Interface between inborn errors of immunity and rheumatological disorders in children: A pediatrician's conundrum

Rheumatological disorders encompass a broad and complex spectrum of conditions, often driven by dysregulated immune responses and autoantibody formation. Increasing evidence highlights the significant overlap between rheumatological diseases and inborn errors of immunity (IEIs). The 2024 update of the International Union of Immunological Societies phenotypic classification describes 559 IEI, including 67 novel monogenic defects and 2 new phenocopies. This review examines the clinical spectrum of rheumatological manifestations associated with IEIs, encompassing arthritis, cytopenias, vasculitis, macrophage activation syndrome, systemic lupus erythematosus, inflammatory bowel disease phenotypes, polyautoimmunity, and autoimmune lung disease. Several soft clinical "red flags" can alert physicians to an IEI in a child with rheumatological disease, including very early age of onset, atypical or severe disease course, recurrent or unusual infections, lymphoproliferation, multi-organ autoimmunity, and poor or refractory response to standard therapies. Understanding the mechanisms of immune dysregulation in IEIs provides critical insight into their clinical expression. Defects in central and peripheral tolerance checkpoints, impaired T- and B-cell regulation, abnormal cytokine signaling, and skewed interferon responses contribute to the loss of self-tolerance and autoimmunity. Pediatric rheumatologists and pediatricians should remain highly vigilant for IEI when evaluating children who present with atypical, severe, or treatment-resistant rheumatologic conditions. While these disorders may mimic polygenic autoimmunity, their aggressive nature, multi-system involvement, and association with infections often distinguish them. Early genetic diagnosis not only clarifies prognosis but also enables precision-based therapies, significantly improving outcomes.