title: Topical rapamycin as a treatment for fibrofolliculomas in Birt-Hogg-Dubé syndrome: a double-blind placebo-controlled randomized split-face trial.
abstract: 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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00928798.
authors.affiliation: Department of Dermatology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: Lieke M C
authors.initials: LM
authors.lastname: Gijezen
authors.affiliation: Department of Dermatology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: Marigje
authors.initials: M
authors.lastname: Vernooij
authors.affiliation: Department of Dermatology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: Herm
authors.initials: H
authors.lastname: Martens
authors.affiliation: Department of Dermatology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: Charlene E U
authors.initials: CE
authors.lastname: Oduber
authors.affiliation: Department of Dermatology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: Charles J M
authors.initials: CJ
authors.lastname: Henquet
authors.affiliation: Department of Dermatology, VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: Theo M
authors.initials: TM
authors.lastname: Starink
authors.affiliation: Department of Epidemiology, CAPHRI Research School for Public Health Primary Care, Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Prins
authors.affiliation: Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: Fred H
authors.initials: FH
authors.lastname: Menko
authors.affiliation: Department of Epidemiology, CAPHRI Research School for Public Health Primary Care, Maastricht University Medical Centre+, Maastricht, The Netherlands.
authors.forename: Patty J
authors.initials: PJ
authors.lastname: Nelemans
authors.affiliation: Department of Dermatology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre+, Maastricht, The Netherlands; Department of Clinical Genetics, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre+, Maastricht, The Netherlands; Institute of Medical Biology, Singapore, Singapore.
authors.forename: Maurice A M
authors.initials: MA
authors.lastname: van Steensel
mesh_terms: D000287:Administration, Topical; D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D058249:Birt-Hogg-Dube Syndrome / Q000188:drug therapy* / Q000473:pathology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; D020123:Sirolimus