Topical rapamycin as a treatment for fibrofolliculomas in Birt-Hogg-Dubé syndrome:a double-blind placebo-controlled randomized split-face trial

Background: Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder characterised by the occurrence of benign, mostly facial, skin tumours called fibrofolliculomas, multiple lung cysts, spontaneous pneumothorax and an increased renal cancer risk. Current treatments for fibrofolliculomas have high rates of recurrence and carry a risk of complications. It would be desirable to have a treatment that could prevent fibrofolliculomas from growing. Animal models of BHD have previously shown deregulation of mammalian target of rapamycin (mTOR). Topical use of the mTOR inhibitor rapamycin is an effective treatment for the skin tumours (angiofibromas) in tuberous sclerosis complex, which is also characterised by mTOR deregulation. In this study we aimed to determine if topical rapamycin is also an effective treatment for fibrofolliculomas in BHD. Methods: We performed a double blinded, randomised, facial left-right controlled trial of topical rapamycin 0.1% versus placebo in 19 BHD patients. Trial duration was 6 months. The primary outcome was cosmetic improvement as measured by doctors and patients. Changes in fibrofolliculoma number and size were also measured, as was occurrence of side effects. Results: No change in cosmetic status of fibrofolliculomas was reported in the majority of cases for the rapamycin treated (79% by doctors, 53% by patients) as well as the placebo treated facial sides (both 74%). No significant differences between rapamycin and placebo treated facial halves were observed (p = 1.000 for doctors opinion, p = 0.344 for patients opinion). No significant difference in fibrofolliculoma number or change in size of the fibrofolliculomas was seen after 6 months. Side effects occurred more often after rapamycin treatment (68% of patients) than after placebo (58% of patients; p = 0.625). A burning sensation, erythema, itching and dryness were most frequently reported. Conclusions: This study provides no evidence that treatment of fibrofolliculomas with topical rapamycin in BHD results in cosmetic improvement. Trial Registration: ClinicalTrials.gov NCT00928798</p

Changes in the number of fibrofolliculomas after treatment with rapamycin.

<p>BHD patients with facial fibrofolliculomas were treated with topical rapamycin and placebo for six months. The number of fibrofolliculomas in a predefined area of the face was determined and compared to baseline. The reduction in the number of fibrofolliculomas was stronger upon placebo treatment.</p

Trial outline.

<p>* The patient who was lost to follow-up at 3 months was excluded from the analysis of the 3 month results. ** For the patients who were lost to follow-up at 6 months, the 3-month data were carried forward in the analysis of the 6-month results.</p

Between-treatment comparison of mean change in fibrofolliculoma size compared to baseline (in mm) using the T-test for paired samples.

<p>SD = standard deviation; CI = confidence interval.</p

Local side effects of topical rapamycin treatment.

<p>Side effects of both topical rapamycin and placebo treatment were registered at each clinical assessment. Burning, erythema, dryness and itching were the most commonly reported local side effects. All side effects other than dryness and itching were reported more frequently for the rapamycin treated facial half.</p

Photographic recording of cosmetic status during rapamycin treatment.

<p>Close up of standardised facial photographs taken at baseline, 3 months and 6 months after starting treatment with topical rapamycin or placebo per facial half. Photos of a representative patient are shown, revealing no visible improvement or worsening of the facial fibrofolliculomas.</p

Baseline characteristics of included patients.

<p>Baseline characteristics of included patients.</p

Changes in cosmetic status of fibrofolliculomas after treatment with rapamycin scored by doctors and patients.

<p>BHD patients with facial fibrofolliculomas were treated with topical rapamycin and placebo for six months. The degree of improvement compared to baseline was scored on a 7-point Likert scale by both doctors (A) and patients (B). Doctors and patients reported no change in the majority of cases. Patients reported improvement more frequently for the rapamycin compared to the placebo treated facial side.</p

Skin features in TSC and BHD.

<p>Photographs taken from a TSC and a BHD patient show angiofibromas and fibrofolliculomas, respectively. Notice the resemblance between the two types of lesion.</p