結節硬化症患者外用rapamycin合併calcitriol於皮膚病灶之臨床試驗

Abstract

結節硬化症(Tuberous Sclerosis Complex)是一種自體顯性遺傳疾病。其臨床表現涉及人體多種器官，如皮膚、腦部、腎臟、肺臟、心臟及其他器官會形成缺陷瘤(hamartomas)。結節硬化症患者有三分之一是遺傳而來,另外三分之二的病人則為新發生(de novo)的突變所致。皮膚表徵是結節硬化症患者臨床最常見的表徵之一，其中臉部血管纖維瘤發生機率為百分之七十五。結節硬化症主要涉及mTOR 路徑(mammalian target of rapamycin pathway)，是一個生物學上非常重要的領域，掌管了細胞增生、血管生成、蛋白合成及代謝等重要功能。已知的結節硬化症兩個致病基因，TSC1(製造Hamartin) 及TSC2(製造Tuberin)皆為 mTOR 的抑制分子。Rapamycin其功能與TSC複合蛋白一樣具有調控mTOR的訊息傳遞，且已運用在臨床治療。迄今為止，臨床對結節硬化症皮膚表現的治療，仍以傳統的外科式的方式治療，例如電燒或手術切除，但會有外科手術副作用的風險，如疼痛、傷口感染，或是產生疤痕，執行上也麻煩許多，且小朋友的局部麻醉不容易進行，全身麻醉又有比較大的健康風險。若以雷射方式治療，治療所需的費用較高，且患部復發機率高需重複治療，所以臨床治療臉部血管纖維瘤還有非常大需要改進的空間。 本次研究使用rapamycin (0.1%)合併calcitriol (3 mcg/g)、rapamycin (0.1%)或calcitriol (3 mcg/g)外用藥膏來治療結節硬化症皮膚表現，為期36週，評估其療效以及副作用，並以次世代定序(Next-generation Sequencing)為方式做受試者基因檢測。本研究針對第一階段納入的11位受試者在第12週解盲做評估。解盲後藥物使用以rapamycin (0.1%)合併calcitriol (3 mcg/g) 和使用單方rapamycin治療臉部血管纖維瘤皆有明顯效果。11位受試者沒有明顯的副作用與不適症狀發生，只有輕微皮膚搔癢和輕微的刺痛感的情況發生。以次世代定序分析受試者基因，帶有TSC2基因突變的有9位(82%)，未偵測到帶有TSC1(0%)突變，2位(18%)未發現帶有突變點。 臺大醫院結節硬化症門診，是目前全台結節硬化症就診人數最多的門診，希望透過這次試驗，提供病患以方便、簡單、費用較低和安全的外用藥膏治療臉部血管纖維瘤，讓結節硬化症病患得到更完善的照護。

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease. It is a syndrome characterized by multiple organs involvement such as skin, brain, kidneys, heart, eyes and lungs with hamartomas. One third of people are hereditary and two thirds are sporadic cause by de novo mutation. Most people with TSC have changes in their skin. Facial angiofibroma is one of skin features which appear in up to 75%. mTOR (mammalian target of rapamycin) pathway is associated with cellular proliferation, angiogenesis, protein synthesis and transcription. Mutation of TSC1or TSC2 causes abnormality of hamartin or tuberin and therefore results in the defects in mTOR pathway inhibition. Rapamycin is a mTOR pathway inhibitor; ingestion of rapamycin has been shown to improve TSC symptoms and/or signs, including skin lesions. At present, available treatment options for facial angiofibroma are limited to surgical therapies such as excision or dermabrasion and laser therapy. However, these therapies often cause pain, discomfort, infection or produce scar, have to be repeated many times, and therefore often require repeated general anesthesia in younger patients. And laser therapy is quite expensive. In this study, we performed a double-blind clinical trial comparing the efficacy and side effects of rapamycin (0.1%) combined with calcitriol (3 mcg/g)、rapamycin (0.1%) alone and calcitriol (3 mcg/g) alone for treatment of facial angiofibroma during a period of 36 weeks. And we applied the next-generation sequencing (NGS) technology for the genetic diagnosis by testing TSC1 and TSC2 genes. Rapamycin (0.1%) combine calcitriol (3 mcg/g) and rapamycin (0.1%) alone showed the best efficacy in our 11 patients at week 12. There were no severe side effects except for mild pruritus, burning sensation or stinging sensation. There were 9 cases with TSC2 mutation and 2 cases with no mutation identified. There was no case with mutation at TSC1. The Joint Tuberous Sclerosis Complex Clinic at the National Taiwan University Hospital is the biggest Joint TSC clinic in Taiwan. Through this experiment, it is hoped that the clinic can provide convenient, cost-effective and safe topical ointments to TSC patients with facial angiofibromas in order to give them a more comprehensive care.