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Therapeutic approaches to prevent disease recurrence in uveitis

Al-Janabi, Ahmed Talib Kasb; (2019) Therapeutic approaches to prevent disease recurrence in uveitis. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Uveitis is a significant cause of visual morbidity in the working-age population and has a high propensity to recur and cause damage to the ocular tissues which compromise the patient's sight and that can be irreversible. This dissertation addresses the question of how different treatment regimens influence disease recurrence, improve visual outcome and reduce the dose of concomitant immunosuppressive therapy in patients with sight-threatening ocular inflammatory conditions. Therapeutic agents targeting specific inflammatory mediators are playing an increasingly important role in the management of non-infectious uveitis. The first study examined the role of anti-TNFα drugs and rituximab (anti-CD20) in controlling ocular inflammation in 82 patients with non-infectious, intermediate posterior and panuveitis refractory to conventional immunosuppression. Treatment with these agents achieved better disease control manifested by significant reduction in concomitant immunosuppressive therapy, substantial decrease in disease relapse rate and stability in visual acuity. Both adalimumab and infliximab have similar efficacy and corticosteroids sparing effect; however, compared to infliximab, adalimumab was better tolerated and was associated with significantly lower drug discontinuation rate (treatment failure). Behcet's patients on TNFα blockers had 75% risk reduction in disease recurrence compared non-Behcet's disease subjects which point to the central role of TNFα in Behcet disease pathogenesis. Finally, treatment with TNFα inhibitors and rituximab was effective for extended follow-up periods (5 years and beyond). Statins used to reduce serum cholesterol and improve cardiovascular outcomes in high-risk patients was shown to have pleiotropic anti-inflammatory effects in several in-vivo and in vitro studies. The second study is a phase II, randomised, placebo-controlled trial, examined the effect of simvastatin (80 mg per day) on the amount of concomitant immunosuppressive drugs in 32 patients with non-infectious intermediate, posterior, and panuveitis, at one and two years follow-up visits. Analysing the mean prednisolone dose did not show a significant difference between the two groups. Therefore, there is no evidence to support the anti-inflammatory effect of simvastatin in uveitis. However, given the long-term exposure to corticosteroid-based immunosuppressive therapy, these patients were found to have high serum cholesterol. Our data shows that intensive lipid lowering with simvastatin significantly decreased total cholesterol and LDL and thus reducing the risk of atherosclerotic cardiovascular diseases. Ocular toxoplasmosis, the most common cause of infectious posterior uveitis, has drastic consequences on vision if it involves vision-sensitive structures. The third study looked retrospectively at the role of co-trimoxazole as a prophylactic agent in patients with recurrent sight-threatening disease. Prophylaxis course with co-trimoxazole treatment resulted in a substantial reduction in disease recurrence and significant improvement in vision in comparison to controls. To our knowledge, this is the first study to report improvement in visual acuity on prophylactic therapy, in a disease where no therapy, over the past two decades, was reported to achieve an increase in vision.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Therapeutic approaches to prevent disease recurrence in uveitis
Event: University College London
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10070028
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