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 clinical effects and biomarkers in three patients with chronic mucocutaneous candidiasis (CMC) caused by gain-of-function (GOF) mutations in the STAT1 gene during treatment with Janus kinase (JAK) inhibitors. Methods Mass cytometry (CyTOF) was used to characterize mononuclear leukocyte populations and Olink assay 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 Overall, JAK inhibitors improved clinical symptoms of CMC, but caused side effects in two patients. Absolute numbers of neutrophils, T cells, B cells, and NK cells were sustained during baricitinib treatment. Detailed analysis of cellular subsets, using CyTOF, revealed increased expression of CD45, CD52, and CD99 in NK cells, reflecting a more functional phenotype. Conversely, monocytes and eosinophils downregulated CD16, consistent with reduced inflammation. Moreover, T and B cells showed increased expression of activation markers during treatment. In one patient with a remarkable clinical effect of baricitinib treatment, the immune response to C. albicans increased after 7 weeks of treatment. Alterations in plasma biomarkers involved downregulation of cellular markers 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 The clinical effect of JAK inhibitor treatment of CMC is promising. Several biological variables were altered during baricitinib treatment demonstrating that lymphocytes, NK cells, monocytes, and eosinophils were affected. In parallel, cellular reactivity against C. albicans was enhanced.

Chinese Chronic Mucocutaneous Candidiasis: A Case Report Series

“… 40 Clinical trials have demonstrated a significant improvement in symptoms in patients with CMC with the use of JAK inhibitors for a short course, although side effects have been reported. 41 Therefore, JAK inhibitors or other gene-targeted drugs could be potential therapeutic options in the future treatment of CMC. 42 Single-cell sequencing of STAT-GOF patients with CMC revealed upregulation of tumor necrosis factor alpha-induced protein 3 (TNFAIP3).…”

Chronic Mucocutaneous Candidiasis: A Case Report

“… 23 In addition, there are also reports of successful treatment with baricitinib. 24 For cases that do not respond to conventional treatment, hematopoietic stem cell transplantation is another possible option. 25 …”

Inborn Errors of Immunity Causing Pediatric Susceptibility to Fungal Diseases

“…In addition, hematopoietic stem cell transplantation (HSCT) is the only curative treatment option, but the current literature indicates high rates of secondary graft failure and mortality [ 65 , 66 ]. The JAKinibs such as ruxolitinib or baricitinib, have been shown to effectively treat many of the aforementioned disease manifestations, and in particular CMC [ 67 , 68 , 69 , 70 , 71 ]. A recent study summarized the experience with JAKinibs in pediatric STAT1 GOF patients and showed a good response rate (82%; 18/22 subjects) after 1–8 weeks of therapy.…”