Jakinibs for the Treatment of Immune Dysregulation in Patients With Gain–of–Function Signal Transducer and Activator of Transcription 1 (STAT1) or STAT3 Mutations

Abstract

To investigate the efficacy of jakinib therapy in patients with gain-of-function (GOF) signal transducer and activator of transcription 1 (STAT1) or signal transducer and activator of transcription 3 (STAT3) mutations.The study included 17 total patients with either a STAT1 GOF (n = 11) or STAT3 GOF (n = 6) mutation who were treated with jakinibs (ruxolitinib or tofacitinib). Patients came from 11 international centers.This was a retrospective study to describe disease-related clinical manifestations and determine indication for treatment, dosage, length of treatment, treatment response, and treatment-associated complications. All subjects underwent thorough pre- and posttreatment clinical and laboratory evaluations and follow-up (follow-up period: 1–34 months).Fourteen patients (82%) responded favorably with clinical improvement to jakinib treatment. Observed clinical improvements included resolution of enteropathy leading to total parenteral nutrition independence, better lung function, improved autoimmune cytopenias, decreased arthritis symptoms, and remission of hemophagocytic lymphohistiocytosis. All patients with STAT1 GOF had resolved chronic mucocutaneous candidiasis with treatment. Most patients tolerated the jakinibs well with minimal or transient adverse effects. An increase in herpes zoster infections (none systemic and all cleared with antiviral agents) was observed in some patients. Four patients died despite treatment with a jakinib. The majority of these patients were critically ill with severe invasive infection or progressive lung disease. One patient died due to posttransplant complications.Jakinibs are both safe and effective in the treatment of patients with STAT1 or STAT3 GOF mutations with clinical manifestations of autoimmunity and/or immune dysregulation.Patients with STAT1 and STAT3 GOF mutations often present in early childhood with severe and/or refractory infections, lymphoproliferation, autoinflammation, and autoimmunity. Jakinibs allow for a targeted therapeutic approach to block the cytokine-induced JAK activation in STAT1 and STAT3 GOF diseases. This is the first study to evaluate the use and clinical impact of jakinibs in STAT1 and STAT3 GOF. The results are overwhelmingly encouraging, with the majority of patients having clinical improvement and reduction or resolution of autoimmune manifestations after treatment with a jakinib. Use of jakinibs late in disease progression or when critically ill was associated with mortality, suggesting early initiation may improve efficacy. This study has significant clinical impact in the treatment of STAT1 and STAT3 GOF and reinforces the notion that early genetic diagnosis of primary immunodeficiency diseases may lead to targeted therapeutic options and improved clinical outcomes.