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Table of Contents 
Year : 2016  |  Volume : 61  |  Issue : 1  |  Page : 119
Use of topical rapamycin in facial angiofibromas in Indian skin type

Department of Dermatology, Rajiv Gandhi Medical College and Chhatrapati Shivaji Maharaj Hospital, Thane, Maharashtra, India

Date of Web Publication15-Jan-2016

Correspondence Address:
Parul Thakur
Room No. 28, Department of Dermatology, Rajiv Gandhi Medical College and Chhatrapati Shivaji Maharaj Hospital, Kalwa, Thane, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-5154.174087

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Introduction: Facial angiofibromas (FA) are the most visible cutaneous manifestations in patients with tuberous sclerosis (TS), often resulting in stigmatization of the affected individuals. Recent studies have suggested that topical rapamycin may be an effective treatment for angiofibromas. Aim: To study the safety and efficacy of topical rapamycin in treatment of FA in Type IV-VI skin type. Materials and Methods: Five female patients with FA were included in the study, four of whom had TS, whereas one had isolated angiofibromas without systemic involvement. The age of the patients varied from 6 to 44 years. After baseline evaluation, they were advised to apply topical rapamycin (0.1-1%) in white soft paraffin base twice daily. Follow-up varied from 1 month to 6 months and is ongoing. Results: A sustained improvement was observed with respect to erythema, size as well as extent of the lesions as early as within 2 weeks of starting treatment. No side effects were observed. A correlation between duration of angiofibromas and effectiveness of treatment was noted. Conclusion: Topical rapamycin appears to be a safe and effective alternative to surgical or laser-based treatments in patients with FA. This treatment shows potential to be a first-line management for FA and appears safe to start in early childhood.

Keywords: Angiofibromas, topical rapamycin, tuberous sclerosis

How to cite this article:
Viswanath V, Thakur P, Pund P. Use of topical rapamycin in facial angiofibromas in Indian skin type. Indian J Dermatol 2016;61:119

How to cite this URL:
Viswanath V, Thakur P, Pund P. Use of topical rapamycin in facial angiofibromas in Indian skin type. Indian J Dermatol [serial online] 2016 [cited 2022 Sep 29];61:119. Available from:

What was known?
Current treatments for facial angiofibromas include vascular laser, ablative lasers, and physically destructive techniques such as shave excision and electrodessication which may even cause scarring.

   Introduction Top

Angiofibromas are hamartomatous tumors of skin usually appearing between 3 and 10 years of age. These are most unsightly of the cutaneous manifestations occurring in patients of tuberous sclerosis (TS) and have a tremendous psychological impact. Recently, a novel promising drug therapy, topical rapamycin has been introduced for the treatment of facial angiofibromas (FA) and has demonstrated good efficacy and safety profile. We report 5 patients with FA, who showed an excellent response to topical rapamycin.

   Materials and Methods Top

This study aimed to evaluate safety and efficacy of topical rapamycin in treatment of FA in Indian skin type.

Five female patients with FA who attended dermatology OPD in between May and December 2014 were included in the study. A cross-sectional evaluation was done at the end of this period and effect of topical rapamycin with respect to the duration for which it had been used until then was noted. All the patients have continued use of rapamycin. Follow-up is ongoing.

Cases 1, 2, 3, and 4 had FA along with other cutaneous features of TS. Case 5 had histopathologically confirmed FA with no other features of TS.

Crushed tablets of rapamycin (Rapacan 1 mg Biocon) were compounded in white soft paraffin to obtain topical rapamycin ointment (0.1% and 1%). Rapamycin of 0.1% composition was used in the first two patients, and 1% in the latter three. It was initially applied once daily at night. If no irritation was observed, the frequency of application was increased to twice a day after 1 week. First follow-up was done at the end of 2 weeks of use of topical rapamycin. Thereafter, monthly follow-up visits were advised. Evaluation was done prior to starting treatment and at the time of follow-up. It was based on subjective improvement as noted by patients and family in minors, whereas objective improvement was noted as a decrease in erythema and size of papules in sequential photographs. Efficacy was graded according to FA severity index (FASI), [1] which is obtained by adding partial scores for erythema, size of lesions, and extent of lesions of FA [Table 1].
Table 1: FASI score for angiofibromas

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   Results Top

The age of the patients varied from 7 to 40 years. No treatment for FA was received prior to recruitment. The results have been summarized in [Table 2]. The earliest response to therapy was seen in the form of resolution of erythema. All patients showed an initial response within 2 weeks. In Case 1, FASI score decreased from 7 to 3 in 6 months, whereas in Case 2 it reduced from 7 to 5 in 1 month [Figure 1] and [Figure 2]. Case 1 and 2 were using 0.1% topical rapamycin. As no irritation was seen with 0.1% rapamycin, the strength was increased to 1% in the next three cases. In Case 3, FASI decreased from 5 to 3 in 3 months. The comparatively lesser improvement in this case can be attributed to poor adherence to therapy [Figure 3]. In Case 4, FASI score decreased from 6 to 3 in 2 months [Figure 4]. In Case 5, where FAs were longstanding, only slight decrease in FASI from 4 to 3 was noted [Figure 5]. All patients showed rapid and excellent improvement subjectively. Improvement with 1% rapamycin was found to be faster than 0.1% rapamycin. No side effects were observed in any patient. Although all the patients started showing improvement after week 2, the overall improvement seemed to be earlier in children (Cases 2-4) than in adults (Cases 1 and 5).
Figure 1: A 19-year-old female, prior to and after application of 0.1% topical rapamycin. Excellent response and sustained improvement after 6 months

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Figure 2: A 11-year-old female, prior to and after application of 0.1% topical rapamycin. Excellent response in 1 month

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Figure 3: A 7-year-old female, prior to and after application on 1% topical rapamycin. Moderate response after 3 months, attributed to poor adherence

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Figure 4: A 10-year-old female, prior to and after application on 1% topical rapamycin. Excellent response in 2 months

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Figure 5: A 44-year-old female, prior to and after application on 1% topical rapamycin for 2 months. Moderate response in 4 months

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Table 2: Summary: Patient profile and results of study

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   Discussion Top

Angiofibromas, also called as fibrous papules, represent benign focal hamartomatous growth of vascular and collagen structures. They are most often presented as small, solitary, flesh-colored to brown-red shiny papules mainly in centrofacial area, including nasolabial folds, cheeks, and chin. Multiple angiofibromas have been most commonly associated with TS (80%). [2] Other associated syndromes include Birt-Hogg-Dubé syndrome and multiple endocrine neoplasia type 1. Angiofibromas without systemic association or genetic syndromes have also been reported as seen in our Case 5. [3] FA can be especially troublesome when they increase in size. Various treatment modalities used include vascular lasers, ablative lasers, and destructive techniques such as electrocautery, radiofrequency, cryotherapy, dermabrasion, and topical podophyllotoxin. [4] These can be painful, uncomfortable and recurrences are common. Surgical approaches may lead to scarring.

Sirolimus (rapamycin) has recently been used for treatment of angiomyolipomas and lymphangioleiomyomatosis because of its antiangiogenic and antiproliferative action. Rapamycin belongs to the category of mammalian target of rapamycin (mTOR) inhibitors. [5] mTOR complex is a serine/threonine protein kinase in mammalian cells and plays a major role in integrating signals from nutrients, energy status, and growth factors to regulate homeostatic processes and hence essential for regulation of normal cell proliferation. [6]

Hamartin and tuberin exert negative control on mTOR complex, mutation of which leads to mTOR activation and formation of hamartomas as in TS. In angiofibromas, mTOR activation and increased vascular endothelial growth factor (VEGF) expression promotes angiogenesis. Rapamycin inhibits mTOR and also decreases VEGF output by inhibiting hypoxia-inducible factor expression. [7]

Patients of TS treated with oral rapamycin after renal transplant showed drastic improvement in their cutaneous angiofibromas. [8],[9] However, systemic administration of rapamycin is not justified unless vital organs are involved as it can cause pancytopenia, urinary infection, hyperlipidemia, etc., Hence, topical rapamycin in ointment form was first used by Haemel et al. for treating FA successfully, thereby avoiding the side effects of systemic rapamycin. [10] Rapamycin has also been used for the treatment of hypomelanotic macules of TS. [11]

Since the first clinical observation in 2010, several different formulations and strengths and formulations of topical rapamycin have been reported with good results. Commercially, rapamycin is available in tablets, solution, and powder form. It can be combined with the desired ointment/cream/gel base to get a topical preparation. Most commonly reported is the use of ointment base using petrolatum as a vehicle. Tacrolimus ointment has also been used in one study. Rapamycin has also been used in combination with commercially available creams such as Skincerity ® , Eucerin ® , Dexeryl ® , as vehicle. Topical application of commercially available rapamycin solution has also been used. [12] Rapamycin is a large lipophilic molecule and hence it is difficult to prepare in easily absorbed formulation. Ointments are better tolerated than solutions and cream. Various concentrations of rapamycin used range from 0.003% to 1%. [12] Optimum concentration with maximum efficacy is yet to be determined. Too high concentrations can be irritating and too low concentrations may not be effective. Hence, it is best to start with lowest effective concentration and watch for irritation. To minimize the risk of irritation, it can be applied at a low dose, for example, thrice a week initially and then gradually increased to a maximum of twice daily application.

In the present study, topical rapamycin in ointment form with white soft paraffin as the base was used. Two different concentrations (0.1% and 1%) were used, with once daily application for the 1 st week, which was then increased to twice daily application.

A recent analysis reviewed 16 clinical studies on the use of topical rapamycin in FA. Of a total of 84 patients, 79 cases (94%) showed improvement and only 5 cases had poor results. This could be related to the low concentrations of rapamycin (0.015-0.03%). [13] A single case of improvement with topical rapamycin has been reported from India. [14] The present study showed improvement in all five patients treated.

The side effects of topical rapamycin reported are mild and local and include irritation and perioral dermatitis. Mild irritant contact dermatitis was seen in patients using rapamycin solution, this subsided on the use of topical steroids. [15] Systemic absorption of topical rapamycin has not been found to be significant, and the serum levels were undetectable in reported studies.

Most studies suggest that the use of rapamycin gives a better response at a younger age. This correlates with our study which also showed better response in younger patients as compared to adults. This may be due to the greater proliferative component of FA in younger age group, making the tumor more sensitive to the inhibitory action of rapamycin.

Given the recent introduction of the use of topical rapamycin, not much follow-up data is available. The longest duration reported (30 months, with 19 patients) has not shown any recurrence of lesions or loss of effectiveness. In this study, the frequency of application of topical rapamycin was reduced to one application 2-3 times/week so as to enhance long-term patient compliance without any decrease in the efficacy. [12]

To conclude, topical rapamycin appears to be safe, effective, noninvasive therapy compared to other modalities for treatment of FA. Cost of topical rapamycin is low in comparison to lasers. However, the optimal dose and topical formulation is still unclear, and use of crushed tablets to prepare topical rapamycin requires standardization. Randomized controlled studies with larger sample size are required to compare the efficacy of topical rapamycin with other conventional therapies. To the best of our knowledge, this is the first case series reported from India.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Salido-Vallejo R, Ruano J, Garnacho-Saucedo G, Godoy-Gijón E, Llorca D, Gómez-Fernández C, et al. Facial Angiofibroma Severity Index (FASI): Reliability assessment of a new tool developed to measure severity and responsiveness to therapy in tuberous sclerosis-associated facial angiofibroma. Clin Exp Dermatol 2014;39:888-93.  Back to cited text no. 1
Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: Revised clinical diagnostic criteria. J Child Neurol 1998;13:624-8.  Back to cited text no. 2
Hunter AG, Nezarati MM, Velsher L. Absence of signs of systemic involvement in four patients with bilateral multiple facial angiofibromas. Am J Med Genet A 2010;152A: 657-64.  Back to cited text no. 3
Türkmen M, Ertam I, Unal I, Dereli T. Facial angiofibromas of tuberous sclerosis: Successful treatment with podophyllin. J Eur Acad Dermatol Venereol 2009;23:713-4.  Back to cited text no. 4
Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 2008;358:140-51.  Back to cited text no. 5
Madke B. Topical rapamycin (sirolimus) for facial angiofibromas. Indian Dermatol Online J 2013;4:54-7.  Back to cited text no. 6
[PUBMED]  Medknow Journal  
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;18:15.  Back to cited text no. 7
Hofbauer GF, Marcollo-Pini A, Corsenca A, Kistler AD, French LE, Wüthrich RP, et al. The mTOR inhibitor rapamycin significantly improves facial angiofibroma lesions in a patient with tuberous sclerosis. Br J Dermatol 2008;159:473-5.  Back to cited text no. 8
Tarasewicz A, Debska-Slizien A, Konopa J, Zdrojewski Z, Rutkowski B. Rapamycin as a therapy of choice after renal transplantation in a patient with tuberous sclerosis complex. Transplant Proc 2009;41:3677-82.  Back to cited text no. 9
Haemel AK, O'Brian AL, Teng JM. Topical rapamycin: A novel approach to facial angiofibromas in tuberous sclerosis. Arch Dermatol 2010;146:715-8.  Back to cited text no. 10
Wataya-Kaneda M, Tanaka M, Nakamura A, Matsumoto S, Katayama I. A novel application of topical rapamycin formulation, an inhibitor of mTOR, for patients with hypomelanotic macules in tuberous sclerosis complex. Arch Dermatol 2012;148:138-9.  Back to cited text no. 11
Tu J, Foster RS, Bint LJ, Halbert AR. Topical rapamycin for angiofibromas in paediatric patients with tuberous sclerosis: Follow up of a pilot study and promising future directions. Australas J Dermatol 2014;55:63-9.  Back to cited text no. 12
Balestri R, Neri I, Patrizi A, Angileri L, Ricci L, Magnano M. Analysis of current data on the use of topical rapamycin in the treatment of facial angiofibromas in tuberous sclerosis complex. J Eur Acad Dermatol Venereol 2015;29:14-20.  Back to cited text no. 13
Vasani RJ. Facial angiofibromas of tuberous sclerosis treated with topical sirolimus in an Indian patient. Indian J Dermatol 2015;60:165-9.  Back to cited text no. 14
[PUBMED]  Medknow Journal  
Koenig MK, Hebert AA, Roberson J, Samuels J, Slopis J, Woerner A, et al. Topical rapamycin therapy to alleviate the cutaneous manifestations of tuberous sclerosis complex: A double-blind, randomized, controlled trial to evaluate the safety and efficacy of topically applied rapamycin. Drugs R D 2012;12:121-6.  Back to cited text no. 15

What is new?
Topical rapamycin is a novel, noninvasive treatment for facial angiofibromas. It is a safe and effective alternative to the currently used modalities such as lasers, cauterization, and excision which are physically destructive. Previously established to be useful in Caucasian skin, this study indicates its efficacy in Indian skin.


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

  [Table 1], [Table 2]

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