Analysis of a randomized, double-blind clinical trial evaluating the efficacy of low and high doses of methotrexate (MTX) in combination with open-label adalimumab (ADA) in patients with rheumatoid arthritis (RA) suggests that tapering MTX from ≥15 mg/week down to 7.5 mg/week after starting ADA may result in reduction of clinical response as compared to maintaining or increasing MTX.1
The data was from derived from the Study to Determine the Effect of Methotrexate Dose on Clinical Outcome and Ultrasonographic Signs in Subjects With Moderately to Severely Active Rheumatoid Arthritis Treated With Adalimumab (MUSICA trial, ClinicalTrials.gov Identifier NCT01185288).
High Yield Data Summary
- MTX-monotherapy inadequate responders with RA who decreased concomitant MTX doses when initiating adalimumab had reduced degrees of clinical responses compared to those maintaining or slightly increasing MTX dose
A subset of patients with RA who were previously designated MTX-monotherapy inadequate responders (MTX-IR) are able to achieve disease control with combination ADA+MTX therapy, however the dose of MTX required to maintain optimal disease control had not previously been studied in a randomized, prospective trial including ultrasound measurements of joint damage.
Thus, the MUSICA trial aimed to address the efficacy of either high-dose MTX (20 mg/week) or low-dose MTX (7.5 mg/week) when combined with ADA (50 mg every other week).
Briefly, MUSICA was a double-blind, randomized, parallel-arm study of 309 patients with active RA already receiving MTX ≥15 mg/week for ≥12 wk randomly assigned to receive either high-dose MTX (20 mg/week) or low-dose MTX once ADA treatment was started.
All patients received concomitant treatment with 40 mg of open-label ADA every other week for the duration of the 24 week trial.
Effects of treatment variations on joint disease were measured by ultrasound, evaluating synovial joint hypertrophy, vascularity, and the presence of bony erosions using a 10-joint semiquantitative system incorporating the Outcome Measures in Rheumatology working group pathology definitions.
The mean 28-joint Disease Activity Score C-reactive protein (DAS28-CRP) scores at 24 weeks post-randomization were designated by researchers as the primary endpoint. Secondary endpoints included proportion of patients with ≥ 30% improvement in synovial vascularity as measured by Power Doppler, American College of Rheumatology 50% (ACR50), ACR70, and change from baseline ≤ –0.22 in the Health Assessment Questionnaire Disability Index (HAQ-DI) at 24 weeks. Noninferiority was defined with a margin of 15%.
At baseline, patients included in the trial had average age of 54.8 years, with mean baseline disease duration of 5.3 years and a mean duration of MTX treatment prior to the study of 1.5 years. Baseline disease activity in all study participants was high (mean DAS28-CRP 5.8, mean simplified disease activity index [SDAI] 42.4, and mean clinical disease activity index [CDAI] 40.9.
Researchers found that clinically significant improvements in disease activity were observed when adding ADA to either lose-dose MTX or high-dose MTX to MTX-IR patients. Initiation of ADA to MTX-IR patients resulted in increased ACR responses across the board, with improvements in physical function (mean DHAQ-DI = –0.5) at 24 weeks.
The differences, however, in mean DAS28-CRP between low-dose MTX (4.12, 95% CI 3.88-4.34) vs high-dose MTX (3.75, 95% CI 3.52-3.97) was significant. Noninferiority of low-dose MTX+ADA was not statistically met for the defined primary endpoint. A statistically significant difference of 0.37 (95% CI: 0.07–0.66) was found between the low and high-dose MTX groups in mean DAS28-CRP at week 24.
Adverse effects were reported by 195 out of 309 study participants (63.1%), with similar numbers in both MTX-stratification groups. The overall incidence rates of anti-ADA antibodies were low in this trial.
Summary and Clinical Applicability
“Lowering the dose of concomitant MTX to 7.5 mg/week from ≥ 15 mg/week upon initiating ADA may reduce the degree of clinical response when compared to steady or slightly increased MTX,” the authors concluded.
Limitations and Disclosures
The study followed patients for only 24 weeks, at which point of time DAS28-CRP, SDAI, and CDAI scores were noted to be increasing (no plateau noted), thus longer treatment duration may result in sustained reduction of disease activity that were not evaluated here.
A relatively large defined noninferiority margin of 15% for ACR50 and ACR70 may have also limited study conclusions.
AbbVie Inc, the manufacturer of adalimumab (Humira©), sponsored the MUSICA clinical trial (NCT01185288) and participated in the collection, analysis, and interpretation of the data.
1. Kaeley G, Evangelisto A, Nishio M et al. Methotrexate dosage reduction upon adalimumab initiation: clinical and ultrasonographic outcomes from the randomized noninferiority MUSICA trial. J Rheumatol. 2016. Published online ahead of print June 15, 2016. doi:10.3899/jrheum.151009.