Key messages
• When compared to placebo, tumor necrosis factor inhibitors (TNFi) may make young people with juvenile idiopathic arthritis (JIA) feel better overall, but the effects of the medicines on joint function, pain, disease control, and harm are uncertain.
• We are uncertain about the benefits and harms of TNFi when compared to another medicine called methotrexate.
• More high-quality studies are needed to understand the benefits and harms of TNFi in JIA.
What is juvenile idiopathic arthritis (JIA)?
JIA is a disease that causes young people's joints to hurt, swell, and not function properly. It results from a lifelong inflammation of unknown cause and can affect other body parts, such as the eyes. It affects individuals under 16 years old, who find that the condition makes it difficult for them to live comfortably.
How is JIA treated?
We treat JIA with:
• physical therapy: special exercises to help joints work better;
• medicines: these include steroidal and non-steroidal anti-inflammatory drugs (NSAIDs), medicines that suppress the immune system like methotrexate and TNFi, and other drugs that target the causes of inflammation. We usually start with milder drugs and move to stronger ones as needed.
Why do we use TNFi for JIA?
We use TNFi when conventional medicines for arthritis do not work well or cause too many problems. TNFi act by targeting the immune system to help control the disease.
What did we want to find out?
We wanted to see if TNFi are effective and safe for individuals with JIA compared to placebo (dummy or sham treatment that does not contain any medicine but looks identical to the medicine being tested), NSAIDs, other conventional arthritis drugs, or other TNFi.
What did we do?
We searched for studies comparing TNFi to placebo, other arthritis medicines, or other TNFi. We compared and summarized the results of the studies and rated our confidence in the evidence based on factors such as study methods and sizes.
What did we find?
We found 9 studies involving a total of 678 individuals with JIA. Their ages ranged from 8 to 15 years, with 80% being female. The average duration of symptoms varied from 0.8 to 6.7 years. The studies were conducted in different countries and lasted between 12 and 54 weeks. Seven studies compared TNFi to a placebo, and two studies compared TNFi to methotrexate. None of the studies compared TNFi to NSAIDs or other medicines besides methotrexate.
Main results
After 16 weeks, 14% of those receiving placebo and 34% of those receiving TNFi showed an improvement in their JIA.
After 16 weeks, pain (0-to-100 scale, with lower scores indicating less pain) was reported as 33 points by those receiving placebo and 11 points by those receiving TNFi.
Function, measured on a scale of 0 to 3 (lower scores indicating better function), was rated as 1 point by those receiving placebo and 0.84 points by those receiving TNFi.
After 16 weeks, participant global assessment of disease activity (0-to-100 scale, with lower scores indicating less disease activity) was reported as 34 points by those receiving placebo and 23 points by those receiving TNFi.
Withdrawals due to unwanted effects occurred in 1% of those receiving placebo and 3% of those receiving TNFi.
Serious unwanted effects were reported in 6% of those receiving placebo and 7% of those receiving TNFi.
Unfortunately, we did not find any information regarding the effect of TNFi on disease remission at up to 16 weeks.
What are the limitations of our findings?
We have little confidence in the evidence due to the limited number of studies available and because it is possible that people in the studies knew which treatment they were getting, which could have influenced the results.
How up-to-date is this information?
The evidence is current to 28 February 2024.
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.
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.
To assess the benefits and harms of TNFi in children with JIA.
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.
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.
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.
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.