Theefficacy andtoxicity of Methotrexate (MTX) monotherapy vs. MTX combination therapy with non-biologic disease-modifying anti-rheumatic drugsin rheumatoid arthritis: A systematic review and metaanalysis

Appendix 2

Efficacy

DMARD naïve, Parallel design

The pooled DAS from these 2 studies also showed a non significant difference between combination of MTX+SSZ compared with MTX alone[1, 2][WMD -0.32 (95%CI 0.77 to 0.12)].

Individual continuous efficacy measure, were available in two of the six studies comparing MTX alone to MTX plus SSZ. There were no significant differences in responses for the number of tender joint count[1], number of swollen joint count[1, 3], pain[3], patient global assessment[1], ESR[1, 3] and CRP[3][WMD -1.7 (95% CI -6.11 to 2.71), WMD -4.18 (95% CI-9.81 to 0.19), WMD -1.36 (95% CI-5.11 to 2.4), WMD 0.7 (95%CI -10.24 to 11.64), WMD -1.62 (95% CI-6.98 to -3.74) and WMD 0.66 (95% CI-2.78 to 4.10) respectively]. However, the HAQ score response was slightly higher in the combination group of those 2 studies[1, 3][WMD 0.1 (95% CI 0.09 to 0.11)](Figure E on website). The radiographic outcome from one study of MTX+CSA[4] showed a small but significant reduced progression in the combination therapy [WMD of Modified Sharp’s score -3.15 (95%CI -5.85 to -0.45)](Figure F on website).

MTX inadequate response, Step-up design

Individual continuous efficacy measure, were also available in four of these five trials. There were significant differences in responses for the number of tender joint count (Figure G on website)[5-7], number of swollen joint count (Figure H on website[5-7], pain (Figure I on website[5-8], patient global assessment (Figure J on website[5-8], CRP (Figure K on website)[6] and HAQ (Figure L on website)[5-7]. The MTX combination responses were significantly greater than monotherapy [WMD -6.57 (95% CI -8.84 to -4.30), WMD -3.46 (95% CI-4.84 to -2.08), WMD -9.72 (95% CI-14.70 to -4.75), WMD -11.57 (95% CI-19.31 to -3.83), WMD -12.10 (95% CI-19.84 to -4.36) and WMD -0.28 (95% CI -0.36 to -0.21) respectively]. However, significant difference was not found for ESR[5-7][WMD -0.53 (95% CI-11.47 to 10.41)]. The radiographic outcome from one study[8] showed significantly less progression in the combination of MTX+ Zolendronic acid [WMD of Modified Sharp’s score -1.40 (95%CI -2.81 to 0.01)].

Non-MTX DMARD inadequate response, Step-up design

Individual continuous efficacy measure, were available in five of the eight trials. There were significant differences in responses for the number of tender joint count (Figure M on website)[9], number of swollen joint count (Figure N on website), [9-11], patient global assessment (Figure O on website), [9] and DAS (Figure P on website), [11]. The MTX combination responses were significantly greater than monotherapy [WMD -4 (95% CI -6.82 to -1.18), WMD -5 (95% CI -8.84 to -1.16), WMD -10 (95% CI-19.16 to -0.40) and WMD -1.3 (95% CI-1.74 to -0.86), respectively]. However, significant difference were not found for pain[10, 11], ESR[9-12], CRP[12] and HAQ[10][WMD -5.99 (95% CI-24.99 to13.02), WMD -4.29 (95% CI -10.72 to 2.13), WMD -1.2 (95% CI -2.95 to 0.55) and WMD -0.17 (95% CI-0.48 to 0.14) respectively].

Toxicity

The toxicity analysis was stratified and pooled by DMARD combinations.

Total adverse reactions(Figure Q on website) were reported in eight of the nineteen trials (797 patients: 400 in the combination vs 397 in the monotherapy groups). Overall, the number of side effects were not increased in the MTX+SSZ[1-3, 11] and MTX+LEF[6] combinations versus MTX monotherapy. There was a trend for increased side effects in the MTX+CSA[4] combination . Both the MTX+AZA[13] and MTX+ im gold[7] combinations increased the risk of total side effects with RR 1.67 (95%CI 1.21 to 2.3) and RR 2.61 (95%CI 1.22 to 5.55) respectively.

Gastrointestinal side effects(Figure R on website) Gastrointestinal related side effects (excluding liver toxicity reported below) were available for seven trials (692 patients: 351 patients in combination vs 341 in monotherapy groups). Both MTX+SSZ[1-3, 11] and MTX+LEF[6] combination increased the risk of GI side effects significantly (RR 1.75, 95%CI 1.14 to 2.67 and RR 1.67, 95%CI 1.17 to 2.4 respectively). GI side effects were not increased in MTX+CSA[4] and MTX+ intramuscular gold[7] combinations.

Abnormal liver function (Figure S on website) was analyzed in seven trials (673 patients: 336 in combination vs 337 in monotherapy341 in monotherapy groups) .MTX+ LEF[6] significantly increased the risk of abnormal LFT with RR 4.3 (95%CI 2.58 to 7.15) respectively. MTX+SSZ[1-3, 11], while MTX+CSA[4] and MTX+BUC[14] showed a non-significant slight increased risk..

Mucositis(Figure T on website) was analyzed in four trials (229 patients:123 patients in combination vs 106 in monotherapy groups).MTX+ intramuscular gold[7] increased the risk of mucositis (RR 9.33, 95%CI 0.55 to 158.98) but it was not significant; there was no increased risk in MTX+SSZ[1-3, 11].

Hematological side effects(Figure U on website) were reported in six trials (415 patients: 215 in combination vs 200 in monotherapy groups). No difference was demonstrated for the combinations of MTX+SSZ[1-3, 11], MTX+ im gold[7] and MTX+ BUC[14] compared with MTX monotherapy.

Infection(Figure V on website) was analyzed in four trials (454 patients: 231 in combination vs 223 in monotherapy).The risk of infection slightly increased in MTX+SSZ[1, 3] and MTX+ im gold[7] but it was not significant. MTX+ LEF[6] did not increase risk of infection.

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