Use of mTOR inhibitors (rapalogs) for the treatment of skin changes in tuberous sclerosis complex

Abstract

Skin manifestations of Tuberous Sclerosis Complex (TSC) are present in more than 90% of patients. Facial angiofibromas (AF) are considered a skin hallmark of TSC. They are responsible for esthetic impact in patients. We aimed at reviewing the data available on the use of rapamycin (sirolimus) and everolimus for the oral or topical treatment of AF and other TSC-related skin changes and reporting our preliminary experience at Angers University Hospital. The literature search has been performed in combining the terms "rapamycin", "sirolimus", "everolimus", "tuberous sclerosis complex", "skin" and "trial". We have splited the findings of the literature search into two parts: 1) the value of rapalogs used systemically for extracutaneous purposes and 2) the role of topical rapalogs used specifically for skin lesions. Large clinical trials using rapamycin or everolimus for the treatment of brain, lung or kidney manifestations of TSC unfortunately poorly define the "skin lesion response rate" they report. Conversely, the trials with topical rapamycin demonstrate significant, albeit transient, efficacy on AF size and visibility and acceptable tolerance. Several trials suggest better efficacy in younger patients than in adults. Long-term evaluation (up to 136 weeks) point to sustained response and good local and systemic tolerance. However, maintenance therapy appears to be mandatory to preserve skin response. Other skin changes, especially shagreen fibrotic plaques, hypomelanotic macules and ungual tumors still need far more research. Our experience in 124 patients (children and adults) treated for facial AF at Angers University Hospital showed that about 80% of them had an impressive and sustained response. The issues of cost and access to affordable topical rapamycin formulations are critical for the patients even if skin changes do not cause serious harm in the context of TSC. We strongly suggest to improve and standardize the formulation of topical rapamycin, to encourage the pharmaceutical industry for providing commercial products, and the Health systems (social welfare) to reimburse them. © 2022 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.