One study (n=29) 1 compared methotrexate (MTX) with placebo in the treatment of systemic sclerosis (SSc) in a 24 week randomized double-blind trial, followed by an observational trial of 24 weeks. 29 SSc patients (mean duration of skin involvement 3.2 years) were allocated to receive weekly intramuscular injections of either 15 mg MTX (n=17) or placebo (n=12). Patients who responded favourably after 24 weeks continued with the same regimen for a further 24 weeks; those who showed a poor response on placebo were allocated to further treatment with 15 mg MTX weekly, and those who responded poorly to treatment with 15 mg MTX had their doses increased to 25 mg. A favourable response was defined as an improvement of total skin score (TSS) by ≥ 30%, of single breath diffusion capacity (DLCO) by ≥ 15%, or of the score on a visual analogue scale of general well-being (VAS) by ≥ 30%, provided that such improvements were not accompanied by persistent digital ulcerations or worsening of DLCO ≥ 15%. After 24 weeks, a significantly larger number of patients receiving MTX had responded favourably compared to patients receiving placebo (53% vs. 10%, P = 0.03). Comparison of separate variables between the two treatment groups by intention-to-treat analysis at week 24 showed improvement in the MTX group of TSS (P = 0.06) and creatinine clearance (P = 0.07). At week 48, 13 patients received MTX from the start of the study and nine during 24 weeks; of these 68% responded favourably and showed significant improvement of TSS (P = 0.04), VAS (P = 0.02), grip strength of the right hand (P = 0.02) and erythrocyte sedimentation rate (P = 0.01) compared with the start of the study.
Another multicenter, randomized, placebo-controlled, double-blind trial 2 included 71 subjects with diffuse SSc of <3 years' duration. MTX (10-15 mg/week given orally) was administered for 12 months. At study completion, results slightly favored the MTX group (mean +/- SEM modified Rodnan skin score 21.4+/-2.8 in the MTX group versus 26.3+/-2.1 in the placebo group, P < 0.17; UCLA skin score 8.8+/-1.2 in the MTX group versus 11.0+/-0.9 in the placebo group, P < 0.15; DLco in the MTX group 75.7+/-4.6 versus 61.8+/-3.4 in the placebo group, P < 0.2). In addition, physician global assessment results favored MTX (P < 0.035), whereas patient global assessment did not differ significantly between groups. When between-group differences for changes in scores from baseline to 12 months were examined using intent-to-treat methodology, MTX appeared to have a favorable effect on skin scores (modified Rodnan score -4.3 in the MTX group versus 1.8 in the placebo group, P < 0.009; UCLA score -1.2 in the MTX group versus 1.2 in the placebo group, P < 0.02), but differences in the degree of change in the DLCO and physician global assessment were not significant. For the UCLA skin score, these differences in results were not statistically significant after adjustment for baseline differences in sex distribution and steroid use.
EULAR 3 recommends that methotrexate may be considered for treatment of skin manifestations of early diffuse SSc.
Comment: The quality of evidence is downgraded by imprecise results (limited study size for each comparison).
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