Introduction
Uveitis is a generic term for a collection of more than 30 different phenotypes of intraocular inflammation centred on the uveal tract.1 There is a broad range of systemic inflammatory disorders associated with uveitis including: sarcoidosis, Behcet’s disease, Vogt-Koyanagi-Harada disease, spondyloarthritis. Important infectious causes of uveitis include the herpesviridae, Toxoplasma gondii, Mycobacterium tuberculosis and Treponema pallidum. In approximately 50% of cases, a specific aetiology is not identifiable following extensive workup and is termed undifferentiated (‘idiopathic’).2 As the anatomical location, clinical course and aetiology of the uveitides vary widely, an individualised management approach is essential.
Over the past 15 years, the Standardisation of Uveitis Nomenclature (SUN) research group has developed classification criteria for the 25 clinical phenotypes of uveitis based on anatomic classification, severity gradings of inflammation and definitions for uveitis activity using a super majority Delphi approach with a large group of 76 international uveitis experts.3 This has standardised data recording in uveitis.
Acute anterior uveitis (AAU) is by far the most common clinical phenotype of uveitis4 and episodes are readily controlled with topical corticosteroid therapy in about 90% of patients. Around 50% of patients with AAU are human leucocyte antigen-B27 positive and up to 70% of such patients have an associated spondyloarthropathy, most frequently ankylosing spondylitis.5 Antitumour necrosis factor alpha (TNF-α) directed monoclonal antibody therapy such as adalimumab therapy typically eliminates recurrences of AAU and results in long-term remission of the uveitis.6
Non-infectious intermediate, posterior and pan-uveitis involve the posterior segment of the eye, behave differently and have a broad range of uveitis severity.7 Although far less frequent than AAU, these phenotypes are frequently vision-threatening, typically requiring systemic corticosteroid in the acute phase, and additional immunosuppressive therapy for long-term control of the uveitis to preserve vision, minimise disease complications and minimise treatment side effects.
Despite the heterogeneous nature of uveitis, there have been a number of well-designed studies providing clinical guidance in the management of uveitis.8 The Multicentre Uveitis Steroid Treatment (MUST) trial was a multicentre, partially masked, randomised controlled study, documenting superiority of ‘treat to target’ systemic immunosuppressive therapy over steroid intravitreal implant monotherapy, in the management of vision-threatening non-anterior, non-infectious uveitis.9 The First-line Antimetabolites as Steroid-sparing Treatment was a randomised controlled trial, double-blind, head-to-head comparison between mycophenolate and methotrexate, concluding that mycophenolate mofetil is not superior to methotrexate in controlling inflammation among individuals with non-infectious uveitis.10 The VISUAL 1, 2 and 3 studies were multicentre, double-masked, randomised clinical trials providing evidence for the safety and efficacy of adalimumab over corticosteroid therapy, in patients with non-anterior, non-infectious uveitis.11–13
The Systemic Immunosuppressive Therapy for Eye disease (SITE) studies, a large retrospective case series of ~15 000 patients with uveitis treated over 20 years, reports that conventional systemic immunosuppressive therapy did not result in higher mortality, compared with non-exposed persons, as had been earlier feared.14 Subgroup analysis of the SITE cohort identified that 5% of the intermediate uveitis (IU) patients had multiple sclerosis. This finding informs current clinical practice that requires baseline neuroimaging to exclude demyelinating disease prior to adalimumab use in patients with IU, as there are reports of adalimumab precipitating demyelinating diseases.15 A study from Sydney has shown an increased risk of non-melanoma skin cancers and non-Hodgkin’s lymphoma in patients with uveitis treated with systemic immunosuppressive therapy.16
These studies provide a solid framework for our current approach to systemic therapy for non-infectious uveitis. Systemic corticosteroids provide rapid control of severe uveitis. Although it remains the most effective therapy for severe uveitis, the many well-recognised potential complications, such as osteoporosis, preclude its long-term use. The aim in patients requiring ongoing systemic therapy is durable steroid free remission or, at a minimum, reduction to a daily dose of <7.5 mg/day of prednisolone.17 Steroid-sparing immunosuppressive therapy is required to achieve this in the majority of patients, most frequently initially with conventional drugs such as methotrexate or mycophenolate.18 The presence of associated systemic diseases may modify and guide the choice of immunosuppressant.19
With increasing recognition of anti-TNF biologics as an effective therapy in the management of vision-threatening uveitis, adalimumab is becoming a preferred second-line drug over conventional steroid-sparing agents.20 Although there are five available anti-TNF biologics, most data and clinical experience in patients with uveitis has been gained using adalimumab and infliximab.21 Salvage therapy for patients who are poor or non-responders to anti-TNFs is most commonly tocilizumab, other anti-TNF biologics and occasionally rituximab.22 The use of adalimumab as steroid-sparing systemic therapy was supported and received level A recommendation in recently published guidelines for the treatment of non-infectious uveitis provided by the fundamentals of care for uveitis initiative.21
Before commencing anti-TNF therapy, appropriate screening of patients for latent infections, left ventricular dysfunction and demyelinating disease is essential to minimise risks. Multidisciplinary team management produces the best ocular outcomes, management of comorbidities and minimisation of complications.23
The current multicentre study aimed to collect real-world data regarding the safety and effectiveness of adalimumab to treat vision-threatening non-infectious uveitis and investigate the utility of early commencement of adalimumab.