Treatment-refractory autoimmune glial fibrillary acidic protein astrocytopathy: Clinical features, predictive models, therapy

Background and objectives A subset of glial fibrillary acidic protein astrocytopathy experiences treatment-refractory disease course, yet the clinical and immunological features defining this subgroup remain incompletely characterized. Methods Patients were classified as treatment-refractory ( n = 23) or treatment-responsive ( n = 30). Clinical, imaging, and outcomes were compared. For subgroup analyses, refractory patients were divided into three groups: no immunoadsorption/plasma exchange (IA/PE) ( n = 9), IA/PE monotherapy ( n = 4), and IA/PE plus rituximab ( n = 10), with functional outcomes compared across groups. Immunoglobulin G (IgG) from refractory patients was applied to a passive transfer mouse model, and single-cell RNA sequencing was performed to explore underlying pathogenic mechanisms. Results The treatment-refractory group had higher proportion of the meningoencephalomyelitis phenotype (82.6% vs. 53.3%, P = 0.026) and more frequent disturbances of consciousness (65.2% vs. 30.0%, P = 0.011), paraplegia (78.3% vs. 33.3%, P = 0.001), and peripheral nervous system involvement (89.5% vs. 22.2%, P < 0.001). Refractory patients had elevated cerebrospinal fluid glial fibrillary acidic protein and neurofilament light chain levels. Refractory patients more frequently exhibited spinal cord lesions involving three or more segments (65.2% vs. 21.4%, P = 0.002). Disability at last follow-up was greater in the refractory group (median modified Rankin Scale score 3 vs. 1, P < 0.0001). Firth penalized regression model identified peripheral nervous system involvement as the independent predictor of treatment refractoriness (odds ratio = 10.74, P = 0.006). Among refractory patients, the IA/PE-plus-rituximab group had significantly lower long-term mRS scores than the no-IA/PE group (adjusted P = 0.031). GFAPA-IgG from refractory patients induced CD45 + cell infiltration in mouse brain. Single cell analysis demonstrated activation of complement and inflammatory pathways, with astrocytes adopting a pro inflammatory state. Conclusion Treatment refractory disease is marked by severe central and peripheral nervous system injury. Convergent clinical and experimental evidence provides a rationale for B cell targeted therapies.