Abstract：
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.
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: Vienna Science and Technology Fund, Austrian Science Fund.
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.
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: Vienna Science and Technology Fund, Austrian Science Fund.
摘要：
背景：结节病是一种炎症性疾病，可影响各种器官和组织，导致肉芽肿的形成和随后的功能障碍。结节病的起源仍然未知，治疗方案很少。雷帕霉素（mTOR）激活的机制靶标通常在不同组织的患者肉芽肿中可见，并已显示在小鼠模型中诱导结节病样肉芽肿。本研究旨在研究mTOR抑制剂西罗莫司治疗皮肤结节病的有效性和安全性。
方法：我们做了一个单中心，维也纳总医院西罗莫司治疗持续性糖皮质激素难治性皮肤结节病患者的随机研究,维也纳医科大学(维也纳,奥地利)。我们招募了有毅力的参与者，活跃,和组织学证实的皮肤结节病。我们在安慰剂对照中使用了n-of-1交叉设计，在同一参与者中进行双盲局部治疗期和随后的单臂全身治疗期，为期4个月。参与者最初在凡士林或安慰剂（仅凡士林）中接受0.1％的局部西罗莫司，每天两次。经过一段冲洗期，所有参与者随后服用6mg负荷剂量，然后口服2mg西罗莫司溶液，每日一次，旨在达到6ng/mL的血清浓度。主要终点是局部或全身治疗后皮肤结节病活动和形态指数（CSAMI）的变化。所有参与者都被纳入安全性分析，和已完成各自治疗期(局部治疗或全身治疗)的患者被纳入主要分析.临床医生在每次研究访视时评估不良事件，并根据其与研究药物的相关性进行分类。严重程度,严肃,和期待。本研究已在EudraCT（2017-004930-27）注册，现已结束。
结果：在2019年9月3日至2021年6月15日期间，有16名患有持续性皮肤结节病的参与者被纳入研究。16名参与者中有6名（37%）是男性，10人（63%）是女性，15人（94%）是白人。参与者的平均年龄为54岁（IQR48-58）。14名参与者被随机分配到局部阶段，2名直接进入全身治疗阶段。每日局部治疗未改善皮肤病变（效果估计-1·213[95%CI-2·505至0·079]，p=0·066）。针对6ng/mL血清浓度的全身治疗导致10名参与者中有7名（70％）的皮肤病变的临床和组织学改善（中位数-7·0[95％CI-16·5至-3·0]，p=0·018）。皮肤结节病的各种形态，包括丘疹,结节状,牌匾,疤痕,和纹身相关的结节病,对西罗莫司全身治疗有反应,在治疗停止后持续超过1年.没有发生严重不良事件，也没有死亡。
结论：对于持续性糖皮质激素难治性结节病患者，短期使用西罗莫司可能是一种有效且安全的治疗选择，具有长期的疾病调节作用。西罗莫司在肉芽肿性炎症中的作用应进一步研究，多中心,随机临床试验。
背景：维也纳科学技术基金，奥地利科学基金。
方法：我们做了一个单中心，维也纳总医院西罗莫司治疗持续性糖皮质激素难治性皮肤结节病患者的随机研究,维也纳医科大学(维也纳,奥地利)。我们招募了有毅力的参与者，活跃,和组织学证实的皮肤结节病。我们在安慰剂对照中使用了n-of-1交叉设计，在同一参与者中进行双盲局部治疗期和随后的单臂全身治疗期，为期4个月。参与者最初在凡士林或安慰剂（仅凡士林）中接受0.1％的局部西罗莫司，每天两次。经过一段冲洗期，所有参与者随后服用6mg负荷剂量，然后口服2mg西罗莫司溶液，每日一次，旨在达到6ng/mL的血清浓度。主要终点是局部或全身治疗后皮肤结节病活动和形态指数（CSAMI）的变化。所有参与者都被纳入安全性分析，和已完成各自治疗期(局部治疗或全身治疗)的患者被纳入主要分析.临床医生在每次研究访视时评估不良事件，并根据其与研究药物的相关性进行分类。严重程度,严肃,和期待。本研究已在EudraCT（2017-004930-27）注册，现已结束。
结果：在2019年9月3日至2021年6月15日期间，有16名患有持续性皮肤结节病的参与者被纳入研究。16名参与者中有6名（37%）是男性，10人（63%）是女性，15人（94%）是白人。参与者的平均年龄为54岁（IQR48-58）。14名参与者被随机分配到局部阶段，2名直接进入全身治疗阶段。每日局部治疗未改善皮肤病变（效果估计-1·213[95%CI-2·505至0·079]，p=0·066）。针对6ng/mL血清浓度的全身治疗导致10名参与者中有7名（70％）的皮肤病变的临床和组织学改善（中位数-7·0[95％CI-16·5至-3·0]，p=0·018）。皮肤结节病的各种形态，包括丘疹,结节状,牌匾,疤痕,和纹身相关的结节病,对西罗莫司全身治疗有反应,在治疗停止后持续超过1年.没有发生严重不良事件，也没有死亡。
结论：对于持续性糖皮质激素难治性结节病患者，短期使用西罗莫司可能是一种有效且安全的治疗选择，具有长期的疾病调节作用。西罗莫司在肉芽肿性炎症中的作用应进一步研究，多中心,随机临床试验。
背景：维也纳科学技术基金，奥地利科学基金。
