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The following is a summary of “Ruxolitinib treatment ameliorates clinical, immunologic, and transcriptomic aberrations in patients with STAT3 gain-of-function disease,” published in the March 2025 issue of Journal of Allergy and Clinical Immunology by Catak et al. 

Signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) disease causes lymphoproliferation, autoimmunity, and growth failure. The impact of Janus kinase (JAK) inhibitors on disease pathogenesis remains unclear. 

Researchers conducted a retrospective study on 4 patients with STAT3 GOF receiving long-term ruxolitinib. 

They evaluated clinical and immunologic parameters at baseline and after 3, 8, 12, and >12 months of ruxolitinib treatment, measuring circulating T follicular helper (cTFH) cells, regulatory T cells, cytokines, and proliferation. Transcriptomic changes were analyzed, and T-cell receptor (TCR) sequencing was performed.  

The results showed that ruxolitinib controlled clinical manifestations, increased naive CD4⁺ and CD8⁺ T cells, and reduced effector memory T cells. Circulating T follicular helper and double-negative T cells decreased, while regulatory T-cell (Treg) percentages and markers declined further. Cytokine production (IL-4, IL-17A, IL-10, IFN-γ) by CD4⁺ T cells remained unchanged. Ruxolitinib normalized the dysregulated transcriptome in PBMCs, notably downregulating STAT3-targeted, interferon-related, myeloid activation, and cytotoxic CD8⁺ T-cell genes, with effects lasting up to 12 months and TCR analysis indicated potential autoreactive clones. 

Investigators found that ruxolitinib reversed cellular and transcriptomic signatures, improving understanding of disease pathophysiology and identifying key immunologic markers for monitoring. 

Source: sciencedirect.com/science/article/pii/S0091674924012843