Ruxolitinib treatment ameliorates clinical, immunologic, and transcriptomic aberrations in patients with STAT3 gain-of-function disease.

Background: Signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) disease presents with lymphoproliferation, autoimmunity, and failure to thrive. Although Janus kinase inhibitors have alleviated symptoms, their effects on disease pathogenesis remain unclear.
Objective: We prospectively investigated the clinical, immunologic, and transcriptomic responses of 4 patients with STAT3 GOF under long-term ruxolitinib treatment.
Methods: We conducted clinical and immunologic evaluations at baseline and after ruxolitinib treatment at 3, 8, 12, and more than 12 months. Our assessments included measurement of levels of circulating T follicular helper cells, regulatory T cells, and cytokines, as well as proliferation assays. Furthermore, we investigated the transcriptomic changes with treatment and conducted T-cell receptor sequencing.
Results: Ruxolitinib achieved substantial control over the clinical manifestations. Posttreatment evaluations demonstrated a notable increase in naive CD4 ⁺ and CD8 ⁺ T-cell populations, alongside a significant reduction in effector memory T-cell levels. Additionally, there was a decrease in levels of circulating T follicular helper cells and double-negative T cells. Regulatory T-cell percentages and their canonical markers, which were already reduced before treatment, declined further with ruxolitinib. The treatment did not alter the production of IL-4, IL-17A, IL-10, and IFN-γ cytokines by the CD4 ⁺  T cells. Importantly, ruxolitinib effectively normalized the previously dysregulated transcriptome profile in PBMCs, bringing it closer to that of healthy controls. This normalization was most striking in the downregulation of STAT3-targeted genes, interferon-related genes, myeloid cell activation, and cytotoxic effector CD8 ⁺ T-cell genes, with effects persisting for up to 12 months. Self-reactive T-cell indices based on T-cell receptor repertoire analysis revealed potential autoreactive cell clones in the patient samples.
Conclusion: Ruxolitinib reversed cellular and transcriptomic signatures, enhancing our understanding of the disease's pathophysiology and highlighting essential immunologic markers for precise monitoring.
Competing Interests: Disclosure statement Supported by the Marmara University Scientific Research Project Coordination Unit (grant ADT-2022-10661 [to S.B.]) and the Scientific and Technological Research Council of Türkiye (grant 121S667 [to B.E.]). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.
(Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)