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Review
. 2009 Jul;68(7):1105-12.
doi: 10.1136/ard.2008.099861. Epub 2008 Dec 3.

Efficacy and toxicity of methotrexate (MTX) monotherapy versus MTX combination therapy with non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systematic review and meta-analysis

W Katchamart  1 , J Trudeau, V Phumethum, C Bombardier
Affiliations
Review

Efficacy and toxicity of methotrexate (MTX) monotherapy versus MTX combination therapy with non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systematic review and meta-analysis

W Katchamart et al. Ann Rheum Dis. 2009 Jul.

Abstract

Objective: To evaluate the efficacy and toxicity of methotrexate (MTX) monotherapy compared with MTX combination with non-biological disease-modifying antirheumatic drugs (DMARDs) in adults with rheumatoid arthritis.

Method: A systematic review of randomised trials comparing MTX alone and in combination with other non-biological DMARDs was carried out. Trials were identified in Medline, EMBASE, the Cochrane Library and ACR/EULAR meeting abstracts. Primary outcomes were withdrawals for adverse events or lack of efficacy.

Results: A total of 19 trials (2025 patients) from 6938 citations were grouped by the type of patients randomised. Trials in DMARD naive patients showed no significant advantage of the MTX combination versus monotherapy; withdrawals for lack of efficacy or toxicity were similar in both groups (relative risk (RR) = 1.16; 95% CI 0.70 to 1.93). Trials in MTX or non-MTX DMARD inadequate responder patients also showed no difference in withdrawal rates between the MTX combo versus mono groups (RR = 0.86; 95% CI 0.49 to 1.51 and RR = 0.75; 95% CI 0.41 to 1.35), but in one study the specific combination of MTX with sulfasalazine and hydroxychloroquine showed a better efficacy/toxicity ratio than MTX alone with RR = 0.3 (95% CI 0.14 to 0.65). Adding leflunomide to MTX non-responders improved efficacy but increased the risk of gastrointestinal side effects and liver toxicity. Withdrawals for toxicity were most significant with ciclosporin and azathioprine combinations.

Conclusion: In DMARD naive patients the balance of efficacy/toxicity favours MTX monotherapy. In DMARD inadequate responders the evidence is inconclusive. Trials are needed that compare currently used MTX doses and combination therapies.

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Conflict of interest statement

Competing interests: CB holds a Canada Research Chair in knowledge transfer for musculoskeletal care.

Figures

Figure 1
Figure 1
Results of the literature search and disposition of the potentially relevant studies. *Number is not equal to the sum of the number from each database owing to duplication among databases. ACR, American College of rheumatology; CCRT, Cochrane Central Register of Controlled Trials; DMARD, disease-modifying antirheumatic drug; EULAR, European League Against Rheumatism; MTX, methotrexate; RA, rheumatoid arthritis; RCT, randomised controlled trial.
Figure 2
Figure 2
American College of Rheumatology (ACR) response: MTX combination vs MTX monotherapy in DMARD naïve group. CSA, ciclosporin; DMARD, disease-modifying antirheumatic drug; DOXY, doxycycline; MTX, methotrexate.
Figure 3
Figure 3
American College of Rheumatology (ACR) response: MTX combination vs MTX monotherapy in MTX inadequate response group. CSA, ciclosporin; IM gold, intramuscular gold; LEF, leflunomide; LEV, levofloxacin; MTX, methotrexate.
Figure 4
Figure 4
American College of Rheumatology (ACR) response: MTX combination vs MTX monotherapy in non-MTX inadequate response group. BUC, bucillamine; MTX, methotrexate; SSZ, sulfasalazine.
Figure 5
Figure 5
Withdrawal due to adverse reaction stratified by combination of disease-modifying antirheumatic drugs (DMARDs). AZA, azathioprine; BUC, bucillamine; CSA, ciclosporin; CQ, chloroquine; HCQ, hydroxychloroquine; IM gold, intramuscular gold; LEF, leflunomide; MTX, methotrexate; SSZ, sulfasalazine.
Figure 6
Figure 6
Withdrawal due to either lack of efficacy or toxicity: MTX combination vs MTX monotherapy in disease-modifying antirheumatic drug (DMARD) naïve, MTX inadequate response and non-MTX inadequate response groups. BUC, bucillamine, CQ, chloroquine; CSA, ciclosporin; DOXY, doxycycline; HCQ, hydroxychloroquine; IM gold, intramuscular gold; LEF, leflunomide; MTX, methotrexate; SSZ, sulfasalazine.
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