Tumor necrosis factor (TNF) inhibitors for juvenile idiopathic arthritis.
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BACKGROUND: Juvenile idiopathic arthritis (JIA) is a rheumatic disorder that causes chronic joint inflammation beginning before the age of 16 years. Pharmacological treatment necessary to prevent joint destruction and functional impairment includes non-steroidal anti-inflammatory drugs (NSAIDs), intra-articular corticosteroids, conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs) like methotrexate (MTX), and biologic DMARDs (bDMARDs) such as tumor necrosis factor inhibitors (TNFi), abatacept, anakinra, and tocilizumab. More recently, targeted synthetic DMARDs (tsDMARDs) like tofacitinib, baricitinib, and upadacitinib have been approved for the treatment of JIA. OBJECTIVES: To assess the benefits and harms of TNFi in children with JIA. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (via Ovid), Embase (via Ovid), and ClinicalTrials.gov and the WHO ICTRP from inception to 28 February 2024, with no language restrictions. SELECTION CRITERIA: We included randomized controlled trials (RCTs), quasi-RCTs, and data from the randomized part of withdrawal trials conducted in individuals with JIA where TNFi were compared to placebo, MTX, NSAIDs, other bDMARDs, tsDMARDs, or other TNFi. Our major outcomes were treatment response, pain, function, participant global assessment of well-being (disease activity), remission, withdrawals due to adverse events, and serious adverse events. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. At least two review authors performed study selection, data extraction, and risk of bias and GRADE assessment. The primary comparison was TNFi versus placebo. The primary time point was up to 16 weeks and up to the end of the trials for efficacy and safety outcomes, respectively. MAIN RESULTS: We included nine studies with 678 participants (80% females) with JIA. The mean age of participants ranged from 8 to 15 years, and the mean duration of symptoms ranged from 0.8 years to 6.7 years. Seven studies compared TNFi to placebo (570 participants), and two studies compared TNFi combined with MTX to MTX alone (108 participants). We identified no studies investigating the other predefined comparisons. Only two studies had a low risk of bias in all domains, while five studies had a high risk of bias in at least one domain, predominantly other bias. Two studies were at unclear risk of selection bias, and two studies were at unclear risk of detection bias. TNFi versus placebo Benefits at up to 16 weeks Low-certainty evidence (downgraded for risk of bias and imprecision) suggests that treatment with TNFi may increase the likelihood of achieving a treatment response, defined as pedACR70 (34% compared to 14% with placebo) (risk ratio [RR] 2.47, 95% confidence interval [CI] 1.48 to 4.14; 4 studies, 245 participants). The evidence is very uncertain (downgraded for indirectness and imprecision) for the effect of TNFi on pain, with mean pain scores (visual analogue scale [VAS] 0 to 100, 0 no pain, minimal clinically important difference [MCID] = 15 mm) lower with TNFi (11 mm) compared to placebo (33 mm) (mean difference [MD] 22 mm, 95% CI 50 mm lower to 5.7 mm higher; 2 studies, 72 participants). Similarly, the effect of TNFi on function (Childhood Health Assessment Questionnaire [CHAQ], 0 to 3, 0 normal function) and quality of life (global assessment of well-being, VAS 0 to 100 mm, 0 no disease activity) is very uncertain. Mean function was 0.84 with TNFi and 1 with placebo (MD 0.16 lower, 95% CI 0.39 lower to 0.06 higher; 3 studies, 194 participants; very low-certainty evidence, downgraded for risk of bias and imprecision). The mean participant global assessment of well-being was 23 mm with TNFi and 34 mm with placebo (MD 11 mm lower, 95% CI 23 mm lower to 1 mm higher; 3 studies, 194 participants; very low-certainty evidence, downgraded for indirectness, imprecision, and risk of bias). No study reported data on remission. Harms at any time We are uncertain about the effect of TNFi on withdrawals due to adverse events (3%) compared to placebo (1%) (RR 3.41, 95% CI 0.73 to 15.9; 6 studies, 448 participants). We are also uncertain about the effect of TNFi on serious adverse events (7%) compared to placebo (6%) (RR 1.09, 95% CI 0.53 to 2.22; 6 studies, 448 participants). The certainty of evidence was very low, downgraded for risk of bias and imprecision. TNFi plus MTX versus MTX alone Benefits at 17 to 26 weeks We are uncertain about the effect of TNFi plus MTX on treatment response. Seventy per cent of participants receiving MTX and 90% receiving TNFi plus MTX achieved treatment response (RR 1.29, 95% CI 0.93 to 1.77; 1 study, 40 participants). We are also uncertain about the effect of TNFi plus MTX on remission. Five per cent of participants on MTX monotherapy and 40% on combination therapy were in remission (RR 8.00, 95% CI 1.10 to 58.19; 1 study, 40 participants). No study reported pain, function, or participant global assessment of well-being. Harms at any time We are uncertain about the effect of TNFi plus MTX on withdrawals due to adverse events and serious adverse events. Very low-certainty evidence from two studies shows that 2/53 participants (4%) receiving MTX alone and 3/55 (5%) receiving TNFi plus MTX withdrew due to adverse events (RR 1.31, 95% CI 0.18 to 9.82; 108 participants), and 5/53 (9%) receiving MTX alone and 0/55 receiving TNFi plus MTX reported serious adverse events (RR 0.16, 95% CI 0.02 to 1.32). Due to risk of bias and imprecision, the certainty of evidence was very low across all major outcomes for this comparison. AUTHORS' CONCLUSIONS: In JIA, TNFi may result in a higher proportion of individuals achieving clinical improvement compared to placebo, but we are uncertain about the effect of TNFi on pain, function, and quality of life. We are also uncertain about the effect of TNFi combined with MTX versus MTX alone on clinical improvement and remission. Evidence for the safety of TNFi compared to placebo or MTX is very uncertain. There are no RCTs comparing TNFi to other treatments. More high-quality studies are warranted to assess the benefits and harms of TNFi in JIA.