Combined methotrexate and short-term superpotent topical corticosteroids compared with prolonged superpotent topical corticosteroids alone in bullous pemphigoid: a multicentre, noninferiority randomised clinical trial.

Abstract

Superpotent topical corticosteroids (STS) are highly effective in bullous pemphigoid (BP), but prolonged use is associated with practical limitations and a risk of relapse. To evaluate whether combining short-term STS with methotrexate (MTX) could maintain efficacy, reduce relapses, and preserve safety compared with prolonged STS alone. In this multicentre, randomised, open-label, non-inferiority trial, adults with BP were assigned to receive either STS (clobetasol propionate) for one month plus low-dose MTX as maintenance (MTX + STS arm), or prolonged STS alone (STS arm). The primary endpoint was 9-month overall survival (OS), with a predefined non-inferiority margin of 15%. Secondary outcomes included relapse-free survival (RFS) and severe adverse events (SAE). Among 266 randomised patients (mean age 80.8 years), 9-month OS was 86.5% in the MTX + STS arm and 83.5% in the STS arm (p=0.498; hazard ratio [HR] 0.80, 95% CI 0.40-1.50). The lower limit of the 90% confidence interval for the difference in survival rates (-4.6%) remained within the predefined non-inferiority margin, meeting the primary endpoint. Among the 87.4% of patients who achieved disease control within 28 days, relapse occurred in 31 patients in the MTX + STS arm and 52 in the STS arm, corresponding to a 9-month RFS of 68.4% (95% CI 59.3-78.8) versus 47.4% (95% CI 37.7-59.5), respectively (p=0.042). SAE were more frequent in the MTX + STS arm than in the STS arm (mean number per patient per month 0.40 [95% CI 0.23-0.57] vs 0.19 [95% CI 0.01-0.36], p=0.005). The study was open-label, did not include a validated disease activity score and was conducted in a selected BP population managed under clinical trial conditions. Maintenance therapy with low-dose MTX is non-inferior to prolonged STS in terms of survival and is associated with a reduced risk of relapse, at the cost of increased toxicity.