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Meta-Analysis
. 2014 Jun 10;2014(6):CD000957.
doi: 10.1002/14651858.CD000957.pub2.

Methotrexate for treating rheumatoid arthritis

Maria Angeles Lopez-Olivo  1 , Harish R Siddhanamatha, Beverley Shea, Peter Tugwell, George A Wells, Maria E Suarez-Almazor
Affiliations
Meta-Analysis

Methotrexate for treating rheumatoid arthritis

Maria Angeles Lopez-Olivo et al. Cochrane Database Syst Rev. .

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 methods: 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).

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.

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Conflict of interest statement

Dr Suarez‐Almazor is the recipient of a K24 career award from the National Institute for Musculoskeletal and Skin Disorders. She is also the Director of the Houston Centre for Education and Research on Therapeutics, funded by the Agency for Healthcare Research and Quality (AHRQ).

Figures

1
1
Flow diagram of the included studies. *Additional data were unavailable since at the time of the publication this information was not required to be reported.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 Efficacy, Outcome 1 ACR 20.
1.2
1.2. Analysis
Comparison 1 Efficacy, Outcome 2 ACR 50.
1.3
1.3. Analysis
Comparison 1 Efficacy, Outcome 3 ACR 70.
1.4
1.4. Analysis
Comparison 1 Efficacy, Outcome 4 Disease Remission.
1.5
1.5. Analysis
Comparison 1 Efficacy, Outcome 5 Number of tender joints.
1.6
1.6. Analysis
Comparison 1 Efficacy, Outcome 6 >50% improvement in TJC.
1.7
1.7. Analysis
Comparison 1 Efficacy, Outcome 7 Number of swollen joints.
1.8
1.8. Analysis
Comparison 1 Efficacy, Outcome 8 >50% improvement in SJC.
1.9
1.9. Analysis
Comparison 1 Efficacy, Outcome 9 Tender Joint Score/Index.
1.10
1.10. Analysis
Comparison 1 Efficacy, Outcome 10 at least 30% improvement in TJS.
1.11
1.11. Analysis
Comparison 1 Efficacy, Outcome 11 Swollen Joint Score/Index.
1.12
1.12. Analysis
Comparison 1 Efficacy, Outcome 12 at least 30% improvement in SJS.
1.13
1.13. Analysis
Comparison 1 Efficacy, Outcome 13 Physician global assessment.
1.14
1.14. Analysis
Comparison 1 Efficacy, Outcome 14 Percent of patients improving in PhGA.
1.15
1.15. Analysis
Comparison 1 Efficacy, Outcome 15 Walking time.
1.16
1.16. Analysis
Comparison 1 Efficacy, Outcome 16 >50% improvement in walking time.
1.17
1.17. Analysis
Comparison 1 Efficacy, Outcome 17 Grip strength.
1.18
1.18. Analysis
Comparison 1 Efficacy, Outcome 18 ESR.
1.19
1.19. Analysis
Comparison 1 Efficacy, Outcome 19 CRP.
2.1
2.1. Analysis
Comparison 2 Patient‐reported outcomes, Outcome 1 HAQ Disability Index.
2.2
2.2. Analysis
Comparison 2 Patient‐reported outcomes, Outcome 2 Percent of improvement in HAQ‐Di.
2.3
2.3. Analysis
Comparison 2 Patient‐reported outcomes, Outcome 3 MHAQ.
2.4
2.4. Analysis
Comparison 2 Patient‐reported outcomes, Outcome 4 Percent of improvement in MHAQ.
2.5
2.5. Analysis
Comparison 2 Patient‐reported outcomes, Outcome 5 Activities of Daily Living (ADL).
2.6
2.6. Analysis
Comparison 2 Patient‐reported outcomes, Outcome 6 Activities of Daily Living (ADL).
2.7
2.7. Analysis
Comparison 2 Patient‐reported outcomes, Outcome 7 SF‐36 Physical component.
2.8
2.8. Analysis
Comparison 2 Patient‐reported outcomes, Outcome 8 SF‐36 Mental component.
2.9
2.9. Analysis
Comparison 2 Patient‐reported outcomes, Outcome 9 Pain.
2.10
2.10. Analysis
Comparison 2 Patient‐reported outcomes, Outcome 10 Pain.
2.11
2.11. Analysis
Comparison 2 Patient‐reported outcomes, Outcome 11 Patient global assessment.
2.12
2.12. Analysis
Comparison 2 Patient‐reported outcomes, Outcome 12 Improvement in PtGA.
2.13
2.13. Analysis
Comparison 2 Patient‐reported outcomes, Outcome 13 Morning stiffness.
2.14
2.14. Analysis
Comparison 2 Patient‐reported outcomes, Outcome 14 Morning stiffness.
2.15
2.15. Analysis
Comparison 2 Patient‐reported outcomes, Outcome 15 Work Productivity.
3.1
3.1. Analysis
Comparison 3 Radiographic outcomes, Outcome 1 Radiographic Progression.
3.2
3.2. Analysis
Comparison 3 Radiographic outcomes, Outcome 2 Total Sharp Score.
3.3
3.3. Analysis
Comparison 3 Radiographic outcomes, Outcome 3 Erosion Score.
3.4
3.4. Analysis
Comparison 3 Radiographic outcomes, Outcome 4 Joint Space Narrowing.
3.5
3.5. Analysis
Comparison 3 Radiographic outcomes, Outcome 5 New Joint Erosions.
4.1
4.1. Analysis
Comparison 4 Discontinuations, Outcome 1 Total.
4.2
4.2. Analysis
Comparison 4 Discontinuations, Outcome 2 Lack of efficacy.
4.3
4.3. Analysis
Comparison 4 Discontinuations, Outcome 3 Adverse events.
4.4
4.4. Analysis
Comparison 4 Discontinuations, Outcome 4 Lost to follow‐up.
4.5
4.5. Analysis
Comparison 4 Discontinuations, Outcome 5 Non‐compliance.
4.6
4.6. Analysis
Comparison 4 Discontinuations, Outcome 6 Protocol violation.
4.7
4.7. Analysis
Comparison 4 Discontinuations, Outcome 7 Voluntary or unclear reasons.
4.8
4.8. Analysis
Comparison 4 Discontinuations, Outcome 8 Alopecia.
4.9
4.9. Analysis
Comparison 4 Discontinuations, Outcome 9 Gastrointestinal adverse events.
4.10
4.10. Analysis
Comparison 4 Discontinuations, Outcome 10 Hematological adverse events.
4.11
4.11. Analysis
Comparison 4 Discontinuations, Outcome 11 Hypertension.
4.12
4.12. Analysis
Comparison 4 Discontinuations, Outcome 12 Infection.
4.13
4.13. Analysis
Comparison 4 Discontinuations, Outcome 13 Interstitial pneumonitis/Pulmonary infiltrates.
4.14
4.14. Analysis
Comparison 4 Discontinuations, Outcome 14 Liver enzyme abnormalities.
4.15
4.15. Analysis
Comparison 4 Discontinuations, Outcome 15 Mucocutaneous adverse events.
4.16
4.16. Analysis
Comparison 4 Discontinuations, Outcome 16 Myocardial infarction.
4.17
4.17. Analysis
Comparison 4 Discontinuations, Outcome 17 Rash.
5.1
5.1. Analysis
Comparison 5 Adverse events, Outcome 1 Total.
5.2
5.2. Analysis
Comparison 5 Adverse events, Outcome 2 Serious Adverse Events.
5.3
5.3. Analysis
Comparison 5 Adverse events, Outcome 3 Abdominal pain.
5.4
5.4. Analysis
Comparison 5 Adverse events, Outcome 4 Alopecia.
5.5
5.5. Analysis
Comparison 5 Adverse events, Outcome 5 Anorexia.
5.6
5.6. Analysis
Comparison 5 Adverse events, Outcome 6 Allergic reactions.
5.7
5.7. Analysis
Comparison 5 Adverse events, Outcome 7 Backpain.
5.8
5.8. Analysis
Comparison 5 Adverse events, Outcome 8 Chest pain.
5.9
5.9. Analysis
Comparison 5 Adverse events, Outcome 9 CNS (Nightmares, Depression).
5.10
5.10. Analysis
Comparison 5 Adverse events, Outcome 10 Cough.
5.11
5.11. Analysis
Comparison 5 Adverse events, Outcome 11 Death.
5.12
5.12. Analysis
Comparison 5 Adverse events, Outcome 12 Diarrhea.
5.13
5.13. Analysis
Comparison 5 Adverse events, Outcome 13 Dyspepsia.
5.14
5.14. Analysis
Comparison 5 Adverse events, Outcome 14 Gastroenteritis/gastrointestinal distress.
5.15
5.15. Analysis
Comparison 5 Adverse events, Outcome 15 Headache.
5.16
5.16. Analysis
Comparison 5 Adverse events, Outcome 16 Hematological adverse events.
5.17
5.17. Analysis
Comparison 5 Adverse events, Outcome 17 Hypertension.
5.18
5.18. Analysis
Comparison 5 Adverse events, Outcome 18 Infections.
5.19
5.19. Analysis
Comparison 5 Adverse events, Outcome 19 Liver enzymes abnormalities.
5.20
5.20. Analysis
Comparison 5 Adverse events, Outcome 20 Mucosal ulcers.
5.21
5.21. Analysis
Comparison 5 Adverse events, Outcome 21 Nausea and/or Vomiting.
5.22
5.22. Analysis
Comparison 5 Adverse events, Outcome 22 New onset Hypertension.
5.23
5.23. Analysis
Comparison 5 Adverse events, Outcome 23 Proteinuria.
5.24
5.24. Analysis
Comparison 5 Adverse events, Outcome 24 Pruritus.
5.25
5.25. Analysis
Comparison 5 Adverse events, Outcome 25 Psoriasis.
5.26
5.26. Analysis
Comparison 5 Adverse events, Outcome 26 Pulmonary events.
5.27
5.27. Analysis
Comparison 5 Adverse events, Outcome 27 Rash.
5.28
5.28. Analysis
Comparison 5 Adverse events, Outcome 28 Stomatitis/oral ulcers.
5.29
5.29. Analysis
Comparison 5 Adverse events, Outcome 29 Stroke.
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