Key messages
• Compared with placebo (dummy pill), methotrexate (a drug to stop or slow inflammatory arthritis) may result in more children and young people achieving an improvement in symptoms at six months, with little or no effect on pain, well-being, risk of serious unwanted effects or the number of people stopping treatment (withdrawals) due to unwanted effects.
• Compared with no methotrexate, methotrexate may have similar benefits and harms in children and young people with oligoarticular arthritis (a type of arthritis that involves fewer than five joints) at 12 months when given together with intra-articular (given into the joint) steroids, with little to no effect on remission or withdrawals due to unwanted effects.
• Methotrexate may have similar benefits and harms to leflunomide (an alternative anti-inflammatory arthritis medicine) in children and young people at four months, with little to no effect on improvement in symptoms, function, well-being, risk of serious unwanted effects, or withdrawals due to unwanted effects.
What is juvenile idiopathic arthritis?
Juvenile idiopathic arthritis is the most common rheumatic disease in childhood, where the immune system, which normally fights infection, attacks the lining of joints, making them swollen, stiff, and painful.
How is juvenile idiopathic arthritis treated?
Juvenile idiopathic arthritis is treated with a group of medications called disease-modifying antirheumatic drugs (DMARDs), which can help prevent damage to joints and relieve pain and stiffness. Methotrexate is the most commonly used DMARD. Other treatments include nonsteroidal anti-inflammatory drugs and steroids.
What did we want to find out?
We wanted to find out if methotrexate was better than no treatment, placebo (dummy pill), or alternative DMARDs for improving symptoms (tender and swollen joints), pain, function, and well-being. We also wanted to know if methotrexate had any serious unwanted effects, or if people were likely to stop using methotrexate because of unwanted effects.
What did we do?
We searched for studies that investigated methotrexate compared with placebo or alternative DMARDs in children and young people with juvenile idiopathic arthritis.
What did we find?
This is an update of a Cochrane review first published in 2001. We included five trials with a total of 575 participants. Three trials compared methotrexate with placebo, one compared methotrexate plus intra-articular (given into the joint) steroid therapy with intra-articular steroid therapy alone, and one compared methotrexate with an alternative DMARD (leflunomide). The studies took place in Australia, Austria, Canada, Denmark, Finland, France, Germany, India, Italy, the Netherlands, New Zealand, the former Soviet Union, Spain, Switzerland, the UK, and the USA.
Methotrexate compared with placebo
Methotrexate compared with placebo may increase the likelihood of improved symptoms but may have little or no effect on pain or well-being up to six months. The studies measured improvement in symptoms (number of tender or swollen joints and other outcomes such as pain and disability) using a composite index. At six months, 40% of participants using methotrexate and 24% of participants on placebo reported improvement in symptoms. At six months, 49% of participants on methotrexate and 40% of participants on placebo reported treatment success. The studies measured pain on a scale of 0 to 100 (0 means no pain). At six months, reported pain was 12.6 points lower in the methotrexate group and 11.5 points lower in the placebo group.
There may be little or no difference between methotrexate and placebo in the risk of serious unwanted events or the rate of withdrawal from treatment due to unwanted events up to six months. Serious unwanted events included inadvertent overdose in the methotrexate group and severe abdominal pain in the placebo group. Less than 1% of the children and young people receiving methotrexate experienced a serious unwanted event, compared to 1.4% of those receiving placebo. There were no withdrawals due to unwanted events in the placebo group and six withdrawals due to unwanted events in the methotrexate group.
No studies measured function or the number of participants with clinically inactive disease.
Other comparisons
Single studies show that methotrexate may not have any additional benefits when used along with intra-articular glucocorticoid injection, or compared with leflunomide.
What are the limitations of the evidence?
We have little confidence in the evidence, which may underestimate the therapeutic effect of methotrexate due to suboptimal dosing, the low event rates, and the small number of participants in the trials. We are uncertain of the risk of serious unwanted events and unwanted events leading to withdrawal from treatment because of the very small number of events.
We did not compare different methods of delivering methotrexate (e.g. tablets, injection) or different doses of methotrexate.
How up to date is this evidence?
The evidence is current to 1 February 2023.
Oral methotrexate (5 mg/m2/week to 15 mg/m2/week) compared with placebo may increase the number of children and young people achieving treatment response but may have little or no effect on pain or participant global assessment of well-being. Oral methotrexate plus IAGC injections compared to IAGC injections alone may have little or no effect on the likelihood of sustained clinically inactive disease among children and young people with oligoarticular JIA. Similarly, methotrexate compared with leflunomide may have little or no effect on treatment response, function, and participant global assessment of well-being. Serious adverse events due to methotrexate appear to be rare. We will update this review as new evidence becomes available to inform the living guideline.
Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. Methotrexate has broad immunomodulatory properties and is the most commonly used disease-modifying antirheumatic drug (DMARD). This is an update of a 2001 Cochrane review. It supports a living guideline for children and young people with JIA.
To assess the benefits and harms of methotrexate for children and young people with juvenile idiopathic arthritis.
The Australian JIA Living Guideline Working Group created a registry of all randomised controlled trials (RCTs) of JIA by searching CENTRAL, MEDLINE, Embase, and trials registries. The date of the most recent search of online databases was 1 February 2023.
We searched for RCTs that compared methotrexate with placebo, no treatment, or another DMARD (with or without concomitant therapies) in children and young people (aged up to 18 years) with JIA.
We used standard Cochrane methods. The main comparison was methotrexate versus placebo. Our outcomes were treatment response, sustained clinically inactive disease, function, pain, participant global assessment of well-being, serious adverse events, and withdrawals due to adverse events. We used GRADE to assess the certainty of evidence for each outcome.
We identified three new trials in this update, bringing the total number of included RCTs to five (575 participants). Three trials evaluated oral methotrexate versus placebo, one evaluated methotrexate plus intra-articular glucocorticoid (IAGC) therapy versus IAGC therapy alone, and one evaluated methotrexate versus leflunomide. Doses of methotrexate ranged from 5 mg/m2/week to 15 mg/m2/week in four trials, and participants in the methotrexate group of the remaining trial received 0.5 mg/kg/week. Trial size varied from 31 to 226 participants. The average age of participants ranged from four to 10 years. Most participants were females and most had nonsystemic JIA. The study that evaluated methotrexate plus IAGC therapy versus IAGC therapy alone recruited children and young people with the oligoarticular disease subtype of JIA.
Two placebo-controlled trials and the trial of methotrexate versus leflunomide were adequately randomised and blinded, and likely not susceptible to important biases. One placebo-controlled trial may have been susceptible to selection bias due to lack of adequate reporting of randomisation methods. The trial investigating the addition of methotrexate to IAGC therapy was susceptible to performance and detection biases.
Methotrexate versus placebo
Methotrexate compared with placebo may increase the number of children and young people who achieve treatment response up to six months (absolute difference of 163 more per 1000 people; risk ratio (RR) 1.67, 95% confidence interval (CI) 1.21 to 2.31; I2 = 0%; 3 trials, 328 participants; low-certainty evidence). However, methotrexate compared with placebo may have little or no effect on pain as measured on an increasing scale of 0 to 100 (mean difference (MD) −1.10 points, 95% CI −9.09 to 6.88; 1 trial, 114 participants), improvement in participant global assessment of well-being (absolute difference of 92 more per 1000 people; RR 1.23, 95% CI 0.88 to 1.72; 1 trial, 176 participants), occurrence of serious adverse events (absolute difference of 5 fewer per 1000 people; RR 0.63, 95% CI 0.04 to 8.97; 3 trials, 328 participants), and withdrawals due to adverse events (RR 3.46, 95% CI 0.60 to 19.79; 3 trials, 328 participants) up to six months. We could not estimate the absolute difference for withdrawals due to adverse events because there were no withdrawals in the placebo group. All outcomes were reported within six months of randomisation. We downgraded the certainty of the evidence to low for all outcomes due to indirectness (suboptimal dosing of methotrexate and diverse outcome measures) and imprecision (few participants and low event rates). No trials reported function or the number of participants with sustained clinically inactive disease. Serious adverse events included liver derangement, abdominal pain, and inadvertent overdose.
Methotrexate plus intra-articular corticosteroid therapy versus intra-articular corticosteroid therapy alone
Methotrexate plus IAGC therapy compared with IAGC therapy alone may have little or no effect on the probability of sustained clinically inactive disease or the rate of withdrawals due to adverse events up to 12 months in children and young people with the oligoarticular subtype of JIA (low-certainty evidence). We could not calculate the absolute difference in withdrawals due to adverse events because there were no withdrawals in the control group. We are uncertain if there is any difference between the interventions in the risk of severe adverse events, because none were reported. The study did not report treatment response, function, pain, or participant global assessment of well-being.
Methotrexate versus an alternative disease-modifying antirheumatic drug
Methotrexate compared with leflunomide may have little or no effect on the probability of treatment response or on function, participant global assessment of well-being, risk of serious adverse events, and rate of withdrawals due to adverse events up to four months. We downgraded the certainty of the evidence for all outcomes to low due to imprecision. The study did not report pain or sustained clinically inactive disease.