The Clinical and Molecular Response of Pyoderma Gangrenosum to IL-23 Blockade: Result from a Proof-of-Concept...

Pyoderma gangrenosum is a severe ulcerative disease with a great need for novel therapies. A major barrier to the development of novel therapies is a lack of understanding of disease pathogenesis. We present the results of a proof-of-concept open-label clinical trial of IL-23p19 antagonism with tildrakizumab in pyoderma gangrenosum. Gene expression analysis identified proinflammatory genes associated with IFN responses and dendritic cell activity, including IFI27, XBP1, SAA1 LGALS3, and signal transducer and activator of transcription 3 significantly downregulated in lesional tissue after 12 weeks of therapy. Immunohistochemistry confirmed reduction in IL-17A- and IL-17F-positive cells as well as reduction in TNF-a-, C5a-, and IL-1B-positive cells in week 12 samples compared with those at baseline. Significant reduction in serum inflammation was observed through serum proteomics, with IL-8, IL-6, and CASP-8 levels reduced comparable with those in healthy controls at week 12. Clinical outcomes demonstrated significant reduction in ulcer size, pain, itch, and QOL outcomes in line with the molecular findings. Differential expression of key inflammatory cytokines such as IL-8, CXCL5, PD-L1, SPP1, and matrix metalloproteinase 1 was observed in tissue and serum when stratified by clinical responders and nonresponders. These data provide insights into the clinical relevance of alterations in molecular markers in pyoderma gangrenosum and the potential for the identification of clinically relevant biomarkers of disease activity.