OBJECTIVES: We conducted a systematic review to analyze clinical and cost-effectiveness evidence of treatment options for facial angiofibroma (FA) associated with tuberous sclerosis complex (TSC) which lacks established therapeutic opportunities.

METHODS: Multiple academic databases, HTA databases, trial registries, conferences, were searched (March-April 2022) for randomized controlled trials (RCTs), non-RCTs, observational and cost-effectiveness studies. Risk of bias, study quality, were assessed using standard checklists. Random effects meta-analysis was conducted using Residual Maximum Likelihood to compute study variances. Findings were reported using Synthesis Without Meta-analysis guidelines.

RESULTS: Of 12459 studies, 8155 and 401 were screened at title-abstract and full text, and 91 were included (6 RCTs, 7 non-RCTs, 78 observational). From 2491 cost-effectiveness studies, 48 underwent full-text screening; none were included. Topical sirolimus 0.1% was most frequently examined (2 RCTs, 1 non-RCTs, 8 observational), followed by sirolimus 0.2% (3 RCTs, 3 observational). Quantitative improvements, including change from baseline using angiofibroma grading scale, was reported in 1 RCT; FA severity index scores (FASI) showed improvement in 2 RCTs with topical sirolimus (0.05%,0.1%,0.2%); 6 cohort studies, 1 case-series and case-report each described post-treatment FASI score improvements with topical sirolimus/rapamycin (0.1%,0.2%,0.4%,1%,0.1%+1%). Pooled meta-analysis of 2 trials showed 63% response rate with topical sirolimus 0.2% gel compared with placebo. Patients with any treatment-emergent-adverse event (TEAE) ranged from 1.6%-62.5%, serious AEs from 3.33%-5.55%. Four trials reported recurrence following treatment cessation. Risk of bias was low (3 RCTs), some concerns (3 RCT), moderate (5 non-RCTs), and serious (2 non-RCTs). Among cohort studies, 4 were moderate, 3 low, and 8 of high quality. Most case-series and case-reports had >5 score (JBI checklists).

CONCLUSIONS: Topical sirolimus is a low risk, well-tolerated treatment. This first comprehensive review of clinical and cost-effectiveness evidence on treating FA associated with TSC may provide clinical guidance for therapeutic selections.