Background: There are currently no approved medical therapies for acute fulminant myocarditis (AFM). Janus kinase (JAK) inhibitors target the JAK-STAT signaling pathway, which is crucial in immune activation. We report the first use of ruxolitinib, a JAK inhibitor, for treatment of AFM. Multi-omics single-cell technologies, including RNA-seq, T-/B-cell receptor seq, and CITE-seq, were employed to analyze immune profiles pre- and post-ruxolitinib treatment. Results: A 20-year-old female presented with AFM with cardiogenic shock and was supported by VA-ECMO and impella CP. Endomyocardial biopsy showed lymphocytic myocarditis. The patient received pulsed steroids and was listed for orthotopic heart transplant. Due to deteriorating conditions, ruxolitinib (10 mg BID) was added with immediate improvement in cardiac and inflammatory biomarkers and hemodynamics. ECMO was decannulated on day 6 and impella CP was removed on day 8. Repeat TTE on day 9 showed normalization of cardiac function (LVEF 58%, increased from 10%). She was discharged on ruxolitinib and is doing well in follow-up. Multi-omics single-cell technologies were employed on PBMCs collected at four time points: prior to ruxolitinib treatment (but after treatment with corticosteroids), and post-ruxolitinib treatment on day 5, day 8, and 2-months. At baseline, prior to treatment, scRNA-Seq and CITE-seq analysis revealed upregulated JAK-STAT signaling in pathogenic immune cells such as NK cells, CCR2 + /CCR5 + /HLA-DR + monocytes and activated T cells. Ruxolitinib treatment significantly decreased these pathogenic immune cells, with inhibition of STAT1/STAT3 signaling. Ruxolitinib also significantly decreased key cytotoxic genes PRF1, GZMB, and TBX21 in T and NK cells. TCR sequencing revealed clonal expansions of activated T cells with high levels of pro-inflammatory genes (IL2/IL6/IFNg) at baseline which were dramatically reduced post-treatment with ruxolitinib. Longitudinal data indicated normalization of naive T and B cell levels and clonal diversity, mirroring her clinical improvement. Conclusions: Ruxolitinib significantly modulates immune profiles and disrupts pathogenic signaling in AFM. This first reported use of ruxolitinib in AFM, coupled with our multi-omics analysis, highlights profound immune reprogramming and supports targeted immune modulation for rapid recovery, underscoring ruxolitinib’s therapeutic efficacy.
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