Methotrexate and Cyclosporin Improve Skin Biomarkers in Paediatric Atopic Dermatitis: Results from the TREAT TrialTo the Editor,Methotrexate (MTX) and cyclosporin (CyA) are the main conventional systemic treatments for severe atopic dermatitis (AD) globally.1,2 The complex interaction of cutaneous immune biomarkers and their modulation during therapy with these drugs is poorly understood.3 In the Treatment of severe Atopic Eczema in children Trial (TREAT) CyA led to faster disease control, while MTX showed sustained disease control post-therapy.4 Here we explore skin immune biomarkers in TREAT participants randomised to either CyA (4mg/kg/day) or MTX (0.4mg per week) for 36 weeks with 24 weeks follow-up after therapy cessation.4 43 participants were included (22 CyA; 21MTX). Tapestrips were taken from the volar forearm at baseline, 12, 36 and 60 weeks. Concentrations of NMF and immune biomarkers were measured. Please see supplementary materials for sampling, laboratory and statistical methods.Baseline demographics were well balanced across study groups, including disease severity, measured by Eczema Area and Severity Index (EASI; Table S1). Changes in EASI scores at the biomarker sampling time points reflect the disease severity changes in the full TREAT trial population (Fig. S1).MTX and CyA drove significant changes in stratum corneum cytokine levels. While there were no statistically significant biomarker differences between the treatment groups, it is noteworthy that the number of biomarkers showing significant change from baseline was higher with MTX than for CyA (Fig. 1, Table S2). Innate cytokines, CXCL8 and IL-18 were altered with both treatments. CXCL8 decreased from baseline at 12 weeks with MTX and CyA, at 36 weeks with MTX only and at 60 weeks with both drugs. IL-18 decreased at 12 weeks with CyA, at 36 weeks with both drugs and at 60 weeks with MTX only. The innate cytokine IL-1α increased at all timepoints compared to baseline only with MTX. Similarly, the skin barrier biomarker NMF increased at weeks 12 and 36 only with MTX. Th2 cytokines decreased with both treatments: CCL17 at 12 and 36 weeks with MTX only and at 60 weeks with both treatments, while CCL27 decreased at 12 weeks with CyA only, at week 36 with both drugs and at 60 weeks with MTX only. IL-17 decreased with both drugs at week 36 and the Th1 biomarker CXCL10 decreased at week 60 with CyA only. All biomarkers except NMF and IL-1α positively correlated with EASI score (Fig. 2). CXCL8/TARC showed the strongest correlation (r=0.50; P<0.0001).Systemic treatment with both MTX and CyA led to clinical improvement with differential cytokine signatures, indicating that MTX and CyA not only suppress inflammation, but also normalize immune responses mediated by cytokines involved in innate (IL-1α, IL-18, CXCL8), Th1 (CXCL10), Th17 (IL-17A) and Th2 (CCL17 and CCL27) immunity. Significant changes from baseline were found for the skin barrier biomarker NMF, but only with MTX.Normalization of NMF levels can also be attributed to a decrease in Th2 cytokines, which inversely regulate filaggrin gene expression. CCL17 and CCL27, Th2 mediators in AD, normalized to a larger extent after MTX compared to CyA, suggesting MTX may modulate Th-2 suppression pathways and normalize skin barrier function. The strong correlation of CXCL8 and CCL27 with EASI score is consistent with previous stratum corneum biomarker studies.5-6In conclusion, MTX and CyA improve clinical outcomes in AD and modulate the cutaneous immune response. MTX has a more pronounced effect on certain immunological and skin barrier biomarkers compared to CyA, indicating potential differences in their mechanisms of action, and suggesting that MTX may offer additional benefits in the treatment of AD, even after treatment cessation.
