Methotrexate for treating rheumatoid arthritis

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Methotrexate for treating rheumatoid arthritis

PMID: 24916606
Methotrexate for treating rheumatoid arthritis
Monitoring Editor: Maria Angeles Lopez‐Olivo , Harish R Siddhanamatha , Beverley Shea , Peter Tugwell , George A Wells , Maria E Suarez‐Almazor ,
and Cochrane Musculoskeletal Group
The University of Texas, M.D. Anderson Cancer Center, Department of General Internal Medicine, 1515 Holcombe Blvd, Unit 1465, HoustonTexasUSA, 77030
University of Ottawa, Department of Epidemiology and Community Medicine, 501 Smyth Road, OttawaOntarioCanada, K1H 8L6
Faculty of Medicine, University of Ottawa, Department of Medicine, OttawaOntarioCanada, K1H 8M5
Maria E Suarez‐Almazor, Email: gro.nosrednadm@rozamlasm .
The University of Texas, M.D. Anderson Cancer Center, Department of General Internal Medicine, 1515 Holcombe Blvd, Unit 1465, HoustonTexasUSA, 77030
University of Ottawa, Department of Epidemiology and Community Medicine, 501 Smyth Road, OttawaOntarioCanada, K1H 8L6
Faculty of Medicine, University of Ottawa, Department of Medicine, OttawaOntarioCanada, K1H 8M5
Maria E Suarez‐Almazor, Email: gro.nosrednadm@rozamlasm .
Corresponding author.
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
This article is an update of " Methotrexate for rheumatoid arthritis. " on page CD000957.
This article has been cited by other articles in PMC.
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.
Plain language summary
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.
Summary of findings
Background
Description of the condition
Rheumatoid arthritis (RA) is a chronic, systemic inflammatory condition of unknown cause. Clinical presentation can include synovial proliferation, symmetric erosive arthritis, and systemic involvement.
Description of the intervention
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.
How the intervention might work
The potential benefits of methotrexate for the treatment of RA were originally suggested by Gubner 1951 in a case series study of six patients with RA. Subsequent open trials supported the efficacy of the drug ( Groff 1983 ; Steinsson 1982 ; Willkens 1980 ). The first controlled trials of methotrexate against placebo in people with RA were reported in the 1980s. Currently, methotrexate is among the most commonly used drugs for the treatment of RA.
Why it is important to do this review
This systematic review synthesizes and updates the evidence of a previous published Cochrane review reporting the benefits and harms of methotrexate monotherapy compared to placebo.
Objectives
To evaluate the short term benefits and harms of methotrexate for the treatment of RA compared to placebo.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials (RCTs) and clinical controlled trials (CCTs) comparing methotrexate with placebo for a minimum duration of 12 weeks. Twelve weeks is thought to be the minimum treatment duration required to adequately assess the efficacy of methotrexate. We included studies reported as full‐text, published as abstract only, and unpublished data. There was no language restriction.
Types of participants
People with a diagnosis of RA that was severe and of long duration, who had a high prevalence of positive rheumatoid factor (RF), and had previously failed other second line disease‐modifying antirheumatic drug (DMARD) therapy.
Types of interventions
We included trials comparing methotrexate (oral or parenteral) at a dose level of at least 5 mg per week with placebo. Only trials with a treatment duration of at least 12 weeks in a double‐blind phase were considered for inclusion.
Types of outcome measures
Major outcomes
1. All the outcome measures in OMERACT 1993 were included for potential analysis. OMERACT measures for efficacy include:
a) number of tender joints per patient; b) number of swollen joints per patient; c) pain (Visual Analogue Scale or VAS); d) physician global assessment; e) patient global assessment; f) Functional status (measured by a validated scale such as the Health Assessment Questionnaire (HAQ)); g) acute phase reactants, including erythrocyte sedimentation rate (ESR) and C‐reactive protein (CRP).
2. American College of Rheumatology (ACR) core set: ACR 20, 50, or 70 responses ( Felson 1995 ).
3. Remission measured by disease activity ( van der Heijde 2005 ) using the disease activity score (DAS) < 1.6 or DAS28 < 2.6, or as specified by the authors.
4. Radiological damage (joint damage shown on x‐ray).
5. Discontinuations. These were analysed as discontinuations because of adverse events, lack of efficacy, and due to system‐specific adverse reactions (e.g. gastrointestinal, renal, etc).
6. Adverse events. Number of patients who experienced serious, total, or individual adverse events.
Minor outcomes
Health‐related quality of life measured by validated scales including the Medical Outcomes Study Short‐Form 36 (SF‐36) and activities of daily living (ADL).
Search methods for identification of studies
Electronic searches
The Cochrane Musculoskeletal Group register, Cochrane Controlled Trials Register (CCTR), MEDLINE (1966 to July 1997) and EMBASE (1988 to July 1997) were searched using the strategy developed by Dickersin 1994 . A further search was performed from 1997 to November 2013 in MEDLINE ( Appendix 1 ), CENTRAL in The Cochrane Library ( Appendix 2 ), EMBASE ( Appendix 3 ), Web of Science ( Appendix 4 ), and ClinicalTrials.gov ( Appendix 5 ). The search was not limited by language, year of publication or type of publication. The MEDLINE search strategy that was used is located in Appendix 1 . This strategy was modified for the other databases.
Searching other resources
Reference lists of all the trials selected through the electronic searches were manually searched to identify additional trials. Key experts in the area were contacted for further published and unpublished articles. The ClinicalTrials.gov (www.ClinicalTrials.gov) website and the World Health Organization (WHO) International Clinical Trials Registry Platform trials portal (www.who.int/ictrp/en/) were also searched to identify any ongoing trials, in November 2013.
For safety assessments, we searched the websites of the regulatory agencies (US Food and Drug Administration‐MedWatch (http://www.fda.gov/Safety/MedWatch/default.htm), European Medicines Evaluation Agency (http://www.ema.europa.eu), Australian Adverse Drug Reactions Bulletin (http://www.tga.gov.au/safety/ews‐monitoring.htm), and UK Medicines and Healthcare products Regulatory Agency (MHRA) pharmacovigilance and drug safety updates (http://www.mhra.gov.uk/Safetyinformation/index.htm) using the keyword ‘methotrexate’ on 19 March 2014.
Data collection and analysis
Selection of studies
Two review authors (MLO, HRS) independently screened the titles and abstracts of all the potential studies identified as a result of the search for inclusion and coded them as 'retrieve' (eligible or potentially eligible or unclear) or 'do not retrieve'. Next, two review authors (MLO, HRS) independently screened the full‐texts and identified studies for inclusion, and recorded reasons for exclusion of the ineligible studies. Disagreement were resolved through discussion or, when required, by a third review author (MSA). We identified and excluded duplicates, and collated multiple reports of the same study.
Data extraction and management
We used a data collection form for study characteristics and outcome data, which was piloted using one study in the review. Two review authors (MLO, HRS) extracted the study characteristics and outcome measures of efficacy and toxicity from the included studies.
Assessment of risk of bias in included studies
Two review authors (MLO, HRS) independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions ( Higgins 2011 ). Disagreements were resolved by consensus. We assessed the risk of bias according to several domains including: a) random sequence generation, b) allocation concealment, c) blinding of participants and personnel, d) blinding of outcome assessment, e) incomplete outcome data, f) selective outcome reporting, g) other bias (that is, baseline imbalance). We graded each potential source of bias as high, low or unclear and provide a quote from the study report together with a justification for our judgement in the 'Risk of bias' table. We summarised the risk of bias judgements across different studies for each of the domains listed. Figures were generated to provide summary assessments of the risk of bias.
Measures of treatment effect
Dichotomous data were analysed as risk ratios (RR) and 95% confidence intervals (CI) were also estimated. Continuous data were pooled as mean differences (MD) with corresponding 95% CI or standardized mean differences (SMD) in the case of joint scores, pain, global and functional assessments. This was necessary because of the variation in the outcome measures included in each study (for example, different number of swollen joints counted). Trial results were entered into RevMan using the same direction in order to enable the pooling of results, with the lower values indicating better responses. Negative values in SMD indicated a benefit of the active drug over placebo. The SMD was back‐translated to a typical scale (for example, 0 to 10 for pain) by multiplying the SMD by a typical among‐person standard deviation (for example, the standard deviation of the control group at baseline from the most representative trial) ( Higgins 2011 ).
Unit of analysis issues
We planned to include cross‐over randomised trials, but only if data from the first period were reported. When multiple methotrexate doses were evaluated in a single trial, we included only the most relevant (close to clinical practice) dosage.
Dealing with missing data
Authors from two trials were contacted to obtain missing numerical outcome data, but no response was obtained. For continuous outcomes, we calculated the effect estimate based on the number of patients analysed at the final visit. If the number of patients analysed was not presented, the number reported at baseline was used. When only median and interquartile ranges were reported, the median was used as the mean and one half of the difference between the first and third quartile range was used as the standard deviation. When the end‐of‐trial standard deviation was not reported we used the baseline standard deviation for the pooled analysis. In our experience, the baseline standard deviation of RA outcome measures is often very close to the end‐of‐trial standard deviation, perhaps slightly larger. This resultant bias would therefore result in decreased weighting of the studies and is preferable to completely excluding them. If no standard deviation was provided at baseline, missing standard deviations were computed from other statistics such as standard errors or imputed from other studies in the meta‐analysis. When numerical data were only reported graphically, the value was extracted from the graph.
Assessment of heterogeneity
The heterogeneity of the trials for each pooled analysis was estimated using the Chi2 test and I2 statistic. For the Chi2 test, a P value ≤ 0.10 indicated evidence of statistical heterogeneity. An I2 value of 0% to 40% might 'not be important'; 30% to 60% may represent 'moderate' heterogeneity; 50% to 90% may represent 'substantial' heterogeneity; and 75% to 100% represents 'considerable' heterogeneity ( Higgins 2011 ).
Assessment of reporting biases
A funnel plot was not planned a priori. In addition, this could not be created for the updated version of the review due to the limited number of studies that were included.
Data synthesis
Fixed‐effect models were used throughout. Random‐effects models were used for outcomes showing statistically significant heterogeneity.
Summary of findings table
A 'Summary of findings' table was created using the following outcomes: 1) ACR 50 response, 2) disease remission, 3) functional status, 4) health‐related quality of life, 5) radiographic progression, 6) discontinuations due to adverse events, 7) serious adverse events.
Two people (MLO, HRS) independently assessed the quality of the evidence. We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of a body of evidence as it related to the studies which contributed data to the meta‐analyses for the prespecified outcomes. In the comments column of the summary of findings table we provided the absolute per cent difference, the relative per cent change from baseline, and the number needed‐to‐treat (NNT).
For dichotomous outcomes, the absolute risk difference was calculated using the risk difference statistic in RevMan and the result expressed as a percentage. For continuous outcomes, the absolute benefit was calculated as the improvement in the intervention group minus the improvement in the control group, in the original units.
The relative per cent change for dichotomous data was calculated as the risk ratio ‐ 1 and expressed as a percentage. For continuous outcomes, the relative difference in the change from baseline was calculated as the absolute benefit divided by the baseline mean of the control group.
The number needed to treat (NNT) was provided only when the outcome showed a statistically significant difference. For dichotomous outcomes, the NNT was calculated from the control group event rate and the relative risk using the Visual Rx NNT calculator ( Cates 2008 ). The NNT for the functional status was calculated using the Wells calculator (available at the CMSG Editorial office).
Subgroup analysis and investigation of heterogeneity
The results on efficacy were analysed for all the study endpoints (12, 18, 27, and 52 weeks). We evaluated subgroup interactions and compared the magnitude of the effects between the subgroups by assessing the overlap of the confidence intervals of the summary measures estimated. Non‐overlap of the confidence intervals indicated statistical significance.
Sensitivity analysis
For the cross‐over trials where data from the first period was not provided for both arms, we explored the impact of including the studies in the overall assessment of results by a sensitivity analysis. For dichotomous outcomes (for example, number of withdrawals due to adverse events), we also compared the magnitude of the effects when using the intention to treat population versus completers as the denominator.
Results


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