Successful Therapy of a Patient with a Novel STAT1 Gain of Function Mutation and Life-Threatening Cytopenias with Janus Kinase Inhibitor Ruxolitinib

Monoallelic gain of function (GOF) mutations in the human Signal Transducer and Activator of Transcription 1 (STAT1) manifest in immunodeficiency and autoimmunity. The immunodeficiency is caused by impaired IL-17 immunity and typically presents with chronic mucocutaneous candidiasis, variably associated with other opportunistic infections. The autoimmune manifestations due to exaggerated responsiveness to interferon are more diverse and include SLE, thyroiditis, hepatitis, and alopecia areata. The phenotypic spectrum of STAT1 GOF mutations is extremely wide, ranging from intermittent localized disease to chronic systemic illness and fatality. Allogeneic bone marrow transplantation has been attempted in severely affected patients but outcomes have been poor, leaving a void for alternate long-term strategies to control the disease and maintain remission. Recently, we diagnosed a patient suffering from chronic mucocutaneous candidiasis and life-threatening autoimmune cytopenias with a novel monoallelic mutation in the linker domain of STAT1 (c.1633G>A; p.E545K). The mutation caused a profound increase in STAT1 phosphorylation in response to type 1 and 2 interferon without affecting dephosphorylation kinetics, which is mechanistically distinct from all reported STAT1 GOF mutations to date. The potential of naïve patient CD4⁺ T cells to become IFN- γ or IL-17 producing cells was investigated under T_H0 (anti-CD3/28), T_H1 (anti-CD3/28, IL-12) and T_H17 (anti-CD3/28, IL6, IL-23, TGF-β1) conditions and revealed that patient CD4+ T cells are biased to produce IFN-γ irrespective of polarizing conditions, and resistant to T_H17 induction upon stimulation with IL6, IL-23 and TGF-β1. In addition, the patient's proportion of T follicular helper cells (T_FH) relative to regulatory T cells (T_reg) was increased. Treatment with the Janus Kinase (JAK) 1/2 inhibitor Ruxolitinib reduced the hyperresponsiveness to interferon, normalized the T_H1 response, enabled naïve T cells to differentiate into T_H17 cells and decreased the T_FH to T_reg ratio. Under therapeutic dose Ruxolitinib the patient maintained clinical remission with respect to both autoimmunity and mucocutaneous candidiasis.

Conclusion: Clinical vigilance for an underlying immune dysregulation syndrome due to abnormal JAK-STAT signaling is critical when evaluating patients with autoimmunity combined with opportunistic infections as JAK-inhibitors represents an effective targeted therapy for long-term disease control even in severely affected patients for whom hematopoietic stem cell transplantation is not available.