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. 2023 May 2;29(5):771-782.
doi: 10.1093/ibd/izac246.

The Clinical Response of Upadacitinib and Risankizumab Is Associated With Reduced Inflammatory Bowel Disease Anti-TNF-α Inadequate Response Mechanisms

Jing Wang  1 , Michael Macoritto  1 , Heath Guay  2 , Justin W Davis  3 , Marc C Levesque  4 , Xiaohong Cao  1
Affiliations

The Clinical Response of Upadacitinib and Risankizumab Is Associated With Reduced Inflammatory Bowel Disease Anti-TNF-α Inadequate Response Mechanisms

Jing Wang et al. Inflamm Bowel Dis. .

Abstract

Background: Janus kinase (JAK) 1 inhibitor upadacitinib and IL-23 inhibitor risankizumab are efficacious in inflammatory bowel disease (IBD) patients who are antitumor necrosis factor (anti-TNF)-α inadequate responders (TNF-IRs). We aimed to understand the mechanisms mediating the response of upadacitinib and risankizumab.

Methods: Eight tissue transcriptomic data sets from IBD patients treated with anti-TNF-α therapies along with single-cell RNAseq data from ulcerative colitis were integrated to identify TNF-IR mechanisms. The RNAseq colon tissue data from clinical studies of TNF-IR Crohn's 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 7 TNF-IR upregulated modules related to innate/adaptive immune responses, interferon signaling, and tissue remodeling and 6 TNF-IR upregulated cell types related to inflammatory fibroblasts, postcapillary venules, inflammatory monocytes, macrophages, dendritic cells, and cycling B cells. Upadacitinib was associated with a significant decrease in the expression of most TNF-IR upregulated 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, 4 of the 6 TNF-IR upregulated 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 upregulated mechanisms, which may account for their clinical response among TNF-IR IBD patients.

Keywords: anti-TNF-α inadequate responder; mechanism; risankizumab; upadacitinib.

Plain language summary

We identified molecular and cellular mechanisms associated with and potentially mediating the response of upadacitinib and risankizumab for IBD patients that inadequately responded to anti-TNF-α treatment.

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