Three adult cases of STAT1-gain-of-function with chronic mucocutaneous candidiasis treated with JAK inhibitors

Abstract Purpose: The aim of this study was to characterize biomarkers in three patients with chronic mucocutaneous candidiasis caused by gain of function mutations in the STAT1 gene during treatment with Janus kinase inhibitors. Methods: We used mass cytometry to characterize mononuclear leukocyte populations and Olink assays to quantify 265 plasma proteins. Flow-cytometric Assay for Specific Cell-mediated Immune-response in Activated whole blood (FASCIA) was used to quantify the reactivity against Candida albicans . Results: While the number of B-, T- and NK-cells remained stable during baricitinib treatment, a detailed analysis revealed that CD4 + central memory T-cells increased during treatment from 25% to around 60% of the total numbers of CD4 + T-cells. In parallel, NK-cells showed an increased expression of CD45, CD52 and CD99, likely reflecting a more functional phenotype. Conversely, monocytes and eosinophils downregulated CD16, which is consistent with reduced inflammation. In the patient for which consecutive samples were available, the immune response to C. albicans was increased above the level found in normal individuals after 7 weeks of treatment. Early changes in plasma biomarkers involved downregulation of CXCL10, annexin A1, granzyme B, granzyme H and oncostatin M, whereas FGF21 was the only upregulated marker after 7 weeks. After 3 months, IFN-ɣ and CXCL10 were downregulated. Conclusions: Several biological variables were altered during baricitinib treatment demonstrating that lymphocytes, NK-cells, monocytes and eosinophils were affected. In parallel, the cellular reactivity against C. albicans was enhanced. Downregulation of CXCL10 could tentatively be used as a biomarker for baricitinib activity, but this needs to be validated in additional patients.