The Risk of Uveitis in Patients With JIA Receiving Etanercept

The Challenges of Analysing Real-World Data

Rebecca Davies; Diederik De Cock; Lianne Kearsley-Fleet; Taunton Southwood; Eileen Baildam; Michael W. Beresford; Helen E. Foster; Wendy Thomson; Athimalaipet V. Ramanan; Kimme L. Hyrich


Rheumatology. 2020;59(6):1391-1397. 

In This Article

Abstract and Introduction


Objectives: To describe and compare the occurrence of newly diagnosed uveitis in children with JIA receiving MTX, etanercept, adalimumab and infliximab.

Methods: This on-drug analysis included patients within UK JIA registries (British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study and Biologics for Children with Rheumatic Diseases) with non-systemic disease, registered at MTX or biologic start with no history of uveitis. Follow-up began from date of first treatment, continuing until first uveitis, discontinuation of registered drug, most recent follow-up up or death, whichever came first. Hazard ratios comparing risk of uveitis between drugs were calculated using propensity-adjusted Cox regression.

Results: A total of 2294 patients were included (943 MTX, 304 adalimumab/infliximab, 1047 etanercept). There were 44 reported cases of uveitis (27 MTX, 16 etanercept, 1 adalimumab). Unadjusted hazard ratio showed a reduced risk of uveitis in biologic cohorts compared with MTX. After adjusting for propensity deciles, there was no significant difference in the risk of uveitis between patients receiving etanercept or MTX [hazard ratio 0.5 (0.2–1.1)]. Fully adjusted comparisons were not possible for adalimumab/infliximab as there were too few events.

Conclusions: In this first paper to compare the rate of new onset uveitis across the three main anti-TNF therapies used in JIA, a new diagnosis of uveitis is less common among patients starting biologics compared with MTX, although this did not reach statistical significance. The suggested protective effect of etanercept is likely explained by confounding, whereby patients in the MTX cohort are younger and earlier in disease, and therefore at greater risk of developing uveitis compared with etanercept patients.


JIA is the most common inflammatory rheumatic disease in childhood, thought to affect around 4 in 1000 children.[1,2] Uveitis is a significant comorbidity associated with JIA, with prevalence reported between 12 and 30%.[3] It is characterized by inflammation of the middle layer of the eye, and can result in significant visual morbidity,[4] suggesting that diagnoses and treatment should be a priority.

There are a number of widely accepted risk factors for the development of JIA-associated uveitis, which include younger age at onset of JIA (<7 years) and the presence of ANAs.[3] There have also been reports of uveitis occurring more frequently in patients with oligoarticular JIA compared with polyarticular JIA, and in female patients.[5,6] Uveitis is also thought to occur early in the JIA disease course, with a German study reporting that 73% of 406 patients who developed uveitis did so within the first year following JIA diagnosis.[6]

In addition to these demographic and clinical factors, etanercept, a common TNF inhibitor treatment for JIA, has been considered as a potential risk factor in the development of uveitis in a cohort of patients with RA.[7] Within JIA, there has been a concern that etanercept can increase the likelihood of recurrence of uveitis in patients with a pre-existing history of the disease,[1,8] with one study suggesting that this was more common when patients were receiving etanercept monotherapy compared with etanercept and MTX in combination.[9] A randomized controlled trial exploring the role of etanercept as a treatment for uveitis found no difference in outcome between etanercept and placebo-treated patients,[10] suggesting that among children with uveitis, etanercept is not an effective treatment, unlike other drugs within the TNF inhibitor class, including adalimumab via a randomized controlled trial (SYCAMORE)[11] and infliximab through a case series.[12] Whether or not etanercept is associated with an increased risk of developing new onset uveitis in patients with JIA is less clear. Similarly, although adalimumab and infliximab are effective treatments for many children with uveitis it is not known whether use of these drugs can prevent the onset of uveitis.

The aims of the present study are therefore to describe and compare the occurrence of newly diagnosed uveitis in children with JIA receiving MTX, etanercept, adalimumab and infliximab who do not have a history of uveitis at the start of therapy.