BACKGROUND: High-dose glucocorticoids are the standard treatment for acute relapses in patients with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD). Therapeutic apheresis can be considered for the escalation of relapse therapy, but some patients still do not recover sufficiently. We aimed to explore the effects of apheresis on humoral and cellular immune parameters and to identify features that correlate with beneficial clinical outcomes. METHODS: We studied two cohorts comprising a total of 63 patients with MS or NMOSD who were undergoing relapse therapy with either methylprednisolone or apheresis. Blood samples were collected immediately before and after therapy to isolate plasma or serum as well as immune cells. We then measured (1) concentrations of the immunoglobulin isotypes IgG, IgM and IgA, (2) antibody reactivities against 12 peptides derived from potential autoantigens and Epstein-Barr virus proteins, (3) frequencies of CD19 RESULTS: The initial therapy with methylprednisolone had no significant effect on immunoglobulin levels and (auto)antibody reactivities ( CONCLUSION: Our data reveal that therapeutic apheresis in MS rapidly leads to a significant decrease in IgG reactivities against EBNA1 (391-410) and cross-reactive targets such as GlialCAM (370-389) and also has an impact on the gene expression of B cells and T cells. Further studies are required to verify whether anti-EBNA1 (391-410) antibody reactivities and the expression of CD4-CTL-related genes may be indicative of the individual clinical response to this therapy.