Ruxolitinib treatment ameliorates clinical, immunologic, and transcriptomic aberrations in patients with STAT3...

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.

We prospectively investigated the clinical, immunologic, and transcriptomic responses of 4 patients with STAT3 GOF under long-term ruxolitinib treatment.

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.

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.

Ruxolitinib reversed cellular and transcriptomic signatures, enhancing our understanding of the disease's pathophysiology and highlighting essential immunologic markers for precise monitoring.