Objective Early diffuse scleroderma (systemic sclerosis; SSc) has no proven treatment. This study was undertaken to examine the efficacy of methotrexate (MTX) in improving the skin and other disease parameters in early diffuse SSc. Methods Seventy‐one patients with diffuse SSc of <3 years' duration were enrolled in a multicenter, randomized, placebo‐controlled, double‐blind trial. Thirty‐five patients were treated with MTX and 36 with placebo. Treatment was administered for 12 months. The primary outcome measures were skin score (as determined with 2 different indices) and physician global assessment. Results At baseline, there were no statistically significant differences in skin scores, carbon monoxide diffusing capacity (DLCO), physician global assessment, or other secondary outcome measurements between the 2 treatment groups. 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. Dropout rates were similar in the 2 groups. Conclusion Although results of this trial demonstrated a trend in favor of MTX versus placebo in the treatment of early diffuse SSc, the between‐group differences were small and the power to rule out false‐negative results was only 50%. Our findings do not provide evidence that MTX is significantly effective in the treatment of early diffuse SSc.

IMPORTANCE Robin sequence (RS) is a congenital condition characterized by micrognathia, glossoptosis, and upper airway obstruction. Currently, no consensus exists regarding the diagnosis and evaluation of children with RS. An international, multidisciplinary consensus group was formed to begin to overcome this limitation. OBJECTIVE To report a consensus-derived set of best practices for the diagnosis and evaluation of infants with RS as a starting point for defining standards and management. EVIDENCE REVIEW Based on a literature review and expert opinion, a clinical consensus report was generated. FINDINGS Because RS can occur as an isolated condition or as part of a syndrome or multiple-anomaly disorder, the diagnostic process for each newborn may differ. Micrognathia is hypothesized as the initiating event, but the diagnosis of micrognathia is subjective. Glossoptosis and upper airway compromise complete the primary characteristics of RS. It can be difficult to judge the severity of tongue base airway obstruction, and the possibility of multilevel obstruction exists. The initial assessment of the clinical features and severity of respiratory distress is important and has practical implications. Signs of upper airway obstruction can be intermittent and are more likely to be present when the infant is asleep. Therefore, sleep studies are recommended. Feeding problems are common and may be exacerbated by the presence of a cleft palate. The clinical features and their severity can vary widely and ultimately dictate the required investigations and treatments. CONCLUSIONS AND RELEVANCE Agreed-on recommendations for the initial evaluation of RS and clinical descriptors are provided in this consensus report. Researchers and clinicians will ideally use uniform definitions and comparable assessments. Prospective studies and the standard application of validated assessments are needed to build an evidence base guiding standards of care for infants and children with RS.

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