2014 April-June; 2(2): 93–98. ISSN: 2282-4103
Published online 2014 July 28.

Topical rapamycin in facial angiofibromas: patients satisfaction versus objective response, and a literature review

Beatriz Rodrigo-Nicolás, Miquel Armengot-Carbó, Paula Molés-Poveda, Fernando Millán-Parrilla, Virginia Pont-Sanjuán, Esther Quecedo-Estébanez, Adela Soriano-Clemente, and Enrique Gimeno-Carpio

Hospital Arnau de Vilanova, Valencia, Spain

Address for correspondence: Beatriz Rodrigo-Nicolás, Hospital Arnau de Vilanova, Valencia, Spain, E-mail: beatrizrod_nic@hotmail.com


Facial Angiofibromas (FA) are a common cutaneous manifestation of Tuberous Sclerosis (TS). Different therapies have been employed until now (surgery, CO2 laser…) without successful and permanent effects. Recently, topical rapamycin has been reported as a new and effective treatment without significant adverse effects.

We present our experience in four adult patients with FA and TS who have been treated with 1% rapamycin ointment for three months. We evaluated the objective response achieved by using the Facial Angiofibromas Severity Index (FASI). On the other hand, in order to know the patients’ subjective satisfaction they completed a questionnaire to evaluate this therapy.

We noticed a slight reduction of erythema, size and number of FA, lower than published in the literature. Despite this, overall satisfaction was high or very high even if the FA reappeared months after discontinuing the application.

We wonder if this subjective response justifies the costs of this treatment nowadays, especially in adult patients in which the established fibrosis in the FA could decrease the efficacy of the ointment. We also present a review of all published cases to date.

Keywords: rapamycin, angiofibromas, tuberous sclerosis, survey


Facial Angiofibromas (FA) are a common cutaneous manifestation of Tuberous Sclerosis (TS). This geno-dermatosis also affects the kidney, brain and heart. It is caused by a mutation in TSC1 or TSC2 genes that code for the mTOR pathway inhibitors, hamartin and tuberin respectively (1). The lack of these proteins leads to persistent activation of this pathway and the development of multisystem hamartomatous tumors. Angiofibromas constitute an important aesthetic problem with psychological impact but no effective treatment.

Sirolimus (or rapamycin) is an inhibitor of the mTOR pathway, which suppresses the growth of visceral tumors. This molecule was obtained from a soil bacterium Streptomyces hygroscopicus (2). Its antifungal properties were first described, but later it showed anti-T cell activity, so it started to be used to prevent rejection after solid organ transplants. In 2008, Hofbauer et al. described an improvement in FA in one patient with TS during the administration of oral sirolimus after a renal transplant (1). Systemic administration of rapamycin can cause thrombocytopenia, leukopenia, anemia, urinary infection, hypercholesterolemia or hypertriglyceridemia. Therefore it is not justified unless the hamartomas involve vital organs. Haemel et al. suggested topical application of rapamycin to avoid its systemic side effects (3). Their approach was based on an animal model and a clinical trial on patients with psoriasis treated with 1% sirolimus ointment. Several cases of FA improvement with this treatment have been published since then (214).

Objective, material and methods

We present our experience in four patients of 25, 45, 48 and 43 years old (1 female, 3 males) with FA and TS. All of them had been previously treated with surgery and CO2 laser achieving a partial improvement. Topical 1% rapamycin ointment was prescribed bid for three months. It was formulated with commercialized 2 mg rapamycin tablets and white petrolatum. We aim to evaluate the objective clinical changes, the side effects occurred and the patient’s subjective improvement after three months of treatment, and also three months after discontinuing the application. The FASI (Facial Angiofibromas Severity Index) score of assessment of FA proposed by Salido et al. (4) was used to measure the presence or lack of improvement. This score is based on the presence of erythema and the size and extension of FA (Table 1) and the result is the sum of the scores of each item (4). In addition to it, the patients completed a questionnaire evaluating the tolerability of the ointment, the benefits and disadvantages of its application, and their personal satisfaction with it.

Table 1Table 1
Facial Angiofibromas Severity Index (FASI) Score (4).

Results (Table 2)

The average of pre-treatment FASI was: 7, 4, 9 and 5. Erythema reduction, decrease in number and size of FA was observed, achieving a reduction in FASI of 34, 11, 11 and 11,5%, with an average of 16,875%. After three months of rapamycin 1% application the FASI was 4 (Figure 1), 3, 8 and 4 respectively. Erythema reduction was the first visible effect. The administration frequency had to be reduced only in the first patient due to irritation. Long term response after treatment was only observed in one of the four patients. Preliminary results show a tendency to recurrent lesions since one month after finishing the application.

Table 2Table 2
Objective and subjective results after three months of treatment.
Figure 1Figure 1
Results in patient 1: FASI 7 pre-treatment (left). FASI 4 post-treatment (right).

According to the patient’s answers to the questionnaire, overall satisfaction during the three months of treatment with rapamycin was high or very high in 3 of the 4 patients. Furthermore, it showed that 3 of them remained satisfied even after reappearance of the lesions three months after treatment was finished. All of them would repeat this therapy if possible and would recommend it to other patients with FA.


The effectiveness of topical rapamycin in FA has been widely reported (214). A review of existing evidence is summarized in Table 3. It has been tested in different formulations by using crashed rapamyicin tablets: 1% in petrolatum for 12 weeks (3), in petrolatum with 0,4% of rapamycin three times a week for nine months (4), and also in a 0,2% concentration in 0,03% tacrolimus ointment (5). It has been reported its direct use as commercialized rapamycin solution (1mg/ml) (6, 7) and even as a blending of this solution in moisturizing cream (8). It has recently been proposed to use polyvinylidene fluoride as a vehicle to improve its organoleptic properties (9).

Table 3Table 3
Summary of the reviewed literature (314).

All these have shown reduction not only of erythema but also in the number of FA in patients with TS. The most common adverse effect was local irritation, as occurred in one patient of our series. This seems to be more severe with the rapamyicin solution than with the ointment (67), although it was usually well-managed by reducing the dosage to once daily, with emollients or applying 1% hydrocortisone cream for 2–3 days (6). The application of topical rapamycin should be avoided in recent wounds, because it could modify the healing process (4, 15). Several studies have reported that sirolimus plasmatic concentration remains undetectable even in daily application (3, 5, 6, 10, 11). These determinations were not made in our patients. Although subjective global satisfaction was high, the objective improvement of our series was not as significant as expected. This may be due to several factors. On one hand the average age of our series (40,25) was older than the reviewed in the literature [16 (3), 17,9 (4), 21,77 (5), 20,5 (6), 8,5 (7), 13,5 (8), 17,6 (11), 11 (12), 27 (13), 10,6 (14)]. In fact it is supposed that the younger patients have an earlier and greater response to topical rapamycin (4, 7, 11, 15). It is possible that FA in children and teenagers are less fibrotic than those of older patients in which fibrosis is established. Indeed the greatest improvement in our series was in the youngest patient (25 years old) (Figure 1), the same case that presented local irritation. This is why we wonder if irritation is in some way related to efficacy. On the other hand it is possible that a longer period of treatment could be necessary to achieve more significant results.

Different patterns are now under research and it is possible that better results could be obtained with less frequent application, more prolonged in time however (i.e. 2–3 applications per week for 9–12 months) (4, 5, 14). Also, lower concentrations of rapamycin [0,4% (4), 0,2% (5, 11), 0,03% (10)] are obtaining good results with longer application.

Recurrence of FA has also been noted after one month of discontinuing the treatment. The first sign is reappearance of erythema and then the growth of FA. This fact has already been reported (3, 5, 7, 11, 14). Nevertheless, our four cases were highly or very highly satisfied with this topical product. We believe this is because we offer them a non-aggressive treatment for lesions without effective therapies so far. Moreover, patients realize that the single decrease of erythema constitutes an evident aesthetic improvement. As a matter of fact, all of them would recommend this treatment to other people with their condition and they would repeat the application of the ointment if possible. Only one patient complained about the sensation of oily skin left by the ointment, but it could be solved by changing the vehicle.

Concerning the pharmacoeconomic issue, in our center, the cost of 30 grams of 1% rapamycin ointment was 232,42€. It was prepared with crushed commercialized 2 mg rapamycin tablets, which makes the product expensive. We wonder if this partial and transient improvement justifies the costs nowadays. Some authors have reported lower costs and better blending by buying the active molecule in powder form (16). This way, a low cost cream could be justified in some cases with this good subjective response, especially in children.

In conclusion, although promising results have been reported with topical rapamycin in FA, the objective response in older patients is less significant, suggesting that topical rapamycin effectiveness decreases with age. However, subjective satisfaction was very high. More confortable dosages and lower sirolimus concentration are now under research pointing the reduction in cost and improvement of tolerance, especially considering chronic application in order to maintain a long course response.

Hofbauer GFL, Marcollo-Pini A, Corsenca A, et al. The mTOR inhibitor rapamycin significantly improves facial angiofibroma lesions in a patient with tuberous sclerosis. Br J Dermatol. 2008;159(2):473–5.
Madke B. Topical rapamycin (sirolimus) for facial angiofibromas. Indian Dermatol Online J. 2013;4(1):54–7.
Haemel AK, O’Brian AL, Teng JM, et al. Topical Rapamycin. A novel approach to facial angiofibromas in tuberous sclerosis. Arch Dermatol. 2010;146(7):715–718.
Salido R, Garnacho-Saucedo G, Cuevas-Asencio I, et al. Sustained clinical effectiveness and favorable safety profile of topical sirolimus for tuberous sclerosis- associated facial angiofibroma. J Eur Acad Dermatol. 2012;26(10):1315–8.
Wataya-Kaneda M, Tanaka A, Nakamura A, et al. A topical combination of rapamycin and tacrolimus for the treatment of angiofibroma due to tuberous sclerosis complex (TSC): a pilot study of nine Japanese Patients with TSC of different disease severity. Br J Dermatol. 2011;165(4):912–6.
Mutizwa MM, Berk DR, Anadkat MJ. Treatment of facial angiofibromas with topical application of oral rapamycin solution (1mg mL-1) in two patients with tuberous sclerosis. Br J Dermatol. 2011;165(4):922–3.
Foster RS, Bint LJ, Halbert AR. Topical 0.1% rapamycin for angiofibromas in pediatric patients with tuberous sclerosis: a pilot study of four patients. Australas J Dermatol. 2012;53(1):52–6.
Kaufman McNamara EK, Curtis AR, Fleischer AB. Successful treatment of angiofibroma of tuberous sclerosis complex with rapamycin. J Dermatolog Treat. 2012;23(1):46–8.
DeKlotz CM, Ogram AE, Singh S, et al. Dramatic improvement of facial angiofibromas in tuberous sclerosis with topical rapamycin: optimizing a treatment protocol. Arch Dermatol. 2011;147(9):1116–1117.
Koenig MK, Hebert AA, Roberson J, et al. Topical rapamycin therapy to alleviate the cutaneous manifestations of tuberous sclerosis complex. Drugs R D. 2012;12(3):121–126.
Tanaka A, Wataya-Kaneda M, Nakamura A, Matsumoto S, Katayama I. First left-right comparative study of topical rapamycin vs vehicle for facial angiofibromas in patients with tuberous sclerosis complex. Br J Dermatol. 2013;169(6):1314–8.
Truchuelo T, Díaz-Ley B, Ríos L, Alcántara J, Jaén P. Facial angiofibromas treated with topical rapamycin: An excellent choice with fast response. Dermatol Online J. 2012;18(1):15.
Valerón-Almazán P, Vitiello M, Abuchar A, Kerdel FA. Topical rapamycin solution to treat multiple facial angiofibromas in a patient with tuberous sclerosis. Actas Dermosifiliogr. 2012;103(2):165–6.
Tu J, Foster RS, Bint LJ, Halbert AR. Topical rapamycin for angiofibromas in pediatric patients with tuberous sclerosis: Follow up of a pilot study and promising future directions. Australas J Dermatol. 2014;55(1):63–9.
Salido-Vallejo R, Garnacho-Saucedo G, Moreno-Giménez JC. Current options of the treatment of facial angiofibromas. Actas Dermosifiliogr. 2013 Mar 21; doi:10.1016/j.ad.2012.11.020. pii S0001-7310(13)00039-2. [Epub ahead of print].
Cuevas I, Albornoz R, Salido R, et al. Topical sirolimus 0’4% formulation for treatment of facial angiofibromas. Farm Hosp. 2012;36(5):433–4.