PMID- 38267106 OWN - NLM STAT- MEDLINE DCOM- 20240205 LR - 20240206 IS - 2665-9913 (Electronic) IS - 2665-9913 (Linking) VI - 6 IP - 2 DP - 2024 Feb TI - Efficacy and safety of mTOR inhibition in cutaneous sarcoidosis: a single-centre trial. PG - e81-e91 LID - S2665-9913(23)00302-8 [pii] LID - 10.1016/S2665-9913(23)00302-8 [doi] AB - BACKGROUND: Sarcoidosis is an inflammatory condition that can affect various organs and tissues, causing the formation of granulomas and subsequent functional impairment. The origin of sarcoidosis remains unknown and there are few treatment options. Mechanistic target of rapamycin (mTOR) activation is commonly seen in granulomas of patients across different tissues and has been shown to induce sarcoidosis-like granulomas in a mouse model. This study aimed to examine the efficacy and safety of the mTOR inhibitor sirolimus as a treatment for cutaneous sarcoidosis. METHODS: We did a single-centre, randomised study treating patients with persistent and glucocorticoid-refractory cutaneous sarcoidosis with sirolimus at the Vienna General Hospital, Medical University of Vienna (Vienna, Austria). We recruited participants who had persistent, active, and histologically proven cutaneous sarcoidosis. We used an n-of-1 crossover design in a placebo-controlled, double-blind topical treatment period and a subsequent single-arm systemic treatment phase for 4 months in the same participants. Participants initially received either 0.1% topical sirolimus in Vaseline or placebo (Vaseline alone), twice daily. After a washout period, all participants were subsequently administered a 6 mg loading dose followed by 2 mg sirolimus solution orally once daily, aiming to achieve serum concentrations of 6 ng/mL. The primary endpoint was change in the Cutaneous Sarcoidosis Activity and Morphology Index (CSAMI) after topical or systemic treatment. All participants were included in the safety analyses, and patients having completed the respective treatment period (topical treatment or systemic treatment) were included in the primary analyses. Adverse events were assessed at each study visit by clinicians and were categorised according to their correlation with the study drug, severity, seriousness, and expectedness. This study is registered with EudraCT (2017-004930-27) and is now closed. FINDINGS: 16 participants with persistent cutaneous sarcoidosis were enrolled in the study between Sept 3, 2019, and June 15, 2021. Six (37%) of 16 participants were men, ten (63%) were women, and 15 (94%) were White. The median age of participants was 54 years (IQR 48-58). 14 participants were randomly assigned in the topical phase and 2 entered the systemic treatment phase directly. Daily topical treatment did not improve cutaneous lesions (effect estimate -1.213 [95% CI -2.505 to 0.079], p=0.066). Systemic treatment targeting trough serum concentrations of 6 ng/mL resulted in clinical and histological improvement of skin lesions in seven (70%) of ten participants (median -7.0 [95% CI -16.5 to -3.0], p=0.018). Various morphologies of cutaneous sarcoidosis, including papular, nodular, plaque, scar, and tattoo-associated sarcoidosis, responded to systemic sirolimus therapy with a long-lasting effect for more than 1 year after treatment had been stopped. There were no serious adverse events and no deaths. INTERPRETATION: Short-term treatment with systemic sirolimus might be an effective and safe treatment option for patients with persistent glucocorticoid-refractory sarcoidosis with a long-lasting disease-modulating effect. The effect of sirolimus in granulomatous inflammation should be investigated further in large, multi-centre, randomised clinical trials. FUNDING: Vienna Science and Technology Fund, Austrian Science Fund. CI - Copyright (c) 2024 Elsevier Ltd. All rights reserved. FAU - Redl, Anna AU - Redl A AD - Department of Dermatology, Medical University of Vienna, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. FAU - Doberer, Konstantin AU - Doberer K AD - Department of Nephrology, Medical University of Vienna, Vienna, Austria. FAU - Unterluggauer, Luisa AU - Unterluggauer L AD - Department of Dermatology, Medical University of Vienna, Vienna, Austria. FAU - Kleissl, Lisa AU - Kleissl L AD - Department of Dermatology, Medical University of Vienna, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. FAU - Krall, Christoph AU - Krall C AD - Institute of Artificial Intelligence, Center for Medical Data Science, Medical University of Vienna, Vienna, Austria. FAU - Mayerhofer, Carolina AU - Mayerhofer C AD - Department of Dermatology, Medical University of Vienna, Vienna, Austria. FAU - Reininger, Barbel AU - Reininger B AD - Department of Dermatology, Medical University of Vienna, Vienna, Austria. FAU - Stary, Victoria AU - Stary V AD - Department of General Surgery, Medical University of Vienna, Vienna, Austria. Electronic address: georg.stary@meduniwien.ac.at. FAU - Zila, Nina AU - Zila N AD - Department of Dermatology, Medical University of Vienna, Vienna, Austria; Division of Biomedical Science, University of Applied Sciences FH Campus Wien, Vienna, Austria. FAU - Weninger, Wolfgang AU - Weninger W AD - Department of Dermatology, Medical University of Vienna, Vienna, Austria. FAU - Weichhart, Thomas AU - Weichhart T AD - Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria. FAU - Bock, Christoph AU - Bock C AD - Institute of Artificial Intelligence, Center for Medical Data Science, Medical University of Vienna, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. FAU - Krausgruber, Thomas AU - Krausgruber T AD - Institute of Artificial Intelligence, Center for Medical Data Science, Medical University of Vienna, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. FAU - Stary, Georg AU - Stary G AD - Department of Dermatology, Medical University of Vienna, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. LA - eng PT - Journal Article PT - Randomized Controlled Trial PL - England TA - Lancet Rheumatol JT - The Lancet. Rheumatology JID - 101765308 RN - 0 (Butylamines) RN - 13366-43-3 (dibutadiamine) RN - 0 (Glucocorticoids) RN - 8009-03-8 (Petrolatum) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Female MH - Humans MH - Male MH - Middle Aged MH - *Butylamines MH - Glucocorticoids/pharmacology MH - Granuloma MH - Petrolatum MH - *Sarcoidosis/drug therapy MH - *Sirolimus/adverse effects COIS- Declaration of interests This work is funded in part by a Vienna Science and Technology Fund project (LS18-058; GS, TK, TW). GS reports receiving a grant from the Austrian Science Fund (FWF; P31494). CB reports grant funding from two FWF Special Research Program (SFB) grants (F6102, F7002) and a European Research Council (ERC) Consolidator Grant (101001971). TK reports grant funding from one FWF SFB grant (F7002). TW reports receiving grants from the FWF (P34023-B, P34266-B), the FWF SFB (F83), and the Ann Theodore Foundation Breakthrough Sarcoidosis Initiative. All other authors declare no competing interests. EDAT- 2024/01/25 00:42 MHDA- 2024/01/26 06:44 CRDT- 2024/01/24 20:58 PHST- 2023/06/28 00:00 [received] PHST- 2023/10/31 00:00 [revised] PHST- 2023/11/03 00:00 [accepted] PHST- 2024/01/26 06:44 [medline] PHST- 2024/01/25 00:42 [pubmed] PHST- 2024/01/24 20:58 [entrez] AID - S2665-9913(23)00302-8 [pii] AID - 10.1016/S2665-9913(23)00302-8 [doi] PST - ppublish SO - Lancet Rheumatol. 2024 Feb;6(2):e81-e91. doi: 10.1016/S2665-9913(23)00302-8.