436 Scalp neuropathy in dermatomyositis patients with recalcitrant scalp pruritus

Abstract

Patients with moderate-to-severe atopic dermatitis (AD) have a high unmet need for safe chronic therapies. IL-22 was suggested to have a pathogenic role in AD, but human data are lacking. In a proof-of-concept, randomized placebo-controlled phase 2a trial in 60 patients, an anti-IL-22mAb (fezakinumab/ILV-094) showed clinical benefit in severe AD. Progressive clinical improvements extended beyond the last dose (10wks) until end-of-study (20wks). Skin biopsy analyses were performed at 0, 4, 12wks, by transcriptomic and immunohistochemistry analyses. Changes in the AD transcriptome were estimated by differentially expressed genes/DEGs criteria of 2-fold change and false discovery rate <0.05 in lesional vs. non-lesional skin. Greater changes in the AD gene-fingerprinting were seen with fezakinumab, as compared to placebo (25.3% and 65.5% vs 10.5% and 13.9% at 4 and 12wks, respectively). Since IL-22 blockade only shows significant efficacy in severe AD, we used median IL-22 expression at baseline to stratify for high (n¼30) and low (n¼29) IL-22expression groups. Much stronger mean transcriptomic improvements were seen with fezakinumab in the IL-22-high drug-group (82.8% and 139.4% at 4 and 12wks, respectively), than in the respective IL-22-high placebo (39.6% and 56.3% at 4 and 12wks; p<10 -9 drug vs placebo). Significant downregulations of key inflammatory axes, including Th1/CXCL9, Th2/ CCL18, CCL22, Th17/CCL20, DEFB4A, and Th22/IL-22, S100As-related markers were restricted to the high-IL-22 group (p<0.05). We also defined a set of baseline predictors of response, mostly involving T-cell and dendritic-cell genes. This is the first human report showing profound effects of IL-22 blockade in AD skin, particularly in patients with high-IL-22. These data suggest a central role for IL-22 in AD, and the need for a precision medicine approach for improving therapeutic outcomes.