Rituximab is a chimeric anti-CD20 B-cell depleting monoclonal antibody, widely used both in MS and in NMOSD, as an effective off-label therapy. However, in a recent study by Durozard et al. the authors showed that up to 30% of MOG-antibody positive patients relapsed following rituximab.
Herein, we report an NMOSD patient with persistent low MOG-antibody titer, who relapsed after rituximab with tumefactive demyelinating lesions(TDLs), a finding not reported to date.
We performed flow cytometric immunophenotypic analysis of peripheral blood mononuclear cells during exacerbation.
A 56-year-old female, presented at the age of 18 with recurrent bilateral optic neuritis, followed by myelitis relapses and generalized tonic-clonic seizures. Brain/Spine MRI revealed a right parietal lesion and extensive transverse myelitis, fulfilling 2017 NMOSD criteria. Erroneously, she was initially treated with interferon-beta and transitioned to fingolimod with new gadolinium-enhancing TDLs(EDSS:6.0). She remained relapse-free for over a year after IVMP/PLEX and cyclophosphamide treatment (EDSS:4.5). Disease exacerbation occurred after transition to rituximab, with right hemiplegia and facial nerve paresis(EDSS:6.5). Brain MRI revealed TDLs. She improved significantly after IVMP(EDSS:3.5). A rituximab trial was attempted again but she relapsed with TDLs (EDSS:5; absence of CD19+B-cells). A low MOG-antibody positive titer was detected in serum, persisting during disease course(MOG-IgG1:1/20;cut-off:1/20). Flow cytometric immunophenotyping of peripheral blood mononuclear cells during rituximab relapse confirmed absence of CD19+cells , and showed high percentages of IFN-γ+CD4+T-cells over IL-17A+CD4+T-cells and CD25+FOXP3+CD4+T-cells, and also high percentages of cytotoxic CD56dimCD16+ NK cells (a subset of activated cells producing IFN-γ).
Our analysis concludes that TDL relapses following rituximab, could be related to IFN-γ+CD4+T-cell and possibly NK-cell mediated pathways, independent of CD19+B-cell depletion, in the presence of low titer MOG-antibodies. We speculate that after rituximab, long-lived plasma cells(CD20-negative) may continue to produce antibodies, including MOG-antibodies. The high frequencies of CD56dimCD16+ NK-cells (an activated NK-subset) may contribute to disease relapse, releasing cytotoxic granules and pro-inflammatory cytokines, like IFN-γ. Further studies of MOG-antibody patients with immunophenotyping analysis and neuroimaging findings are needed, to identify predictors of poor response to rituximab.