Summary

• REMICADE should be administered in combination with methotrexate (MTX) for the treatment of rheumatoid arthritis (RA).¹
• In a randomized, double-blind, placebo-controlled study, patients treated with REMICADE alone demonstrated similar rates of efficacy, as measured by Paulus 20% response criteria, compared with patients treated with REMICADE in combination with MTX. There were no statistically significant differences in duration of Paulus response between patients receiving REMICADE and MTX compared to those receiving REMICADE alone.²
• Several retrospective and observational studies have been conducted to evaluate the effect of REMICADE monotherapy in patients with RA.^3-5

CLINICAL DATA

Controlled Trial

Maini et al (1998)² evaluated 101 patients with active RA in a multicenter, randomized, double-blind, placebo-controlled trial to determine the safety and efficacy of multiple doses of REMICADE alone or in combination with MTX.

Study Design/Methods

• To be eligible for the trial, patients must have been using MTX (7.5 to 15 mg/week) for at least 6 months and exhibited an incomplete response or flare of disease activity. The use of disease modifying antirheumatic drugs (DMARDs), other than MTX, was not permitted during the study.
• Stable doses of steroids (less than 7.5 mg/day) and/or nonsteroidal antiinflammatory drugs (NSAIDs) were permitted.
• Patients were randomized to 1 of 7 treatment groups which included 1, 3, or 10 mg/kg doses of REMICADE with or without MTX (7.5 mg/week) or MTX (7.5 mg/week) alone. Patients were infused at week 0, 2, 6, 10, and 14 and were followed for 26 weeks.
• The primary measure of efficacy was the total time (in weeks) that the patient exhibited a response based on Paulus 20% improvement during the 26-week evaluation period. The Paulus response is achieved by improvement in 4 of 6 of the following: 20% or 50% improvement in tender joint scores, swollen joint scores, duration of morning stiffness, or erythrocyte sedimentation rate (ESR), or a 2-grade improvement in the patient’s or observer’s assessment of disease severity.
• Secondary measures of efficacy included the proportion of patients responding based on Paulus 20% improvement and a 20% reduction of signs and symptoms based on the American College of Rheumatology (ACR) criteria. Components of the ACR criteria include tender and swollen joint counts, physician and patient global assessments, and levels of inflammatory markers in the blood; the score represents a percentage reduction of these parameters from pre-treatment levels.

Efficacy Results

• Approximately 60% of patients receiving REMICADE at 3 or 10 mg/kg, with or without MTX, achieved the 20% Paulus criteria for response to treatment; substantially greater than the rates observed in patients treated with MTX alone.
• Although consistently longer periods of response were observed when REMICADE and MTX were given together, the differences between REMICADE with or without MTX were not statistically significant (P=0.264 at 3 mg/kg and P=0.111 at 10 mg/kg).
• Patients treated with and without MTX and REMICADE 3 or 10 mg/kg demonstrated similar Paulus 20% improvement and ACR 20 response.
• Patients in the REMICADE treatment group receiving 1 mg/kg without MTX became unresponsive to repeated infusions.  However, coadministration of REMICADE at 1 mg/kg with MTX appeared to be synergistic, prolonging the duration of response.
• Although a synergistic trend was observed at 10 mg/kg of REMICADE, at 3 mg/kg coadministration of MTX did not reveal a synergistic effect.

Safety Results

• The effect of the therapeutic regimens on the development of antibodies to REMICADE was examined at week 26, 12 weeks after the last infusion.  
• The overall incidence of antibodies to REMICADE in all REMICADE treated patients was 17.4%, and the incidence of antibody development was inversely proportional to the dose of REMICADE.
• Concomitant therapy with low dose MTX diminished the occurrence of antibodies to REMICADE. These data suggest that immunologic tolerance to REMICADE was induced by higher dosages of REMICADE and enhanced by the simultaneous administration of MTX.  However, there was no relationship between the dosage of REMICADE or the concomitant use of MTX and the incidence of adverse events (AEs) observed in this trial.
• In addition, at 3 mg/kg and 10 mg/kg of REMICADE, similar peak serum concentrations were observed in patients receiving REMICADE alone or in combination with MTX (although serum REMICADE concentrations were consistently higher from week 20 to 26 in patients receiving MTX).

Observational Studies

Weaver et al (2006)³ evaluated patients enrolled in the RADIUS (Rheumatoid Arthritis DMARD Intervention and Utilization Study) program to assess the effectiveness of biologics in the treatment of RA.

Study Design/Methods

• The RADIUS program comprises 2 observational registries designed to collect data related to use patterns, efficacy, and safety of DMARDs for the treatment of RA.
• Two separate patient cohorts were enrolled; RADIUS 1 consists of patients that switched to or initiated to a new DMARD therapy at study entry, and RADIUS 2 consists of patients that initiated etanercept at study entry.
• The primary endpoint for RADIUS 1 was the proportion of patients achieving a modified ACR20 (mACR20) response at 12 months. The mACR20 scoring system excludes the ESR and C-reactive protein (CRP) criterion and is based on at least a 20% improvement in the tender and swollen joint counts and at least a 20% improvement in 3 of the following 4 criteria: patient global assessment, physician global assessment, patient pain assessment, and the health assessment questionnaire score (HAQ).
• The biologic drug regimens compared in this analysis included: 1) MTX monotherapy (n=941); 2) etanercept monotherapy (n=1251); 3) REMICADE monotherapy (n=120); 4) etanercept + MTX (n=1783); 5) REMICADE + MTX (n=540); 6) leflunomide monotherapy (n=204); 7) MTX + hydroxychloroquine (n=325); 8) MTX + leflunomide (n=191); and 9) MTX + hydroxychloroquine + sulfasalazine (n=42).

Results

• At 12 months, the proportion of patients achieving a mACR20 response (unadjusted for various baseline covariates) was 37% vs 26% and 35% for patients treated with MTX monotherapy vs REMICADE monotherapy and REMICADE + MTX, respectively.
• Patients receiving REMICADE + MTX or REMICADE monotherapy did not have a statistically significant improvement in 5 of 6 individual core component scores of the mACR20 when compared to MTX monotherapy at 12 months.
• Patients receiving REMICADE + MTX achieved a statistically significant improvement in the swollen joint count vs MTX monotherapy.
• After adjustment for the relevant baseline covariates, no statistically significant differences were observed in the odds of achieving a mACR20 response in patients receiving either REMICADE monotherapy or REMICADE + MTX vs MTX monotherapy.

Hyrich et al (2006)⁴ compared the therapeutic response to REMICADE or etanercept monotherapy with the response to cotherapy with MTX or another DMARD in patients with RA enrolled in the British Society for Rheumatology Biologics Register (BSRBR).

Study Design/Methods

• Therapeutic response was determined using the European League against Rheumatism (EULAR) response criteria and classified patients into 3 groups (good response, moderate response, or no response) based on the 6-month Disease Activity Score in 28 joints (DAS28) and the absolute change from baseline in the EULAR criteria.
• A good response was defined as an improvement in EULAR criteria of at least 1.2 units and an absolute DAS28 score of <3.2. A nonresponse was defined as an improvement in EULAR criteria of ≤0.6 and a final DAS28 score of >5.1. A moderate response was defined as an improvement in EULAR criteria and DAS28 score falling between these 2 data sets.
• A total of 1453 patients receiving REMICADE and 1258 patients receiving etanercept were included in this analysis.
• Nine-percent (n=128) of patients initiating REMICADE did not receive concurrent DMARD therapy. However, most patients receiving etanercept (61%) were not administered concomitant DMARD therapy.

Results

• Overall, patients receiving REMICADE + MTX achieved a greater improvement in mean DAS28 score compared to patients receiving REMICADE monotherapy.
• The difference was not statistically significant. A higher rate of non-response was observed in patients receiving REMICADE monotherapy (47%) compared to patients receiving REMICADE + MTX (34%).
• There was no difference in the proportion of patients who achieved a good response. There was a trend toward a better EULAR response, although not statistically significant, in patients receiving MTX monotherapy (OR 1.35 [95% CI 0.92-2.00]) as compared with patients receiving REMICADE monotherapy.
• Twenty-one percent of patients (n=249) receiving REMICADE + MTX and 30% (n=38) of patients receiving REMICADE monotherapy discontinued therapy for lack of efficacy, an AE or any other reason. A trend towards a higher rate of discontinuation due to an AE was observed with the REMICADE monotherapy treatment group, but this difference was not explained by a higher rate of infusion reactions.

Gaylis (2004)⁵ conducted a retrospective chart review of RA patients (n=35) who were unresponsive to or were contraindicated to receive MTX at a single rheumatology office.

Study Design/Methods

• Patients were treated with REMICADE monotherapy.  Monotherapy was defined as not receiving concomitant MTX, leflunomide, azathioprine, or other immunosuppressive agents. Patients could receive prednisone and NSAIDS.

Results

• Patients received 3 to 14 infusions of REMICADE at doses 3 to 6 mg/kg.
• Almost all patients had improvement in their patient and physician global assessments. Prednisone was discontinued in 12 patients and reduced in 16 patients.
• Four patients experienced mild infusion reactions (itching and rash), all of which resolved with standard treatment.  Four of the 15 patients who were antinuclear antibodies (ANA) negative at baseline converted to being ANA positive.  None of these patients developed symptoms of autoimmune disease. REMICADE monotherapy was well- tolerated, and no patients discontinued therapy because of an AE.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 03 April 2023.