[Analysis of the protective effects of low-dose sirolimus on lung function in patients with lymphangioleiomyomatosis]

Objective: To determine whether sirolimus therapy at lower trough concentrations is non-inferior to the conventional target concentration (≥5 μg/L) with respect to pulmonary protective effects and lung function preservation in patients with lymphangioleiomyomatosis (LAM). Methods: A retrospective analytical dataset was constructed using patient-level data from the Peking Union Medical College Hospital LAM cohort registry between April 2017 and April 2022. Patients were stratified into a conventional-concentration group (≥5 μg/L) and a low-concentration group (<5 μg/L) according to the time-weighted average sirolimus trough concentration. The conventional concentration group comprised 103 LAM patients (mean age 40.1 years), and the low concentration group included 80 patients (mean age 38.8 years). All patients were female. Changes in FEV₁ were analyzed with a linear mixed-effects model, and marginal mean FEV₁ changes from baseline were estimated at prespecified time points after treatment initiation. The primary endpoint was the change in FEV₁ after 1 year of sirolimus therapy. If no statistically significant difference was observed at one year, the change at three years was compared. The estimated marginal means of FEV1 change between groups at the same time point were compared using Welch's t-test or Welch's analysis of variance (ANOVA). Results: After one year, the estimated marginal mean FEV₁ increase was 45.2 ml (95%CI: 13.9-76.5) in the low-concentration group versus 33.7 (95%CI: 6.6-60.8) ml in the conventional-concentration group (t=0.55, P=0.585). At three years, the between-group difference in the estimated marginal mean change in FEV₁ from baseline remained statistically non-significant (low-concentration group:-24.9 ml, 95%CI:-115.7-65.9 ml; conventional-concentration group:-4.1 ml, 95%CI:-78.9-70.8 ml; t=0.35, P=0.728). Conclusions: Maintaining sirolimus at lower trough concentrations (median 4.1 μg/L, 3.5-4.5 μg/L) provides similar FEV₁ preservation to that achieved with the conventional target concentration. This suggested that the therapeutic target for sirolimus in LAM could be safely reduced.