Autoimmune clustering in neuro-inflammatory disorders - mechanism, diagnostic pitfalls and therapeutic implications

Autoimmune diseases frequently coexist within individuals, a phenomenon increasingly recognized as autoimmune clustering rather than coincidental comorbidity. This clustering is particularly prominent in neuroinflammatory disorders, reflecting shared genetic susceptibility, convergent immune pathways, epitope spreading, and common environmental triggers. Neuromyelitis Optica spectrum disorder (NMOSD) exemplifies this complexity, with well- established associations with systemic autoimmunity and non-organ- specific autoantibodies. We present a woman with recurrent optic neuritis and systemic autoimmune features who was ultimately diagnosed with aquaporin – 4 antibody – positive neuromyelitis Optica and spectrum disorder (NMOSD) with overlapping Sjogren’s syndrome and lupus features. This case highlights how autoimmune clustering can mimic multiple sclerosis, contributing to diagnostic delays and exposure to disease – modifying therapies that are ineffective or potentially harmful in NMOSD. This case exemplifies how autoimmune clustering manifests clinically across time and organ systems, providing a framework to understand the shared immunological mechanisms and diagnostic challenges underlying overlapping autoimmune disorders. We review the mechanistic basis for autoimmune clustering, common clinical associations, and the implications for diagnostic evaluation and therapeutic strategy in demyelinating disease.