Topical Rapamycin and Calcitriol Therapy Trial and genetic testing for Cutaneous Lesions in Tuberous Sclerosis Complex (TSC) Patients
| Autor: | Shiue-Jen Wang, 王雪貞 |
|---|---|
| Rok vydání: | 2017 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 105 Tuberous sclerosis complex (TSC)-associated facial angiofibroma is psychologically debilitating to both patients and their family members. The pathogenesis of TSC stems from TSC1 or TSC2 mutations, leading to the defect in mTOR inhibition. Rapamycin is an mTOR inhibitor and is effective for TSC facial angiofibroma through topical administration. Calcitriol, a vitamin D3 analogue, has been shown to lessen skin fibrosis in scleroderma and may be therapeutically beneficial to angiofibromas. The aim of the study is to determine the effect and safety of topical rapamycin or calcitriol and their combination for the treatment of TSC-associated facial angiofibroma. Detected cutaneous lesions using targeted NGS. A total of 52 TSC patients including 20 male and 32 female subjects were recruited, and 50 of them completed the period 1 study. In period 1, topical rapamycin (0.1%) or calcitriol (3 mcg/g) single-agent therapy versus their combination were applied twice a day by a left-right randomized, split-face comparison for 12 weeks. The primary end point was the reduction of Facial Angiofibroma Severity Index (FASI) for the grade of erythema, papule size, elevation and extension of the lesions at week 12. In period 2, the patients entered an open-label study and were reassigned to use the more effective ointment on both cheeks for another 12 weeks (week 13-24). A follow-up FASI analysis for recurrence after drug discontinue for 12 weeks was also performed (week 36). The secondary end point was the reduction of Visual Analysis Score (VAS) evaluated by the subjects themselves at week 12. A total of 8 patients of cutaneous lesions in TSC were recruited, using NGS identified mutation. All the three topical agents showed a significant reduction of FASI compared to the baseline at week 12. Rapamycin-calcitriol combination treatment resulted in faster and greater improvements than calcitriol or rapamycin along. The efficacy of combination treatment caused a statistically significant reduction of FASI at week 24 after switching from single calcitriol treatment at week 12. The combination treatment continuously decreased papule elevation after keeping its use for 24 weeks or switching from the single rapamycin treatment at week 12, although the FASI was not significantly improved between week 12 and 24. After discontinuing treatment for 12 weeks, although recurrence was observed, a significant reduction of FASI compared to the baseline still remained. No adverse reactions except transient mild itch on the application site was noted. All the three topical agents showed a significant reduction of VAS compared to the baseline at week 12. No somatic mutation were detected, excepted for two mosaic mutations. All the three topical agents, which were safe and well-tolerated, showed a significant reduction of FASI and VAS compared to the baseline at week 12. Topical rapamycin-calcitriol combination demonstrated a higher and sustained clinical response compared with the single-agent treatment for TSC-related facial angiofibroma. That are challenges of detecting mosaic mutations and non-coding region even using NGS. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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