Key messages
Adalimumab appears to be beneficial for the treatment of JIA-associated uveitis while the evidence is very limited to etanercept. We did not find enough evidence to say whether these medications prevent vision loss; however, the studies may not have been long enough to detect changes in vision. Side-effects from TNF inhibitors are usually mild, although rare serious side effects can occur.
What is juvenile idiopathic arthritis-associated uveitis?
Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition in childhood and causes inflammation of the joints (arthritis). Some people with JIA also develop inflammation of the eye, known as uveitis. If not adequately detected and treated, uveitis can lead to permanent eye damage, visual impairment, or blindness.
How is JIA-associated uveitis treated?
There are several types of medications for treating JIA-associated uveitis. A group of medications called tumor necrosis factor (TNF) inhibitors are among the treatments used for JIA and JIA-associated uveitis. These treatments target a protein called 'tumor necrosis factor' that causes inflammation. These medications suppress the immune system to reduce inflammation and prevent eye damage.
What did we want to find out?
The main aim of this review was to determine whether TNF-inhibitors can improve the symptoms of JIA-associated uveitis and to summarize the possible harms of these treatments.
What did we do?
We searched the medical literature for studies comparing TNF inhibitor to placebo for JIA-associated uveitis. We summarized the evidence for our pre-defined outcomes and graded our confidence in the evidence. Given that included studies did not measure or report our pre-defined outcomes, we additionally summarized the evidence as report by the individual studies
What did we find?
We identified three relevant studies that included 134 participants. Two studies investigated a TNF inhibitor called adalimumab and one study investigated a TNF inhibitor called etanercept. Each study measured the effect of the medications differently from one another, so it was difficult to compare the studies and draw conclusions. Our initial analysis showed no clear difference between TNF inhibitors and placebo with regard to the risk of treatment success or treatment failure. On reviewing outcomes assessed in the individual studies, TNF inhibitors improved the chance of treatment success and reduced the risk of treatment failure when compared with placebo. One study showed that more patients taking adalimumab than placebo were able to reduce the number of eye drops used, suggesting that the adalimumab may have reduced inflammation.
Medication-related side effects including injection site reactions and infections were generally mild and were more common in the TNF inhibitor group. Serious adverse events were uncommon but were also seen more often in the TNF inhibitor groups. The overall side effects were similar to those commonly seen in the medications in other diseases.
What does it mean?
Our review suggests that adalimumab, one TNF inhibitor, increases the chance of improving ocular symptoms of uveitis and decrease the chance of worsening uveitis when compared with placebo.
How up-to-date is the evidence?
The evidence is current to 3 February 2022.
Adalimumab appears to increase the likelihood of treatment success and decrease the likelihood of treatment failure when compared with placebo. The evidence was less conclusive about a positive treatment effect with etanercept. Adverse events from JIA-U trials are in keeping with the known side effect profile of TNF inhibitors. Standard validated JIA-U outcome measures are required to homogenize assessment and to allow for comparison and analysis of multiple datasets.
Uveitis is the most common extra-articular manifestation of juvenile idiopathic arthritis (JIA) and a potentially sight-threatening condition characterized by intraocular inflammation. Current treatment for JIA-associated uveitis (JIA-U) is largely based on physician experience, observational evidence and consensus guidelines, resulting in considerable variations in practice.
To evaluate the effectiveness and safety of tumor necrosis factor (TNF) inhibitors used for treatment of JIA-U.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature Database (LILACS); ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We last searched the electronic databases on 3 February 2022.
We included randomized controlled trials (RCTs) comparing TNF inhibitors with placebo in participants with a diagnosis of JIA and uveitis who were aged 2 to 18 years old.
We used standard Cochrane methodology and graded the certainty of the body of evidence for seven outcomes using the GRADE classification.
We included three RCTs with 134 participants.
One study conducted in the USA randomized participants to etanercept or placebo (N = 12). Two studies, one conducted in the UK (N = 90) and one in France (N = 32), randomized participants to adalimumab or placebo. All studies were at low risk of bias. Initial pooled estimates suggested that TNF-inhibitors may result in little to no difference on treatment success defined as 0 to trace cells on Standardization of Uveitis Nomenclature (SUN)-grading; or two-step decrease in activity based on SUN grading (estimated risk ratio (RR) 0.66; 95% confidence interval (CI) 0.21 to 2.10; 2 studies; 43 participants; low-certainty evidence) or treatment failure defined as a two-step increase in activity based on SUN grading (RR 0.31; 95% CI 0.01 to 7.15; 1 study; 31 participants; low-certainty evidence). Further analysis using the individual trial definitions of treatment response and failure suggested a positive treatment effect of TNF inhibitors; a RR of treatment success of 2.60 (95% CI 1.30 to 5.20; 3 studies; 124 participants; low-certainty evidence), and RR of treatment failure of 0.23 (95% CI 0.11 to 0.50; 3 studies; 133 participants). Almost all the evidence was on adalimumab and the evidence on etanercept was very limited. For secondary outcomes, one study suggests that adalimumab may have little to no effect on risk of recurrence after induction of remission at three months (RR 2.50, 95% CI 0.31 to 20.45; 90 participants; very low-certainty evidence) and visual acuity, but the evidence is very uncertain; mean difference in longitudinal logMAR score change over six months was -0.01 (95% CI –0.06 to 0.03) and -0.02 (95% CI –0.07 to 0.03) using the best and worst logMAR measurement, respectively (low-certainty evidence). Low-certainty evidence from one study suggested that adalimumab treatment results in reduction of topical steroid doses at six months (hazard ratio 3.58; 95% CI 1.24 to 10.32; 74 participants who took one or more topical steroid per day at baseline). Adverse events, including injection site reactions and infections, were more common in the TNF inhibitor group. Serious adverse events were uncommon.