bs_bs_banner
Australasian Journal of Dermatology (2014) 55, 63–69
doi: 10.1111/ajd.12125
SMALL CASE SERIES
Topical rapamycin for angiofibromas in paediatric patients with tuberous sclerosis: Follow up of a pilot study and promising future directions Jenny Tu,1 Rachael S Foster,1 Lewis J Bint2 and Anne R Halbert1 1
Department of Paediatric Dermatology, and 2Pharmacy Department, Princess Margaret Hospital for Children, Subiaco, Western Australia, Australia
ABSTRACT One of the most visible and potentially disfiguring cutaneous manifestations of tuberous sclerosis complex is the development of multiple facial angiofibromas, present in over 80% of patients. Topical rapamycin has been shown in many reports to be a safe and effective treatment for facial angiofibromas. In February 2012 we reported the results of a pilot study of four patients undertaken at a paediatric tertiary hospital in Australia. Since then, we have continued to refine the optimal formulation and concentration of topical rapamycin and expanded our selection of patients. We present an update on our current cohort of treated patients, discuss the optimal formulation of topical rapamycin and include a literature review on all published cases to date. Although topical rapamycin is not a curative treatment, we have demonstrated that its early institution significantly reduces both the vascularity and palpability of angiofibromas and prevents their progression with age. It is well tolerated and now a cost effective option. Key words: angiofibroma, sirolimus, rapamycin, tuberous sclerosis.
topical
multiple organs, including the skin, brain, kidneys, heart and lungs. One of the most common cutaneous manifestations is facial angiofibromas, a stigmatising hallmark of the condition, appearing in early childhood. It is known that in TSC, failure of tumour suppressor complexes to control a key regulatory kinase, mammalian target of rapamycin (mTOR), results in uncontrolled cellular proliferation and differentiation in the target organ.1 Therapies targeting these pathways are effective in halting further growth and development of hamartomas. Due to their cutaneous location, facial angiofibromas have the advantage of being amenable to topical therapy, minimising the risk of side effects. Over the past 18 months we have treated a total of 19 patients with topical rapamycin through the dermatology outpatient clinics of Princess Margaret Hospital, Perth, Western Australia. During this period we have been able to optimise the formulation of the topical rapamycin compound, with flexibility in trialing different strengths. Instead of being admitted to hospital for vascular and ablative laser therapies, patients may use a simple, safe and effective self-application of topical rapamycin.2 In our pilot study we found that utilizing crushed sirolimus tablets (e.g. 1 mg) in a petrolatum base was the easiest way to compound a topical 0.1% preparation, causing less irritation than the oral Rapamune 1 mg/mL solution (Mississaugi, ON, Canada) used topically. As rapamycin powder has become more available and affordable we have found it is a more convenient source of rapamycin than crushed tablets, also allowing more flexibility in the concentrations formulated.
INTRODUCTION
METHOD
Tuberous sclerosis complex (TSC) is an autosomal dominant genodermatosis resulting in hamartoma formation in
A chart review of all patients receiving treatment with topical rapamycin through the dermatology outpatient clinics at Princess Margaret Hospital was conducted. In all, 19 patients had been prescribed topical rapamycin, all
Correspondence: Dr Jenny Tu, Department of Dermatology, Princess Margaret Hospital for Children, Roberts Road, Subiaco, WA 6008, Australia. Email: [email protected] Jenny Tu, MBBS (Hons). Rachael S Foster, FACD. Lewis J Bint, B Pharm MBA. Anne R Halbert, FACD. Conflict of interest: none Submitted 6 November 2013; accepted 8 November 2013. © 2013 The Australasian College of Dermatologists
Abbreviations: mTOR TSC
mammalian target of rapamycin tuberous sclerosis complex
64 Table 1
J Tu et al. Patients’ details and results
Sex
Age (years)
Age (trial entry)
Rapamycin crushed tablet formulation (%) + date started
Rapamycin powder formulation (%)
Improvement
M M F F F M M M M M M F F M M M F M M
6 6 7 8 8 9 9 11 11 12 13 14 15 15 16 17 18 20 20
4.5 5 6.5 5.5 6 6.5 7 9 9 10.5 11 12 13 14 14.5 15 17 17.5 18.5
0.1: 09/05/2012 0.1: 28/05/2012 Straight to powder: 5/11/2012 0.1: 20/06/2011 0.1: 20/06/2011 0.1: 20/06/2011 0.1: 19/11/2011 0.1: 14/11/2011 0.1: 12/12/2011 0.1: 14/11/2011 0.1: 07/11/2011 0.1: 28/11/2011 0.1: 10/11/2011 Straight to powder: 08/10/2012 0.1: 06/02/2012 0.1: 31/10/2011 0.1: 12/03/2012 0.1: 21/01/2011 0.1: 06/02/2012
0.5 0.1 3 x/week 0.5 0.5 3–4 x/week. 0.5 3 x/week 0.5 0.5 0.5 0.1 0.1 1 0.5 1 0.5 1 0.1 0.1 0.5 0.1
Good Excellent Good Excellent Excellent Excellent Good Good Good Good Excellent Excellent Good Excellent Moderate Excellent Good Moderate Good
Improvement defined as: minimal < 30%, moderate 30–59%, good 60–89%, excellent >90%. Formulation changed to use Rapamycin (sirolimus) powder from July 2012. F, female; M, male.
parents having given their consent for their children to be included in a clinical study. The characteristics of these 19 patients are summarised in Table 1. Their mean age on entry to the trial was 10.5 years (range 4.5–18.5 years) and the duration of treatment ranged from 8 to 30 months. Parents were instructed to apply the preparation twice daily, but most reduced to a single night-time application for convenience. Two patients, previously reported in our pilot study, were initially started on Rapamune 1 mg/mL solution applied topically. On developing irritation, these children were changed to rapamycin 0.1% in petrolatum, formulated from crushing 1 mg sirolimus tablets. This crushed tablet formulation was used for the next 15 patients until June 2012. We then accessed affordable rapamycin powder from Cleo Pharmaceuticals, Shanghai (imported into Australia by S and D Chemicals, Brookvale New South Wales, Australia). The powder was mixed into a simple petrolatum base, with attention paid to distributing the small quantity evenly through the base, allowing trituration by geometric dilution. All children were transitioned to 0.1% powder formulation, the concentration then being adjusted if there was insufficient response (Table 1). Ten of the 19 patients had a rapamycin blood level taken 8 weeks after starting the ointment to ensure there was no significant systemic absorption. Having previously shown it was highly unlikely for a 0.1% preparation to be systemically absorbed, we concentrated on testing children treated with 0.5 and 1% preparations. At each 8-week follow-up visit, one of the primary investigators (AH) estimated the percentage of clinical improvement, with the assistance of pretreatment and post-treatment photography. Minimal improvement was defined as less than 30% improvement, moderate as 30–59%, good as 60–90% and excellent as > 90% improvement (near or complete clearance). © 2013 The Australasian College of Dermatologists
RESULTS All 19 patients demonstrated a significant and sustained improvement in facial angiofibromas with both topical 0.1% rapamycin (crushed tablet formulation) and 0.1–1% rapamycin (powder formulation). Of these patients 17 had good or excellent improvement, but in two of the older children with severe, widespread and raised angiofibromas only a moderate improvement was found (Table 1). Figures 1–5 demonstrate the clinical results from a representative group of the patients. One patient had a fibrous plaque on his right lateral neck, which also seemed to respond to topical rapamycin 0.5% (Fig. 6). The response to treatment was rapid, and parents commented they could see a difference even in the first 2 weeks of treatment, particularly with a reduction in erythema. In keeping with our pilot study, the most striking responses were seen when treatment was started in the younger patients in whom the angiofibromas were smaller and less raised. Unexpectedly, the parents of six of the 17 patients who were transitioned from the crushed tablet to the powder formulation felt the 0.1% crushed tablet preparation worked slightly better than the 0.1% powder preparation. An assay was carried out on the powder being used, to verify its potency, through multiple dilutions and assay, by the Biochemistry Service at PathWest, Perth, Western Australia. The powder was found to be 95% of its stated potency. The treatment of these six patients was then increased to a 0.5% powder preparation, after which they rapidly returned to their previous improved clinical appearance. Treatment of two of the older children with very raised angiofibromas was further increased to 1%, with noticeable improvement. If patients and parents were content with their level of improvement we did not continue increasing the strength. The reason for the perceived superiority of crushed tablets
Topical rapamycin for angiofibromas
65
(a)
(b)
(a)
(b)
Figure 1 (a) pretreatment. (b) posttreatment with topical rapamycin.
Figure 2 (a) pretreatment; (b) posttreatment with topical rapamycin.
compared with powder is unknown, but may be due to another chemical in the tablet interacting with the sirolimus. Only two patients had a detectable blood rapamycin level of 0.5 and 0.8 micrograms/L, much less than the level required for immunosuppression (8–20 μg/L, depending on the type of organ transplantation). Both crushed tablet and powder preparations were well tolerated, although one child had a minor bleed from an angiofibroma after being scratched by a small fragment of crushed tablet. One child
developed perioral dermatitis that resolved with a course of erythromycin and did not recur despite continuing with rapamycin. No child complained of itching or irritation. There was no evidence of tachyphylaxis over time. Indeed, the younger children with near complete clearance were able to reduce to thrice weekly applications without a loss of efficacy. As a guide, 50g of 0.1% rapamycin made from crushed sirolimus tablets at the time of writing costs approximately A$410 to manufacture, while 50g of 0.5% rapamycin made © 2013 The Australasian College of Dermatologists
66
J Tu et al.
(a)
(b)
Figure 3 (a) pretreatment; (b) posttreatment with topical rapamycin.
(a)
(b)
Figure 4 (a) pretreatment; (b) posttreatment with topical rapamycin.
from powder (Cleo Pharmaceuticals) costs A$125 and lasts approximately 3 months.
DISCUSSION A comprehensive Medline literature search identified 12 articles using the keywords topical rapamycin or sirolimus and angiofibromas (Table 2).2–13 The articles were limited to those available in the English language and they were read, and any relevant articles referred to in the references were also included in the study. Of these, 11 were case series and one was a review article.13 Since the first case report of © 2013 The Australasian College of Dermatologists
topical rapamycin ointment having being used in a patient with tuberous sclerosis in 2010, there have been 66 additional patients who have had good response rates to it. Apart from a 73% response rate in 23 patients in a randomised controlled trial performed by Koenig and colleagues in September 2012, all other studies have reported 100% response rates. The difference may be in part attributable to the low concentrations of rapamycin (0.003% and 0.015%) used in Koenig study.9 In our experience, 0.1–1% topical rapamycin is a safe and effective treatment for facial angiofibromas. Following our pilot study, we did not pursue treatment with oral
Topical rapamycin for angiofibromas
67
(a)
(b)
(a)
(b)
Figure 5 (a) pretreatment; (b) posttreatment with topical rapamycin.
Figure 6 (a) fibrous plaque on neck pre-treament; (b) fibrous plaque on neck post-treatment with topical rapamycin.
Rapamune 1 mg/mL solution applied topically, due to unacceptable facial irritation. Crushed sirolimus tablets in a 0.1% petrolatum formulation were effective, but compounding pharmacists found the process labour intensive and time consuming and there were concerns about the unintentional inhalation of aerosolised immunosuppressant. The patients’ parents complained that the batches varied in quality, some being more gritty than others. The patients felt embarrassed about going to school with crushed tablet on their face and rapidly insisted on a nighttime application only.
The ability to purchase rapamycin powder has simplified the manufacturing process for pharmacists and improved patients’ satisfaction. It was surprising that six of the 17 patients noted that the 0.1% powder formulation did not seem to be quite as effective as the 0.1% crushed tablet formulation, but increasing the dose to a 0.5% powder formulation overcame this problem. Despite increasing the concentration, blood levels remained well below that required for immunosuppression. Most patients ended up applying it once daily for convenience, without loss of efficacy. For young children with nearly complete clearance, a © 2013 The Australasian College of Dermatologists
68 Table 2 Case no
J Tu et al. Summary of cases using topical rapamycin to treat angiofibromas in tuberous sclerosis patients Total patients
Year of publication
Authors 3
Topical Rapamycin formulation
Response All patients All patients All patients All patients had greater improvement with combination rapamycin-tacrolimus treatment than with tacrolimus ointment alone All patients All patients
1 2 3,4 5–13
1 1 2 9
Jul 2010 Sept 2011 Oct 2011 Oct 2011
Haemel et al. DeKlotz et al.4 Mutizwa et al.5 Wataya-Kaneda et al.6
1% rapamycin ointment 1% rapamycin compound 1% rapamycin solution Half face with tacrolimus ointment, other with addition of 0.2% rapamycin ointment.
14 15,16
1 2
Jan 2012 Feb 2012
Truchuelo et al.7 Kaufman McNamara et al.8
17–20
4
Feb 2012
Foster et al.2
21–43
23
Sept 2012
Koenig et al.9
44–53 54,55
10 2
Oct 2012 July 2013
56–67
11
Aug 2013
Salido et al.10 Wheless and Almoazen11 Tanaka et al12
1% rapamycin cream Case 1: 60 mL rapamycin 1 mg/mL solution compounded with 60 g of Eucerin (Hamburg, Germany) + oral sirolimus 3mg daily. Case 2: 60 mL rapamycin 1 mg/mL solution compounded with 60 g of emollient daily 0.1% rapamycin in petrolatum, 0.1% rapamycin solution 0.003%, 0.015% rapamycin + Skincerity (NuCerity International, Houston, TX, USA) 0.4% sirolimus ointment 0.1% crushed sirolimus tablets in ointment 0.2% rapamycin ointment or gel on one cheek & vehicle on other cheek.
thrice weekly application maintained the benefit, making it even more cost effective. We have not noted irritation, allergy or other topical complications. We were concerned that the greasy formulation would be comedogenic for our teenage patients, but even this has not been a significant problem. Our families have been extremely positive about the treatment and were delighted with the clinical outcome. There are also reports in the literature describing responses of hypomelanotic macules to topical rapamycin 0.2% gel.14 Hypomelanotic macules in TSC may arise from abnormal melanisation. Rapamycin may alter factors implicated in melanogenic gene expression, explaining its effectiveness in treating hypomelanotic macules.14 We did not pursue the use of topical rapamycin for hypomelanotic macules as they are mostly not located on cosmetically sensitive sites. While discussions in the literature with regard to oral mTOR inhibitors to treat neurological and renal complications of TSC have been increasing, angiofibromas continue to be one of the earliest cutaneous stigmata to appear in children and are a major concern to patients and families. In view of the safety and reasonable cost of topical rapamycin we urge clinicians involved with TSC patients to give consideration to using topical rapamycin therapy, starting as soon as the angiofibromas begin to appear in early childhood. We suggest starting with 0.1% rapamycin powder in petrolatum, applied once daily until clearance and then reducing the dose to thrice weekly. For older children, 0.5% is the usual concentration initially required, reserving 1% for the management of teenagers and adults with protuberant or numerous lesions. In this simple, safe © 2013 The Australasian College of Dermatologists
All patients 73% of 23 (i.e., 17 patients) All patients All patients All patients
and cost effective way, a potentially disfiguring and stigmatising complication of this genetic disorder can be minimised and controlled.
ACKNOWLEDGEMENTS We would like to thank Eamonn McNulty and the team at Medical Illustration, Princess Margaret and King Edward Hospitals for their serial photography input. The copyright of these images belongs to the respective medical illustration departments and to the patients involved. This article has been supported with funding from the F. & E. Bauer Foundation Prize.
REFERENCES 1. 2.
3.
4.
5.
Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet 2008; 372: 657–68. Foster R, Bint L, Halbert A. Topical 0.1% rapamycin for angiofibromas in paediatric patients with tuberous sclerosis: a pilot study of four patients. Australas. J. Dermatol. 2012; 53: 52–6. Haemel AK, O’Brian AL, Teng JM. Topical rapamycin: a novel approach to facial angiofibromas in tuberous sclerosis. Arch. Dermatol. 2010; 146: 715–8. 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: 1116–7. Mutizwa M, Berk D, Anadkat M. Treatment of facial angiofibromas with topical application of oral rapamycin solution (1 mg mL)) in two patients with tuberous sclerosis. Br. J. Dermatol. 2011; 165: 922–3.
Topical rapamycin for angiofibromas 6.
7.
8.
9.
10.
Wataya-Kaneda M, Tanaka M, 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: 912–6. Truchuelo T, Díaz-Ley B, Ríos L et al. Facial angiofibromas treated with topical rapamycin: an excellent choice with fast response. Dermatol. Online J. 2012; 18: 15. Kaufman McNamara E, Curtis AR, Fleischer AB Jr. Successful treatment of angiofibromata of tuberous sclerosis complex with rapamycin. J. Dermatolog. Treat. 2012; 23: 46–8. Koenig M, Hebert A, Roberson J 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. Salido R, Garnacho-Saucedo G, Cuevas-Asencio I et al. Sustained clinical effectiveness and favorable safety profile of
11.
12.
13. 14.
69
topical sirolimus for tuberous sclerosis – associated facial angiofibroma. J. Eur. Acad. Dermatol. Venereol. 2012; 26: 1315–8. Wheless JW, Almoazen H. A novel topical rapamycin cream for the treatment of facial angiofibromas in tuberous sclerosis complex. J. Child Neurol. 2013; 28: 933–6. Tanaka M, Wataya-Kaneda M, Nakamura A et al. First left-right comparative study of topical rapamycin versus vehicle for facial angiofibromas in patients with tuberous sclerosis complex. Br. J. Dermatol. 2013; doi: 10.1111/bjd.12567. [Epub ahead of print]. Madke B. Topical rapamycin (sirolimus) for facial angiofibromas. Indian Dermatol. Online J. 2013; 4: 54–7. Wataya-Kaneda M, Tanaka M, Nakamura A et al. 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.
© 2013 The Australasian College of Dermatologists
Australasian Journal of Dermatology (2014) 55, 63–69
doi: 10.1111/ajd.12125
SMALL CASE SERIES
Topical rapamycin for angiofibromas in paediatric patients with tuberous sclerosis: Follow up of a pilot study and promising future directions Jenny Tu,1 Rachael S Foster,1 Lewis J Bint2 and Anne R Halbert1 1
Department of Paediatric Dermatology, and 2Pharmacy Department, Princess Margaret Hospital for Children, Subiaco, Western Australia, Australia
ABSTRACT One of the most visible and potentially disfiguring cutaneous manifestations of tuberous sclerosis complex is the development of multiple facial angiofibromas, present in over 80% of patients. Topical rapamycin has been shown in many reports to be a safe and effective treatment for facial angiofibromas. In February 2012 we reported the results of a pilot study of four patients undertaken at a paediatric tertiary hospital in Australia. Since then, we have continued to refine the optimal formulation and concentration of topical rapamycin and expanded our selection of patients. We present an update on our current cohort of treated patients, discuss the optimal formulation of topical rapamycin and include a literature review on all published cases to date. Although topical rapamycin is not a curative treatment, we have demonstrated that its early institution significantly reduces both the vascularity and palpability of angiofibromas and prevents their progression with age. It is well tolerated and now a cost effective option. Key words: angiofibroma, sirolimus, rapamycin, tuberous sclerosis.
topical
multiple organs, including the skin, brain, kidneys, heart and lungs. One of the most common cutaneous manifestations is facial angiofibromas, a stigmatising hallmark of the condition, appearing in early childhood. It is known that in TSC, failure of tumour suppressor complexes to control a key regulatory kinase, mammalian target of rapamycin (mTOR), results in uncontrolled cellular proliferation and differentiation in the target organ.1 Therapies targeting these pathways are effective in halting further growth and development of hamartomas. Due to their cutaneous location, facial angiofibromas have the advantage of being amenable to topical therapy, minimising the risk of side effects. Over the past 18 months we have treated a total of 19 patients with topical rapamycin through the dermatology outpatient clinics of Princess Margaret Hospital, Perth, Western Australia. During this period we have been able to optimise the formulation of the topical rapamycin compound, with flexibility in trialing different strengths. Instead of being admitted to hospital for vascular and ablative laser therapies, patients may use a simple, safe and effective self-application of topical rapamycin.2 In our pilot study we found that utilizing crushed sirolimus tablets (e.g. 1 mg) in a petrolatum base was the easiest way to compound a topical 0.1% preparation, causing less irritation than the oral Rapamune 1 mg/mL solution (Mississaugi, ON, Canada) used topically. As rapamycin powder has become more available and affordable we have found it is a more convenient source of rapamycin than crushed tablets, also allowing more flexibility in the concentrations formulated.
INTRODUCTION
METHOD
Tuberous sclerosis complex (TSC) is an autosomal dominant genodermatosis resulting in hamartoma formation in
A chart review of all patients receiving treatment with topical rapamycin through the dermatology outpatient clinics at Princess Margaret Hospital was conducted. In all, 19 patients had been prescribed topical rapamycin, all
Correspondence: Dr Jenny Tu, Department of Dermatology, Princess Margaret Hospital for Children, Roberts Road, Subiaco, WA 6008, Australia. Email: [email protected] Jenny Tu, MBBS (Hons). Rachael S Foster, FACD. Lewis J Bint, B Pharm MBA. Anne R Halbert, FACD. Conflict of interest: none Submitted 6 November 2013; accepted 8 November 2013. © 2013 The Australasian College of Dermatologists
Abbreviations: mTOR TSC
mammalian target of rapamycin tuberous sclerosis complex
64 Table 1
J Tu et al. Patients’ details and results
Sex
Age (years)
Age (trial entry)
Rapamycin crushed tablet formulation (%) + date started
Rapamycin powder formulation (%)
Improvement
M M F F F M M M M M M F F M M M F M M
6 6 7 8 8 9 9 11 11 12 13 14 15 15 16 17 18 20 20
4.5 5 6.5 5.5 6 6.5 7 9 9 10.5 11 12 13 14 14.5 15 17 17.5 18.5
0.1: 09/05/2012 0.1: 28/05/2012 Straight to powder: 5/11/2012 0.1: 20/06/2011 0.1: 20/06/2011 0.1: 20/06/2011 0.1: 19/11/2011 0.1: 14/11/2011 0.1: 12/12/2011 0.1: 14/11/2011 0.1: 07/11/2011 0.1: 28/11/2011 0.1: 10/11/2011 Straight to powder: 08/10/2012 0.1: 06/02/2012 0.1: 31/10/2011 0.1: 12/03/2012 0.1: 21/01/2011 0.1: 06/02/2012
0.5 0.1 3 x/week 0.5 0.5 3–4 x/week. 0.5 3 x/week 0.5 0.5 0.5 0.1 0.1 1 0.5 1 0.5 1 0.1 0.1 0.5 0.1
Good Excellent Good Excellent Excellent Excellent Good Good Good Good Excellent Excellent Good Excellent Moderate Excellent Good Moderate Good
Improvement defined as: minimal < 30%, moderate 30–59%, good 60–89%, excellent >90%. Formulation changed to use Rapamycin (sirolimus) powder from July 2012. F, female; M, male.
parents having given their consent for their children to be included in a clinical study. The characteristics of these 19 patients are summarised in Table 1. Their mean age on entry to the trial was 10.5 years (range 4.5–18.5 years) and the duration of treatment ranged from 8 to 30 months. Parents were instructed to apply the preparation twice daily, but most reduced to a single night-time application for convenience. Two patients, previously reported in our pilot study, were initially started on Rapamune 1 mg/mL solution applied topically. On developing irritation, these children were changed to rapamycin 0.1% in petrolatum, formulated from crushing 1 mg sirolimus tablets. This crushed tablet formulation was used for the next 15 patients until June 2012. We then accessed affordable rapamycin powder from Cleo Pharmaceuticals, Shanghai (imported into Australia by S and D Chemicals, Brookvale New South Wales, Australia). The powder was mixed into a simple petrolatum base, with attention paid to distributing the small quantity evenly through the base, allowing trituration by geometric dilution. All children were transitioned to 0.1% powder formulation, the concentration then being adjusted if there was insufficient response (Table 1). Ten of the 19 patients had a rapamycin blood level taken 8 weeks after starting the ointment to ensure there was no significant systemic absorption. Having previously shown it was highly unlikely for a 0.1% preparation to be systemically absorbed, we concentrated on testing children treated with 0.5 and 1% preparations. At each 8-week follow-up visit, one of the primary investigators (AH) estimated the percentage of clinical improvement, with the assistance of pretreatment and post-treatment photography. Minimal improvement was defined as less than 30% improvement, moderate as 30–59%, good as 60–90% and excellent as > 90% improvement (near or complete clearance). © 2013 The Australasian College of Dermatologists
RESULTS All 19 patients demonstrated a significant and sustained improvement in facial angiofibromas with both topical 0.1% rapamycin (crushed tablet formulation) and 0.1–1% rapamycin (powder formulation). Of these patients 17 had good or excellent improvement, but in two of the older children with severe, widespread and raised angiofibromas only a moderate improvement was found (Table 1). Figures 1–5 demonstrate the clinical results from a representative group of the patients. One patient had a fibrous plaque on his right lateral neck, which also seemed to respond to topical rapamycin 0.5% (Fig. 6). The response to treatment was rapid, and parents commented they could see a difference even in the first 2 weeks of treatment, particularly with a reduction in erythema. In keeping with our pilot study, the most striking responses were seen when treatment was started in the younger patients in whom the angiofibromas were smaller and less raised. Unexpectedly, the parents of six of the 17 patients who were transitioned from the crushed tablet to the powder formulation felt the 0.1% crushed tablet preparation worked slightly better than the 0.1% powder preparation. An assay was carried out on the powder being used, to verify its potency, through multiple dilutions and assay, by the Biochemistry Service at PathWest, Perth, Western Australia. The powder was found to be 95% of its stated potency. The treatment of these six patients was then increased to a 0.5% powder preparation, after which they rapidly returned to their previous improved clinical appearance. Treatment of two of the older children with very raised angiofibromas was further increased to 1%, with noticeable improvement. If patients and parents were content with their level of improvement we did not continue increasing the strength. The reason for the perceived superiority of crushed tablets
Topical rapamycin for angiofibromas
65
(a)
(b)
(a)
(b)
Figure 1 (a) pretreatment. (b) posttreatment with topical rapamycin.
Figure 2 (a) pretreatment; (b) posttreatment with topical rapamycin.
compared with powder is unknown, but may be due to another chemical in the tablet interacting with the sirolimus. Only two patients had a detectable blood rapamycin level of 0.5 and 0.8 micrograms/L, much less than the level required for immunosuppression (8–20 μg/L, depending on the type of organ transplantation). Both crushed tablet and powder preparations were well tolerated, although one child had a minor bleed from an angiofibroma after being scratched by a small fragment of crushed tablet. One child
developed perioral dermatitis that resolved with a course of erythromycin and did not recur despite continuing with rapamycin. No child complained of itching or irritation. There was no evidence of tachyphylaxis over time. Indeed, the younger children with near complete clearance were able to reduce to thrice weekly applications without a loss of efficacy. As a guide, 50g of 0.1% rapamycin made from crushed sirolimus tablets at the time of writing costs approximately A$410 to manufacture, while 50g of 0.5% rapamycin made © 2013 The Australasian College of Dermatologists
66
J Tu et al.
(a)
(b)
Figure 3 (a) pretreatment; (b) posttreatment with topical rapamycin.
(a)
(b)
Figure 4 (a) pretreatment; (b) posttreatment with topical rapamycin.
from powder (Cleo Pharmaceuticals) costs A$125 and lasts approximately 3 months.
DISCUSSION A comprehensive Medline literature search identified 12 articles using the keywords topical rapamycin or sirolimus and angiofibromas (Table 2).2–13 The articles were limited to those available in the English language and they were read, and any relevant articles referred to in the references were also included in the study. Of these, 11 were case series and one was a review article.13 Since the first case report of © 2013 The Australasian College of Dermatologists
topical rapamycin ointment having being used in a patient with tuberous sclerosis in 2010, there have been 66 additional patients who have had good response rates to it. Apart from a 73% response rate in 23 patients in a randomised controlled trial performed by Koenig and colleagues in September 2012, all other studies have reported 100% response rates. The difference may be in part attributable to the low concentrations of rapamycin (0.003% and 0.015%) used in Koenig study.9 In our experience, 0.1–1% topical rapamycin is a safe and effective treatment for facial angiofibromas. Following our pilot study, we did not pursue treatment with oral
Topical rapamycin for angiofibromas
67
(a)
(b)
(a)
(b)
Figure 5 (a) pretreatment; (b) posttreatment with topical rapamycin.
Figure 6 (a) fibrous plaque on neck pre-treament; (b) fibrous plaque on neck post-treatment with topical rapamycin.
Rapamune 1 mg/mL solution applied topically, due to unacceptable facial irritation. Crushed sirolimus tablets in a 0.1% petrolatum formulation were effective, but compounding pharmacists found the process labour intensive and time consuming and there were concerns about the unintentional inhalation of aerosolised immunosuppressant. The patients’ parents complained that the batches varied in quality, some being more gritty than others. The patients felt embarrassed about going to school with crushed tablet on their face and rapidly insisted on a nighttime application only.
The ability to purchase rapamycin powder has simplified the manufacturing process for pharmacists and improved patients’ satisfaction. It was surprising that six of the 17 patients noted that the 0.1% powder formulation did not seem to be quite as effective as the 0.1% crushed tablet formulation, but increasing the dose to a 0.5% powder formulation overcame this problem. Despite increasing the concentration, blood levels remained well below that required for immunosuppression. Most patients ended up applying it once daily for convenience, without loss of efficacy. For young children with nearly complete clearance, a © 2013 The Australasian College of Dermatologists
68 Table 2 Case no
J Tu et al. Summary of cases using topical rapamycin to treat angiofibromas in tuberous sclerosis patients Total patients
Year of publication
Authors 3
Topical Rapamycin formulation
Response All patients All patients All patients All patients had greater improvement with combination rapamycin-tacrolimus treatment than with tacrolimus ointment alone All patients All patients
1 2 3,4 5–13
1 1 2 9
Jul 2010 Sept 2011 Oct 2011 Oct 2011
Haemel et al. DeKlotz et al.4 Mutizwa et al.5 Wataya-Kaneda et al.6
1% rapamycin ointment 1% rapamycin compound 1% rapamycin solution Half face with tacrolimus ointment, other with addition of 0.2% rapamycin ointment.
14 15,16
1 2
Jan 2012 Feb 2012
Truchuelo et al.7 Kaufman McNamara et al.8
17–20
4
Feb 2012
Foster et al.2
21–43
23
Sept 2012
Koenig et al.9
44–53 54,55
10 2
Oct 2012 July 2013
56–67
11
Aug 2013
Salido et al.10 Wheless and Almoazen11 Tanaka et al12
1% rapamycin cream Case 1: 60 mL rapamycin 1 mg/mL solution compounded with 60 g of Eucerin (Hamburg, Germany) + oral sirolimus 3mg daily. Case 2: 60 mL rapamycin 1 mg/mL solution compounded with 60 g of emollient daily 0.1% rapamycin in petrolatum, 0.1% rapamycin solution 0.003%, 0.015% rapamycin + Skincerity (NuCerity International, Houston, TX, USA) 0.4% sirolimus ointment 0.1% crushed sirolimus tablets in ointment 0.2% rapamycin ointment or gel on one cheek & vehicle on other cheek.
thrice weekly application maintained the benefit, making it even more cost effective. We have not noted irritation, allergy or other topical complications. We were concerned that the greasy formulation would be comedogenic for our teenage patients, but even this has not been a significant problem. Our families have been extremely positive about the treatment and were delighted with the clinical outcome. There are also reports in the literature describing responses of hypomelanotic macules to topical rapamycin 0.2% gel.14 Hypomelanotic macules in TSC may arise from abnormal melanisation. Rapamycin may alter factors implicated in melanogenic gene expression, explaining its effectiveness in treating hypomelanotic macules.14 We did not pursue the use of topical rapamycin for hypomelanotic macules as they are mostly not located on cosmetically sensitive sites. While discussions in the literature with regard to oral mTOR inhibitors to treat neurological and renal complications of TSC have been increasing, angiofibromas continue to be one of the earliest cutaneous stigmata to appear in children and are a major concern to patients and families. In view of the safety and reasonable cost of topical rapamycin we urge clinicians involved with TSC patients to give consideration to using topical rapamycin therapy, starting as soon as the angiofibromas begin to appear in early childhood. We suggest starting with 0.1% rapamycin powder in petrolatum, applied once daily until clearance and then reducing the dose to thrice weekly. For older children, 0.5% is the usual concentration initially required, reserving 1% for the management of teenagers and adults with protuberant or numerous lesions. In this simple, safe © 2013 The Australasian College of Dermatologists
All patients 73% of 23 (i.e., 17 patients) All patients All patients All patients
and cost effective way, a potentially disfiguring and stigmatising complication of this genetic disorder can be minimised and controlled.
ACKNOWLEDGEMENTS We would like to thank Eamonn McNulty and the team at Medical Illustration, Princess Margaret and King Edward Hospitals for their serial photography input. The copyright of these images belongs to the respective medical illustration departments and to the patients involved. This article has been supported with funding from the F. & E. Bauer Foundation Prize.
REFERENCES 1. 2.
3.
4.
5.
Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet 2008; 372: 657–68. Foster R, Bint L, Halbert A. Topical 0.1% rapamycin for angiofibromas in paediatric patients with tuberous sclerosis: a pilot study of four patients. Australas. J. Dermatol. 2012; 53: 52–6. Haemel AK, O’Brian AL, Teng JM. Topical rapamycin: a novel approach to facial angiofibromas in tuberous sclerosis. Arch. Dermatol. 2010; 146: 715–8. 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: 1116–7. Mutizwa M, Berk D, Anadkat M. Treatment of facial angiofibromas with topical application of oral rapamycin solution (1 mg mL)) in two patients with tuberous sclerosis. Br. J. Dermatol. 2011; 165: 922–3.
Topical rapamycin for angiofibromas 6.
7.
8.
9.
10.
Wataya-Kaneda M, Tanaka M, 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: 912–6. Truchuelo T, Díaz-Ley B, Ríos L et al. Facial angiofibromas treated with topical rapamycin: an excellent choice with fast response. Dermatol. Online J. 2012; 18: 15. Kaufman McNamara E, Curtis AR, Fleischer AB Jr. Successful treatment of angiofibromata of tuberous sclerosis complex with rapamycin. J. Dermatolog. Treat. 2012; 23: 46–8. Koenig M, Hebert A, Roberson J 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. Salido R, Garnacho-Saucedo G, Cuevas-Asencio I et al. Sustained clinical effectiveness and favorable safety profile of
11.
12.
13. 14.
69
topical sirolimus for tuberous sclerosis – associated facial angiofibroma. J. Eur. Acad. Dermatol. Venereol. 2012; 26: 1315–8. Wheless JW, Almoazen H. A novel topical rapamycin cream for the treatment of facial angiofibromas in tuberous sclerosis complex. J. Child Neurol. 2013; 28: 933–6. Tanaka M, Wataya-Kaneda M, Nakamura A et al. First left-right comparative study of topical rapamycin versus vehicle for facial angiofibromas in patients with tuberous sclerosis complex. Br. J. Dermatol. 2013; doi: 10.1111/bjd.12567. [Epub ahead of print]. Madke B. Topical rapamycin (sirolimus) for facial angiofibromas. Indian Dermatol. Online J. 2013; 4: 54–7. Wataya-Kaneda M, Tanaka M, Nakamura A et al. 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.
© 2013 The Australasian College of Dermatologists
