Upadacitinib effector pathways unravelled

Upadacitinib therapy suppresses pathogenic inflammatory pathways and positively affects tissue-resident cells associated with gut barrier function and mucosal repair in participants with ulcerative colitis (UC), according to an analysis of the phase 2b U-ACHIEVE data. In addition, participants who achieved the stringent histo-endoscopic mucosal response (HEMR) endpoint displayed a unique transcriptional modulation of the gut microenvironment.

Dr Bram Verstockt (KU Leuven, Belgium) and colleagues aimed to investigate the effect of upadacitinib on the inflamed intestinal microenvironment in patients with UC and link molecular modulations of pathogenic pathways to upadacitinib efficacy outcomes [1]. For this purpose, data was analysed from the placebo, 15 mg, 30 mg, and 45 mg upadacitinib arms of the phase 2b U-ACHIEVE study (NCT02819635). Differential expression analysis, pathway enrichment, responder analysis, and gut cell deconvolution were performed.

Responders to upadacitinib showed significantly more differentially expressed genes (DEGs) than non-responders. The amount of DEGs increased for participants who responded to more stringent endpoints, such as endoscopic improvement or histologic improvement. Notably, responders displayed an increase in both downregulated and upregulated DEGs. Furthermore, upadacitinib was able to modulate many pathways that are key in UC pathogenesis, including chemokine signaling, B-cell receptor signaling, and Th17 cell differentiation. In addition, more general pathways were modulated, such as inflammatory bowel disease or chemotactic pathways (see Figure).

Figure: KEGG pathway enrichment of downregulated genes from baseline to week 8 [1].



 

 

 

 

 

 

 

 

Next, cell deconvolution demonstrated significant downregulation of inflammatory cells after 8 weeks of upadacitinib treatment in responders, including CD4-effector T cells, T-regulatory cells, and plasma cells. Notably, the data showed that these effects were counterbalanced by an increase in enterocytes, secretory goblet cells, and myofibroblasts. This suggests that upadacitinib therapy is not only resulting in downregulation of inflammatory pathways but also actively contributes to gut barrier function and wound healing mechanisms in responders. Additional data on the downregulation of CD4 T cells indicates that Th17, Th2, Th9, and Th1 subsets of CD4 T cells may be involved. However, this result should be interpreted with caution and further studies are needed to confirm this.

Finally, the more stringent the endpoint, the more genes were differentially modulated in responders. This was particularly the case for various histologic outcomes. Especially the HEMR, the most stringent endpoint, showed a large modulation of differentially expressed genes in responders.

“There seems to be a robust and unique transcriptional modulation of the gut microenvironment that is associated with this novel endpoint,” according to Dr Verstockt.

1. Verstockt B, et al. Upadacitinib modulates inflammatory pathways in gut tissue in patients with Ulcerative Colitis: Transcriptomic profiling from the Phase 2b study, U-ACHIEVE. OP30, ECCO 2022, 16–19 February.

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Posted on 12 April 20228 April 2024