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The Clinical Response of Upadacitinib and Risankizumab is Associated with Reduced Inflammatory Bowel Disease Anti-TNFα Inadequate Response Mechanisms

By Jing Wang, Michael Macoritto, Heath Guay, Justin W Davis, Marc C Levesque, Xiaohong Cao

Posted 18 May 2022
bioRxiv DOI: 10.1101/2022.05.16.492167

Background and Aims: JAK1 inhibitor upadacitinib and IL23 inhibitor risankizumab are efficacious in inflammatory bowel disease (IBD) patients who are anti-TNF inadequate responders (TNF-IR). We aimed to understand the mechanisms mediating the response of upadacitinib and risankizumab. Methods: Eight tissue transcriptomic datasets from IBD patients treated with anti-TNF therapies along with single-cell RNAseq data from ulcerative colitis were integrated to identify TNF-IR mechanisms. RNAseq colon tissue data from clinical studies of TNF-IR Crohn disease patients treated with upadacitinib or risankizumab were used to identify TNF-IR mechanisms that were favorably modified by upadacitinib and risankizumab. Results: We found seven TNF-IR up-regulated modules (M1-M7) related to innate/adaptive immune responses, interferon signaling and tissue remodeling, and five TNF-IR down-regulated modules (M8-M12) primarily related to metabolism. TNF-IR up-regulated cell types were inflammatory fibroblasts, post-capillary venules, inflammatory monocytes, macrophages, dendritic cells, and cycling B cells while subtypes of immature enterocytes, WNT5B+ cells and myofibroblasts were TNF-IR down-regulated cell types. Upadacitinib was associated with a significant decrease in the expression of most TNF-IR up-regulated modules in JAK1 responders (JAK1-R); in contrast, there was no change in these modules among TNF-IR patients treated with a placebo or among JAK1 inadequate responders (JAK1-IR). In addition, four of the six TNF-IR up-regulated cell types were significantly decreased after upadacitinib treatment in JAK1-R but not among subjects treated with a placebo or among JAK1-IR patients. We observed similar findings from colon biopsy samples from TNF-IR patients treated with risankizumab. Conclusions: Collectively, these data suggest that upadacitinib and risankizumab affect TNF-IR up-regulated mechanisms, which may account for their clinical response among TNF-IR IBD patients.

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