The efficacy and safety of topical rapamycin-calcitriol for facial angiofibromas in patients with tuberous sclerosis complex: a prospective, double-blind, randomized clinical trial

Background The efficacy of topical rapamycin is well documented for tuberous sclerosis complex (TSC)-related facial angiofibromas (FAs). Calcitriol has been shown to lessen skin fibrosis and may be therapeutically beneficial to FAs. Objectives To evaluate whether topical rapamycin-calcitriol combination is an effective and safe treatment for TSC-related FAs. Methods Fifty-two patients with TSC with FAs were enrolled in this prospective study including three 12-week periods. In period 1, either topical rapamycin 0 center dot 1% or calcitriol 0 center dot 0003% single-agent therapy vs. their combination was applied in a double-blind, left-right-randomized, split-face comparison. The primary outcome was the reduction of modified Facial Angiofibroma Severity Index (mFASI) at week 12. In period 2, the patients were reassigned to use on both cheeks the ointment that resulted in the better primary outcome in period 1. The treatment was discontinued in period 3 (week 25-36) and a follow-up mFASI was scored to evaluate the degree of recurrence. Results The mean changes in mFASI at week 12 compared with baseline were -0 center dot 92, -0 center dot 44 and -1 center dot 09 for rapamycin (P <= 0 center dot 001), calcitriol (P = 0 center dot 039) and rapamycin-calcitriol combination (P <= 0 center dot 001), respectively. Although rapamycin-calcitriol combination and rapamycin had similar statistically significant decreases of mFASI at week 12, rapamycin-calcitriol combination resulted in faster improvement in erythema, greater reduction of papule elevation and longer durability after discontinuing treatment than rapamycin alone. The treatments were well tolerated. Conclusions This randomized clinical trial demonstrates that topical rapamycin-calcitriol combination therapy is an effective and safe regimen for TSC-related FAs. What is already known about this topic? Facial angiofibromas (FAs) cause substantial psychological distress in individuals with tuberous sclerosis complex (TSC), but invasive procedural treatments are not applicable to all patients. Topical rapamycin has been demonstrated as an effective and safe treatment regimen for TSC-related FAs. What does this study add? Compared with baseline (day 0), both topical rapamycin 0 center dot 1% and rapamycin 0 center dot 1%-calcitriol 0 center dot 0003% combination ointment achieved statistically significant reductions in modified Facial Angiofibroma Severity Index at week 12. Compared with rapamycin alone, extended use of the rapamycin-calcitriol combination regimen until week 24 showed more effectiveness in decreasing papule elevation and could maintain a longer therapeutic effect after treatment discontinuation.