Immune dysregulation in children with Down syndrome: clinical implications and emerging therapies

PURPOSE OF REVIEW: People with Down syndrome experience significant immune dysregulation, conferring elevated risk of autoimmune and inflammatory conditions. Despite the growing prevalence of adults living with Down syndrome, significant gaps remain in understanding and treating immune-mediated disease in this population. This review synthesizes current knowledge of immune dysregulation in Down syndrome, with focus on rheumatic manifestations and emerging therapeutic approaches. RECENT FINDINGS: Trisomy 21 drives constitutive, global immune remodeling characterized by mixed interferon hyperactivation, hypercytokinemia, and myeloid and lymphoid subset remodeling toward an autoimmunity-prone, pro-inflammatory state. Down syndrome associated arthritis is a distinct and aggressive entity warranting recognition separate from juvenile idiopathic and rheumatoid arthritis. People with Down syndrome face elevated risk of SJIA-associated lung disease and diffuse alveolar hemorrhage. Medication tolerance is a significant consideration, including intolerance to methotrexate and diminished response to TNF inhibitors. Early clinical trials of JAK inhibitors demonstrate promising results across multiple immune-mediated manifestations, including skin disease, arthritis, and Down syndrome regression disorder. SUMMARY: Immune dysregulation in Down syndrome is pervasive and mechanistically distinct, with interferon signaling as a central therapeutic target. Clinicians should be aware of Down syndrome specific diagnostic and management considerations, and future research should prioritize rigorous placebo-controlled trials and Down syndrome informed outcome measures.