Wanfeng Xu, Haoyue Xing, Ling Hou
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease that mostly affects the central nervous system, and Sjögren's disease (SjD) is an autoimmune disease that mostly affects the exocrine glands. Recent evidence indicates that these conditions frequently coexist and may have overlapping immunopathogenic mechanisms. Patients with NMOSD often exhibit serological or clinical features of SjD, and patients with SjD may develop inflammatory demyelinating events resembling NMOSD. This overlap can pose significant diagnostic and therapeutic challenges. Our narrative review synthesizes recent evidence on the epidemiology, clinical characteristics, immunopathogenic links, diagnostic considerations, and therapeutic implications of NMOSD-SjD overlap. This overlap phenotype is characterized by a diverse autoantibody profile, B-cell hyperactivity, cytokine dysregulation (particularly interleukin-6 and type I interferon signaling), and loss of immune tolerance. Blood-brain barrier dysfunction may enable circulating pathogenic antibodies and inflammatory mediators to access the central nervous system, although direct evidence for this in the overlap disease remains limited. We propose a structured diagnostic approach that integrates clinical phenotype, antibody testing, neuroimaging, and systemic autoimmune assessment to distinguish NMOSD-SjD overlap from SjD-related central nervous system involvement and myelin oligodendrocyte glycoprotein antibody-associated disease. We also describe therapeutic strategies that emphasize prevention of NMOSD relapse, selection of biologic treatments, assessment of systemic safety, and avoidance of misclassification. Recognition of NMOSD-SjD overlap has important implications for personalized diagnosis, assessment of systemic risk, and long-term management, and illustrates the relationship of systemic autoimmunity with organ-specific antibody-mediated central nervous system disease.