Guidance on JAK inhibitor treatment for inborn errors of JAK-STAT signaling, 2026: International consensus statement on behalf of the European Society for Immunodeficiencies/European Society for Blood and Marrow Transplantation-Inborn Errors Working Party and ERN-RITA.

Abstract

Inborn errors of immunity (IEI) associated with gain of function (GOF) in the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways (JAK-STAT-GOF IEI) are rare disorders characterized by immune dysregulation, autoimmunity, malignancy, and increased infection susceptibility. To date, no JAK inhibitors (JAKi) are licensed for these conditions, but they are frequently prescribed off-label, even though high-quality evidence and treatment guidelines remain limited. We developed evidence- and consensus-based recommendations for JAKi treatment in JAK-STAT-GOF IEI across all age groups on the basis of a systematic literature review and expert consensus. An international expert group conducted a systematic literature review and developed recommendations on JAKi treatment in JAK-STAT-GOF IEI using a modified Delphi approach. Recommendations were developed based on published evidence, data from an international retrospective cohort study, and patient representative input. These statements were then tested for consensus in a 2-round Delphi survey procedure in a larger, interdisciplinary expert panel. Consensus- and evidence-based guidance is presented across 5 thematic areas: (1) JAKi indications/contraindications, (2) pretreatment assessment, (3) pharmacology/dosing, (4) monitoring, and (5) use in the context of hematopoietic stem cell transplantation. A total of 51 statements were established and contextualized with the available evidence. This consensus provides structured guidance for clinicians managing JAK-STAT-GOF IEI with JAKi. While prospective trials will further refine these strategies, this guidance represents the current international standard of care, reflecting the synthesis of clinical experience and the best available evidence.