Methotrexate for treating rheumatoid arthritis

We looked at studies until November 2013 on the effect of receiving methotrexate alone compared to placebo (no treatment) over 12 to 52 weeks in 732 people with rheumatoid arthritis.

Key findings

In the short term treatment of people with rheumatoid arthritis, methotrexate:

- improves pain, function and other symptoms;

- probably reduces joint damage as seen on the x-ray.

Precise information about side effects and complications was not always available. Common side effects may include nausea, vomiting, diarrhoea, loss of appetite, stomach pain, and sores on lips, mouth or throat. Rare complications may include birth defects, kidney, lung and liver problems.

What is rheumatoid arthritis and what is methotrexate?

When you have rheumatoid arthritis, your immune system, which normally fights infection, attacks the lining of your joints making your joints swollen, stiff and painful.
Treatments aim to decrease symptoms and improve your ability to move.

Methotrexate is one of a group of medications called disease-modifying antirheumatic drugs (DMARDs) and it is the most common treatment for rheumatoid arthritis. Methotrexate helps prevent further permanent damage that can happen if rheumatoid arthritis is not treated.

What happens to people with rheumatoid arthritis who take methotrexate alone?

ACR 50 (number of tender or swollen joints and other outcomes such as pain and disability)
- 15 more people out of 100 experienced major improvement in the symptoms of their rheumatoid arthritis after 12 months with methotrexate when compared to placebo (15% absolute improvement).
- 23 people out of 100 who took methotrexate alone experienced major improvement.
- 8 people out of 100 who took a placebo experienced major improvement.

Remission or absence of active disease

In people who took either placebo or methotrexate, none had absence of active disease.

Disability (lower scores mean lower disability)

- People who took methotrexate rated their disability to be 0.27 points lower on a scale of 0 to 3 after 3 to 12 months with methotrexate when compared to placebo (9% absolute improvement).
- People who took methotrexate rated their disability to be between 0.39 and 1.04.
- People who took placebo rated their disability to be between 0.53 and 1.34.

Quality of life - physical component (ability to perform physical activities at least 20% better)

- 12 more people out of 100 perceived their ability to perform physical activities at least 20% better after 12 months with methotrexate alone compared to placebo (12% absolute improvement).
- 39 people out of 100 who took methotrexate alone perceived their ability to perform physical activities at least 20% better.
- 27 people out of 100 who took a placebo perceived their ability to perform physical activities at least 20% better.

Quality of life - mental component

- 5 more people out of 100 perceived their mental well-being better after 12 months with methotrexate alone compared to placebo (5% absolute improvement).
- 26 people out of 100 who took methotrexate alone perceived their mental well-being better.
- 21 people out of 100 who took a placebo perceived their mental well-being better.

X-rays of the joints
- 8 more people out of 100 had less x-ray damage to joints measured by increase in erosion scores of more than 3 units on a scale ranging from 0 to 448 in people who took methotrexate compared to placebo after 12 months (8% absolute reduction).
- 4 people out of 100 who took methotrexate alone had increased damage to joints measured by x-ray.
-12 people out of 100 who took a placebo had increase damage to joints measured by x-ray.

Discontinuations due to adverse events (side effects and complications)
- 9 more people out of 100 discontinued methotrexate due to adverse events after 3 to 12 months compared to placebo (9% absolute withdrawals).
- 16 people out of 100 who took methotrexate alone discontinued methotrexate due to adverse events.
- 8 people out of 100 who took a placebo discontinued placebo due to adverse events.

Serious adverse events
- 1 more person out of 100 experienced serious side effects after 3 to 12 months with methotrexate alone compared to placebo (1% absolute harm).
- 3 people out of 100 who took methotrexate alone experienced serious side effects.
- 2 people out of 100 who took a placebo experienced serious side effects.

Authors' conclusions: 

Based on mainly moderate to high quality evidence, methotrexate (weekly doses ranging between 5 mg and 25 mg) showed a substantial clinical and statistically significant benefit compared to placebo in the short term treatment (12 to 52 weeks) of people with RA, although its use was associated with a 16% discontinuation rate due to adverse events.

Read the full abstract...
Background: 

Methotrexate is a folic acid antagonist widely used for the treatment of neoplastic disorders. Methotrexate inhibits the synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and proteins by binding to dihydrofolate reductase. Currently, methotrexate is among the most commonly used drugs for the treatment of rheumatoid arthritis (RA). This is an update of the previous Cochrane systematic review published in 1997.

Objectives: 

To evaluate short term benefits and harms of methotrexate for treating RA compared to placebo.

Search strategy: 

The Cochrane Musculoskeletal Group Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE were searched from 1966 to 1997 and then updated to November 2013. The search was complemented with a bibliography search of the reference lists of trials retrieved from the electronic search.

Selection criteria: 

Randomized controlled trials and controlled clinical trials comparing methotrexate (MTX) monotherapy against placebo alone in people with RA. Any trial duration and MTX doses were included.

Data collection and analysis: 

Two review authors independently determined which studies were eligible for inclusion, extracted data and assessed risk of bias. Outcomes were pooled using mean differences (MDs) for continuous variables or standardized mean differences (SMDs) when different scales were used to measure the same outcome. Pooled risk ratio (RR) was used for dichotomous variables. Fixed-effect models were used throughout, although random-effects models were used for outcomes showing heterogeneity.

Main results: 

Five trials with 300 patients were included in the original version of the review. An additional two trials with 432 patients were added to the 2013 update of the review for a total of 732 participants. The trials were generally of unclear to low risk of bias with a follow-up duration ranging from 12 to 52 weeks. All trials included patients who have failed prior treatment (for example, gold therapy, D-penicillamine, azathioprine or anti-malarials); mean disease duration that ranged between 1 and 14 years with six trials reporting more than 4 years; and weekly doses that ranged between 5 mg and 25 mg.

Benefits

Statistically significant and clinically important differences were observed for most efficacy outcomes. MTX monotherapy showed a clinically important and statistically significant improvement in the American College of Rheumatology (ACR) 50 response rate when compared with placebo at 52 weeks (RR 3.0, 95% confidence interval (CI) 1.5 to 6.0; number needed to treat (NNT) 7, 95% CI 4 to 22). Fifteen more patients out of 100 had a major improvement in the ACR 50 outcome compared to placebo (absolute treatment benefit (ATB) 15%, 95% CI 8% to 23%).

Statistically significant improvement in physical function (scale of 0 to 3) was also observed in patients receiving MTX alone compared with placebo at 12 to 52 weeks (MD -0.27, 95% CI -0.39 to -0.16; odds ratio (OR) 2.8, 95% CI 0.23 to 32.2; NNT 4, 95% CI 3 to 7). Nine more patients out of 100 improved in physical function compared to placebo (ATB -9%, 95% CI -13% to -5.3%). Similarly, the proportion of patients who improved at least 20% on the Short Form-36 (SF-36) physical component was higher in the MTX-treated group compared with placebo at 52 weeks (RR 1.5, 95% CI 1.0 to 2.1; NNT 9, 95% CI 4 to 539). Twelve more patients out of 100 showed an improvement of at least 20% in the physical component of the quality of life measure compared to placebo (ATB 12%, 95% CI 1% to 24%). No clinically important or statistically significant differences were observed in the SF-36 mental component.

Although no statistically significant differences were observed in radiographic scores (that is, Total Sharp score, erosion score, joint space narrowing), radiographic progression rates (measured by an increase in erosion scores of more than 3 units on a scale ranging from 0 to 448) were statistically significantly lower for patients in the MTX group compared with placebo-treated patients (RR 0.31, 95% CI 0.11 to 0.86; NNT 13, 95% CI 10 to 60). Eight more patients out of 100 showed less damage to joints measured by an increase in erosion scores compared to placebo (ATB -8%, 95% CI -16% to -1%). In the one study measuring remission, no participants in either group met the remission criteria. These are defined by at least five of (≥ 2 months): morning stiffness of < 15 minutes, no fatigue, no joint pain by history, no joint tenderness, no joint swelling, and Westergren erythrocyte sedimentation rate (ESR) of < 20 mm/hr in men and < 30 mm/hr in women.

Harms

Patients in the MTX monotherapy group were twice as likely to discontinue from the study due to adverse events compared to patients in the placebo group, at 12 to 52 weeks (16% versus 8%; RR 2.1, 95% CI 1.3 to 3.3; NNT 13, 95% CI 6 to 44). Compared to placebo, nine more people out of 100 who took MTX withdrew from the studies because of side effects (ATB 9%, 95% CI 3% to 14%). Total adverse event rates at 12 weeks were higher in the MTX monotherapy group compared to the placebo group (45% versus 15%; RR 3.0, 95% CI 1.4 to 6.4; NNT 4, 95% CI 2 to 17). Thirty more people out of 100 who took MTX compared to those who took placebo experienced any type of side effect (common or rare) (ATB 30, 95% CI 13% to 47%). No statistically significant differences were observed in the total number of serious adverse events between the MTX group and the placebo group at 27 to 52 weeks. Three people out of 100 who took MTX alone experienced rare but serious side effects compared to 2 people out of 100 who took a placebo (3% versus 2%, respectively).

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