Efficacy of Rapamycin in Tuberous Sclerosis–Associated Hypopigmented Macules

Abstract

The study by Wataya-Kaneda et al 1 in this issue of JAMA Dermatology examines the response of hypopigmented macules in tuberous sclerosis (TS) to topical rapamycin. The authors found that topical rapamycin, 0.2%, gel led to substantial improvement of hypopigmented macules without systemic absorption and that the improvement was more marked in sun-exposed skin. This improvement was reflected in the normalization of melanosome abnormalities in treated skin. Finally, the authors note that knockdown of tuberin (tsc2) caused abnormalities in melanosome numbers compared with controls.This study is the first to examine the benefit of topical rapamycin for the treatment of TSassociated hypopigmentation. Rapamycin, an inhibitor of the target of rapamycin complex (mTOR), has been used topically for the treatment of cutaneous angiofibromas and systemically for other complications of TS, including renal angiomyolipomas, subependymal giant cell astrocytomas, and pulmonary lymphangiomyomatosis. 2,3 Mutations in the 2 genes responsible for TS (TSC1 and TSC2) have been shown to cause activation of the small GTPase Rheb, and downstream of Rheb activation is activation of mTOR, which can exist as 2 complexes, mTORC1 and mTORC2. 4

Identification of a novel TSC1 gene variant in a patient with atypical vitiligo‐like skin lesions: Unveiling the hidden tuberous sclerosis complex

“…Earlier reports have described the existence of “vitiligo” and “depigmented nevi” in patients with TSC. Finally, it has been demonstrated that the hypopigmentation in TSC is different from that of vitiligo in that the number of melanocytes is not decreased in TSC hypopigmentation but is greatly decreased in vitiligo (Arbiser, 2015 ). The hypomelanotic macules that are characteristic of TSC mainly depend on the melanocytes of the TSC patients displaying autophagic dysregulation, thereby reducing the pigmentation (Yang et al., 2017 ).…”

Targeting CTLA‐4, PD‐L1 and IDO to modulate immune responses in vitiligo

“…Furthermore, rapamycin has also an effect on melanosomes as hypopigmentation associated with tuberous sclerosis improved with topical rapamycin. As such, rapamycin may have a dual effect by normalizing melanosome function and exerting an anti‐inflammatory capacity by the inhibition of mTOR . Low‐dose IL‐2 also enhances the activity and expansion of Tregs without impairment of immunity to infections, vaccination and cancer .…”