Filgotinib treatment modulates frequency and gene expression of circulating immune cell subsets in ulcerative colitis

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BACKGROUND AND AIMS: Ulcerative colitis (UC) is a chronic inflammatory condition of the colon with heterogeneous patient responses to treatment. Janus kinase (JAK) inhibitors such as filgotinib reduce inflammation through the blockade of cytokine signaling. We sought to characterize the mechanism of action of filgotinib on peripheral immune cells to improve our understanding of dysregulated cell populations in UC and their response to treatment. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from UC patients at baseline or after 10 weeks of filgotinib treatment in the SELECTION trial. PBMCs were analyzed alongside healthy controls by flow cytometry and sorted into 12 cell populations for transcriptome sequencing to correlate with treatment response. RESULTS: Following 10 weeks of filgotinib treatment, changes in the frequency of peripheral B cell populations were observed, with more significant changes seen in treatment-responsive patients in memory B cells and plasmablasts. Transcriptomic changes associated with filgotinib treatment were modest but overall reverted UC-induced gene expression changes toward control samples in B cells and phagocytic mononuclear cells. These changes were greater in treatment-responsive than in non-responsive patients. CONCLUSIONS: Filgotinib response was associated with normalization of the cellular frequency and gene expression levels of B cells and phagocytic mononuclear cells in UC patients, resulting in immune profiles resembling those of healthy controls.

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