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

doi:10.21203/rs.3.rs-1428511/v1

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

https://doi.org/10.21203/rs.3.rs-1428511/v1

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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.

tuberous sclerosis complex

facial angiofibroma

mechanistic target of rapamycin

topical mTOR inhibitor

surgical removal.

Facial angiofibroma is the most predominant cutaneous manifestation of tuberous sclerosis complex (TSC), occurring in about 75–90% of patients (1, 2). TSC is an autosomal dominant genetic disorder with an estimated incidence of approximately 1 per 5800 live births (3, 4) affecting about 1 million people worldwide and ~ 50,000 individuals in the United States. Loss-of-function mutations in either the TSC1 or TSC2 gene encode dysfunctional hamartin or tuberin, respectively, disrupting the negative regulation of mechanistic target of rapamycin (mTOR) signaling pathway (3). The chronic activation of mTOR leads to uncontrolled cell proliferation and, consequently, the appearance of hamartomas in multiple organs, including the skin, brain, eyes, heart, and kidneys (5, 6).

Facial angiofibromas are multiple small, pinkish, erythematous hamartomas, typically appearing between 2–5 years of age and deteriorate with advancing age. Facial angiofibromas can bleed spontaneously, impair eyesight, and cause aesthetic disfiguration that can lead to psychological and social stress (2, 3, 5). Various approaches are available for the treatment of facial angiofibroma related to TSC (7). Physical removal of facial angiofibroma 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).

The effectiveness of oral mTOR inhibitors for the treatment of TSC-related manifestations is established for subependymal giant cell astrocytoma (SEGA), renal angiomyolipoma, lymphangioleiomyomatosis (LAM), epilepsy, and skin lesions (10–14). However, oral mTOR inhibitors are not recommended for treatment of facial angiofibroma due to the risk of systemic side effects. Various topical formulations of the mTOR inhibitor sirolimus (rapamycin) are effective and generally well tolerated for the management of facial angiofibroma based on several short-term studies (15, 16). which was further established over the long term (17, 18). Hatano et al. reported improvements in health-related quality of life (HRQoL) in patients treated with sirolimus gel for the management of facial angiofibroma (19). While the evidence and consensus recommendations suggest the use of topical mTOR inhibitors for the management of facial angiofibroma (3), lack of FDA-approved topical therapy means there is no standardized formulation available, and many individuals do not have access to topical mTOR inhibitor therapy in the US. Here we present results of a retrospective analysis of the TSC Natural History Database characterizing the natural history of facial angiofibroma and understand the current treatments in practice in the United States.

Data for this analysis were obtained from the TSC Natural History Database Project, which was launched in 2006 by the TSC Alliance, in partnership with a network of TSC clinics in the United States. The TSC Natural History Database Project was created to collect medical data on TSC’s clinical features, treatments, and long-term outcomes. Data from individuals diagnosed with TSC based on genetic or clinical criteria (20) were included in this database. Institutional review board approval was obtained for all the 18 TSC participating clinics in the United States.

A computer-generated unique identifier was assigned to each patient. After the confirmation of the TSC diagnosis and informed consent, all data were extracted from clinical charts under the supervision of the principal investigator (TSC site medical director) and entered into a longitudinal database by a research coordinator at that site. Information was updated regularly with new data from follow-up visits, telephone calls, hospitalizations, and diagnostic tests or procedures.

Patient records in the database are updated at least annually and include information about TSC-related care received at the clinics, as well as retrospectively captured information regarding TSC-related care received outside of the clinics. At the time of the analysis, the database housed information regarding demographics, genotypes, clinical features, diagnostics, and treatments for 2240 patients with TSC. Out of 2240 patients, 2088 patients were enrolled from the United States and data of 31 deceased patients was excluded for this analysis.

The demographics and baseline characteristics that include age, age groups, age at diagnosis of TSC, age groups at diagnosis of TSC, biological sex, race, TSC1 and TSC2 mutations, TSC-related manifestations, and the number of TSC-related manifestations in each patient were analyzed. The age and age at diagnosis were categorized into 0–2 years, 3–5, 6–17, 18–45, ≥ 46 years. Information on the TSC-manifestations was available in the NHD for rhabdomyoma, aneurysm, arrhythmia/dysrhythmia, coarctation aorta, valve dysfunction, other cardiovascular disease, gingival fibromas, dental pits, other dental conditions, liver hamartoma, subependymal giant cell astrocytoma (SEGA), infantile spasms, focal seizures, epilepsy, autism, attention deficit hyperactivity disorder (ADHD), depression, anxiety, other psychiatric disorder, retinal hamartoma, LAM, angiomyolipoma, renal cyst, polycystic kidneys, adrenal angiomyolipoma, bone sclerotic foci, chordoma, calvarium sclerosis and thickening, hemi hypertrophy, lipoma, lymphedema, perivascular epithelial cell tumor (PEComa) of uterus or ovary, scoliosis, spleen angiomyolipoma, stomach hamartoma, testicular angiomyolipoma, and other rare conditions.

The treatments noted for the management of facial angiofibroma include laser therapy, abrasive therapy, topical mTOR inhibitors, systemic mTOR inhibitors, and other treatments for facial angiofibroma. In addition, the use of systemic mTOR inhibitor noted for other conditions was also analyzed.

Statistical Analyses

Disease and patient characteristics were summarized using descriptive statistics. The counts and frequency were reported for categorical variables and the mean and standard deviation were reported for continuous variables. The statistical analyses for comparisons were performed using chi-square tests for categorical variables and t-tests for continuous variables. The association of demographics and baseline characteristics with facial angiofibroma or with the use of a topical mTOR inhibitor was analyzed by univariate and further by multivariate analysis. All the demographic parameters (except the parameters with < 2% of total patients) and all the major TSC manifestations present in the patients (> 10% in at least one group) were included in the analysis. The p-value ≤ 0.05 was considered statistically significant. Statistical analysis was performed using R studio version 1.1.383.

Demographics and baseline characteristics

Of the total 2057 patients with TSC included in this retrospective analysis, 1329 (64.4%) patients had facial angiofibroma. Overall, the mean age (SD) of patients was 23.8 (14.1) years. Patients with facial angiofibroma versus without facial angiofibroma were significantly older (27.3 versus 17.4 years, p < 0.0001) on average. The frequency of patients in the age groups was significantly different between the two groups. The majority of patients with facial angiofibroma (66.6%) were in the 18–45 years age group, while the majority of patients without facial angiofibroma (60.6%) were in the 6–17 years age group (Figure. 1). None of the patients were aged below 3 years at the time of analyses and only 28 patients were noted in the 3–5 years age groups and were observed only in the group of patients without facial angiofibroma. The mean age of diagnosis of TSC was significantly higher in patients with facial angiofibroma (4.7 versus 3.8 years, p = 0.045). The majority of patients were diagnosed with TSC within 2 years of age in both groups (Fig. 1). Very few patients were diagnosed with TSC at ≥ 46 years of age (patients with facial angiofibroma, 15 [1.1%]; patients without facial angiofibroma, 11 [1.5%]).

The frequency of women and men is similar in both groups. The majority of patients were white in both the groups and a significantly higher proportion of whites was observed in the facial angiofibroma group. Overall, the presence of TSC2 mutation was more common than the

TSC1 mutation in both groups. The frequency of TSC1 mutation was significantly lower and TSC2 mutation was significantly higher in patients with versus without facial angiofibroma (Fig. 1).

TSC-related manifestations

The clinical presentation of TSC varied widely between patients with and without facial angiofibroma. The burden of most of the TSC-related manifestations was significantly higher in patients with facial angiofibroma (Fig. 1).

The number of TSC-related manifestations observed in this population varied widely, ranging from 0–14 manifestations in any given patient with TSC. Patients with facial angiofibroma showed a significantly higher mean number of TSC manifestations than that observed in patients without facial angiofibroma (6.2 vs. 3.4, p < 0.0001).

Patient features associated with facial angiofibroma

The univariate regression analysis showed a significantly higher risk of facial angiofibroma with the age groups 18–45 years and ≥ 46 years, the 18–45 years age group at diagnosis, being white, and the presence of TSC-related manifestations such as focal seizures, angiomyolipoma, renal cysts, SEGA, autism, retinal hamartoma, ADHD, anxiety, and liver hamartoma (Figure. 1). In the multivariate regression, a significantly higher risk of facial angiofibroma was observed for the 6–17 years age group, the 18–45 years age group, TSC2 mutation, angiomyolipoma, and renal cysts (Table 1). The risk of facial angiofibroma almost doubled from 6–17 years to 18–45 years age groups (Table 1).

Table 1

Features associated with significantly higher or lower risk of facial angiofibroma based on multivariate logistic regression
Parameter	Odds Ratio (95% CI)	P value
6–17 years age group	3.37 (1.46–8.40)	< 0.01
18–45 years age group	6.38 (3.23–13.19)	< 0.0001
TSC2 mutation	1.31 (1.00–1.69)	< 0.05
Angiomyolipoma	2.38 (1.79–3.17)	< 0.0001
Renal cysts	2.15 (1.63–2.84)	< 0.0001
Data included for multivariate analysis was from 1897 patients (Patients with facial angiofibroma, N = 1235; Patients without facial angiofibroma, N = 662)
CI, confidence; TSC, tuberous sclerosis complex

Treatments

Physical removal of facial angiofibroma using laser therapy was noted for 17.1% of patients and abrasive therapy was noted for 2.6% of patients (Fig. 2). Systemic mTOR inhibitors were received by 163 (12.3%) participants for the management of facial angiofibroma. However, only 16 (1.2%) patients received systemic mTOR inhibitors exclusively for the management of facial angiofibroma after excluding other TSC comorbid manifestations observed in those patients. Additionally, 222 (16.7%) patients were receiving systemic mTOR inhibitors for other conditions (but not noted under facial angiofibroma treatment). Topical mTOR inhibitor was used by 329 (24.8%) patients for the management of facial angiofibroma (Fig. 2). A total of 601 (45.2%) patients were not receiving any treatment for the management of facial angiofibroma or noted for an ongoing systemic mTOR inhibitor for other TSC manifestations (Fig. 2).

Patient features associated with use of topical mTOR inhibitors

Topical mTOR inhibitor use was most commonly associated with the 6–17-years age group, the 0–2 years age group at diagnosis, TSC2 gene mutation, being white, and the presence of manifestations such as renal cysts, angiomyolipoma, rhabdomyoma, autism, and retinal hamartoma based on the univariate regression (Fig. 3). In the multivariate regression, whites, and individuals with angiomyolipoma were significantly associated with the higher use of topical mTOR inhibitors (Table 2.)

Table 2

Patient characters significantly associated with higher or lower use of topical mTOR inhibitors based on the multivariate logistic regression
Parameter	Odds Ratio (95% CI)
White	1.72 (1.19–2.54)	< 0.01
Angiomyolipoma	1.56 (1.16–2.11)	< 0.01
Data included in the multivariate analysis was from 1235 patients (Patients using topical mTOR inhibitor, N = 309; Patients not using topical mTOR inhibitor, N = 926)
CI, confidence interval; mTOR, mechanistic target of rapamycin

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.

In this retrospective analysis, the risk of facial angiofibroma correlated with age groups 6–17 years and 18–45 years, presence of a TSC2 gene mutation, being white, and presence of angiomyolipoma and renal cysts. The burden of TSC-related manifestations was significantly higher in patients with facial angiofibroma, illustrating the importance of accurate diagnosis by dermatologists and referral to a comprehensive multi-disciplinary TSC Clinic for surveillance and management of other TSC manifestations. The majority of patients did not receive treatment for the management of facial angiofibroma. Despite the lack of an FDA-approved formulation, nearly one-fourth of individuals with TSC have used a topical mTOR inhibitor for the management of facial angiofibroma, and a few individuals (1.2%) have used a systemic mTOR inhibitor solely for the management of facial angiofibroma. Topical mTOR inhibitor use was most commonly associated with being white, and the presence of angiomyolipoma and renal cysts.

Author Contributions:

All the authors contributed for this retrospective study. SB has conducted the statistical analyses and drafted the manuscript, and all the authors critically reviewed the manuscript.

Funding:

None to declare

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

The Natural History Database is managed and maintained by the TSC Alliance, MD, USA, data were de-identified, and no ethics committee approval was sought. Statistical analysis was performed on the de-identified data.

Consent to participate

Not applicable.

Competing interests

SB and EB are employees of Nobelpharma America, LLC. SR and JN are employees of TSC Alliance, a non-profit organization which reports revenue from individual donors and corporations including Aeovian, Jazz Pharmaceuticals, BridgeBio, LivaNova, Lundbeck, Mallinckrodt, MassMutual, Neurelis, Nobelpharma America, Novartis, Ovid, UCB, and Upsher-Smith.

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Editorial decision: Major revision
26 May, 2022
Reviews received at journal
13 Mar, 2022
Reviewers invited by journal
13 Mar, 2022
Editor assigned by journal
11 Mar, 2022
First submitted to journal
07 Mar, 2022

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

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Version 1

Abstract

Figures

Introduction

Methods

Statistical Analyses

Results

Demographics and baseline characteristics

TSC-related manifestations

Patient features associated with facial angiofibroma

Treatments

Patient features associated with use of topical mTOR inhibitors

Discussion

Conclusions

Declarations

References

Status:

Version 1