Abstract
BackgroundNon-infectious uveitis represents a sub-type of intraocular inflammation often associated with disorders of immune dysregulation. If untreated, the intraocular inflammation may progress to severe visual impairment and blindness. Current treatment is heavily reliant on systemic corticosteroid, often at doses associated with severe side effects. There is a need for efficacious corticosteroid-sparing immunomodulatory therapy for these patients. Current immunomodulators include various immunosuppressants and biologics but mammalian target of rapamycin (mTOR) inhibitors (such as sirolimus and everolimus) may also be contenders for this role.The systematic review proposed here will evaluate the evidence for the use of sirolimus and everolimus in the context of non-infectious uveitis.Method/designStandard systematic review methodology will be used to identify, select and extract data from any comparative or non-comparative study of mTOR inhibitors in patients with non-infectious uveitis excluding case reports. Searches of bibliographic databases (MEDLINE, EMBASE, The Cochrane Library and CINAHL) and clinical trials registers will be performed, with no restriction on language or date of publication. Translation of non-English language articles will be undertaken where necessary.The primary outcome of interest will be uveitis activity as measured by vitreous haze. Secondary outcomes will include other pre-specified measures of uveitis activity (such as anterior chamber cells or central macular thickness) best corrected visual acuity, heath-related quality of life, requirement for concurrent treatment and adverse events.Risk of bias assessment will be performed appropriate to each study design. Study selection, data extraction and risk of bias assessment will be undertaken by two reviewers independently. Data will be grouped, tabulated and narratively synthesised. Meta-analysis will be undertaken where appropriate clinical and methodological homogeneity exists. The review will be published according to PRISMA guidance.DiscussionStudies of various designs have investigated the clinical use of mTOR inhibitors for non-infectious uveitis, and a large international randomised controlled trail of sirolimus for non-infectious uveitis is due to report. The findings of this systematic review will help inform ophthalmologists and aid the improvement of treatment protocols for non-infectious uveitis with regard to the use of mTOR inhibitors.Systematic review registrationPROSPERO CRD42017056390
Highlights
Non-infectious uveitis represents a sub-type of intraocular inflammation often associated with disorders of immune dysregulation
Registers of clinical trials ○ World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) portal which comprises a portal to multiple registers including Clinicaltrials.gov, the European Clinical Trials Database (EudraCT; www.clinicaltrialsregister.eu) and the International Standard Randomised Controlled Trials Number database (ISRCTN; www.controlled-trials.com)
Various immunomodulatory therapies can be used as second-line agents for uveitis; these agents are often limited by a slower onset of action and reduced efficacy compared to corticosteroids, whilst being associated with different but detrimental side effects
Summary
Non-infectious uveitis represents a sub-type of intraocular inflammation often associated with disorders of immune dysregulation. Current treatment is heavily reliant on systemic corticosteroid, often at doses associated with severe side effects. Most cases of non-infectious uveitis appear to be autoimmune in nature, occurring in either isolation (termed ‘idiopathic uveitis’) or in association with systemic conditions featuring immune dysregulation (e.g. sarcoidosis, Behcet’s disease) [2, 4, 5]. Treatment options include mycophenolate mofetil, azathioprine and calcineurin inhibitors (such as tacrolimus and ciclosporin); these agents lack the speed of onset and efficacy of corticosteroids and many are associated with the development of different, but limiting side effects [5]. There remains a clear need for efficacious steroid-sparing immunomodulatory therapy for patients with non-infectious uveitis, aiming to achieve uveitis control at a cost of the fewest possible side effects [5]
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