Topical Sirolimus for Darier Disease: a Multicentre Case Series and Immunostaining of Patient Biopsies Implicating mTORC1-associated Signalling

BACKGROUND: Darier disease (DD) is caused by pathogenic ATP2A2 variants that impair calcium homeostasis and keratinocyte adhesion. Responses to MEK inhibition support investigating additional pathway-directed treatments. Phosphorylated ribosomal protein S6 (pS6) Ser240/244 provides a downstream readout of mTORC1-associated signalling. OBJECTIVES: To describe outcomes with topical sirolimus 1% in DD and quantify epidermal pS6 Ser240/244 in paired lesional and non-lesional skin and healthy controls. METHODS: We retrospectively reviewed six patients treated with compounded sirolimus 1% cream, including three who received it as an add-on to ongoing systemic therapy. Treated areas were assessed using a retrospective Physician Global Assessment (PGA). Epidermal pS6 Ser240/244 immunofluorescence was quantified in nine pairs of lesional and non-lesional DD biopsies and nine healthy-control biopsies, using one aggregate value per biopsy. RESULTS: All five evaluable patients showed symptomatic and/or clinical improvement at a median PGA assessment time of 1 month (range 10 days to 6 weeks). One patient discontinued treatment after three days because of local intolerance, precluding efficacy assessment. Mean (SD) corrected pS6 intensity was 10.3 (2.0) arbitrary units in controls, 60.0 (53.5) in non-lesional DD and 99.5 (41.2) in lesional DD. Both DD groups differed from controls (Holm-adjusted P = 0.00185 and P = 0.0000823, respectively). Non-lesional values were heterogeneous, and the paired lesional-non-lesional difference was not significant (P = 0.36). CONCLUSIONS: Topical sirolimus showed promise as a local treatment, including as an adjunct for persistent lesions during systemic therapy. Increased epidermal pS6 provides complementary biological support for investigating mTORC1 inhibition in DD.