstrates that subcutaneous abatacept and adalimumab are equally efficacious in clinical, functional, and radiographic outcomes.”

—Michael H. Schiff, MD receiving a stable dose of background methotrexate. Participants were randomized to 1 year of treatment with subcutaneous abatacept or subcutaneous adalimumab.

The 1-year results of AMPLE were presented last year at EULAR, and

showed that both drugs achieved comparable efficacy for the signs and symptoms of RA: 64.8% of the abatacept arm and 63.4% of the adalimu­ mab arm achieved a response of at least a 20% American College of Rheumatology (ACR20) criteria for improvement. Radiographic progression was inhibited in approximately 85% of patients in both arms.

The 2-year results presented at EULAR 2013 demonstrated that responses were similar between the 2 arms and were maintained over the longer-term. ACR20 was achieved in 60% of the abatacept arm versus 59% of the adalimumab arm, ACR50 was achieved in approximately 45% of patients in both arms, and ACR70 was achieved in approximately 30% of both arms. ACR90 was observed in 14.5% of the patients treated with abatacept versus in 8.2% of those who received adalimumab. Overall, 85% of patients in each arm remained free of radiographic progression for the study duration.

Safety was similar in both arms.

Fewer treatment discontinuations resulting from adverse events (3.8%) were seen in the abatacept arm versus

EULAR Updates Its Arthritis Guidelines... enna, Austria. Dr Smolen was quick to point out that the 2013 version is not writ in stone and will not be until it is published later this year.

The updated guidelines differ from the previous 2010 EULAR guidelines in several ways. The new guidelines: • Recommend the use of methotrexate alone or in combination with conventional disease-modifying anti­rheumat­ic drugs (DMARDs) as first-line therapy • Consider all approved biologics as similarly effective, instead of singling out anti­–tumor necrosis factor (TNF) agents, which were the only biologics available in 2010 • State a preference for biologics in combination with methotrexate instead of biologics as monotherapy • Advocate corticosteroid use with DMARDs for up to 6 months, but taper as soon as possible.

The 2013 EULAR guidelines are more general than the 2012 American College of Rheumatology (ACR) guidelines, Dr Smolen told the audience.

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of patients with RA,” he stated, noting that, compared with the 2012 ACR guidelines, there is less focus on safety and contraindications for biologics, because more recent data provide assurance that these drugs do not lead to an increased risk of cancer and infections,

“Following the 2013 EULAR guidelines will avoid overtreatment of 20% to 30% of patients with RA.” —Josef S. Smolen, MD

as had been feared.

A multidisciplinary 33-member task force developed 3 overarching principles and 14 recommendations based on a systematic review of data

—Ulf Müller-Ladner, MD, PhD 9.5% in the adalimumab arm. Discontinuation resulting from serious adverse events was reported in 1.6% of patients receiving abatacept versus 4.9% of patients in the adalimumab arm. The rate of infections leading to discontinuation was very low.

The slight numerical edge for abatacept regarding adverse events was not clinically meaningful, according to EULAR’s Chairperson of the Scientific Programme Committee, Ulf MüllerLadner, MD, PhD, of the JustusLiebig-Universität Giessen, and the Kerckhoff Klinik, Germany.

“The side effects of both drugs were in line with previous experience and, therefore, these safety data shouldn’t affect decision-making. We can use both of these 2 subcutaneous anti-TNF agents. This study provides proof for what we are already doing with RA patients,” Dr Müller-Ladner stated. n

Continued from page 1

on conventional DMARDs, biologics, and their safety. The 3 overarching principles are: 1. The treatment of patients with RA should aim at the best care and be based on shared decision-making with the patient and physician 2. Rheumatologists should provide the primary care for these patients 3. RA incurs high individual, societal, and medical costs, which should all be considered by the rheuma­tologist.

Additional areas of focus are: 1. Focus on early diagnosis and treat to target according to EULAR criteria 2. Initiate treatment of RA as soon as possible with methotrexate plus with a conventional DMARD or a combination of conventional DMARDs 3. Aim to reach disease remission or low disease activity 4. Monitor patients and consider changing therapy if no good response is achieved at 3 months or if the treatment target is not reached in 6 months august 2013

“This study provides proof for what we are already doing with RA patients.”

I

5. Methotrexate monotherapy is no longer recommended for initial treatment 6. No high-dose steroids should be used; low-dose steroids can be part of a treatment strategy, but should be tapered as soon as possible within 6 months 7. After failing conventional DMARD therapy, stratify patients according to better or worse prognosis and treat accordingly: the former, with another conventional DMARD, and the latter with a biologic DMARD 8. In patients with suboptimal response to methotrexate, consider all the biologics as the next step, including TNF inhibitors, as well as abatacept (Orencia), tocilizumab (Actemra), and biosimilars 9. Patients failing an initial TNF inhibitor may try another TNF inhibitor, or a biologic with a different mechanism of action 10.

Tofacitinib (Xeljanz) should be considered after biologic therapy failure, but preferably after 2 failures, until more safety data are available. n

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The Rheumatology Nurse

™

Nurse-Led RA Programs Can Improve... than twice as many necessary medical interventions per patient compared with the control group. The second analysis showed that teaching patients how to self-assess dis-

“Patients with RA have high rates of comorbidity that often go undetected.

Screening by nurses is feasible, and our results show it is valuable. Nurseled programs align with EULAR’s projects to promote nurse involvement in patient management.”

—Laure Gossec, MD, PhD ease activity and bringing booklets with patients’ recorded DAS28 scores to clinic visits resulted in significantly more changes in disease-modifying antirheumatic drug (DMARD) therapy compared with controls.

Both studies were part of COMEDRA, a 6-month trial of 488 patients with stable RA who were attending 1

of 20 treatment centers in France. Patients were randomly assigned to a nurse-led screening program for comorbidity or to a nurse-led disease self-management program.

After 6 months, patients in one group switched to the other group.

“We wanted all patients to be able to have the advantage of participating in these 2 nurse-led programs,” stated lead investigator Maxime Dougados, MD, Professor of Rheumatology, René Descartes University, and Chief, Department of Rheumatology, Hôpital Cochin, Paris, France.

In the comorbidity screening program, nurses screened patients for cardiovascular disease, infection, cancer, and osteoporosis, and then flagged patients’ records if further action was necessary (ie, a mammogram screening or a vaccination).

Rheumatologists then had the choice of following up or not.

Improved Outcomes Screening led to twice as many medical interventions per patient ordered by the rheumatologist compared with in the control group (4.54 vs 2 interventions per patient, respectively; P <.001).

“Patients with RA have high rates

Continued from page 1

“Treat-to-Target and EULAR recommendations suggest that nurses should be promoting self-management skills so that patients can regularly assess their disease activity. Nurses can teach patients these skills.

Within 6 months, patients’ assessments led to significant changes in RA treatment.”

—Susan M. Oliver, RN, MSc

of comorbidity that often go undetected. Screening by nurses is feasi-

ble, and our results show it is valuable. Nurse-led programs align with EULAR’s projects to promote nurse involvement in patient management,” explained Laure Gossec, MD, PhD, of the Service de Rhumatologie B, Hôpital Cochin, Paris, France.

“Treat-to-Target and EULAR recommendations suggest that nurses should be promoting self-management skills so that patients can regularly assess their disease activity.

Nurses can teach patients these skills.

Within 6 months, patients’ assessments led to significant changes in RA treatment,” said Susan M. Oliver, RN, MSc, Chairperson, Standing Committee of Health Professionals in Rheumatology, EULAR, and Nurse Consultant, Susan Oliver Associates, United Kingdom.

After 6 months, the nurse-led selfassessment program resulted in changes in DMARD therapy in 17.2% of the patients in the self-assessment group versus 10.2% in the control group (P = .012).

“We know the Treat-to-Target treatment regimen is based on the DAS score, and if patients understand how that works, it makes it easier for them to comply and become partners in treatment,” Ms Oliver said. n

EULAR Annual Meeting

Conventional DMARD Regimen Comparable to Biologic, but Patient’s Response Faster with the Biologic Regimen

By Phoebe Starr

Madrid, Spain—A 3-drug regimen of methotrexate, sulfasalazine, and hydroxychloroquine was as effective as a combination of etanercept (Enbrel) and methotrexate, and was $10,200 cheaper annually for patients with active rheumatoid arthritis (RA) who failed to respond to methotrexate, according to a study presented at the European League Against Rheumatism and published online concurrently (O’Dell JR, et al. N Engl J Med. 2013;369:307-318).

But not so fast, say experts. This was a noninferiority, not a superiority, study, and patients feel dramatically better more rapidly with the biologic plus methotrexate than with the 3-agent conventional disease-modifying antirheumatic drug (DMARD) regimen, said Philip J. Mease, MD, Rheumatologist, Swedish Hospital, Seattle, WA,

10

who was not involved in the study.

The horse may already be out of the barn, according to an editorial in the same issue (Bathon JM, McMahon DJ. N Engl J Med. 2013;369:384-385). “We have to consider, however, whether these findings have arrived too late to influence modern practice, in which arguably a TNF inhibitor is the preferred next step when methotrexate alone is inadequate,” Bathon and McMahon wrote. They also noted that it will be interesting to see if third-party payers will change their reimbursement policy to require failure of triple-drug therapy before okaying a biologic.

“Our findings suggest that a strategy of first administering triple therapy, with a switch to etanercept-methotrexate in patients who do not have an adequate response to triple thera-

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py, will allow a substantial percentage of patients to be treated in a more cost-effective way without adversely affecting the clinical outcomes,” stated lead investigator James R. O’Dell, MD, Chief, Rheumatology, VA Nebraska-Western Iowa Health Care System, Omaha Medical Center.

The study randomized 353 patients with active RA despite methotrexate therapy to receive the triple regimen (ie, sulfasalazine, hydroxychloroquine, and methotrexate) versus etanercept plus methotrexate. Nonresponders were switched to the other arm for the next 24 weeks (total of 48 weeks).

Both groups had comparable characteristics at baseline. The mean 28-joint Disease Activity Score (DAS28) was 5.8 and mean disease duration was 5.2 years. Patients had an adequate trial on methotrexate before randomization.

During the first 24 weeks, both groups had comparable and significant improvement from baseline (P <.001), according to the DAS28.

Among the 27% of patients in each group with an inadequate response who switched therapy at 24 weeks, both groups of former nonresponders achieved similar and significant improvement on the DAS28 at 48 weeks.

At 48 weeks, the change in disease activity on the DAS28 was –2.1 for triple therapy and –2.3 for etanercept plus methotrexate. Radiographic progression was not significantly different between the 2 groups at 48 weeks, but trended slightly toward etanercept/methotrexate at 24 weeks.

No difference was observed between the groups’ function, pain, and quality of life, and major treatment-related adverse events. n VOL. 2

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NO. 4

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

Health Economics

Ample: Comparing Cost-Effectiveness of 2 Biologics for the Treatment of Rheumatoid Arthritis

By Alice Goodman Madrid, Spain—Abatacept (Orencia) and adalimumab (Humira) were similarly cost-effective for the treatment of adults with rheumatoid arthritis (RA) who had an inadequate response to methotrexate, according to a cost-effectiveness subanalysis of the AMPLE (Abatacept Versus Adalimumab Com­ parison in Biologic Naive RA Subjects with Background Methotrexate) trial (see article on page 9).

AMPLE is notable as the first randomized, controlled, head-to-head comparison of 2 biologics for the treatment of active RA despite methotrexate treatment. “AMPLE demonstrated the comparable efficacy and safety of subcutaneous abatacept and adalimumab, an anti-TNF [tumor necrosis factor] biologic, on background methotrexate at 12 months,” the investigators stated.

“The cost-effectiveness is comparable, based on measures of clinical efficacy and patient-reported outcomes,” said lead investigator Dinesh

Khanna, MD, MS, MBBS, Division of Rheumatology, University of Michigan, Ann Arbor, who presented the poster at the 2013 annual meeting of the European League Against Rheumatism.

“The cost-effectiveness is comparable, based on measures of clinical efficacy and patient-reported outcomes” in AMPLE. —Dinesh Khanna, MD, MS, MBBS

AMPLE included adult patients with RA for at least 5 years with moderate-to-high disease activity, defined as a 28-joint Disease Activity Score (DAS28) C-reactive protein of at least 3.2, despite treatment with methotrexate of at least 15 mg week-

ly. AMPLE is an ongoing trial of 24 months, duration. The primary end point was efficacy at 1 year.

Cost Comparisons At year 1, the cost-efficacy ratio between the 2 agents for all American College of Rheumatology response rates was comparable for both treatments in US dollars and in Euros.

Other outcomes that were comparable for both treatments at 1 year included: • Cost per remission: abatacept, $63,282; adalimumab, $67,947 • Cost per Health Assessment Questionnaire response: abatacept, $45,366; adalimumab, $49,947 • Cost per day gained without ac­ tivity limitation: abatacept, $323; adalimumab, $380.

These costs reflect the cost of the biologic therapy only, excluding any other direct or indirect costs, the investigators note.

Patients in the United States and in

Germany were randomly assigned to self-administer subcutaneous abatacept 125 mg weekly (N = 318) or to adalimumab 40 mg biweekly (N = 328) with prefilled syringes. No loading dose was administered to patients in the abatacept arm of the study. During the study, patients also received stable doses of methotrexate, between ≤15 mg and ≥25 mg weekly, except for patients with documented intolerance to methotrexate, who received ≥7.5 mg weekly.

The annual cost of therapy was based on the approved net costs per unit dose of both drugs in the United States and in Germany multiplied by the frequency of administration per dose. The cost of methotrexate was not included in the calculation, based on the assumption that it was the same for both treatments.

The investigators caution that this study did not evaluate safety, which could affect the costs that were factored into the economic analysis. n

In The Literature Partial Remission Sustained with TNF Inhibitors in Patients with Ankylosing Spondylitis

Few studies have addressed whether certain clinical and laboratory characteristics predict partial remission (PR) in patients with ankylosing spondylitis who are taking the anti–tumor necrosis factor (TNF) inhibitors infliximab (Remicade), etanercept (Enbrel), or adalimumab (Humira). A recent study has investigated the possibility of achieving PR in patients with ankylosing spondylitis who were treated with 1 of these 3 agents in a real-world clinical practice setting (Spadaro A, et al. Rheumatology [Oxford]. 2013 July 22.

[Epub ahead of print]).

This retrospective, multicenter study was conducted to determine PR rates in patients with ankylosing spondylitis who were treated with adalimumab, etanercept, or infliximab from June 2000 to March 2012 (range of follow-up, 6-142 months). Clinical and laboratory features at baseline that were associated with PR were also assessed.

A total of 283 patients were treated

14

with adalimumab (N = 53), etanercept (N = 76), or infliximab (N = 154).

Adali­mumab 40 mg every other week and etanercept 25 mg twice weekly or 50 mg weekly were administered subcutaneously; infliximab was given intravenously (3 mg/kg-5 mg/kg) at weeks 0, 2, and 6, and then every 6 to 8 weeks. PR was reached when the score was <20 mm (on a visual analog scale of 0 mm-100 mm) in each of the 4 domains—patient global assessment, pain, function, and inflammation.

At 12 weeks of exposure to the first anti-TNF drug, the PR rate was 26.5%, and it continued to increase, to 57.6%, after a median (25th-75th percentile) interval of 4 (range, 3-9) months. Using Kaplan-Meier survival curves, the probability of obtaining PR with 1 of these 3 agents was not significantly different among the different patient groups. The overall rate of discontinuation after the first anti-TNF agent was 19.8% (N = 56).

Of these 56 patients, 37 started treatment with a second anti-TNF agent and achieved a PR rate of 40.5%. In patients switching for lack of a response, the probability of achieving

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PR with the second anti-TNF agent was significantly lower than with the first anti-TNF agent (P = .003). Furthermore, the presence at baseline of enthesitis (P = .04), psoriasis (P = .001), or low levels of C-reactive protein (P = .022) values yielded a lower probability of achieving PR compared with patients without these clinical or laboratory manifestations at baseline.

The results from this real-world setting on PR confirmed the sustained effectiveness of TNF inhibition for patients with ankylosing spondylitis.

Increasing Vitamin D Intake in Patients with Lupus Provides Modest Benefit

Several studies have suggested a possible link between systemic lupus erythematosus (SLE) and vitamin D insufficiency. In a new study of patients with SLE who had low levels of vitamin D, researchers investigated whether vitamin D supplementation was associated with improvements in disease activity (Petri M, et al. Arthritis Rheum. 2013;65:1865-1871).

This longitudinal, observational, 128-week study included 1006 patients with SLE from the Hopkins Lupus Cohort; patient serum levels of 25-hydroxyvitamin D (25[OH]D) were measured at each visit. Patients whose levels were below the recommended 40 ng/mL were given weekly doses of 50,000 units of vitamin D2 plus 200 units of calcium/vitamin D3 twice daily. The association between vitamin D levels and disease activity was estimated through longitudinal regression models. Outcomes were disease activity as measured on the Physician’s Global Assessment score, the Safety of Estrogens in Lupus Erythematosus—National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and the urine protein-to-creatinine ratio. The cohort was primarily women (91%), with a mean age of 49.6 years.

For patients with 25(OH)D levels of <40 ng/mL, a 20-unit increase in supplementation was associated with a decline in the Physician’s Global Assessment score of disease activity of 0.04 points (95% confidence interval Continued on page 16

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Lupus

New Diagnostic Algorithm for SLE Can Facilitate Early Treatment, Improve Outcomes

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By Rosemary Frei, MSc he diagnosis of systemic lupus erythematosus (SLE) is challenging, because of the heterogeneous nature of this disease. Early disease is especially challenging because patients often present with severe but uncharacteristic features. A team of rheumatologists has created a diagnostic algorithm based on the differential diagnosis of SLE (Bertsias GK, et al. Nat Rev Rheumatol. 2013 July 9 [Epub ahead of print]).

Although the American College of Rheumatology (ACR) criteria and the recently revised ACR/Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for lupus are helpful, no diagnostic criteria are available. SLE remains a clinical diagnosis.

“The diagnosis of SLE, especially early disease or when major organs are affected in the absence of typical serology, can be challenging,” lead investigator George K. Bertsias, MD, PhD, Rheumatologist, Division of Rheumatology, Clinical Immunology and Allergy, and Faculty of Medicine at the University of Crete, Heraklion, Greece, told Value-Based Care in Rheumatology.

“The proposed algorithm was derived from a combination from the ACR and the revised ACR/SLICC clas-

sification criteria to increase sensitivity, with some amendments and additions based on evidence and our experience with these patients,” Dr Bertsias said.

Dr Bertsias and his colleagues express concerns about the revised ACR criteria, which miss many cases of SLE, particularly in early or minimal disease.

“Common features denoting a collagen vascular disease, such as Raynaud phenomenon, have been left out, whereas photosensitivity—a distinct feature of SLE—has been combined with rash, which might lead to a delay in diagnosis,” the team wrote. “Major organ manifestations (namely myocarditis, pneumonitis, pulmonary hemorrhage, aseptic meningitis, Libman-Sacks endocarditis and chorea), although not common, were left out; these features, although rare, might provide helpful hints in the diagnosis of SLE.” The Algorithm The algorithm provides a detailed guide to the differential diagnosis of SLE, outlines the manifestations of major and minor organ involvement combined with the presence of an immunologic disorder that suggest SLE, possible SLE, or undifferentiated connective tissue disease.

The algorithm lists the suggested

“The diagnosis of SLE, especially early disease or when major organs are affected in the absence of typical serology, can be challenging.”

—George K. Bertsias, MD, PhD workup for the large range of clinical presentations that may indicate the presence of SLE. For example, patients with a fever “not suggestive of a self-limited disease,” such as a viral infection, should have a complete blood count with a differential white blood cell test; blood chemistry, including lactate dehydrogenase and liver function tests; erythrocyte sedimentation rate or C-reactive protein; urinalysis; blood and urine cultures if the urinalysis is abnormal; and imaging of the lungs or abdomen as indicated by symptoms.

The features at initial presentation that are not suggestive of idiopathic SLE include recurrent infections, hypogammaglobulinemia, autoimmune cytopenias, familial SLE, and many other conditions that are more likely

to have complementary deficiencies suggestive of other conditions.

Once other diseases have been ruled out with this extensive differential, it is likely that a patient who meets the ACR/SLICC criteria for SLE does have this disease. For patients who do not meet the criteria, the physician should evaluate how many forms of major and minor organ involvement the patient has, and whether a SLICC-defined immunologic disorder is involved.

Patients with 1 manifestation of major organ involvement plus 1 manifestation of minor organ involvement and an immunologic disorder, or 1 major organ manifestation and 3 minor organ manifestations, are likely to have SLE. Patients with only 1 manifestation of major organ involvement plus 2 manifestations of minor organ involvement, or 3 manifestations of minor organ involvement plus the presence of an immunologic disorder are deemed to have possible SLE. All other cases are likely to have undifferentiated connective tissue disease.

Dr Bertsias and his colleagues are now prospectively validating the algorithm at the University of Crete in a cohort of 500 patients with SLE. n

Survey Shows Significant Disease Burden on Patients with Lupus and Limitations of Current Treatment Regimens Corticosteroids associated with most side effects, patient dissatisfaction

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n independent survey conducted in 2012 and recently published of patients with systemic lupus erythematosus (SLE) and their physicians confirms the significant burden SLE confers on patients in quality of life and work productivity and the limitations of currently available drug regimens in relieving the considerable impairment (Strand V, et al. Lupus. 2013;22:819826). Despite the limitations of the treatment regimens in controlling disease activity, patients and physicians reported overall satisfaction with current treatment regimens.

Patients taking corticosteroids fared the worst, reporting lower quality of life and less satisfaction with their treatment regimen than patients not using these agents. Fatigue was a major side effect reported by patients

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and caused a low satisfaction level.

“These findings are sufficiently important to encourage us to work to

“These findings are sufficiently important to encourage us to work to develop new therapies.”

—Vibeke Strand, MD

develop new therapies,” said lead investigator Vibeke Strand, MD, Adjunct Clinical Professor of Immun­

ology and Rheumatology, Stanford School of Medicine, Palo Alto, CA. The data for this study came from the Adelphi Real World Lupus Disease- Specific Programme and covered 886 patients treated by 233 rheu­ma­­ tologists. Of these patients, 515 completed a self-assessment questionnaire at the request of their rheumatologists. Overall, 33% of patients reported moderate-to-severe disease activity and 31% had lupus flares in the past 12 months. The treatment regimens included 3 drug classes—cortico­ steroids, immunosuppressants, and antimalarials. Responders with more severe disease activity and with current flares received ≥2 medication classes, including a corticosteroid.

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Overall, 73% of patients and 79% of physicians were satisfied with the current treatment regimens. The numbers dipped, however, to 67.6% and 70.7%, respectively, when only patients receiving corticosteroid-containing regimens were counted. Patient satisfaction with the treatment regimen was 81% when it did not include a corticosteroid compared with 68% when it did (P >.01).

Patients taking corticosteroids reported lower quality-of-life scores and more fatigue than the patients taking the other 2 drug classes.

In addition, patients with moderate or severe disease were less likely to be employed than patients with mild disease activity, at 47%, 44%, and 59%, respectively. More severe disease activity also resulted in more overall work impairment.—RF n

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Ankylosing Spondylitis

Tapering, Not Stopping, Anti-TNF Therapy Appropriate in Patients with Stable Ankylosing Spondylitis

By Alice Goodman Madrid, Spain—Patients with active ankylosing spondylitis who achieve stable disease with anti–tumor necrosis factor (TNF) agents may be able to maintain low disease activity for as long as 2 years after dose reduction of an anti-TNF agent. A small observational cohort study showed that more than 40% of patients who had their doses of an anti-TNF agent reduced substantially still had low disease activity at 2 years.

“In view of the high costs and possible side effects, our aim was to investigate whether dose reduction of TNF-α blocking agents is possible without loss of effectiveness in ankylosing spondylitis patients in daily clinical practice,” according to lead investigator Suzanne Arends, PhD, University Medical Center Groningen, the Netherlands, who presented the results at the 2013 annual meeting of the European League Against Rheumatism (EULAR).

Participants in the trial were drawn from the Groningen Leeuwarden Ankylosing Spondylitis cohort in the Netherlands. The majority of the 49 patients were men (mean age, 46 years);

“In view of the high costs and possible side effects, our aim was to investigate whether dose reduction of TNF-α blocking agents is possible without loss of effectiveness in patients in daily clinical practice.”

—Suzanne Arends, PhD

the mean duration of anky­losing spondylitis symptoms was 20 years.

After treatment with an anti-TNF agent, the mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) of 6.2 was reduced to a mean of 1.8; all patients were stable for 6 months after starting lower doses

of etanercept (Enbrel), infliximab (Remicade), or adalimumab (Humira) before they entered the dose-reduction study. A total of 35 patients were taking etanercept; 8 patients were taking infliximab, and 6 were taking adalimumab.

The anti-TNF therapy doses were lowered by a mean of 37% during the study. After 2 years, 18 (47%) patients had stable, reduced disease activity with the lower doses of the anti-TNF drugs.

The data on dose reduction, reasons for change, and disease activity were collected at 6, 12, 18, and 24 months.

Overall, 71%, 54%, 47%, and 42% of the patients were maintained on dose reduction after 6, 12, 18, and 24 months, respectively.

Among the 25 patients who did not continue to use the lower dose, 23 returned to a conventional dose regimen and 2 withdrew from all TNFalpha blocking therapy: 1 discon­ tinuation was because of an adverse event and 1 was because of an immune reaction.

For the 18 patients who continued to use the reduced dose for 2 years,

disease activity levels remained low (BASDAI score <4) in 86%.

patient self-reported quality of OA care was developed using published QIs, patient interviews, and expert panel assessments. The questionnaire includes QIs that are related to patient education and information, regular provider assessments, referrals, and pharmacologic treatment. Self-reported data were collected from individuals in a Norwegian cohort of patients with OA. The primary end points were test–retest reliability and validity and QI pass rates.

The study included 351 patients (mean age, 64 years; 70% women).

The patient self-reported questionnaire was completed with minimal respondent burden. The test–retest kappa coefficients ranged from 0.20 to 0.80, and the percentage of exact agreement ranged from 62% to 90%.

The content validity of the OA-QI was supported by 2 patient research partners and 2 expert panels. All 10 predefined hypotheses used to construct validity were confirmed (P <.05). The hypotheses reflected antic-

ipated response patterns among patients with OA, including relation to pain level, functional ability, and medication use.

The results indicated large variations in pass rates for separate QIs, with a mean pass rate of 31%. The QI regarding referral for weight reduction had the lowest pass rate (5%) compared with the highest pass rate (49%) related to having received information about the importance of physical activity. Overall, 8 of the 17 QIs had pass rates of <25%. The median score for summary QI pass rates was 27% (interquartile range, 12%-50%). The median summary QI pass rate was lower for nonpharmacologic treatments than for pharmacologic treatments (20% vs 33%, respectively).

These results indicate that the OA-QI questionnaire is appropriate for patients with OA. The low patient self-reported QI pass rates suggest overall suboptimal OA care, highlighting the need for quality improvement in the care of patients with OA. n

Rapid Relapse in Peripheral Spondyloarthritis However, a small study by Dutch investigators from the Academic Medical Center at the University of Amsterdam, who also presented their findings at EULAR 2013, showed that most patients with peripheral spondyloarthritis who achieved disease remission with anti-TNF therapy could not discontinue anti-TNF therapy without relapsing.

Among 26 patients with low disease activity who were using adalimumab for 12 weeks (N = 12) or 24 weeks (N = 14), more than 70% had their disease relapse within 16 weeks of therapy discontinuation, with a concomitant and significant increase in disease activity.

The disease relapse after discontinuation of anti-TNF therapy was rapid, with a mean onset of 10 weeks. Only 4 patients maintained a 66 swollen joint count of zero or an Ankylosing Spondylitis Disease Activity Score of inactive disease for 16 weeks. n

In The Literature Increasing Vitamin D Intake in Patients with Lupus...

Continued from page 14

[CI], −0.08 to −0.01; P = .026). Similarly, a 20-unit increase was associated with a mean decrease of 0.22 (95% CI, −0.41 to −0.02; P = .032) in the SELENA-SLEDAI, corresponding to a 21% decrease in the risk of having a SLEDAI score of ≥5 (95% CI, 1-37). Furthermore, an increase of 20 units was associated with a 2% decrease in the urine protein-to-creatinine ratio (95% CI, −0.03 to −0.01; P <.001), which corresponded to a 15% lower likelihood of having a ratio of less than 0.5 (95% CI, 2-27). In looking at patients with a history of proteinuria and after adjustment for the use of medications, including angiotensin-converting enzyme inhibitors and im­ muno­ sup­ pressants, the 20-ng/mL increase was associated with a 4% decline in the urine protein-to-creatinine ratio (95% CI, 2-5), and the chance of having a ratio of less than 0.5 was decreased again by 15%.

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Although these positive results were statistically significant, the researchers noted that the clinical importance is relatively modest, but real.

No additional benefit was achieved when 25(OH)D levels were increased to more than 40 ng/mL.

First Patient-Reported Osteoarthritis Quality Care Questionnaire Highlights Need to Improve Quality

Quality indicators (QIs) for osteoarthritis (OA) care have been developed to measure QI “pass rates” using medical records or healthcare provider questionnaires. However, the patient perspective of pass rates for QIs in OA has not been investigated. A team of experts has developed the first instrument for patient-reported quality of OA care to assess QI pass rates as reported by patients with OA (Osterås N, et al. Arthritis Care Res [Hoboken]. 2013;65:1043-1051).

The OsteoArthritis Quality Indicator (OA-QI) 17-item questionnaire for

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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 joing us for Surfing Through Rheumatology where nationally known speakers will discuss: 2013 HIPAA changes, healthcare reform, increasing leverage in payer negotiations, effective communication in your practice, and social media. Break-out 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 Conference Registration $350 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

Personalized Medicine in Rheumatology

™

New Biomarkers and Biomarker Panels... challenges and prospects for the future. Ther Adv Musculoskelet Dis. 2013;5:210-233).

The diagnosis of SLE is very challenging, because the disease comprises a wide array of abnormalities and clinical manifestations across many organs, as well as the significant variation between patients. The search for biomarkers for lupus has intensified, and in recent years, the knowledge of SLE pathogenesis has burgeoned, together with an increase in the number of candidate biomarkers.

Focus on Biomarker Panels in Lupus Management According to the authors of this review, new biomarker panels show particular promise for increasing the accuracy of diagnosing, monitoring, and stratifying the severity of SLE. “We have at least one potentially interesting panel, but we need to work more collaboratively to increase the use and refining of the panels that are currently available,” senior author Joseph M. Ahearn, MD, Chief Scientific Officer, Allegheny Singer Research Institute, and Codirector of the Lupus Center of Excellence, West Penn Allegheny Health System, Pittsburgh, PA, told Value-Based Care in Rheu­ma­tology.

Dr Ahearn is a coinventor of one of

the biomarker panels for the diagnosis of SLE. His view, which is shared by many others in the field, is that single biomarkers cannot accurately track this complex disease. Therefore, refining lupus biomarker panels is necessary for optimizing the clinical diagnosis and follow-up of the individual patient.

Continued from page 1

Several groups have tackled the task of creating biomarker panels for lupus: • One panel has been tested on a small number of patients and appears to have some promise. It consists of 30 genes involved in aberrant T-cell function in patients with

“It’s critical that there be continued support for research on biomarkers and biomarker panels. To be able to move forward with personalized or precision medicine, we need to be able to deliver the right drug to the right patient at the right time.”

—Joseph M. Ahearn, MD The array of lupus biomarkers being developed for clinical use includes molecules involved in reduced DNA methylation and histone modification, as well as interferon-inducible proteins, a number of interferons and interleukins, and T-cell–related biomarkers. In addition, anti-C1q antibodies have been shown by several research teams to be very useful for monitoring renal involvement and/or predicting renal flares, noted Dr Ahearn and colleagues.

SLE. Dr Ahearn and his team wrote in their review that this array has potential for diagnosis and stratification of patients with lupus, but it needs to be validated in larger numbers of patients • Another panel comprises a subset of genes that are associated with poor prognosis in patients with SLE, but is in very early stages of testing and refining • The third panel is a 5-biomarker panel called Avise SLE, which is

the one Dr Ahearn coinvented.

“We started with ANA [antinuclear antibodies] and anti-dsDNA [double-stranded DNA]—which have been used for SLE diagnosis for dec­ ades—and added 3 other biomarkers to them. That way, physicians don’t have to relinquish what they’ve been using for a long time,” explained Dr Ahearn.

A study that comprised 210 patients with SLE, 178 patients with other rheumatic diseases, and 205 healthy participants showed that the use of a subset of 4 of these 5 biomarkers— erythrocyte-bound C4d, B-cell–bound C4d, ANA, and antimutated citrullinated vimentin antibody—correctly identified 72% of the patients with SLE. Adding the remaining biomarker, anti-dsDNA, led to 80% sensitivity and 87% specificity rates among the SLE-positive patients.

“It’s critical that there be continued support for research on biomarkers and biomarker panels,” said Dr Ahearn.

“To be able to move forward with personalized or precision medicine, we need to be able to deliver the right drug to the right patient at the right time.

And that starts with getting the diagnosis right—if we don’t have the right diagnosis, then everything else downstream is going to be misdirected and will lead to wasted resources.” n

Psoriatic Arthritis

Updated, Long-Term Results: Apremilast a Promising Oral Option

By Phoebe Starr Madrid, Spain—Apremilast, a novel oral inhibitor of phosphodiesterase 4, achieved sustained improvement in the signs and symptoms of psoriatic arthritis, physical function, and skin improvement in the longer-term follow-up of 52 weeks in the PALACE 1 trial, according to results reported for the first time at the 2013 European League Against Rheumatism (EULAR) annual meeting.

Of patients who failed methotrexate, 63% showed 20% improvement by the American College of Rheumatology 20% criteria for improvement (ACR20) at week 52, and no new safety signals were reported. Few laboratory abnormalities were found, suggesting that frequent monitoring may not be necessary with this agent.

For patients with psoriatic arthritis, “Longer-term follow-up of PALACE 1

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shows that apremilast maintains its efficacy and safety for over a year in patients previously treated with DMARDs [disease-modifying antirheumatic drugs] and/or biologic agents. The longer the data we have, the better,” said lead investigator Arthur F. Kavanaugh, MD, Director of the Center for Innovative Therapy, Division of Rheumatology, Allergy and Immunology, University of California, San Diego.

“We are very happy with these data. We still need to see where its role will be, and perhaps apremilast will be useful for patients who are not refractory to other treatments,” Dr Kavanaugh added.

PALACE 1 is a phase 3, multicenter, double-blind, placebo-controlled, parallel-group study of 504 patients with active psoriatic arthritis despite receiving DMARDs and/or

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biologics for the previous 4 months.

Patients were allowed to continue using background DMARD therapy during the trial.

Patients were randomized to apremilast 20 mg or 30 mg twice daily or to placebo for 24 weeks. At week 24, all patients in the placebo arm were rerandomized to 1 of the 2 apremilast arms.

In 2012, results from week 16 demonstrated the superiority of apremilast versus placebo on ACR20 in 31.3% of the apremilast 20-mg group and in 40% of the apremilast 30-mg group (P <.001 vs placebo) versus 19.4% in the placebo group.

The 52-week results were presented for the first time at EULAR 2013: ACR20 was reached by 63% of the apremilast 20-mg group and by 54.8% of the apremilast 30-mg group. Up to 20% of the patients reached ACR50

and ACR70 (ie, at least a 50% or 70% response in the signs and symptoms of psoriatic arthritis).

Skin improvement was also seen.

Apremilast achieved a 75% improvement on the Psoriasis Area Severity Index in 37% of those receiving the 30-mg dose and in 25% of patients receiving the 20-mg dose.

Treatment-related adverse events were few and comparable between groups. Diarrhea or nausea were the most common adverse events, but were manageable with anticipation and medication.

Most notable is that few laboratory abnormalities were reported for patients who were taking apremilast up to 1 year. “We may not need to monitor patients on apremilast as carefully as those on anti-TNF inhibitors,” Dr Kavanaugh commented. n VOL. 2

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Psoriatic Arthritis

Rapid Response with Brodalumab... ment in the skin, reducing psoriatic plaques markedly. Based on these promising data, brodalumab will enter phase 3 testing.

“Unlike TNF [tumor necrosis factor] inhibitors, brodalumab works more rapidly at the skin than at the joints, while the TNF inhibitors show an effect on the joints earlier than on the skin in PsA [psoriatic arthritis],” said lead investigator Philip J. Mease, MD, of Seattle Rheumatology Associates, and Swedish Medical Center, Seattle, WA, at the 2013 European League Against Rheumatism (EULAR) annual meeting.

Dr Mease told listeners that brodalumab represents one of the first agents with a different mechanism of action than TNF inhibition to show an effect on psoriatic arthritis, providing another treatment option for patients who have had a poor response to TNF inhibitors or who are intolerant to those agents.

Brodalumab is an inhibitor of the IL-17 receptor. IL-17 is implicated in

the pathogenesis of psoriasis and psoriatic arthritis.

“The results suggest that cytokine-targeting strategies aimed at blocking signals through the IL-17

“The results suggest that cytokine-targeting strategies aimed at blocking signals through the IL-17 receptor may represent an important new treatment strategy.”

—Philip J. Mease, MD

receptor may represent an important new treatment strategy,” he stated.

A previous study of brodalumab in patients with psoriasis and >3% skin involvement was conducted by Dr Mease and colleagues. In that

Continued from page 1

study, responses of 75% on the Psoriasis Area and Severity Index (PASI 75) were observed in 77% to 83% of patients, and 100% improvement (PASI 100) was achieved in 39% to 63% of patients.

The study that Dr Mease presented at EULAR 2013 randomized 113 patients with psoriatic arthritis to brodalumab 280 mg (N = 56) or to brodalumab 140 mg (N = 57) and 55 patients to placebo for 12 weeks of double-blind treatment. After that, all patients received open-label brodalumab 280 mg.

At baseline, disease duration was approximately 8 to 9 years, 50% of patients had been previously exposed to a TNF inhibitor, the median number of swollen joints was approximately 13, and the median number of tender joints was approximately 24.

At 12 weeks, a response of at least 20% on the American College of Rheumatology 20% criteria for improvement (ACR20) was reached in

18.2% of patients receiving placebo, 36.8% of patients receiving brodalumab 140 mg, and in 39.3% of patients receiving the 280-mg dose.

There was no difference in response in biologic-naïve or biologic-exposed patients.

Psoriatic arthritis responses were improved over time. At week 24, the ACR20 response was 43.5% with placebo, 51.5% with brodalumab 140 mg, and 64.4% with brodalumab 280 mg. ACR50 and ACR70 were reached in smaller percentages of patients.

Brodalumab improved all components of the ACR measures (ie, swollen joints and tender joints), C-reactive protein level, 28-joint disease activity score, and dactylitis and enthesitis, as well as skin involvement.

Dr Mease noted that the safety data were reassuring, with few serious adverse events. No new safety signals emerged for brodalumab, and there were no opportunistic infections or deaths during the trial. n

Lupus Conference Reports from ACR OCTOBER 26-30, 2013

an e-newsletter brought to you by the publishers of

TOPICS INCLUDE:

Information for payers and healthcare providers treating patients with lupus On-site coverage from ACR/ARHP 2013 Annual Meeting • Review of currently approved and future therapies for lupus • •

www.ValueBasedRheumatology.com VBCR_ACR81313

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Arthritis Update

Depression Predicts Early Retirement in Patients with RA

By Phoebe Starr Madrid, Spain—It is well known that patients with rheumatoid arthritis (RA) have a greater frequency of depression than the general population.

A study presented at the 2013 Euro­ pean League Against Rheumatism (EULAR) annual meeting showed that depression in patients with early RA was the strongest predictor of early retirement, even stronger than disease activity level, response to RA therapy, work-related stress, or comorbid conditions. These findings underscore the need for rheumatologists to ask patients about their mood and to refer them for help if they exhibit signs or symptoms of depression.

“Work absences and work disabil­ ity account for a large proportion of work. Inadequate management of diseases like RA can produce a significant economic burden. Identifying patients who are depressed early in the course of RA using a simple question may help patients remain in the workforce,” said lead investigator Angela Zink, MD, PhD, Head of the Epidemiology Unit, German Rheumatism Research Center, Berlin.

Patients were asked whether they felt a lack of interest in activities on most or some days in the past 2 weeks. Those who answered “most

days” were considered to have more severe depression, whereas those who answered “some days” were deemed to have mild-to-moderate depression.

mately 50% of the sample reported mild-to-moderate or severe depression, as reflected by the response to the statement, “I have had little plea-

“Inadequate management of diseases like RA can produce a significant economic burden. Identifying patients who are depressed early in the course of RA using a simple question may help patients remain in the workforce.”

—Angela Zink, MD, PhD

The study enrolled 573 patients. At baseline, the mean duration of disease was 13 weeks; 67% of patients had rheumatoid factor and/or anticit­ rinullated protein antibody, and 65% fulfilled the 2010 American College of Rheumatology EULAR RA classification criteria at baseline. At 12 months, 87% of patients were taking disease-modifying antirheumatic drugs (DMARDs).

Of the 573 patients, 82% were working, were on sick leave, or were actively employed at baseline. Approxi-

sure or interest in doing things some/ most of the days during the past 2 weeks.”

At 12 months, 67 (12%) patients were actively considering or receiving a disability pension <18 months after the onset of arthritis; of these, 2.6% retired early.

In a univariate analysis, significant predictors of early retirement within the first year of DMARD treatment were age, low education level, fatigue, disease activity, and chronic pain; the strongest predictors were

severe depression and moderate depression. Patients with severe depression (little or no interest in daily activities for most of the days in the previous 2 weeks) were 4.4 times more likely to seek early retirement than those without depression, and those with mild-to-moderate depression (little interest on some of the days in the previous 2 weeks) were 3.1 times more likely to seek early retirement than those without depression.

A multivariate analysis revealed that age and functional level were associated with early retirement; severe depression had the strongest associ­ ation with early retirement. Patients with severe depression were 8.7 times more likely to apply for early retirement than nondepressed patients; patients with mild-to-moderate depression were 3.4 times more likely to apply for early retirement than those without depression.

Dr Zink said she hopes that this study would alert rheumatologists to the importance of screening patients with RA for depression using a simple method like the one she and her coinvestigators used, and then referring patients who exhibit signs of depression for appropriate care. n

Quality-of-Life Data in RA Are Scarce, but Valuable to Rheumatologists and to Patients

By Rosemary Frei, MSc New Orleans, LA—Researchers are highlighting the lack of quality-of-life (QOL) data in studies related to the treatment of patients with rheumatoid arthritis (RA).

In a poster presented at the International Society for Pharmacoeconomics and Outcomes Research 2013 annual meeting, a team of researchers from the United Kingdom showed that QOL information is gathered in only approximately 20% of studies related to RA. They also determined that overall only 26.6% of QOL data “reflect the psychosocial implications of RA and its treatment.”

Lead investigator George Miles, BSc (Hons), Analyst, Costello Medical Consulting Limited, Cambridge, Unit-

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“Rather than collecting more QOL data, the key issue is communicating the current QOL data to rheumatologists, who can then include this in their treatment decisions and inform the patient about these benefits.”

—George Miles, BSc (Hons)

ed Kingdom, told Value-Based Care in Rheumatology that “rather than collect-

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ing more QOL data, the key issue is communicating the current QOL data to rheumatologists, who can then include this in their treatment decisions and inform the patient about these benefits.”

He and his coinvestigators, all of Costello Medical Consulting Limited, searched ClinicalTrials.gov in April 2013 for all completed phase 3 and 4 clinical trials in RA. The team identified 288 studies, 59 of which involved QOL measurement in RA. The most common QOL instrument used in the studies was the Short Form 36-Item (SF-36) health survey questionnaire: 42 trials used this instrument, including 6 that also used the EuroQol (EQ)-5D. In total, 10 stud-

ies used the EQ-5D instrument.

Two trials incorporated the Child Health Questionnaire Parent Form 50 (because several trials included young patients), and 1 trial used the Rheumatoid Arthritis Quality of Life questionnaire. The remaining trials did not specify which QOL instruments were used.

The SF-36 questionnaire produces more information about psychosocial function than the other instruments, the team noted.

Based on their research, the researchers concluded that only a small proportion of trials measure QOL information, and only 26.6% of the data collected in RA-related studies involve psychosocial data. n VOL. 2

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Drug Update

Ilaris (Canakinumab) Receives a New Indication for the Treatment of Systemic Juvenile Idiopathic Arthritis

By Lisa A. Raedler, PhD, RPh

S

ystemic juvenile idiopathic arthritis (SJIA) is a rare inflammatory disease, affecting approximately 10% of children diagnosed with juvenile idiopathic arthritis in the United States.1,2 The classic symptoms of SJIA include pain in the small joints of the hands, wrists, knees, and ankles; rash; and a high, spiking fever of ≥103°F that can last for weeks to months.3 By definition, SJIA can pre­ sent at any point until the age of 16 years. However, a long-term outcomes study found that the median age at diagnosis of SJIA was 4 years.4 The distribution of the disease by sex is roughly equal.1,4 Studies of long-term outcomes of juvenile idiopathic arthritis have demonstrated that disease-related morbidity continues to be evident in adulthood.4,5,6 Among adult patients with SJIA who were evaluated more than 16 years after diagnosis, 66% described joints with limited range of motion, 52% had joint pain, and 30% reported morning stiffness.4 Adult patients with SJIA also experience impaired quality of life and poor physical functioning, as well as long-term challenges with social functioning and sexual activity.5,6 Although analyses of healthcare costs associated with SJIA are few, it is clear that children with juvenile idiopathic arthritis consume inordinate amounts of healthcare resources. A 2007 study of Canadian children showed that the total annual average direct medical cost for patients with juvenile idiopathic arthritis was almost $1700 higher (2005 Canadian dollars; range, $875-$2500) than for the control patients without juvenile idiopathic arthritis.7 Higher costs for patients with juvenile idiopathic arthritis were related to specialist visits, diagnostic tests, and medication use.7 A more recent German study showed that the average total cost of juvenile idiopathic arthritis was highest among patients with seropositive polyarthritis and SJIA.8 The cost of medications, including biologics, comprised almost 50% of the total healthcare costs for these patients.8 Until very recently, the treatment options for patients with SJIA included methotrexate (Trexall); nonsteroidal anti-inflammatory drugs (NSAIDs); systemic corticosteroids; and tociliz­ umab (Actemra), an interleukin (IL)-6 inhibitor. Tocilizumab is indicated for patients with active SJIA aged ≥2 years

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and is administered once every 2 weeks as a 1-hour intravenous (IV) infusion.9 One additional medication was recently added as a new treatment option for this patient population.

FDA Approves Canakinumab for SJIA In May 2013, the US Food and Drug Administration (FDA) approved a new indication for canakinumab (Ilaris; Novartis) for the treatment of active SJIA in patients aged ≥2 years. Canakinumab is the first IL-1 beta inhibitor approved for the treatment of SJIA, and the only approved SJIA treatment that is given as a subcutaneous (SC) injection once monthly.10 The FDA approval of the new indication for canakinumab was based on 2 phase 3 clinical trials of patients with SJIA and demonstrated significant symptom improvement in the majority of patients receiving cana­ kinumab.11 This drug is already approved by the FDA for the treatment of the rare autoinflammatory diseases that form cryopyrin-associated periodic syndromes.

Canakinumab Fills an Unmet Need In an interview regarding the treatment of SJIA with canakinumab, Alberto Martini, MD, Professor of Pediatrics, University of Genoa, Italy, stated, “In…a sizable proportion of patients [with SJIA], there was a big improvement in symptoms, [and] there was the possibility to reduce substantially the amount of steroids that these children were receiving….

Treatment with this type of cytokine inhibitor could radically change the way we are treating [SJIA].”12 The availability of canakinumab for patients with SJIA offers an easier-­touse alternative for children and their families who wish to avoid the logistic and tolerability challenges associated with an IV therapy given every 2 weeks. “The efficacy of Ilaris, along with its monthly subcutaneous dosing, make it an exciting new option for children who are living with this debilitating disease,” said Daniel J. Lovell, MD, MPH, Associate Director, Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, OH.13 Dosing and Administration The recommended dose and schedule of canakinumab in patients with SJIA is 4 mg/kg, with a maximum of 300 mg for patients with a body weight

of ≥7.5 kg. Canakinumab is administered subcutaneously every 4 weeks.11 There are no contraindications to the use of canakinumab, with the exception of patients who have confirmed hypersensitivity to the active substance of canakinumab or to any of its excipients.11 Each monthly SC injection of canakin­ umab costs $16,000.14 Canakinumab’s manufacturer offers financial assistance to eligible patients who are unable to afford treatment with canakinumab.14 Mechanism of Action Canakinumab is a selective fully human monoclonal antibody that inhibits IL-1 beta, one of the proinflammatory cytokines that comprise the body’s immune system’s defenses.11 Excess production of IL-1 beta plays a prominent role in inflammatory diseases, including in patients with juvenile rheumatoid arthritis. Canakin­ umab inhibits inflammation by neutralizing IL-1 beta for a sustained period of time.11

patients received canakinumab 4 mg/ kg (maximum, 300 mg) in part 1 of study 2, and 100 patients received canakinumab 4 mg/kg (maximum, 300 mg) or placebo every 4 weeks in part 2 of study 2.11,15 The primary objective of study 1 was to demonstrate the superiority of a single dose of canakinumab relative to placebo in the proportion of patients who achieved ≥30% improvement in an adapted pediatric American College of Rheumatology (ACR) response criterion, which included the pediatric ACR core set (ACR 30% criteria for improvement [ACR30] response) and the absence of fever (temperature of ≤38°C in the preceding 7 days) at day 15.11,15 The primary objective of study 2 was to demonstrate the prevention of flare with the use of canakinumab in patients with active SJIA. Flare was defined by a worsening of ≥30% in at least 3 of the 6 core pediatric ACR response variables, combined with an improvement of ≥30% in no more than 1 of the 6 variables, or the reappearance of fever not resulting from infection for at least 2 consecutive days.11,15

Phase 3 Clinical Trials Canakinumab was approved by the FDA for the treatment of SJIA on the basis of 2 randomized, multicenter, double-blind phase 3 clinical trials.15 Both trials enrolled patients who had a confirmed diagnosis of SJIA at least 2 months before enrollment in the study (mean disease duration at baseline, 3.5 years); active disease, defined as ≥2 joints with active arthritis (mean number of active joints, 15.4); documented spiking, intermittent fever (>38°C) for at least 1 day within 1 week before study drug administration; and C-reactive protein >30 mg/L.11,15 Patients were allowed to continue treatment with stable doses of methotrexate, corticosteroids, and/ or NSAIDs. The tapering of cortico­ steroid doses was allowed according to the design of the study 2.11,15

Efficacy: Study 1 The analysis of study 1 data revealed a significant improvement in patients receiving a single dose of canakinumab versus placebo at day 15.11 Table 1 presents the percentages of patients by pediatric ACR response rate.11 Among patients with SJIA who returned for their day 15 visit, the mean change in patient pain score (0-100 mm visual analog scale) was –50.0 mm with canakinumab (N = 43) compared with +4.5 mm with placebo (N = 25).11 The mean change in pain score among canakinumab-treated patients was consistent through day 29.11 All patients treated with canakinumab had no fever at day 3 compared with 87% of patients who received placebo.11

Trial Design In study 1, patients with SJIA received a single dose of canakinumab 4 mg/kg (N = 43) or of placebo (N = 41) via SC injection. Patients were then assessed for efficacy at day 15, and had a safety analysis done up to day 29.11,15 The SJIA study 2 had a 2-part design that included an open-label, single-arm, active-treatment period (part 1), followed by a randomized, double-blind, placebo-controlled, event-driven withdrawal design (part 2). Overall, 177

Efficacy: Study 2 Corticosteroid dose tapering. A total of 128 patients who entered part 1 (the open-label portion) of study 2, were taking corticosteroids. Of these, 92 patients attempted corticosteroid tapering. Of these 92 patients, 57 (62%) successfully tapered their corticosteroid doses.11 Almost half (N = 42 [46%]) of the patients discontinued treatment with corticosteroids.11,15 Time to flare. In part 2, the probability of having a flare over time was

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Drug Update

Ilaris (Canakinumab) Receives a New Indication...

Table 1 Pediatric ACR Response in Patients with SJIA at Days 15 and 29 in Study 1: Canakinumab versus Placebo Day 15

ACR30

10

70 (95% CI, 56-84)

Canakinumab (N = 43), %

Placebo (N = 41), % 10

70 (95% CI, 56-84)

67

5

65 (95% CI, 50-80)

79

5

76 (95% CI, 63-88)

60

2

64 (95% CI, 49-79)

67

2

67 (95% CI, 52-81)

Placebo (N = 41), %

ACR70

Weighted differencea %

Weighted differencea %

Canakinumab (N = 43), %

ACR50

Day 29

84

81

Weighted difference is the difference between the canakinumab and placebo response rates, adjusted for the stratification factors (ie, number of active joints, previous response to anakinra, and level of oral corticosteroid use).

ACR indicates American College of Rheumatology; ACR30, ACR 30% criteria for improvement; CI, confidence interval; SJIA, systemic juvenile idiopathic arthritis.

Source: Ilaris (canakinumab) injection [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; May 2013. a

Table 2 Adverse Reactions from 2 Pivotal Clinical Trials of Canakinumab in Patients with SJIA Study 2

Part 1

Part 2

Study 1

Canakinumab (N = 177) N (%); IRa

Canakinumab (N = 50) N (%); IRa

Placebo (N = 50) N (%); IRa

Canakinumab (N = 43) N (%); IRa

Placebo (N = 41) N (%); IRa

Infection (eg, nasopharyngitis, [viral] upper respiratory tract infection, pneumonia, rhinitis, pharyngitis, tonsillitis, sinusitis, urinary tract infection, gastroenteritis, viral infection)

97 (54.8); 0.91

27 (54); 0.59

19 (38); 0.63

13 (30.2); 1.26

5 (12.2); 1.37

Upper abdominal pain

25 (14.1); 0.16

8 (16); 0.15

6 (12); 0.08

3 (7); 0.25

1 (2.4); 0.23

19 (10.7)

6 (12.0)

2 (4.0)

0

3 (7.3)

2 (1.1)

1 (2.0)

0

0

0

Infections

Skin reactions

Injection-site reaction, moderate

b

Incidence rate represents the exposure-adjusted incidence rate per 100 patient-days.

No injection-site reaction led to study discontinuation.

IR indicates incidence rate; SJIA, systemic juvenile idiopathic arthritis.

Source: Ilaris (canakinumab) injection [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; May 2013. a

b

significantly lower for the canakinu­ mab-treated group versus the placebo group. Patients in the canakinumab group had a 64% relative reduction in the risk of flare compared with the patients receiving placebo (hazard ratio, 0.36; 95% confidence interval, 0.17-0.75).11,15 Safety Profile of Canakinumab in SJIA The most common (≥10%) adverse drug reactions in patients with SJIA who received canakinumab were infections (ie, nasopharyngitis, upper respiratory tract infections), abdo­ minal pain, and mild-to-moderate injection-site reactions (Table 2).11,15 Serious infections. IL-1 blockade may interfere with the body’s immune response to infections. Treatment with medications that work through the inhibition of IL-1, including canakinumab, has been associated with an increased risk of serious infections. Physicians should exercise caution when administering canakin­

22

treatment with anti–IL-1 therapy on the development of malignancies is not known. However, treatment with immunosuppressants, including canakinumab, may result in an increase in the risk of malignancies.11 Conclusion For children and adolescents with SJIA, canakinumab offers clinically and statistically significant efficacy benefits, a favorable tolerability profile, and a convenient schedule and route of administration. Experts suggest that biologics, including canakin­ umab, are effective alternatives for children with SJIA who wish to avoid the potentially devastating toxicities of treatment with high-dose corticosteroids.16 Clinical studies are under way to assess the safety and efficacy of the prolonged use of various canakin­umab doses, as well as to elucidate the role of canakinumab and other bio­logics relative to corticosteroids in patients with SJIA.16,17 n References

Gastrointestinal disorders

Injection-site reaction, mildb

Continued from page 21

umab to patients with infections and/or a history of recurring infections or underlying conditions that may predispose them to infections.11 Canakinumab should not be administered to any patient who has an active infection that requires medical intervention.11 Canakinumab should be discontinued if a patient develops a serious infection.11 Immunizations. Live vaccines should not be given concurrently with canakinumab.11 Patients should receive all recommended vaccinations before the initiation of therapy with canakinumab.11 Hypersensitivity. Canakinumab should not be administered to any patients with a known clinical hypersensitivity to canakinumab.11 No anaphylactic reactions have been reported during clinical trials of treatment with canakinumab in patients with SJIA.11 Immunogenicity. A biosensor binding assay or a bridging immunoassay was used to detect antibodies directed against canakinumab in patients who

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received the drug. Antibodies against canakinumab were observed in 3.1% of patients who were treated with canakinumab for SJIA.11 No neutralizing antibodies were detected.11 No apparent correlation of antibody development to clinical response or adverse events was observed.11 Macrophage activation syndrome.

Macrophage activation syndrome is a life-threatening disorder that can develop in patients with rheumatic conditions, in particular in patients with SJIA. Physicians should be attentive to any symptoms of infection or worsening of SJIA, because these are known triggers for macrophage activation syndrome. Of 201 patients with SJIA who were treated with canakinumab in clinical trials, 11 cases of macrophage activation syndrome were observed.11 In clinical trials, canakinumab did not increase the incidence of macrophage activation syndrome in patients with SJIA, but no definitive conclusion can be made at this point.11 Immunosuppression. The impact of

1. Arthritis Foundation. Kids get arthritis too.

Understanding JIA: What is juvenile arthritis? www. kidsget arthritistoo.org/about-ja/the-basics/what-isjuvenile-arthritis-2.php. Accessed July 17, 2013.

2. Gurion R, Lehman TJA, Moorthy LN. Systemic arthritis in children: a review of clinical presentation and treatment. Int J Inflam. 2012;2012:271569.

3. Arthritis Foundation. Juvenile arthritis fact sheet. www.arthritis.org/ja-fact-sheet.php. Accessed June 11, 2013.

4. Minden K, Niewerth M, Listing J, et al. Long-term outcomes in patients with juvenile idiopathic arthritis.

Arthritis Rheum. 2002;46:2392-2401.

5. Bernatsky S, Duffy C, Malleson P, et al. Economic impact of juvenile idiopathic arthritis. Arthritis Rheum.

2007;57:44-48.

6. Minden K, Niewerth M, Listing J, et al. The economic burden of juvenile idiopathic arthritis: results from the German paediatric rheumatologic database. Clin Exp Rheumatol. 2009;27:863-869.

7. Packham JC, Hall MA. Long-term follow-up of 246 adults with juvenile idiopathic arthritis: functional outcome. Rheumatology (Oxford). 2002;41:1428-1435.

8. Packham JC, Hall MA. Long-term follow-up of 246 adults with juvenile idiopathic arthritis: social function, relationships and sexual activity. Rheumatology (Oxford). 2002;41:1440-1443.

9. Actemra (tocilizumab) injection [prescribing information]. South San Francisco, CA: Genentech, Inc; April 2013.

10. Grogan K. Second FDA thumbs-up for Novartis Ilaris. Pharma Times Online. May 10, 2013. www.pharma times.com/article/13-05-10/Second_FDA_thumbsup_for_Novartis_Ilaris.aspx. Accessed June 19, 2013.

11. Ilaris (canakinumab) injection [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; May 2013.

12. SBARTSTV. Global medical news: ACZ885 a targeted therapy for SJIA and TRAPS. YouTube. June 6, 2013. www.youtube.com/watch?v=N5hyY7anV7M. Accessed June 19, 2013.

13. Novartis Media Relations. Novartis drug Ilaris approved by FDA to treat active systemic juvenile idiopathic arthritis, a serious form of childhood arthritis.

Press release; May 10, 2013. www.novartis.com/news room/media-releases/en/2013/1700796.shtml.

Accessed June 19, 2013.

14. Rath L. FDA approves Ilaris for systemic JIA: a biologic drug holds promise for kids with severe childhood arthritis. Arthritis Today. May 17, 2013. www.arthritistoday.org/news/ilaris-approved-forjia-272.php. Accessed June 19, 2013.

15. Ruperto N, Brunner HI, Quartier P, et al; for the Paediatric Rheumatology International Trials Organisation and the Pediatric Rheumatology Collaborative Study Group. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis.

N Engl J Med. 2012;367:2396-2406.

16. Schneider R, Laxer RM. Systemic juvenile idiopathic arthritis. Rheumatologist. May 2012. www. the-rheumatologist.org/details/article/2041587/ Systemic_Juvenile_Idiopathic_Arthritis.html. Accessed June 19, 2013.

17. ClinicalTrials.gov. Canakinumab SJIA.Search results. http://clinicaltrials.gov/ct2/results? term= cana­ kinumab+SJIA&Search=Search. Accessed June 19, 2013.

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Continuing Education

Expert Perspectives in Rheumatology: Case-Based Scenarios for Using Personalized Biologic Therapy in Rheumatoid Arthritis

By Sy Schlager, MD, PhD

R

heumatoid arthritis (RA) is the most common chronic autoimmune inflammatory arthritis, with a prevalence of approximately 1%, with women being affected twice as frequently as men.1 The pathogenesis of RA involves an overexpression of several inflammatory cytokines, in cluding tumor necrosis factor (TNF)-α, interleukins, and proteinases, which results in an inflammatory synovitis that can lead to cartilage and bone destruction. Indeed, most patients with RA show evidence of joint erosions within the first year of being diagnosed with the disease.2,3 RA is a progressive disease

and leads to a number of characteristic signs and symptoms, including pain and swelling of the synovial joints, constitutional symptoms, and extraarticular manifestations that eventually lead to functional decline and disability, reduced quality of life (QOL), and premature mortality, all of which contribute to a significant economic impact to society.2 The objectives of RA therapy are to control clinical symptoms and slow or halt the radiographic progression and structural damage of the disease, improve function, and normalize QOL. Recently, there have been several important paradigm changes in the treat-

Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Commercial Support Acknowledgment This activity is supported by an educational grant from Amgen, Inc. Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the management of patients with rheumatoid arthritis.

Purpose Statement The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the treatment of rheumatoid arthritis.

Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Registered Nurse Designation Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.0 contact hour.

Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this application-based activity provides for 1.0 contact hour (0.1 CEU) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-13-015-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Discuss safety and efficacy data on existing and emerging biologic agents in the treatment of patients with rheumatoid arthritis, and how to integrate key findings into clinical practice • Outline advances in the use of prognostic molecular biomarkers and objective disease metrics in managing patients with rheumatoid arthritis Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships.

Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute Inc for fair balance, scientific objectivity

ment of RA with respect to selecting and modifying initial therapy based on objective measures of disease activity and patient responses, balancing the efficacy of biologic therapy with the safety issues associated with biologic agents, and personalizing therapy through the improved use of biomarkers and pharmacodynamic measurements to drive treatment. This article will summarize these concepts and provide a perspective on how they can be applied to daily practice.

The Treat-to-Target Paradigm A major advance in the treatment of RA is the concept that optimal

clinical outcomes are achieved with an early, aggressive treat-to-target approach, in which the target is disease remission or low disease activity.

A number of clinical trials (including the CAMERA,4 TICORA,5 BeSt,6 SWEFOT,7 FIN-RACo,8 and TEAR9 trials) have shown the effectiveness of early intensive therapy and tight control in providing the best clinical outcomes for patients with RA, especially those with early disease. Taken together, these and other studies have also demonstrated that it is possible to implement such strategies into clinical practice.10,11 The latest updates to the American College of Rheumatology

of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

The associates of Medical Learning Institute Inc, the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CPE/CE activity for any amount during the past 12 months.

Planners’ and Managers’ Disclosures Sy Schlager, MD, PhD, Medical Writer, has nothing to disclose. He does not intend to discuss any non–FDA-approved or investigational use for any products/devices.

William J. Wong, MD, MLI Reviewer, has nothing to disclose.

Faculty Disclosure Ronald F. van Vollenhoven, MD, PhD, has received research support from AbbVie, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Roche, and UCB, has received trial support from Lilly, is a consultant for AbbVie, Biotest, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Merck, Pfizer, Roche, and UCB, and is a global principal investigator for Biotest. He does not intend to discuss any non–FDA-approved or investigational use for any products/devices.

Disclaimer The information provided in this CME/CPE/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition.

Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this program should be inferred.

Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CPE/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P13014.html.

Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records.

For questions regarding the accreditation of this activity, please contact Medical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org.

For pharmacists, Medical Learning Institute Inc will report your participation in this educational activity to the NABP only if you provide your NABP e-Profile number and date of birth. For more information regarding this process or to get your NABP e-Profile number, go to www.mycpemonitor.net.

Estimated time to complete activity: 1.0 hour Date of initial release: August 8, 2013 Valid for CME/CPE/CE credit through: August 8, 2014

Supported by an educational grant from Amgen, Inc.

This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC.

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Continuing Education terms of halting inflammation and radiographic progression of disease. The controversy regarding the need for continuous maintenance biologic therapy may be resolved in future trials of longer duration.

Case 1: Rachel is a 37-year-old woman with a 6-month history of pain

and swelling in both wrists, hands, feet, and knees. On physical exam, you note tenderness over several pressure points in arms and legs, knees, and lumbar spine as well as moderate swelling and pain to palpation in both knees and the metatarsophalangeal joints of both hands.

Laboratory results show that she is RF negative, with an ESR of 14 mm/hr. Plain X-rays are unremarkable. Your provisional diagnosis is early RA with moderate disease activity.

Q: What are your management options for this patient?

• Further diagnostic workup • Multimodal evaluation of disease activity • Trial course of nonsteroidal anti-inflammatory drugs • Trial course of corticosteroids • Trial course of methotrexate • 3-Month course of methotrexate; if no improvement, discuss options for biologic therapy A: Once a diagnosis of early RA is made, ACR guidelines recommend a course of methotrexate, with reevaluation at 3 months. If there is still evidence of active disease, addition of a biologic should be discussed. Objective multimodal disease activity assessment at baseline and with each treatment change should be monitored using the ACR guidelines discussed in this article.

Q: What is your treatment target for this patient?

A: Using treat-to-target guidelines, disease remission is your target, with low disease activity as a fallback objective.

(ACR) recommendations concur with this approach.12 Results from a series of pivotal trials largely confirm these earlier findings.

For example, results from the CERTAIN trial showed that patients with moderate RA benefit significantly from anti-TNF therapy and that this incremental benefit is maintained as long as the patients continue treatment with the biologic.13 Moreover, numerous trials, such as the one shown in Figure 1, have demonstrated that early, aggressive treatment with biologic therapy (in this case, the TNF inhibitor etanercept), can significantly reduce absenteeism from the workplace due to disability caused by RA.14 However, there is some controversy as to whether it is necessary to maintain a biologic agent once an initial response is obtained with biologic in-

duction therapy. In the OPTIMA trial, patients who responded initially to adalimumab plus methotrexate were subsequently able to discontinue the biologic and maintain good clinical responses with methotrexate alone.15 However, in the HIT HARD trial, patients with early RA treated with adalimumab plus methotrexate who showed a positive clinical response required continued biologic therapy to maintain their improvements in radiographically measured outcomes; methotrexate alone was not effective in preventing further radiographic damage.16 The take-away message from all of these trials is that patients with newly diagnosed or mild to moderate RA do benefit significantly from early induction therapy with a biologic agent in combination with methotrexate in

Balancing Efficacy and Safety of Biologic Therapy RA is a chronic, progressive disease that can result in significant disability and poor QOL in patients who are not treated aggressively,4-11 but which is clearly improved with aggressive treatment.17 However, biologic agents that have been approved for RA are associated with increased risks for certain adverse events, including a heightened susceptibility to opportunistic infections, a risk of reactivation of tuberculosis, and a greater risk for certain malignancies such as lymphoma.18-22 Benefits of biologic therapy in preventing or delaying disease progression and disability include reductions in hospitalizations, utilization of healthcare resources, job-related loss in income, and loss of work productivity.

Balancing such benefits against the increased risk for serious adverse events that may be associated with these agents has been of primary concern to healthcare providers and remains a major issue in the use of biologic therapy in RA.23 Treatment is further complicated because patients with RA often experience comorbidities of an inflammatory nature and have a heightened risk of cardiovascular disease (CVD).24-28 Evidence has accumulated that early and aggressive treatment of the primary rheumatic disease has a salutary effect on other inflammatory conditions in these patients and reduces their risk of heart attack and stroke, diabetes, renal dysfunction, and other microvascular morbidities,26,29,30 thereby further reducing their potential utilization of healthcare resources.

Figure 1 Reduction in absenteeism in patients with RA treated with a TNFi, alone or with MTX in the RADIUS 2 trial.14

2.4 P<.0001

2.0 1.6

Combination Therapy (MTX + ETN)

P<.0001

Mean No. of Times Missed Work for Half a Day or More in Prior Month

Mean No. of Times Missed Work for Half a Day or More in Prior Month

ETN Monotherapy

1.64

1.2 0.72

0.8

0.83

0.4 0 Baseline (n = 596)

6 months (n = 577)

12 months (n = 596)

P<.0001

2.4 P<.0001

2.0 1.6

1.43

1.2 0.66

0.8 0.4 0 Baseline (n = 895)

ETN indicates etanercept; MTX, methotrexate; RA, rheumatoid arthritis; TNFi, tumor necrosis factor inhibitor.

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6 months (n = 875)

12 months (n = 596)

These findings were solidified by the results of a number of presentations reflecting epidemiologic studies from around the world. In each case from large cohort studies in the United States, Europe, Asia, and South America, a clear association was found between the disease severity of patients with RA and the likelihood of them developing CVD (including myocardial infarction, stroke, diastolic heart failure, and other atherosclerotic processes), venous thromboembolism, dyslipidemia, anemia of chronic disease, thyroid disease, and reduced life expectancy.31-43 What is particularly striking about many of these studies is that they showed that the likelihood of patients with RA developing CVD was more closely linked to their rheumatoid disease activity than to their cardiovascular risk profile, the increased risk of these comorbid events frequently occurred early in the course of their RA, and persistence of the comorbid diseases was dependent on RA disease activity more than on effective treatment of the comorbid condition.32,33,38,40,42 In contrast, early and aggressive treatment of RA with biologic therapy was shown to reduce the risk of cardiovascular events more effectively than attempts to reduce conventional cardiovascular risks; such treatment increased patients’ life expectancy.44,45 For example, in a study by Singh and colleagues, combination therapy with a TNF inhibitor plus methotrexate reduced the risk for acute myocardial infarction by 80% over methotrexate alone and significantly better than steroids (Figure 2).46 Thus, we have the following benefit–risk conundrum: • There is clear evidence that early and aggressive treat-to-target biologic therapy of RA provides improved clinical outcomes compared with conventional disease-modifying antirheumatic drugs (DMARDs) alone, in terms of both halting the progression of RA and reducing the risks of life-threatening comorbid conditions • There is clear evidence that most biologic agents are associated with a small but measurable increased risk in potentially serious adverse events compared with conventional DMARDs alone.

Using Biomarkers and Disease Activity Measures to Personalize Treatment A significant advance in the treatment of RA that attempts to circumvent the benefit–risk conundrum described above is the adoption of a highly selective, personalized approach to therapy, based on authoritative guidelines and emerging clinical data. For example, VOL. 2

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Continuing Education Figure 2 The combination 46of a TNFi plus MTX reduces the risk of acute MI in patients with RA. 6 TNFi/DMARD

Acute MI relative risk (relative to MTX Rx)

5 4 TNFi

3 2 DMARD 1

Combo DMARDs TNFi/MTX

Steroids

0 DMARD indicates disease-modifying antirheumatic drug; MI, myocardial infarction; MTX, methotrexate; RA, rheumatoid arthritis; Rx, treatment; TNFi, tumor necrosis factor inhibitor.

in 2010, the ACR and The European League Against Rheumatism (EULAR) presented new criteria for the diagnosis of RA that stressed early diagnosis and emphasized the relative importance of joint disease, the presence of rheumatoid factor (RF) and/or anticyclic citrullinated peptide (anti-CCP) antibody, disease duration >6 weeks, and an elevated erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP).47 In addition, ACR recommendations that were updated in 2012 suggest that treatment decisions should be based on the severity of disease activity as measured by objective quantitative methods such as Disease Activity Score 28-joint count (DAS28) scores or the Clinical Disease Activity Index (CDAI), as well as on prognostic factors associated with poor outcomes.12 Poor prognostic features include functional limitation as measured by the Health Assessment Questionnaire (HAQ), the presence of extraarticular disease (including nodules, vasculitis, or Felty syndrome), positive serology for RF or the presence of anti-CCP antibody, and/or bony erosions on plain radiographs.12 The ACR 2012 RA treatment recommendations also include the use of quantitative disease activity measures to drive therapeutic choices; these measures are either patient reported (eg, the Patient Activity Scale [PAS or PAS-II] or the Routine Assessment of Patient Index Data 3 [RAPID3]) or composite measures of patient-reported and physician-determined assessments (eg, tender and swollen joint counts, DAS28, CDAI, and the Simplified Disease Activity Index [SDAI]).12 The ACR recommendations include the need to achieve disease remission or low disease activity and also describe the value of a new treat–to-target strategy to achieve control of disease activity. Both EULAR48 and an international task force on RA49 emphasize similar recommendations, which include: VOL. 2

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• The primary target for treatment of RA should be a state of clinical remission (defined as the absence of signs and symptoms of significant inflammatory disease activity) or, as an acceptable alternative in established long-standing disease, low disease activity • Until the desired treatment target is reached, drug therapy should be adjusted every 3 months • Objective measures of disease activity must be obtained and documented regularly (monthly for patients with high/moderate disease activity, or every 3 to 6 months for those in sustained low disease activity or remission) • The use of validated composite measures of disease activity, which include joint assessments, is needed in routine clinical practice to guide treatment decisions, in addition to considering structural changes and functional impairment • The desired treatment target should be maintained throughout the course of the disease • The choice of composite measures of disease activity and the level of target value may be influenced by the patient’s comorbidities and drugrelated risks • The patient should be appropriately informed about the treatment target and the therapeutic strategy to reach this target—treatment should be based on a shared decision between patient and rheumatologist.

What do these evidence-based guidelines on treat-to-target mean to the practicing rheumatologist in his or her approach to patients with RA? They mean that objective, quantitative measures of disease activity should be obtained and documented regularly (as often as monthly for patients with high or moderate disease activity) and that therapy must be reevaluated and adjusted at least every 3 months based on these measures until the treatment target is reached. Indeed, adjustments

Case 2: Jack is a 64-year-old man with newly diagnosed moderate to severe RA (TJC/SJC = 12, DAS28 = 4.0, CDAI = 22) and a history of CVD (mild myocardial infarction 2 years ago, now on multiple cardiovascular medications). Your treatment plan is to start methotrexate, reassess at 3 months, and if there is no improvement, initiate biologic therapy.

Q: After starting a biologic, how often should this patient be reevaluated?

• Every 3 to 6 months • Every 1 to 3 months • Monthly until treatment goal is reached, every 3 to 6 months thereafter A: This patient needs to be followed closely, so you may want to see him monthly until his treatment goal is achieved, then every 3 months thereafter.

Q: What measure(s) of disease activity will you evaluate at each visit?

• TJC/SJC • PGA • ESR/CRP • DAS28 • X-rays/Ultrasound • SDAI/CDAI • HAQ scores • RAPID A: Several measures of disease acitivity are recommended in this article. A practical, office-based protocol includes TJC/SJC, HAQ score, and SDAI or RAPID. Plain radiographs and ESR or CRP could be considered at 6-month intervals.

Q: What is your ultimate management goal for this patient considering the severity of his disease and comorbidity?

A: This is a patient in whom remission is an important goal. Minimizing inflammatory disease acitivity would have effects on his RA and CVD. to therapy every 1 to 3 months has been shown to lead to a higher likelihood of disease remission.4-6 The definition of disease remission, long a subject of debate within the rheumatology community, has also been recently redefined: the ACR and EULAR guidelines define remission as a tender joint count (TJC) ≤1, a swollen joint count (SJC) ≤1, a CRP ≤1 mg/dL, and a Patient Global Assessment (PGA) score ≤1 on a 10point scale.12,48,49 The ACR and EULAR guidelines also emphasize that treatment decisions should be shared between physicians and patients, and that lifestyle choices and individual patient comorbidities should be factored into all treatment decisions.4,12,49 n References

1. Tayar JH, Lopez-Olivo MA, Suarez-Almazor ME. Adalimumab: 8 years of experience in rheumatoid arthritis. Int J Clin Rheumatol. 2013;8(2):165-184.

2. Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet.

2001;358(9285):903-911.

3. Lindqvist E, Jonsson K, Saxne T, Eberhardt K. Course of radiographic damage over 10 years in a cohort with early rheumatoid arthritis. Ann Rheum Dis. 2003;62(7):611-616.

4. Verstappen SM, Jacobs JW, van der Veen MJ, et al.

Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial). Ann Rheum Dis. 2007;66(11):1443-1449.

5. Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet. 2004;364(9430):263-269.

6. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum. 2008;58(suppl 2):S126-S135.

7. Saevarsdottir S, Wallin H, Seddighzadeh M, et al. Predictors of response to methotrexate in early DMARD naive rheumatoid arthritis: results from the initial open-label phase of the SWEFOT trial. Ann Rheum Dis. 2011;70(13):469-475.

8. Rantalaiho V, Korpela M, Laasonen L, et al. Early combination disease-modifying antirheumatic drug therapy and tight disease control improve long-term

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radiologic outcome in patients with early rheumatoid arthritis: the 11-year results of the Finnish Rheumatoid Arthritis Combination Therapy Trial. Arthritis Res Ther.

2010;12(3):R122.

9. Moreland RW, O’Dell JR, Paulus H, et al. TEAR: treatment of early aggressive RA: a randomized, double-blind, 2-year trial comparing immediate triple DMARD versus MTX plus etanercept to step-up from initial MTX monotherapy. Arthritis Rheum.

2009;60(suppl 10). Abstract 1895.

10. Bakker MF, Jacobs JW, Verstappen SM, Bijlsma JW. Tight control in the treatment of rheumatoid arthritis: efficacy and feasibility. Ann Rheum Dis. 2007;66(suppl 3):iii56-iii60.

11. Knevel R, Schoels M, Huizinga TW, et al. Current evidence for a strategic approach to the management of rheumatoid arthritis with disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis. 2010;69(6):987-994.

12. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res. 2012;64(5):625639.

13. Smolen JS, Emery P, Ferraccioli GF, et al. Efficacy and safety of certolizumab pegol after incomplete response to DMARDs in RA patients with low moderate disease activity: results from CERTAIN, a phase IIIB study. Presented at: EULAR Congress 2012; June 6-9, 2012; Berlin, Germany. Abstract THU0244.

14. Gibofsky A, Palmer WR, Goldman JA, et al. Realworld utilization of DMARDS and biologics in rheumatoid arthritis: the RADIUS (Rheumatoid Arthritis Disease-Modifying Anti-Rheumatic Drug Intervention and Utlization Study) study. Curr Med Res Opin.

2006;22(1):169-183.

15. Smolen JS, Fleischmann R, Gurerette B, et al. Adalimumab plus methotrexate vs methotrexate monotherapy for early rheumatoid arthritis: 26-week results (firstphase) from the 78-week OPTIMA study. Presented at: EULAR Congress 2012; June 6-9, 2012; Berlin, Germany. Abstract OP0146.

16. Detert J, Bastian H, Listing J, et al. Induction therapy with adalimumab plus methotrexate versus methotrexate monotherapy in recent onset rheumatoid arthritis (RA)—an investigator initiated randomized controlled trial. Presented at: EULAR Congress 2012; June 6-9, 2012; Berlin, Germany. Abstract OP0145.

17. Allaire S, Wolfe F, Niu J, Lavalley MP. Contemporary prevalence and incidence of work disability associated with rheumatoid arthritis in the US. Arthritis Rheum. 2008;59(4):474-480.

18. Singh JA, Wells GA, Christensen R, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev. 2011;16(2):CD008794.

19. Nurmohamed MT. Newer biological agents in the treatment of rheumatoid arthritis: do the benefits outweigh the risks? Drugs. 2009;69(15):2035-2043.

20. Gäwert L, Hierse F, Zink A, Strangfeld A. How well do patient reports reflect adverse drug reactions reported by rheumatologists? Agreement of physician-

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Continuing Education and patient-reported adverse events in patients with rheumatoid arthritis observed in the German biologics register. Rheumatology (Oxford). 2011;50(1):152-160.

21. Korkina L, Trakhtman P, DeLuca C, et al. Efficacy and safety of biologicals against immune-mediated diseases: do benefits outweigh risks? Drugs Today (Barc).

2010;46(2):119-136.

22. Curtis JR, Xie F, Chen L, et al. The comparative risk of serious infections among rheumatoid arthritis patients starting or switching biological agents. Ann Rheum Dis. 2011;70(8):1401-1406.

23. Kavanaugh A. Pharmacoeconomics of emerging therapies for rheumatoid arthritis. Am J Manag Care.

1999;5(suppl 8):S483-S488.

24. Kremers HM, Crowson CS, Therneau TM, et al. High 10-year risk of cardiovascular disease in newly diagnosed rheumatoid arthritis (RA) patients: a population-based cohort study. Arthritis Rheum.

2008;58(8):2268-2274.

25. Briggs AM, March L, Lassere M, et al. Baseline comorbidities in a population-based cohort of rheumatoid arthritis patients receiving biological therapy: data from the Australian Rheumatology Association Database. Int J Rheumatol. 2009;2009:861481.

26. Klarenbeek NB, van der Kooij SM, Huizinga TJ, et al. Blood pressure changes in patients with recent-onset rheumatoid arthritis treated with four different treatment strategies: a post hoc analysis from the BeSt trial.

Ann Rheum Dis. 2010;69(7):1342-1345.

27. Toms TE, Panoulas VF, Douglas KM, et al. Statin use in rheumatoid arthritis in relation to actual cardiovascular risk: evidence for substantial undertreatment of lipid-associated cardiovascular risk? Ann Rheum Dis. 2010;69(4):683-688.

28. Daoussis D, Panoulas VF, Antonopoulos I, et al.

Cardiovascular risk factors and not disease activity,

severity or therapy associate with renal dysfunction in patients with rheumatoid arthritis. Ann Rheum Dis. 2010;60(3):517-521.

29. Atzeni F, Turiel M, Caporali R, et al. The effect of pharmacological therapy on the cardiovascular system of patients with systemic rheumatic diseases. Autoimmunn Rev. 2010;9(12):835-839.

30. Solomon DH, Massarotti E, Garg R, et al. Association between disease-modifying antirheumatic drugs and diabetes risk in patients with rheumatoid arthritis and psoriasis. JAMA. 2011;305(24):2525-2531.

31. van Sijl AM, van den Oever IA, Raterman HG, et al.

SCORE and Framingham predict CV disease incidence in RA patients better than intima-media thickness.

Presented at: EULAR Congress 2012; June 6-12, 2012; Berlin, Germany. Abstract THU0045.

32. van Sijl AM, van den Oever IA, Peters MJ, et al.

Sustained development of cardiovascular disease in rheumatoid arthritis despite cardioprotective treatment: the 7-year prospective CARRE-Study. Presented at: EULAR Congress 2012; June 6-12, 2012; Berlin, Germany. Abstract FRI0100.

33. Hong SJ, Kim SM, Song R, et al. Rheumatoid arthritis patients with higher disease activity and subclinical carotid plaque experience more cardiovascular events despite a favorable conventional cardiovascular risk profile. Presented at: EULAR Congress 2012; June 6-12, 2012; Berlin, Germany. Abstract FRI0131.

34. Karpouzas GA, Malpeso J, Choi TY, et al. Differential impact of traditional cardiac risk factors on coronary plaque prevalence in coronary artery disease (CAD)-naive subjects with rheumatoid arthritis compared to controls. Presented at: EULAR Congress 2012; June 6-12, 2012; Berlin, Germany. Abstract THU0057.

35. Sugioka Y, Koike T, Mamoto K, et al. Rheumatoid arthritis is a risk factor for atherosclerosis—the TO-

MORROW study. Presented at: EULAR Congress 2012; June 6-12, 2012; Berlin, Germany. Abstract FRI0141.

36. Gottwald M, Schau T, Neuss M, et al. Increased rate of diastolic heart failure in rheumatoid arthritis correlates with systemic inflammation and persistent disease activity, independent from treatment strategy.

Presented at: EULAR Congress 2012; June 6-12, 2012; Berlin, Germany. Abstract THU0069.

37. Schau T, Gottwald M, Neuss M, et al. Increased risk of diastolic heart failure in RA—what should we be screening for? Presented at: EULAR Congress 2012; June 6-12, 2012; Berlin, Germany. Abstract FRI0124.

38. Holmqvist M, Wallberg-Jonsson S, Jacobsson L, Askling J. Thromboembolism in rheumatoid arthritis: increased risks unrelated to hospitalization and disease duration. Presented at: EULAR Congress 2012; June 6-12, 2012; Berlin, Germany. Abstract FRI0122.

39. Kim SC, Schneeweiss S, Liu J, et al. The risk of venous thromboembolism in patients with rheumatoid arthritis compared to the general population: a very large cohort study. Presented at: EULAR Congress 2012; June 6-12, 2012; Berlin, Germany. Abstract THU0075.

40. Margerit M, Nguyen P, Pereira B, et al. Prevalence of dyslipidemia in an early arthritis rheumatoid cohort (ESPOIR cohort). Lack of improvement after 4 years of follow-up. Presented at: EULAR Congress 2012; June 6-12, 2012; Berlin, Germany. Abstract THU0068.

41. Back J, Baecklund E, Birgegard G. Anemia in patients with rheumatoid arthritis: a cross-sectional study. Presented at: EULAR Congress 2012; June 6-12, 2012; Berlin, Germany. Abstract THU0061.

42. Abou-Raya A, Abou-Raya S, Helmii M. Prevalence of vitamin D deficiency in rheumatoid arthritis patients: association with anaemia of inflammation and effect of vitamin D supplementation. Presented

at: EULAR Congress 2012; June 6-12, 2012; Berlin, Germany. Abstract THU0046.

43. Gomez R, Gutierrez JM, Fernandez-Avila DG, et al.

Autoimmune thyroid disease in patients with rheumatoid arthritis: case-control study. Presented at: EULAR Congress 2012; June 6-12, 2012; Berlin, Germany. Abstract THU0051.

44. Nurmohamed MT, Bao Y, Signorovitch PM, et al.

Use of anti-TNF therapy is associated with reduced cardiovascular event risk in rheumatoid arthritis. Presented at: EULAR Congress 2012; June 6-12, 2012; Berlin, Germany. Abstract OP0002.

45. Listing J, Pattloch D, Kekow J, et al. Successful control of disease activity and treatment with biologics increase the life expectancy in rheumatoid arthritis patients. Presented at: EULAR Congress 2012; June 6-12, 2012; Berlin, Germany. Abstract OP0047.

46. Singh G, Wang H, Mithal A, et al. Added bonus: Combination of TNF inhibitor-methotrexate is superior to methotrexate monotherapy in reducing the risk of acute myocardial infarction in patients with rheumatoid arthritis. Presented at: EULAR Congress 2007; June 13-16, 2007; Barcelona, Spain. Abstract OP0106.

47. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum.

2010;62(9):2569-2581.

48. Smolen JS, Landewe R, Breedveld FC, et al.

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatoid drugs. Ann Rheum Dis. 2010;69(6):964-975.

49. Smolen JS, Aletaha D, Bijlsma JW, et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2010;69(4):631-637.

Expert Commentary

Ronald F. van Vollenhoven, MD, PhD Professor and Chief, Unit for Clinical Therapy Research, Inflammatory Diseases (ClinTRID) Karolinska Institute Stockholm, Sweden

O

ver the past 2 decades, the treatment of rheumatoid arthritis (RA) has undergone dramatic changes. This is due in part to the introduction of a large number of new antirheumatic drugs (mostly biologics). However, in parallel, treatment approaches and paradigms in RA have also been thoroughly rethought and revised. Thus, the principles of tight control, treat-to-target, and individualized therapy have received much attention and have, to some extent, been codified in international guidelines and recommendations. Confusion about the meanings and implications of these terms may also have been introduced, and it is therefore timely that these are discussed in more detail in the accompanying article. Here, let me just add some thoughts on the current state of affairs and prospects for the future.

The concept of tight control for RA was borrowed from disciplines outside rheumatology and was most notably influenced by advances in the management of diabetes mellitus. The principal idea is that by frequently monitoring the patient, better suppression of the pathologic disease process can be achieved—with improved long-term outcomes as a result. The most noted trial to demonstrate the success of this approach in RA was the TICORA study,1 in which monthly vis-

its proved superior to the more standard 3 monthly visits. Of course, there was the understanding that something needed to be done at these visits if the patient was not doing well. Similar results were demonstrated subsequently in the CAMERA study2 and others.

Although these results are all very compelling, it has been pointed out that the use of glucocorticoids in these trials as one of the main interventions for patients who were not doing well may, in the long term, have distinct disadvantages. A more down-to-earth concern is that rheumatology practices today will simply not be able to offer monthly visits for all patients with RA.

A more down-to-earth concern is that rheumatology practices today will simply not be able to offer monthly visits for all patients with RA. The concept of treat-to-target for RA is quite similar to tight control. As was the case for the latter, treat-to-target was borrowed from disciplines such as the management of hypertension and diabetes. The principle is that a therapeutic target must be chosen for each patient. At each encounter, the current

status of the patient must be compared with the target, and if the patient has not achieved the target (at an appropriate point in time) then the therapy must be adjusted. A consensus panel has proposed that the most appropriate target for most patients with RA is remission, while for some patients, low disease activity can be appropriate.3 Although highly appealing and commendable, some conceptual and practical difficulties with this approach remain: current definitions of remission may be too stringent (ACR/ EULAR4) or too lax (DAS285), and they reflect disease manifestations rather than the underlying disease process.

Personalized treatment is a term used quite freely and with such obvious appeal that it runs the risk of losing all meaning. Obviously, each patient must be approached by the healthcare provider as a unique individual with her/his own specific needs, limitations, and priorities. What is at issue here is something else: the belief that one should be able to analyze each patient’s disease in such detail that the optimal therapy for that particular patient can be chosen. Unfortunately, the truth is that we are still quite far removed from this lofty goal, and some experts have expressed pessimism as to the feasibility of any such approach.

I have a more optimistic view. While I recognize that personalized treat-

ment (in this sense of the term) is not really possible at this point in time, I am convinced that within 5 years the development of appropriate biomarkers, advances in ultrasound and other imaging capabilities, and analyses of large data sets from clinical trials and registries will allow for personalized treatment to a very significant and clinically meaningful extent.

In summary, the principles of tight control, treat-to-target, and personalized treatment, with considerable overlap, point at important changes that have occurred and are continuing to occur in the treatment of RA, the full potential of which will be realized in the years to come with dramatically improved outcomes as a result. n References

1. Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet. 2004;364(9430):263-269.

2. Verstappen SM, Jacobs JW, van der Veen MJ, et al.

Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial). Ann Rheum Dis. 2007;66(11):1443-1449.

3. Smolen JS, Aletaha D, Bijlsma JW, et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2010; 69(4):631-637.

4. Felson DT, Smolen JS, Wells G, et al. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis. 2011;70:404-413.

5. Prevoo ML, van Gestel AM, van T Hof MA, et al.

Remission in a prospective study of patients with rheumatoid arthritis. American Rheumatism Association preliminary remission criteria in relation to the disease activity score. Br J Rheumatol. 1996;35(11):11011105.

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