Evaluating novel & established therapies for uveitis.
Doctoral thesis, UCL (University College London).
Ocular inflammatory diseases, which include uveitis, are a leading cause of visual impairment. A number of systemic immunosuppressive agents (ISAs) are available, as well as biological therapies. However, these therapies may not always be effective and can be limited by toxicity. This thesis aimed to evaluate established and emerging therapies in ocular inflammatory disease. The reasons for changing ISAs and the success of subsequent ISA regimes have not previously been investigated for ocular inflammatory diseases. A review of a case series of 64 uveitis patients on ISAs revealed that the commonest reason for a treatment failing was lack of efficacy. A comparison between the most commonly used strategies after treatment failure, such as switching strategies (eg switch-to mycophenolate vs switch-to methotrexate) and add-on strategies (eg add-on azathioprine vs mycophenolate) revealed no significant difference in the time-to-success and retention times. The long-term efficacy and effects of repeat therapy with rituximab (anti-B cell therapy) in ocular Wegener’s granulomatosis (WG) was evaluated in the largest case series reported to date. Rituximab was effective in inducing remission, but relapse occurred in 33% of patients at about 12 months, and could be predicted by rising anti-PR3 titres. Retreatment with rituximab was effective. The work presented in the final part of this thesis utilised murine models of experimental autoimmune uveitis (EAU) to evaluate novel tumour necrosis factor (TNF) inhibitory therapies. EAU was initially characterised in two strains of mice, C57B/6 and B10.RIII, to identify key therapeutic windows and key target inflammatory cytokines. When testing the TNF inhibitor therapies, the EAU model failed due to possible genetic contamination of the B10.RIII strain from the supplier, this is still an on-going issue. However, some of the TNF inhibitory therapies administered by intravitreal injection increased the degree of inflammation compared to those injected with a placebo control.
|Title:||Evaluating novel & established therapies for uveitis|
|Additional information:||Permission for digitisation not received|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology|
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