This retrospective analysis of the TSC Natural History Database was aimed to characterize facial angiofibroma and to understand the real-world use of treatments in the United States. The risk of facial angiofibroma was increased with age (until 18–45 years). Patients with versus without facial angiofibroma were older on average. The burden of other TSC-related manifestations was significantly higher in patients with facial angiofibroma in this study. The 6–17 years and the 18–45 years age groups, TSC2 mutation, angiomyolipoma, and renal cysts were significantly associated with a higher risk of facial angiofibroma. Increase in the incidence with age was reported for other major TSC manifestations such as angiomyolipoma, ungual fibroma, and LAM (1).
In this retrospective study, the proportion of whites was significantly higher in the facial angiofibroma group. It is not known whether angiofibroma is more common in white skin for biological reasons, e.g. less protection against ultraviolet radiation-induced mutations, or whether angiofibroma are underdiagnosed in non-white individuals. Underdiagnosis is plausible due to different physical manifestations on non-white skin, or due to biased descriptive criteria (eg. redness may be less obvious on non-white skin). We cannot rule out socioeconomic barriers to accurate diagnosis by expert TSC healthcare, which unfortunately also correlate with non-white skin; however, given that all participants in this study have been seen at expert TSC centers, this may be a less likely explanation in this specific study. We urge additional research to understand the reasons underlying differences in diagnosis of angiofibroma in people of different skin colors.
In this population recruited from TSC Clinics at major medical centers, 45.2% of patients did not receive any treatment for the management of facial angiofibroma or noted for an ongoing oral mTOR inhibitors treatment for other TSC manifestations that could improve facial angiofibroma. It is not known whether this gap in treatment is due to low medical need (eg. very small and mild angiofibroma) or lack of access to a safe and effective therapy. Topical mTOR inhibitor use was noted for one-fourth of patients with facial angiofibroma, and its use was most commonly associated with being white and having angiomyolipoma. Although the number of Black or African American individuals with angiofibroma in this study is relatively small (n = 85), utilization of topical mTOR inhibitor is much less common in this group than in whites or Asians. Additional research is urgently needed to understand whether this is due to less medical need (e.g., less severe angiofibroma manifestations) or inability to access compounded topical mTOR inhibitor preparation due to cost or other barriers.
TSC is a rare disease with various manifestations that can predominantly involve the skin, the central nervous system, heart, kidneys, lungs, and less frequently, the retina, gingiva, and other abdominal organs (20, 21). The clinical presentation varies largely ranging from mild dermatological findings to severe neurologic morbidity (21). In this study, we found that patients with facial angiofibroma had a higher burden of most of the TSC manifestations compared with patients without facial angiofibroma. The number of manifestations present in an individual also varied ranging from 0–14 with an average number of TSC-manifestations being significantly higher in patients with facial angiofibroma. The most frequent TSC-related manifestation was focal seizures in patients with and without facial angiofibroma. However, a significant association with facial angiofibroma was observed for liver hamartoma, followed by angiomyolipoma, renal cysts, and anxiety in the univariate regression. This observation is of particular importance because these manifestations have no externally visible physical signs. Because findings of angiofibroma may precede many potentially severe internal manifestations, accurate and timely diagnosis of angiofibroma could be important for informing clinical surveillance of individuals with TSC.
Management of TSC requires a multidisciplinary approach involving dermatologists, neurologists, pulmonologists, urologists, cardiovascular specialists, pediatricians, and geneticists. Skin lesions are the most frequent TSC manifestations and one of the major reasons for seeking medical attention (2). The association 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.
Facial angiofibroma requires chronic treatment throughout life. The updated International TSC Consensus Group recommendations mention that more evidence is necessary to guide the choice of treatment for TSC-related skin lesions, however, recognize existing evidence (22). Current recommendations also acknowledge the 2018 regulatory approval of topical sirolimus gel 0.2% for facial angiofibroma in Japan (22). Consensus recommendations call for topical interventions as a first line for flat to moderately raised lesions; surgical interventions are recommended for lesions that do not respond, are more protuberant, or require immediate intervention (22). The International TSC Consensus Group does not recommend systemic therapy for the exclusive treatment of facial angiofibroma due to the risk of systemic side effects and has found insufficient evidence regarding an additive effect of topical mTOR inhibitors for facial angiofibroma as an adjunct to systemic therapy (22).
Physical removal of facial angiofibroma is painful; often requires anesthesia, which may lead to neurotoxicity in children; can lead to hyperpigmentation or scarring; and carry a risk of posttreatment infection (23–29). In addition, physical removal does not address the underlying cause of TSC, and facial angiofibroma can recur. In this study, 2.6% and 17.1% of patients undergone abrasive and laser therapy, respectively.
Studies with oral mTOR inhibitors showed concurrent improvement in facial angiofibroma and other TSC skin lesions (30–33). However, side effects associated with systemic exposure to mTOR inhibitors may not justify its use solely for the treatment of facial angiofibroma in most cases. In addition, Kitayama et al. reported that topical application, particularly gel formulation, showed more efficient drug delivery to the skin than the oral sirolimus in a hairless mice study (34). In our study 12.3% of patients received treatment with systemic mTOR inhibitors. Most patients receiving systemic mTOR inhibitor for the management of facial angiofibroma had other TSC-related manifestations, but 16 patients received systemic mTOR inhibitors without having other eligible indications for treatment.
Topical formulations of mTOR inhibitors have the potential to improve facial angiofibroma related to TSC without systemic exposure and associated side effects. In 2010, Haemel et al. (8) reported the improvement in facial angiofibroma with topical sirolimus treatment for the first time. The effectiveness and safety of topical mTOR inhibitors were further established in several studies (15–17, 35–37). including the long-term safety and sustained efficacy over 52 weeks (9). 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 (37). The most frequent regimen observed in the systematic review and metanalysis was 0.1% sirolimus, with 1 or 2 applications per day for 12 weeks (37). Based on these positive reports, many physicians have been prescribing “off-label” topical sirolimus made by compounding pharmacies (21). The effectiveness and safety of topical sirolimus are further established in a recent systematic review by Cortell Fuster et al. (38). Most of the improvement in facial angiofibroma with topical sirolimus occurred during the first month of treatment (15). In a study by Okanishi et al. early sirolimus gel intervention was effective for the treatment of facial angiofibroma and fibrous plaques and reported the potential to maintain the skin at near-normal levels in patients with TSC (39). In the Natural History Database, 45.2% of patients with facial angiofibroma did not receive any treatment for the management of facial angiofibroma or noted an ongoing systemic mTOR inhibitor treatment for other TSC manifestations, and about one-fourth of patients in this retrospective analysis were treated with topical mTOR inhibitors for the management of facial angiofibroma. Despite the strong evidence for the effectiveness and safety of topical mTOR inhibitors in the management of facial angiofibroma, the major unmet need is the unavailability of FDA-approved topical formulation for the management of facial angiofibroma in the United States. In a study by Crall et al. topical mTOR inhibitors were used by 47.3% patients for the management of facial angiofibroma. Of these patients, 47.7% had difficulties with insurance coverage (40). In addition, due to their compounded production, these treatments currently vary widely in dosage (0.03–1.00%), excipients, quality control, and cost (37, 41).
The major limitation of this study is being a retrospective analysis rather than a prospective collection of data. The study was limited to 18 participating TSC Clinics associated with major medical centers; patients managed locally or at other centers may have different characteristics. Also, this study does not include patient-reported outcomes such as impact on quality of life or patient and caregiver perceptions of benefits and risks.