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.