An estimated two-thirds of patients with moderate to severe rheumatoid arthritis (RA) do not adequately respond to monotherapy with methotrexate (MTX).1 While adding an anti-tumor necrosis factor (TNF) agent can improve disease control in some patients, it is not known whether a higher or lower dosage of MTX is indicated in such cases.
The phase IV, double-blind, randomized MUSICA trial (ClinicalTrials.gov Identifier NCT01185288), funded by AbbVie, investigated the efficacy of combining MTX at a high or low doses in combination with open-label administration of the anti-TNF agent adalimumab in patients with rheumatoid arthritis (RA) who have failed high-dose MTX monotherapy. The results were reported in the Journal of Rheumatology.2
The analyzed data included 309 adult patients with RA from multiple sites across the mainland US and Puerto Rico who had been taking MTX at a dosage of ≥ 15 mg/week for 12 weeks or more prior to screening for the study. The primary endpoint was defined by researchers as the Disease Activity Score for 28 Joints C-reactive Protein (DAS28[CRP]) at week 24, testing for noninferiority of low-dose MTX with a 15% margin.
The researchers selected 15% as the noninferiority margin “to associate 15% of high-dosage MTX Week 24 DAS28-CRP value of 3.6 ( 0.15 × 3.6 = 0.54) with a clinically acceptable diminished treatment effect of 25% of the change from the baseline (i0.25 × 2.15 = 0.54)”.
High Yield Data Summary
- Noninferiority was not met for mean DAS28-CRP for low vs high dosage MTX in the MUSICA trial
Participants were randomly assigned to receive either a high (20 mg) or low (7.5 mg) weekly oral dosage of MTX, in addition to 40 mg of open-label adalimumab every 2 weeks throughout the 24-week trial period.
At baseline and every 4 weeks throughout the study, efficacy and safety outcomes were evaluated, and blood samples were collected for analysis of adalimumab pharmacokinetics.
Ultrasound imaging was used to assess for synovial hypertrophy, vascularity, and the presence of bony erosions. The authors noted that while conventional radiography has previously failed to show evidence of joint disease at RA diagnosis in 70% of patients, ultrasonography may have greater sensitivity and has detected synovitis even in patients who are in remission or have low disease activity.
Findings show that while both treatment groups rapid improvements in clinical measures of disease activity, the difference in mean DAS-CRP [0.37, 95% confidence interval (CI) 0.07–0.66] was statistically significant between the low-dosage and high-dosage MTX groups [(4.12, 95% CI 3.88–4.34) vs (3.75, 95% CI 3.52–3.97)].
Noninferiority of the low dose MTX compared to high dose MTX was not met according to the 15% margin. However, there were no significant differences between dosages for most outcomes, and both groups reported similar numbers of adverse events (AE), which were experienced by 63.1% of all patients.
Of particular interest, more events per 100 patient years were observed patients receiving low-dose MTX for some AE as compared to the those receiving high-dose MTX.
“Overall, these data do not support MTX dosage reductions in patients initiating ADA… however, in a proportion of patients who may need to reduce MTX because of toxicity, much of the clinical efficacy of combination therapy may still be retained [with lose dosage MTX], especially if dosage reductions of MTX are modest,” the study authors concluded.
Summary and Clinical Applicability
While the MUSICA trial did not establish noninferiority for a lower dosage of MTX when combined with adalimumab, it may be an appropriate option for patients who require a reduction due to MTX toxicity.
Limitations and Disclosures
- The number of patients achieving remission or low disease activity was still increasing at the end of the study period, suggesting that the duration of the trial (24 weeks) may not allow for accurate interpretation of outcomes
- When data is interpreted, it should be noted that 15% was selected to define the noninferiority margin defined by researchers for ACR50 and ACR70
AbbVie Inc , manufacturer of adalimumab (Humira®), sponsored clinical trial NCT01185288. GSK is a consultant for AbbVie Inc.
- Emery P, Breedveld FC, Hall S, Durez P, Chang DJ, Robertson D, et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial. Lancet 2008;372:375-82.
- Kaeley GS, Evangelisto AM, Nishio MJ, et al. Methotrexate dosage reduction upon adalimumab initiation: clinical and ultrasonographic outcomes from the randomized noninferiority MUSICA trial. J Rheumatol. 2016; 43(8):1480-9.