Cochrane corner: why we still don’t know whether anti-TNF biologic therapies impact uveitic macular oedema

Abstract

In this Cochrane Corner commentary article, we considered the findings of the recent Cochrane systematic review by Robert Barry and colleagues on, “Anti-tumour necrosis factor biological therapies for the treatment of uveitic macular oedema (UMO) for non-infectious uveitis”. The review reported that whilst the VISUAL I and VISUAL II randomised controlled trials both demonstrated that, in comparison to placebo subcutaneous injection, adalimumab significantly reduced the time to uveitis flare in patients whose intermediate, posterior, or pan uveitis had first been brought under control by oral steroid therapy, neither trial reported data on UMO. We discuss the meaning of composite clinical trial endpoints, and summarise key discussion points from the recent March 2019 American Uveitis Society workshop with international uveitis specialists, and representatives from the pharmaceutical and imaging industries, and the Food and Drug Administration (FDA) on, “Objective Measures of Intraocular Inflammation for Use in Clinical Trials”. We explain why UMO is not currently considered to be an acceptable trial endpoint for drug licensing purposes. Finally, we return to the patient perspective and identify research priorities that would help to advance the field, and future updates of this Cochrane Review. Last month a 54-year-old woman with over 1000 μ of recurrent uveitic macular oedema (UMO) in her only-seeing eye presented to the uveitis clinic. The central vision in her other eye had been lost to a full-thickness macular hole, the fovea having succumbed to the chronic effects of waxing and waning UMO. As I turned to the electronic patient record with thoughts of a second-line agent, my heart sank to find that she had already tried both methotrexate and mycofenolate mofetil (antimetabolite immunosuppressants), and had developed a rash on adalimumab (a human monoclonal anti-TNF antibody). She had also since tried certolizumab-pegol (a monoclonal anti-TNF-α antibody fragment), which was ineffective for her joint inflammation, and was currently on secukinumab (a human monoclonal antibody targeting interlukin-17A). Fortunately, the UMO reduced to 400 μ after a week of high dose oral prednisolone followed by an Ozurdex implant, and since her psoriatic joints were actively inflamed again, she was able to switch to funded infliximab (a chimeric monoclonal anti-TNF-α antibody). But, I wondered, will this third anti-TNF agent reduce the severity or duration of UMO, or the risk of UMO relapse? To find out, I turned to the recent Cochrane systematic review by Robert Barry and colleagues on, “Anti-tumour necrosis factor biological therapies for the treatment of uveitic macular oedema (UMO) for non-infectious uveitis” [1]. Uveitis is a leading cause of vision loss, estimated to cause between 10 and 25% of all blindness in high and lowmiddle income countries, respectively [2–5]. UMO accounts for 41% of vision impairment and 29% blindness in uveitis [6, 7]. We have numerous, effective off-license immunosuppressive drugs, but these have major side effects, both acutely and over the long haul [8]. One of the many new biologic therapies, adalimumab, was approved by NICE in October 2017 for patients in England who fail to respond, or are unable to tolerate, second line immunosuppressive therapy for sightthreatening active, non-infectious uveitis [9]. This funding * Tasanee Braithwaite [email protected]