Thangaraj A, Aggarwal R, Sarkar S, Pilania RK. Interface between inborn errors of immunity and rheumatological disorders in children: A pediatrician’s conundrum. World J Clin Pediatr 2026; 15(3): 118174 [DOI: 10.5409/wjcp.118174]
Corresponding Author of This Article
Rakesh Kumar Pilania, MD, DM, MAMS, Assoc-FAMS, Assoc-FNA, Associate Professor, Pediatric Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India. kumarpilania007@gmail.com
Research Domain of This Article
Pediatrics
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review-article
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Thangaraj A, Aggarwal R, Sarkar S, Pilania RK. Interface between inborn errors of immunity and rheumatological disorders in children: A pediatrician’s conundrum. World J Clin Pediatr 2026; 15(3): 118174 [DOI: 10.5409/wjcp.118174]
Abarna Thangaraj, Ridhima Aggarwal, Soumyadeep Sarkar, Rakesh Kumar Pilania, Pediatric Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
Co-first authors: Abarna Thangaraj and Ridhima Aggarwal.
Author contributions: Thangaraj A, Aggarwal R, and Sarkar S conducted the literature review, performed the analysis, created the artwork, interpreted the data, and drafted the original manuscript; Pilania RK conceptualized and designed the study, and critically revised the manuscript. All authors prepared the draft and approved the submitted version. Thangaraj A and Aggarwal R contributed equally to this work and are co-first authors.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Corresponding author: Rakesh Kumar Pilania, MD, DM, MAMS, Assoc-FAMS, Assoc-FNA, Associate Professor, Pediatric Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India. kumarpilania007@gmail.com
Received: December 29, 2025 Revised: February 20, 2026 Accepted: April 3, 2026 Published online: September 9, 2026 Processing time: 213 Days and 21.6 Hours
Abstract
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.
Core Tip: Rheumatological disorders in children may represent the initial manifestation of inborn errors of immunity (IEIs), a rapidly expanding group of monogenic immune dysregulation syndromes. Increasing overlap exists between IEIs and pediatric rheumatologic diseases, including arthritis, vasculitis, cytopenias, lupus, macrophage activation syndrome, and polyautoimmunity. Early age of onset, atypical or severe disease, recurrent infections, multi-organ involvement, and poor response to standard therapy are key red flags. Early recognition and genetic diagnosis enable precision-based targeted therapies, significantly improving outcomes.
