title: A Comprehensive Review of mTOR-Inhibiting Pharmacotherapy for the Treatment of Non-Infectious Uveitis.
abstract: Non-infectious uveitis is a sight-threatening inflammatory disease that often necessitates prolonged use of high-dose corticosteroids, resulting in significant systemic side effects. There is a need for efficacious steroid-sparing immunomodulatory therapy for these patients, and the mTOR inhibitors (sirolimus and everolimus) may be contenders for this role.
  
  
  
  A comprehensive review of preclinical and clinical research on mTOR inhibitors for non-infectious uveitis was performed. Articles were identified by a search of MEDLINE (PubMed/OVID) and EMBASE (OVID) the terms (uveitis OR non-infectious uveitis) AND (mTOR inhibitor OR sirolimus OR everolimus). Assessment of study aims, methods, efficacy outcomes and adverse events was performed.
  
  
  
  Seven pre-clinical and nine clinical studies were identified. One study in each group was on everolimus, the rest sirolimus. Preclinical studies have been performed in rabbit, rat, mouse and in-vitro models. Clinical studies range from comparative open-label trials to case reports, with reported clinical efficacy ranging from 40% to 100% depending on endpoint assessed. The overall rate of drug-related adverse events (such as ocular irritation, visual floaters, nausea and vomiting) was 0.640 events per patient-year with sirolimus, and 0.111 events per patient-year with everolimus.
  
  
  
  Published evidence suggests that sirolimus and everolimus may be useful in the management of noninfectious uveitis. Both appear to be well tolerated, especially when locally administered. Further high-quality RCTs adopting standardised end-points are required to definitively determine the efficacy of each agent.
authors.affiliation: Department of Ophthalmology, University Hospitals Birmingham NHS Foundation Trust, Birmingham. United Kingdom.
authors.forename: Joshua
authors.initials: J
authors.lastname: Blair
authors.affiliation: Department of Ophthalmology, University Hospitals Birmingham NHS Foundation Trust, Birmingham. United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Barry
authors.affiliation: Institute of Applied Health Research, University of Birmingham, Birmingham. United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Moore
authors.affiliation: Centre for Translational Inflammation Research, Institute of Inflammation & Ageing, University of Birmingham. United Kingdom.
authors.forename: Alastair K
authors.initials: AK
authors.lastname: Denniston
mesh_terms: D000068338:Everolimus / Q000627:therapeutic use*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D020123:Sirolimus / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014605:Uveitis / Q000188:drug therapy*
chemical_list: D007166:Immunosuppressive Agents; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Non-infectious uveitis; Uveitis; corticosteroids; immunosuppression; mTOR inhibitors; mammalian target of rapamycin