Targeting Hedgehog Signaling in Steroid-Refractory Cutaneous Sclerodermatous Chronic GVDH: Clinicopathologic Insights

Summary: Background: Chronic GVHD (cGVHD) affects 40% to 70% of patients with allogeneic hematopoietic cell transplantation, with cutaneous cGVHD in up to 80%. Sclerodermatous cGVHD (scGVHD), a severe subtype involving skin and deeper tissues, is often refractory to standard therapies. Overexpression of Sonic Hedgehog (Shh) has been observed in cGVHD skin samples. This study evaluates histological and clinicopathologic correlations pre- and post-treatment in 12 patients with steroid-refractory scGVHD treated with a targeted Hedgehog pathway inhibitor. Methods: Skin biopsies pre- and post-treatment from 12 patients, clinically classified as responders (n=6) or non-responders (n=6), were reviewed. Demographic and clinical data were extracted from medical records. Histological rejection grades were assessed with paired t-tests, and a mixed-effects model analyzed treatment response and time interaction. Analyses were performed in IBM SPSS Statistics 25. Results: Clinical responders showed significant reductions in histological rejection grades post-treatment (p < 0.001), with decreased interface inflammation, dermal fibrosis, and epidermal atrophy. Non-responders showed minimal improvement. Conclusions: Hedgehog pathway inhibition in steroid-refractory scGVHD significantly improves histological features in responders. This study advances our understanding of scGVHD pathophysiology and introduces a histology scoring system that correlates with clinical response. This system may be valuable for evaluating treatment efficacy in future clinical trials.