Angiofibromas In Patients Research Articles

Therapeutic effect of Topical Sirolimus on Facial Angiofibromas in Patients of Tuberous Sclerosis Complex

Abstract Introduction: Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder. Facial angiofibromas are the most common cutaneous findings of TSC. Treatment modalities such as laser, surgery, and/or cryotherapy are employed. Topical therapy with Sirolimus, an mTOR inhibitor, showed beneficial effects. Objective: To study the effects of topical sirolimus (0.1%) on Facial Angiofibromas in patients of TSC. Methodology : Four patients with facial angiofibromas were included. They applied Sirolimus preparation twice daily, for 3 months. The Facial Angiofibroma Severity Index (FASI) was recorded pre-intervention, at 3 months and after 6 months. Results: All the patients showed a reduction in the FASI score at the end of three months of therapy. In three patients, on discontinuing therapy, there was no change in the FASI score at the end of six months, i.e., FASI 3 and FASI 6 were the same. Conclusion: Topical sirolimus is an effective treatment for facial angiofibroma in patients with TSC.

A survey of patients with facial angiofibromas associated with tuberous sclerosis complex: Short-, medium- and long-term efficacy and safety of topical rapamycin

AimsTopical rapamycin is used to reduce facial angiofibromas in patients with tuberous sclerosis (TSC). In the absence of a commercially available preparation, numerous formulations have been tested clinically, although only in the short term. MethodsThe pharmacy at Angers University Hospital (France) produced a cream formulation that was administered to people presenting this genetic disease. We conducted a questionnaire-based survey among 79 patients with TSC about their perceptions regarding the short-, medium- and long-term efficacy and safety of a topical rapamycin preparation in relation to facial angiofibromas. ResultsThis formulation was very well tolerated and its efficacy was sustained over the long term with a mean treatment duration of 33 months (extremes 1–60). Efficacy was rated ≥ 8/10 by 67.1% of patients while safety was rated ≥ 8/10 by 84.8% of patients. ConclusionThis survey supports the safety and efficacy of topical rapamycin in the short-, medium- and long-term in the treatment of facial angiofibromas in a cohort of 79 patients with TSC.

Can Radiofrequency Ablation Be Utilized With Equal Effect in Place of Carbon Dioxide Laser in the Treatment of Facial Angiofibromas in Patients of Tuberous Sclerosis?

Can Radiofrequency Ablation Be Utilized With Equal Effect in Place of Carbon Dioxide Laser in the Treatment of Facial Angiofibromas in Patients of Tuberous Sclerosis?

Efficacy and Safety of Topical Mechanistic Target of Rapamycin Inhibitors for Facial Angiofibromas in Patients with Tuberous Sclerosis Complex: A Systematic Review and Network Meta-Analysis.

Previous studies have suggested that the topical mechanistic target of rapamycin (mTOR) inhibitors may be effective in treating facial angiofibromas in patients with tuberous sclerosis complex (TSC). Various concentrations of topical sirolimus for TSC have been tested, but their comparative efficacy and safety remained unclear. To assess the effects of topical mTOR inhibitors in treating facial angiofibromas, we conducted a systematic review and network meta-analysis (NMA) and searched MEDLINE, Embase, and Cochrane Library for relevant randomized controlled trials on 14 February 2022. The Cochrane Collaboration tool was used to assess the risk of bias of included trials. Our outcomes were clinical improvement and severe adverse events leading to withdrawal. We included three trials on 261 TSC patients with facial angiofibromas. The NMA found when compared with placebo, facial angiofibromas significantly improved following the application of various concentrations of topical sirolimus (risk ratio being 3.87, 2.70, 4.43, and 3.34 for 0.05%, 0.1%, 0.2%, and 1%, respectively). When compared with placebo, all concentrations of topical sirolimus did not differ in severe adverse events leading to withdrawal. The ranking analysis suggested topical sirolimus 0.2% as the most effective drug. In conclusion, topical sirolimus 0.05–1% are effective and safe in treating facial angiofibromas in patients with TSC, with topical sirolimus 0.2% being the most effective.

A new treatment regime for facial angiofibromas in patients with tuberous sclerosis complex

British Journal of DermatologyVolume 183, Issue 4 p. e127-e127 Plain Language SummaryFree Access A new treatment regime for facial angiofibromas in patients with tuberous sclerosis complex First published: 04 October 2020 https://doi.org/10.1111/bjd.19438AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Abstract Tuberous sclerosis complex (TSC) is a genetic disorder affecting approximately one in every 6,000 to 10,000 people. The disease causes hamartomas, which are non-cancerous growths, to develop in many parts of the body. Facial growths that are composed of blood vessels and fibrous tissues, called facial angiofibromas (FAs), occur in up to 80% of TSC cases and cause significant distress to the patients. This study, from Taiwan, aimed to find out if a new treatment regime using two topical (applied to the skin) medicines, rapamycin and calcitriol, in combination would be an effective and safe treatment for TSC-related FAs. We enrolled 52 TSC patients with FAs who were assigned to apply either topical rapamycin (0.1%) or calcitriol (0.0003%) single-agent therapy (on its own) to one side of the face, and the two medicines as a combined treatment regime to the other side of the face, for 12 weeks. The patients were reassigned to use the ointment which worked best for another 12 weeks, and the treatment was then discontinued for 12 weeks. We evaluated the improvement of FAs by comparing the modified Facial Angiofibroma Severity Index (mFASI; score 0-10), which was calculated by the sum of erythema, meaning redness (0-3), papule (a raised area of skin tissue) size (0-3), papule elevation (0-3), and extent of lesions (0-1), at weeks 12 (used as the primary outcome), 24, and 36 from baseline (the start of the trial). We found that the mean reduction of mFASI at week 12 compared to baseline was -0.92 and -1.09 for rapamycin and rapamycin-calcitriol combination, respectively. Compared to rapamycin alone, extended use of the rapamycin/calcitriol combination regimen for 24 weeks showed more effectiveness in decreasing papule elevation and could maintain a longer improvement after stopping treatment. We concluded that topical rapamycin/calcitriol combination therapy is an effective and safe regimen for TSC-related FAs. Linked Article: Chen et al. Br J Dermatol 2020; 183:655–663. Volume183, Issue4October 2020Pages e127-e127 RelatedInformation

The efficacy and safety of topical rapamycin-calcitriol for facial angiofibromas in patients with tuberous sclerosis complex: a prospective, double-blind, randomized clinical trial.

The efficacy of topical rapamycin is well documented for tuberous sclerosis complex (TSC)-related facial angiofibromas (FAs). Calcitriol has been shown to lessen skin fibrosis and may be therapeutically beneficial to FAs. To evaluate whether topical rapamycin-calcitriol combination is an effective and safe treatment for TSC-related FAs. Fifty-two patients with TSC with FAs were enrolled in this prospective study including three 12-week periods. In period 1, either topical rapamycin 0·1% or calcitriol 0·0003% single-agent therapy vs. their combination was applied in a double-blind, left-right-randomized, split-face comparison. The primary outcome was the reduction of modified Facial Angiofibroma Severity Index (mFASI) at week 12. In period 2, the patients were reassigned to use on both cheeks the ointment that resulted in the better primary outcome in period 1. The treatment was discontinued in period 3 (week 25-36) and a follow-up mFASI was scored to evaluate the degree of recurrence. The mean changes in mFASI at week 12 compared with baseline were -0·92, -0·44 and -1·09 for rapamycin (P ≤ 0·001), calcitriol (P = 0·039) and rapamycin-calcitriol combination (P ≤ 0·001), respectively. Although rapamycin-calcitriol combination and rapamycin had similar statistically significant decreases of mFASI at week 12, rapamycin-calcitriol combination resulted in faster improvement in erythema, greater reduction of papule elevation and longer durability after discontinuing treatment than rapamycin alone. The treatments were well tolerated. This randomized clinical trial demonstrates that topical rapamycin-calcitriol combination therapy is an effective and safe regimen for TSC-related FAs. What is already known about this topic? Facial angiofibromas (FAs) cause substantial psychological distress in individuals with tuberous sclerosis complex (TSC), but invasive procedural treatments are not applicable to all patients. Topical rapamycin has been demonstrated as an effective and safe treatment regimen for TSC-related FAs. What does this study add? Compared with baseline (day 0), both topical rapamycin 0·1% and rapamycin 0·1%-calcitriol 0·0003% combination ointment achieved statistically significant reductions in modified Facial Angiofibroma Severity Index at week 12. Compared with rapamycin alone, extended use of the rapamycin-calcitriol combination regimen until week 24 showed more effectiveness in decreasing papule elevation and could maintain a longer therapeutic effect after treatment discontinuation. Linked Comment: Lee. Br J Dermatol 2020; 183:604-606.

Topical sirolimus for the treatment of angiofibromas in tuberous sclerosis.

The skin is one of the most affected organs in tuberous sclerosis complex and angiofibromas are seen in almost 80% of such patients. These benign tumors impose a great psycho-social burden on patients. The aim of the study was to evaluate the effectiveness and tolerability of topical sirolimus for facial angiofibromas in patients with tuberous sclerosis complex. This was a prospective, single-blinded, cross-over study which involved twelve patients. We investigated the effect and safety of topical 0.1% sirolimus, which was obtained by crushing sirolimus tablets and mixing it with petrolatum. The patients were asked to apply the cream to one side of their face, and vaseline to the other side. The effect of topical sirolimus was evaluated using the "facial angiofibroma severity index." There was a significant improvement in the redness and extension of the tumors on the sides to which the active ingredient was applied. Some side effects such as itching and irritation occurred in three patients, which were treated with topical hydrocortisone cream. Topical sirolimus appears to be a promising, fairly well tolerated treatment for facial angiofibromas in patients with tuberous sclerosis complex. Although its efficacy diminishes with time, repetitive usage is effective.

Topical rapamycin for angiofibromas in patients with tuberous sclerosis: how does it work in clinical practice?

Topical rapamycin for angiofibromas in patients with tuberous sclerosis: how does it work in clinical practice?

Efficacy and safety of topical sirolimus in the treatment of facial angiofibromas in children with tuberous sclerosis complex

Objective To investigate the efficacy and safety of sirolimus 0.1% ointment in the treatment of facial angiofibromas in children with tuberous sclerosis complex. Methods Sirolimus 0.1% ointment was prepared. Twenty children with tuberous sclerosis complex who had facial angiofibromas were enrolled in this study. Facial angiofibromas were topically treated with the self-prepared sirolimus 0.1% ointment twice a day for 12 weeks. The facial angiofibroma severity index (FASI)was calculated, the degree of satisfaction with the treatment was evaluated, and adverse reactions were analyzed at weeks 4 and 12. Plasma sirolimus concentrations as well as blood biochemical and immunological parameters were measured, blood coagulation activity was evaluated, and routine blood tests as well as urine tests were performed at baseline and week 12. Results The FASI of patients significantly decreased at weeks 4 (4.400±1.284)and 12 (2.975±1.543)compared with that at baseline (5.750±1.175, both P < 0.000 1), and was significantly lower at week 12 than at week 4 (P < 0.000 1). The efficacy index was 49.87%±22.08% at week 12, significantly higher than that at week 4 (24.43%±10.18%, t = 7.338, P < 0.01). The color, size and number of lesions significantly decreased in all the patients, and facial angiofibromas completely disappeared in 2 patients at week 12. At week 4, 10 parents were satisfied with the improvement of erythema, 3 parents with that of lesion volume, and 3 parents with that of lesion area. The degree of parent satisfaction increased at week 12 in all the cases. The blood concentration of sirolimus was lower than 1.0 μg/L both before and after the treatment. No severe systemic or local adverse reactions were noted in these patients. Conclusion Sirolimus 0.1% ointment is markedly effective and safe for the treatment of facial angiofibromas in patients with tuberous sclerosis complex. Key words: Tuberous sclerosis; Angiofibroma; Sirolimus; Treatment outcome

First left-right comparative study of topical rapamycin vs. vehicle for facial angiofibromas in patients with tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder causing multiple hamartomas. Treatment of TSC lesions with mammalian target of rapamycin inhibitors is effective. Recently, several reports have shown the efficacy of topical rapamycin (sirolimus) for angiofibromas. However, almost all studies have been case studies and the 0·1% solution caused skin irritation. A comparative study of topical rapamycin and a vehicle has not yet been reported. To compare the efficacy of topical rapamycin formulation with that of vehicle for angiofibromas. A left-right comparative study between rapamycin 0·2% topical formulation and vehicle was conducted in 11 patients with TSC. Two formulations, an ointment and a gel, were prepared and in vitro percutaneous absorption of rapamycin was determined. In vitro percutaneous absorption of rapamycin was significantly greater with the gel compared with the ointment. In the clinical study, the rapamycin-treated cheek showed significant improvements relative to the vehicle-treated cheek in all outcome measures after 12 weeks of treatment. The improvement was particularly remarkable in children aged ≤ 10 years. No side-effects were noted, and rapamycin was not detected in the blood of the patients. Topical rapamycin was significantly effective against angiofibromas. Both formulations used were effective and safe. The 0·2% gel is especially useful because of its better skin penetration and low irritancy. Initiation of topical rapamycin therapy in early childhood would be beneficial for patients with TSC.

Topical Rapamycin Therapy to Alleviate the Cutaneous Manifestations of Tuberous Sclerosis Complex

Facial angiofibromas are disfiguring facial lesions, present in up to 80% of patients with tuberous sclerosis complex. Recent elucidation of the complex cell signaling pathways that are disrupted in tuberous sclerosis indicates that rapamycin may be successful in alleviating the appearance of these lesions. The objectives of the current study were to evaluate the safety of topically applied rapamycin in patients with tuberous sclerosis complex and to determine its potential effectiveness in treatment of facial angiofibromas. The study was a prospective, randomized, double-blind, placebo-controlled study performed at the University of Texas Health Science Center at Houston. Study subjects were recruited from the patient populations at the University of Texas Tuberous Sclerosis Center of Excellence. All subjects were over the age of 13 years and had a diagnosis of tuberous sclerosis complex. Subjects were excluded if they were using any form of rapamycin or if they were pregnant. Study subjects applied the study product to their facial angiofibromas nightly for a duration of 6 months. The investigational product contained one of three doses of rapamycin compounded with Skincerity®: (i) no rapamycin; (ii) 1 mg of rapamycin per 30 cc (0.003%); or (iii) 5 mg of rapamycin per 30 cc (0.015%). Plasma rapamycin concentrations were measured monthly to test for systemic absorption. Complete blood counts were performed monthly to test for anemia, neutropenia, or thrombocytopenia. Upon completion of the trial, subjects were asked if the formulation had improved the appearance of their facial angiofibromas. Twenty-three subjects completed the study. There was no detectable systemic absorption of rapamycin (all blood concentrations were <1.0 ng/mL). There were no significant changes in white blood cell, red blood cell, or platelet counts. Seventy-three percent of subjects in the treatment arms versus 38% of subjects in the placebo arm reported a subjective improvement in the appearance of their facial angiofibromas. The application of low-dose topical rapamycin (0.003–0.015%) to the face can safely decrease the appearance of facial angiofibromas in patients with tuberous sclerosis complex. ClinicalTrials.gov Identifier: NCT01031901

Topical Rapamycin Therapy to Alleviate the Cutaneous Manifestations of Tuberous Sclerosis Complex

Background and ObjectivesFacial angiofibromas are disfiguring facial lesions, present in up to 80% of patients with tuberous sclerosis complex. Recent elucidation of the complex cell signaling pathways that are disrupted in tuberous sclerosis indicates that rapamycin may be successful in alleviating the appearance of these lesions. The objectives of the current study were to evaluate the safety of topically applied rapamycin in patients with tuberous sclerosis complex and to determine its potential effectiveness in treatment of facial angiofibromas.Patients and MethodsThe study was a prospective, randomized, double-blind, placebo-controlled study performed at the University of Texas Health Science Center at Houston. Study subjects were recruited from the patient populations at the University of Texas Tuberous Sclerosis Center of Excellence. All subjects were over the age of 13 years and had a diagnosis of tuberous sclerosis complex. Subjects were excluded if they were using any form of rapamycin or if they were pregnant. Study subjects applied the study product to their facial angiofibromas nightly for a duration of 6 months. The investigational product contained one of three doses of rapamycin compounded with Skincerity®: (i) no rapamycin; (ii) 1 mg of rapamycin per 30 cc (0.003%); or (iii) 5 mg of rapamycin per 30 cc (0.015%). Plasma rapamycin concentrations were measured monthly to test for systemic absorption. Complete blood counts were performed monthly to test for anemia, neutropenia, or thrombocytopenia. Upon completion of the trial, subjects were asked if the formulation had improved the appearance of their facial angiofibromas.ResultsTwenty-three subjects completed the study. There was no detectable systemic absorption of rapamycin (all blood concentrations were <1.0 ng/mL). There were no significant changes in white blood cell, red blood cell, or platelet counts. Seventy-three percent of subjects in the treatment arms versus 38% of subjects in the placebo arm reported a subjective improvement in the appearance of their facial angiofibromas.ConclusionThe application of low-dose topical rapamycin (0.003–0.015%) to the face can safely decrease the appearance of facial angiofibromas in patients with tuberous sclerosis complex.Trial RegistrationClinicalTrials.gov Identifier: NCT01031901

Giant angiofibromas in tuberous sclerosis complex: A possible role for localized lymphedema in their pathogenesis

Giant angiofibromas in patients with tuberous sclerosis complex (TSC) are rare. We sought to report two patients who had TSC with unusually large and disfiguring facial angiofibromas and to identify underlying histopathologic changes that may possibly explain the clinical features. We performed a clinicopathologic, immunohistochemical, and molecular biologic study using 42 lesional specimens and peripheral blood from one of the two patients. The immunohistochemical investigations were mainly focused on the vascular moiety of the lesions. TSC1 and TSC2 alterations were studied using multiplex ligation-dependent probe amplification for large deletion/duplication mutations, whereas screening for small mutations was performed using polymerase chain reaction amplification of individual coding exons and exon-intron junctions of both genes followed by an analysis on denaturation gradient gel electrophoresis. Histopathologic examination revealed, in addition to findings typical of angiofibroma, several unusual features including multinucleated giant cells containing multiple intracytoplasmic vacuoles, Touton-like cells, emperipolesis, pagetoid dyskeratosis, vacuolar alteration at the dermoepidermal junction, Civatte bodies, and melanophages in the subjacent dermis. Numerous dilated lymphatic vessels were detected indicating localized lymphostasis, probably caused by secondary lymphedema. The lymphatic nature of the vessels was confirmed by immunohistochemical study. Genetic testing for TSC1 and TSC2 gene mutations revealed a substitution on position c.2251C>T resulting in a nonsense mutation R751X in fragment 20.2. Histopathologic specimens and peripheral blood were available from only one patient. Localized lymphedema may contribute to the formation of large disfiguring angiofibromas in patients with TSC.

Transforming growth factor-β enhances matrix metalloproteinase-2 expression and activity through AKT in fibroblasts derived from angiofibromas in patients with tuberous sclerosis complex

Patients with tuberous sclerosis complex (TSC) develop fibrous tumours in the brain, skin, kidney, heart and lungs due to TSC1/2 mutations. In the skin, patients develop angiofibromas that have vascular and fibrotic components in which transforming growth factor (TGF)-β and matrix metalloproteinase (MMP)-2 are important. To investigate if the TGF-β axis and MMP-2 play an important role in the pathogenesis of TSC angiofibromas. Samples from TSC angiofibromas and normal skin were measured for expression of TGF-β and MMP-2 by immunohistochemistry and real-time polymerase chain reaction. Fibroblasts grown from TSC angiofibromas (TSC fibroblasts) were incubated with TGF-β. Expression of ERK, AKT and S6K was measured by Western blotting, and MMP-2 expression and activity were determined by enzyme-linked immunosorbent assay and gelatin zymography, respectively. There was an increase in the expression of TGF-β and MMP-2 in TSC tumours compared with those in normal skin. The baseline expression of MMP-2 was increased in conditioned medium from TSC fibroblasts. In addition, TGF-β enhanced MMP-2 production and activity, which could be abrogated by pretreatment with an AKT inhibitor (LY294002) but not with rapamycin. Finally, there was a significant colocalization of TGF-β and MMP-2 in the TSC tumours. There is an increase of MMP-2 as a result of TGF-β acting through AKT in TSC tumour cells. This regulation of the TGF-β-AKT-MMP-2 axis is independent of mammalian target of rapamycin (mTOR) signalling. In addition to targeting the mTOR pathway, targeting TGF-β simultaneously could block dysregulated tissue remodelling in TSC tumours.

CO2, Er:YAG and Pulsed Dye Laser Treatment of Angiofibromas in Patients with Tuberous Sclerosis

Summary Background: Facial angiofibromas in tuberous sclerosis have been treated using various methods, without reproducible efficiency. Laser therapy could be a viable alternative. Objective: The purpose of this study was to evaluate the efficacy and side-effects of pulsed CO2 laser (10600 nm wavelength) or Erbium-YAG laser (2940 nm wavelength), and 595 nm wavelength pulsed dye laser in the treatment of facial angiofibromas. We attempted to make a comparison between these two treatments, and to perform a clinical assessment of pulsed CO2 laser or Erbium-YAG laser and pulsed dye laser treatment of angiofibromas. Methods: We treated 18 patients. We utilised a 595 nm wavelength pulsed dye laser, using a skin cooling system (Spray or Cryo), with a 7 mm spot size, energy density (fluence J/cm2) from 6 to 8 J/cm2, emission modality (repetition rate) at 0.5 Hz to 2, and a short pulse duration of 2 to 0.5 msec or Erbium-YAG laser (1000 mJ, 200 s); KTP 532 nm; Nd:YAG 1064 long pulse (300 J/cm2, 50 ms); and pulsed CO2 laser. Results: Nine patients with fibrous angiofibromas of the entire face were treated using pulsed CO2 laser (ultra or superpulsed). The patients treated showed remarkable cosmetic improvements, without scarring. Mild hyperpigmentation was observed in 2/9 patients, which disappeared within 6 months. Facial erythema persisted for about 2 months in 5/9 patients. The results on fibrous and protuberant angiofibromas were good, with an improvement of 51–75% of the lesions. Seven patients were satisfied after the first pulsed CO2 laser treatment, and only 2 required 1 further treatment at 6-month intervals (mean number of treatments: 1.22). Er:YAG laser was used for 4 patients, with 1 to 2 sessions at 2-month intervals, with good improvement on the fibrous component, and limited adverse effects (1 patient developed hypochromia). Vascular lasers were used for 11 patients. The pulsed Nd:YAG KTP (532 nm) (3 patients) and Nd:YAG-long pulse 1064 nm (1 patient) was used to times and always required the use of another type of laser. With the use of the Nd:YAG KTP (532 nm) a perinasally localised scar occurred. Conclusions: Laser therapy is indicated for angiofibromas in the first instance. Carbon dioxide laser is advocated as the preferable treatment for fibrous or protuberant angiofibromas, while pulsed dye laser is more successful for those with a vascular component. The CO2 laser, however, involves a risk of depigmentation or scarring, so that a combination of lasers may be required to achieve the best results.