Long-Term Exposure and Safety of a Novel Topical Rapamycin Cream for the Treatment of Facial Angiofibromas in Tuberous Sclerosis Complex: Results From a Single-Center, Open-Label Trial

Wheless, Margaret C.; Takwi, Apana A.; Almoazen, Hassan; Wheless, James W.

doi:10.1177/2329048x19835047

Cited by 10 publications

(8 citation statements)

References 28 publications

(40 reference statements)

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“…The effectiveness and safety of topical mTOR inhibitors were further established in several studies [ 18 – 20 , 34 – 36 ]. including the long-term safety and sustained efficacy over 52 weeks [ 37 ]. A systematic review and meta-analysis by Leducq et al concluded that topical mTOR inhibitors (primarily sirolimus) were effective in 95% (115 of 121) of patients for the management of facial angiofibroma [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Characterization and management of facial angiofibroma related to tuberous sclerosis complex in the United States: retrospective analysis of the natural history database

Boggarapu¹,

Roberds

Nakagawa

et al. 2022

Orphanet J Rare Dis

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Background Facial angiofibroma is the most predominant cutaneous manifestation of tuberous sclerosis complex (TSC), a rare autosomal dominant genetic disorder impacting the mechanistic target of rapamycin (mTOR). Facial angiofibroma can bleed spontaneously, impair eyesight, and cause aesthetic disfiguration causing psychological and social stress. To date, there is little or no evidence on the demographics, and other TSC features associated with facial angiofibroma or the use of mTOR inhibitor for the management of facial angiofibroma. This is a retrospective study of TSC Alliance’s Natural History Database aimed to characterize facial angiofibroma and to evaluate features associated with a higher risk of facial angiofibroma or the use of topical mTOR inhibitors for the management of facial angiofibroma. Data in the NHD was obtained from 18 clinical sites in the US since 2006. Results Of the 2240 patients, 2088 patients were enrolled in the US and data from 2057 patients were included in this analysis. The mean (median) age of overall TSC patients was 22.4 (19.0) years. A total of 69 patients were ≤ 5 years of age. Facial angiofibroma was noted in 1329 (64.6%) patients with TSC. Patients with facial angiofibroma were older on average (Mean: 25.9 [median, 23.0] vs. 16.0 [12.4 years] years, p < 0.0001). In patients with vs. without facial angiofibroma, TSC2 mutation (38.9% vs. 34.8%) was more common than TSC1 mutation (12.3% vs. 18.1%), and the incidence rate of most of the other TSC-related manifestations was significantly higher in patients with facial angiofibroma. Majority of patients had focal seizures (72.8% vs. 60.7%), followed by angiomyolipoma (63.7% vs. 21.8%) and renal cysts (59.4% vs. 33.5%). The age groups, 11–17 (odds ratio [OR], 2.53) and 18–45 years (5.98), TSC2 mutation (1.31), focal seizures (1.50), ADHD (1.47) angiomyolipoma (2.79), and renal cysts (2.63) were significantly associated with a higher risk of facial angiofibroma based on multivariate logistic regression. Abrasive or laser therapy was used by 17.1% and 2.6% patients, respectively. Topical mTOR inhibitor use was noted for 329 (24.8%) patients with facial angiofibroma. Overall systemic mTOR inhibitor use was observed in 399 (30.0%) patients for management of one or more TSC manifestations. Use of systemic mTOR inhibitor for facial angiofibroma was noted for 163 (12.3%) patients, among whom only 9 (0.7%) patients used exclusively for the management of facial angiofibroma. Of the patients with facial angiofibroma, 44.6% did not receive any treatment. Significantly higher use of topical mTOR inhibitor was associated with the 11–17 years age group (OR, 1.67), anxiety (1.57), angiomyolipoma (1.51), and renal cysts (1.33). Conclusions The presence of TSC2 mutations and most other TSC-related manifestations was significantly higher in patients with facial angiofibroma. About one-fourth of patients with facial angiofibroma used a topical mTOR inhibitor and use of systemic mTOR inhibitor for the management of facial angiofibroma or for the other manifestations was noted for 30.0%. About 44.6% of patients did not receive any treatment for the management of facial angiofibroma.

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Section: Discussionmentioning

confidence: 99%

Characterization and management of facial angiofibroma related to tuberous sclerosis complex in the United States: retrospective analysis of the natural history database

Boggarapu¹,

Roberds

Nakagawa

et al. 2022

Orphanet J Rare Dis

View full text Add to dashboard Cite

show abstract

“…The effectiveness and safety of topical mTOR inhibitors were further established in several studies (15)(16)(17)(35)(36)(37). including the long-term safety and sustained e cacy over 52 weeks (9). A systematic review and metaanalysis by Leducq et al concluded that topical mTOR inhibitors (primarily sirolimus) were effective in 95% (115 of 121) of patients for the management of facial angio broma (37).…”

Section: Discussionmentioning

confidence: 99%

“…Various approaches are available for the treatment of facial angio broma related to TSC (7). Physical removal of facial angio broma through surgical dermabrasion, electrocoagulation, excision, curettage, cryosurgery, or laser therapy are effective short-term approaches, but these are associated with pain, hyperpigmentation, scarring, bleeding, the risk for complication, and recurrence of the lesions (5,8,9).…”

Section: Introductionmentioning

confidence: 99%

Characterization and Management of Facial Angiofibroma Related to Tuberous Sclerosis Complex in the United States: Retrospective Analysis of the Natural History Database

Boggarapu

Roberds

Nakagawa

et al. 2022

Preprint

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Background: Facial angiofibroma is the most predominant cutaneous manifestation of tuberous sclerosis complex (TSC), a rare autosomal dominant genetic disorder impacting the mechanistic target of rapamycin (mTOR). Facial angiofibroma can bleed spontaneously, impair eyesight, and cause aesthetic disfiguration causing psychological and social stress. To date, there is little or no evidence on the demographics, and other TSC features associated with facial angiofibroma or the use of mTOR inhibitor for the management of facial angiofibroma. This is a retrospective study of TSC Alliance’s Natural History Database aimed to characterize facial angiofibroma and to evaluate features associated with a higher risk of facial angiofibroma or the use of topical mTOR inhibitors for management of facial angiofibroma. Data in the NHD was obtained from 18 clinical sites in the US since 2006.Results: Of the 2240 patients, 2088 patients were enrolled in the US and data from 2057 patients were included in this analysis. Patient features associated with a higher risk of facial angiofibroma or the use of topical mTOR inhibitors. Facial angiofibroma was noted in 1329 (64.4%) patients with TSC. Patients with facial angiofibroma were older on average. TSC2 mutation was more common, and the burden of other TSC-related manifestations was significantly higher in patients with facial angiofibroma. The 6–17 and the 18–45 -year-old age groups, TSC2 mutation, angiomyolipoma, and renal cysts were significantly associated with a higher risk of facial angiofibroma. Topical mTOR inhibitor use was noted for 329 (24.8%) patients with facial angiofibroma. Being white and presence of angiomyolipoma were significantly associated with higher use of a topical mTOR inhibitor.CONCLUSIONS: Patients with facial angiofibroma were older and more commonly had a TSC2 mutation. The higher burden of TSC-related manifestations in patients with facial angiofibroma illustrates the importance of accurate diagnosis by dermatologists and referral to a comprehensive multi-disciplinary TSC Clinic for surveillance and management of other TSC manifestations. About one-fourth of patients with facial angiofibroma used a topical mTOR inhibitor.

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“…Most of these studies specifically involving a topical formulation of sirolimus showed effectiveness to facial angiofibroma [14][15][16]. The clinical trials reported that within an approximate 2.5 years of duration, patients applying topical rapamycin showed improved appearance of skin lesions [17]. In contrast, a limited case report displays the application of topical everolimus for facial angiofibroma [18].…”

Section: Discussionmentioning

confidence: 99%

The Efficacy of Everolimus for Facial Angiofibromas in Tuberous Sclerosis Complex Patients Treated for Renal Angiomyolipoma/Subependymal Giant Cell Astrocytoma

et al. 2020

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Background: Facial angiofibromas may be present since early childhood in individuals with tuberous sclerosis complex (TSC), causing substantial cosmetic disfigurement. Current therapies are partially effective, but they are uncomfortable, produce scarring, and are especially expensive. Objective: The aim of the present study was to evaluate the efficacy of oral everolimus for TSC-associated angiofibromas. Methods: This retrospective study included TSC patients being treated with oral everolimus for subependymal giant cell astrocytomas (SEGAs) and angiomyolipomas (AMLs). We recorded the changes in facial angiofibromas. Changes in the Angiofibroma Grading Scale (AGS) indicators were recorded according to erythema, average lesion size, lesion density, and percent involvement on the forehead, nose, cheeks, and chin. The scores were recorded before and after the administration of oral everolimus. Results: Twenty-one patients being treated with oral everolimus were enrolled in this study. The mean age was 20.5 years (range 11–44 years, 4 males, and 17 females). The mean dose of oral everolimus was 3.6 mg/day. Clinically meaningful and statistically significant improvement was observed in erythema (p = 0.001), average lesion size (p < 0.001), lesion density (p < 0.001), and percent involvement (p < 0.001). Changes in the AGS findings were statistically significant on the forehead (p = 0.001), nose (p < 0.001) cheeks (p < 0.001), and chin (p = 0.004). Conclusion: Everolimus shows evident improvement and is approved for TSC-associated SEGAs and AMLs. The current study demonstrated the efficacy of oral everolimus in reducing facial angiofibromas, showing the parallel benefits of the treatment protocol for TSC.

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Long-Term Exposure and Safety of a Novel Topical Rapamycin Cream for the Treatment of Facial Angiofibromas in Tuberous Sclerosis Complex: Results From a Single-Center, Open-Label Trial

Cited by 10 publications

References 28 publications

Characterization and management of facial angiofibroma related to tuberous sclerosis complex in the United States: retrospective analysis of the natural history database

Characterization and management of facial angiofibroma related to tuberous sclerosis complex in the United States: retrospective analysis of the natural history database

Characterization and Management of Facial Angiofibroma Related to Tuberous Sclerosis Complex in the United States: Retrospective Analysis of the Natural History Database

The Efficacy of Everolimus for Facial Angiofibromas in Tuberous Sclerosis Complex Patients Treated for Renal Angiomyolipoma/Subependymal Giant Cell Astrocytoma

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