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


Uveitis is accepted to be one of the most common complications of JIA, with a variety of recognized risk factors such as younger age and oligoarticular subtype.[3] There is concern that etanercept may flare disease in those with pre-existing uveitis.[1,8] As a consequence, etanercept is rarely the first choice of biologic in patients with JIA with a history of uveitis. However, the relationship between etanercept and the new development of uveitis in patients with JIA remains unclear.

From this analysis, which has used data from children and young people enrolled in national cohort studies of treatments for JIA, no association was found between the use of etanercept and the occurrence of new uveitis when compared with those receiving MTX for the first time, although the crude incident rates were lower in patients receiving etanercept. Concurrent MTX use with etanercept did not appear to have a further protective effect in this cohort. Given the low occurrence of events in the adalimumab/infliximab cohort, it is difficult to conclude whether these drugs had any protective effect over the occurrence of uveitis and the data should not be used to preferentially treat children with no history of uveitis with one treatment over another.

The lower rates of uveitis among patients starting etanercept do not support a causative link between etanercept and the development of uveitis. However, it should be noted that the patients in the MTX and etanercept cohorts differed significantly with respect to their baseline risk of uveitis. Patients starting MTX did so early in disease course and were also more likely to have oligoarthritis. Subsequently, they also developed their uveitis at a younger age (median 4 vs 7 years). Younger age (<7 years) is an accepted risk factor in the development of uveitis[5] and may explain in part the difference in crude rates observed between etanercept- and MTX-treated patients. Thus, by the time patients with JIA start etanercept, they may be inherently at a lower overall risk of developing uveitis, a so-called 'healthy user' effect, which may be more prominent in the 'older' etanercept cohort who are further along in their disease course, consistent with recent findings that uveitis is most common in the first year of disease.[6] It is also possible that a further selection bias occurred with regard to choice of first biologic in more recent years. As knowledge about a possible association between etanercept and uveitis became more widespread, patients who were perceived by their treating paediatric rheumatologist as having a higher risk of developing uveitis, such as those who were younger, ANA positive or had an oligoarticular subtype, might have been steered away from etanercept treatment towards an alternative biologic. Unfortunately information on ANA was not captured in this study at the time of recruitment of patients included in this analysis, but no significant different in age between patients starting adalimumab/infliximab or etanercept was observed.

The main strengths of the study are related to the size of the cohorts, with close to 2300 patients included in this study, the detailed follow-up procedures used and the prospective study design minimizing potential recall bias. Furthermore, extensive uveitis information is captured from centres using specially designed proformas, which ask for the type, localization and course of uveitis, as well as establishing whether it is a new or recurrent event. This minimizes the risk of events being misclassified as new if in fact the patient has had uveitis previously.

As a non-randomized observational treatment study, the study is subject to the limitations common to all such research. Despite the overall large sample size, the size of the cohort of children starting adalimumab or infliximab who did not already have uveitis was relatively low. There were also missing data across all covariates, although there was not a complete lack of information for any patient and therefore, multiple imputation was used to account for these missing covariate data.

In conclusion, this study found that a new diagnosis of uveitis is less common among patients with JIA starting etanercept compared with MTX, although this did not reach statistical significance. The suggested protective effect of etanercept is likely explained by the influence of age and disease duration, whereby patients in the MTX cohort are, on average, younger and so more 'at risk' of developing uveitis compared with etanercept patients. As a consequence, and in the absence of a sufficient comparison group, our understanding of what additional risk etanercept adds when looking at the risk of developing uveitis remains unclear.