In patients with rheumatoid arthritis (RA), a 50% reduction in methotrexate (MTX) dose may be feasible with tumor necrosis factor inhibitor (TNFi) initiation, according to study findings published in Lancet Rheumatology.
Researchers sought to assess the efficacy and safety of adalimumab plus a reduced MTX dose vs the maximum-tolerated dose in patients with RA with an inadequate response to MTX monotherapy.
The MIRACLE trial (ClinicalTrials.gov Identifier: NCT03505008) was a 48-week, parallel-arm, open-label, multinational, randomized, controlled trial, the aim of which was to evaluate the noninferiority of adalimumab used concomitantly with a reduced dose vs maximum-tolerated dose of MTX.
Participants were enrolled from 24 sites in Japan, Taiwan, and South Korea. Eligibility criteria were age of 18 years and older; diagnosis of RA, according to the 1987 revised American College of Rheumatology (ACR) or the 2020 ACR/European Alliance of Associations for Rheumatology (EULAR) criteria, duration of disease of less than 2 years; Simplified Disease Activity Index (SDAI) of at least 11; and no previous treatment with MTX, biologic disease-modifying antirheumatic drugs (bDMARDs), or Janus kinase (JAK) inhibitors.
All patients received MTX and then the dose was increased by 12 weeks. Those who did not attain SDAI remission with at least 10-mg/week MTX dose at week 24 were randomly assigned 1:1 to receive adalimumab in combination with a maximum-tolerated dose of MTX or adalimumab in combination with a reduced dose of MTX.
The primary study endpoint was the percentage of patients who achieved remission in SDAI (≤3.3) at week 48. Secondary study endpoints included the percentage of patients who achieved SDAI remission or LDA (SDAI ≤11); 20%, 50%, or 70% improvement in ACR criteria (ACR20/50/70, respectively); functional remission, based on the Health Assessment Questionnaire Disability Index (HAQ-DI) of 0.5 or lesser; and radiographic remission.
A total of 291 individuals (75% women; mean age, 57.7 years; and 100% Asian) were included in the full set analysis.
Results of the study showed that at 24 weeks, 36% of the participants achieved SDAI remission and continued to receive MTX monotherapy at the same dose through week 48. Overall, 46% of the participants who did not achieve SDAI remission at week 24 were assigned into treatment groups.
The modified full analysis set included 127 participants (66 received adalimumab plus maximum-tolerated dose MTX and 61 received adalimumab plus a reduced dose MTX. Overall, 96% of participants who achieved SDAI remission at week 24 completed the study protocol through week 48.
At week 48, 38% of patients who received adalimumab plus maximum-tolerated dose of MTX and 44% of those who received adalimumab plus reduced dose of MTX achieved remission; the adjusted risk difference between the 2 groups was 6.4% (90% CI, -7.0% to 19.8%), which fulfilled the predefined noninferiority margin of -15%.
Adverse events (AEs) after week 24 were more common in the maximum-tolerated dose vs reduced dose MTX group (35% vs 20%; P =.054). From week 24 to 48, a total of 14 serious AEs were reported.
Study limitations included the open-label design; discrepancy in the evaluation of disease activity, as the treatment regimens were known to both the patients and the researchers; the inclusion of only East Asian patients; and the relatively small sample size.
The study authors concluded, “[O]ur study highlights that a 50% reduction from the maximum tolerated dose might be possible for [MTX] administered concomitantly with a TNF inhibitor in patients with [RA] and an inadequate response to [MTX] in terms of achieving clinical remission, inhibiting joint destruction, and [minimizing] immunogenicity of TNF inhibitors.”
Disclosure: This research was supported by Eisai. Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Tamai H, Miyamoto T, Taguchi H, et al; MIRACLE study collaborators. Reduced versus maximum tolerated methotrexate dose concomitant with adalimumab in patients with rheumatoid arthritis (MIRACLE): a randomised, open-label, non-inferiority trial. Lancet Rheumatol. 2023;5(4):e215-e224. doi:10.1016/S2665-9913(23)00070-X