Download The efficacy and toxicity of Methotrexate (MTX) monotherapy vs

The efficacy and toxicity of Methotrexate (MTX) monotherapy vs. MTX combination
therapy with non-biologic disease-modifying anti-rheumatic drugs in 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% CI2.78 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 [58], 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[13, 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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