IL-12/IL23 blockade reveals patterns of asynchronous inflammation in pyoderma gangrenosum

• Published in: bioRxiv
• Main Authors: Yadav, Rashi, Vague, Morgan, Rettig, Malia, Loo, Christopher P, Brown, Kasidy, Samiea, Abrar, Moreau, Joshua M, Ortega-Loayza, Alex G
• Format: Journal Article Paper
• Language: English
• Published: United States Cold Spring Harbor Laboratory 29.04.2024
• Edition: 1.1
• Subjects: Immunology; ustekinumab; spatial transcriptomics; tertiary lymphoid structures; B cells; T cells; IL-12; IL-23; Pyoderma gangrenosum
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2024.04.26.591387

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis causing chronic and recalcitrant painful ulcerations. Pathogenic mechanisms are yet poorly understood limiting therapeutic options, however, IL-12/IL-23 inhibition via ustekinumab has previously been associated with positive outcomes. We aimed to elucidate the dysregulated immune landscape of PG and lesional skin changes associated with IL-12/IL-23 blockade. We applied spatial transcriptomics and comparative computation analysis on lesional biopsies from two patients obtained before and after IL-12/IL-23 blockade with ustekinumab. Our data indicate lesional PG skin exhibits complex patterns of inflammation, including a not previously described major infiltration of B cells and establishment of tertiary lymphoid structures. In both patients, IL-12/IL-23 blockade led to marked clinical improvement but was associated with amelioration of contrasting inflammatory pathways. Notably, plasma cell markers and tertiary structures were recalcitrant to the treatment regime suggesting that B cells might play a role in the refractory nature of PG.