Janus Kinase Inhibitors in Treatment of Primary Immune Regulatory Disorders.

Abstract

Genetic diagnosis in inborn errors of immunity has not only helped to shorten the diagnostic odyssey but has advanced targeted therapeutic interventions leading to improved clinical outcomes. Primary immune regulatory disorders are a group of inborn errors of immunity characterized by dysregulated cytokine signaling, impaired immune tolerance, and pathological inflammation, leading to autoimmunity, autoinflammation, lymphoproliferation, and end-organ damage. Treatment of primary immune regulatory disorders caused by aberrant activation of the Janus kinase (JAK)-signal transducer and activator of transcription pathway leading to gain-of-function disease syndrome, type I interferonopathies, cytotoxic lymphocyte disorders with hyperinflammation, and selected refractory immune dysregulation provide a strong rationale for pathway-targeted therapy with JAK inhibitors. JAK inhibition is reported to reduce inflammatory burden, improve autoimmune and infectious complications, restore immune balance, and provide meaningful steroid-sparing effects in both pediatric and adult patients. However, use remains off-label and requires careful patient selection, individualized dosing, and structured monitoring for cytopenias, infections, and viral reactivation. This review summarizes the molecular rationale for JAK inhibition in primary immune regulatory disorders, evaluates available clinical evidence for efficacy and safety across key disease categories, and discusses practical considerations for implementation within a multidisciplinary care framework. As clinical experience grows, collaborative registries and prospective studies are essential to define dosing, safety, and biomarker-guided use of JAK inhibitors in immune dysregulation.