Author Of 3 Presentations
P0291 - Association of Headache with B-cell Targeted Therapies in Multiple Sclerosis patients. (ID 1796)
Abstract
Background
Patients with Multiple Sclerosis (MS) have an increased incidence of headache, whereas the mechanism and the various co-factors are poorly understood. Among them, MS therapies are considered to play a role. Nonetheless, there is not enough data that correlate MS therapies with headache.
Objectives
The aim of the present study is to conduct a systematical review of the current literature towards identifying any possible association between B-cell MS therapies and increased headache incidence.
Methods
Systematic literature search was conducted using PubMed/MEDLINE database, clinicaltrials.gov and clinicaltrialsregister.eu searching clinical trials of B-cell depleting therapies in MS (i.e. ofatumumab, ocrelizumab, rituximab, ublituximab, cladribine) and investigating a possible role in the incidence of headache in MS patients. PRISMA guidelines for systematic reviews were applied. Risk of bias was evaluated using the Cochrane Risk of Bias tool. Relative risk (RR) and confidence intervals (CI) were calculated.
Results
In total, 9 randomized-control trials with 3785 patients were included in this study. The overall pooled relative risk of headaches in MS patients receiving B-cell depleting therapies was estimated to 1.12; p=0.15 (95% CI: 0.96 – 1.30; I2=9.32%; Q=7.42 [p=0.49]). Subgroup analysis of the studies in which cladribine was given as B-cell targeted therapy, showed a statistically significant higher increased risk of headache with a risk ratio of 1.19; p=0.04 (95% CI 1.01 – 1.42; I2=0%; Q=1.07 [p=0.59]).
Conclusions
B-cell targeted MS therapies do not correlate with increased incidence of headache as an adverse effect, even though a trend is shown. Further sub-analysis revealed that cladribine alone is associated with increased incidence of headache. More research is needed to elucidate the pathogenetic mechanism of headache induction, as well as, to identify headache prevention strategies.
P0704 - Cortical involvement in MOG IgG–positive patients : a multicenter MRI study (ID 1853)
Abstract
Background
Cortical involvement in neuropathological studies has been identified in Multiple Sclerosis (MS) and recently in myelin oligodendrocyte glycoprotein antibody disease (MOGAD) patients. Neuroimaging findings also seem to confirm cortical involvement as cerebral cortical lesions (CCLs) and leptomeningeal contrast enhancement (LMCE) have been shown in 3D-FLAIR sequences in MS patients.We described recently LMCE in MOGAD-patients with 3D-FLAIR post-gadolinium (3D-FLAIRED) sequences.
Objectives
To assess the presence and type of CCLs and the possible relation between CCLs and LMCE in MOGAD-patients using a 3 Tesla-MRI-scanner.
Methods
We conducted a brain MRI study including 11 MOGAD patients (MOG-IgG1 serum detection with cell-based-assay) with CNS demyelination and 12 Relapsing-Remitting MS (RRMS) patients as a control-group. In these groups, 8/11 and 6/12 were females, with a mean age at MRI acquisition 45.2 years and 38.25years in MOGAD and RRMS groups respectively. Exclusion criteria of this study were a clinical relapse or administration of intravenous corticosteroids within one month preceding MRI acquisition. LMCE foci were identified as hyperintensities on 3D-FLAIRED and not on 3D-T1-weighted-post-gadolinium sequences. For the detection of CCLs both high signal on 3D-FLAIR and low in 3D-T1-weighted sequences were required. Due to limitations of 3Tesla, CCLs were classified in two subgroups: a) intracortical/subpial or b) leukocortical lesions.
Results
CCLs were detected in 8 out of 11 patients in the MOGAD-group with mean-number-of-lesions (MNLs) 4.375 and in all of the RRMS-group with MNLs 12.25. In MOGAD, leukocortical-MNLs (2.143) was similar to intracortical/subpial-MNLs (2.714), whereas a predomidance of leukocortical (MNLs 9.82) versus intracortical/subpial (MNLs 4.82) lesions was observed in RRMS. LMCE was observed in 3 out of 11 in the MOGAD-group and in 1 out of 12 in the RRMS–group. In the MOGAD-group, LMCE presence was related to a higher lesion number in both lesion subtypes when compared to the MOGAD patients without LMCE.
Conclusions
Our study showed the ability of 3D-FLAIR joint with 3D-T1-weighted sequences in disclosing and classifying CCLs in MOGAD. An association between LMCE and the extent of cortical demyelination in MOGAD was evident, suggesting that meningeal inflammation may contribute in cortical lesion development. Moreover, cerebral cortical lesion number was higher in RRMS compared to MOGAD.
P0760 - Tumefactive demyelination following rituximab in an anti-MOG positive NMOSD patient: evidence of T-cell and NK-cell involvement (ID 1001)
Abstract
Background
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.
Objectives
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.
Methods
We performed flow cytometric immunophenotypic analysis of peripheral blood mononuclear cells during exacerbation.
Results
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).
Conclusions
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.
Presenter Of 2 Presentations
P0291 - Association of Headache with B-cell Targeted Therapies in Multiple Sclerosis patients. (ID 1796)
Abstract
Background
Patients with Multiple Sclerosis (MS) have an increased incidence of headache, whereas the mechanism and the various co-factors are poorly understood. Among them, MS therapies are considered to play a role. Nonetheless, there is not enough data that correlate MS therapies with headache.
Objectives
The aim of the present study is to conduct a systematical review of the current literature towards identifying any possible association between B-cell MS therapies and increased headache incidence.
Methods
Systematic literature search was conducted using PubMed/MEDLINE database, clinicaltrials.gov and clinicaltrialsregister.eu searching clinical trials of B-cell depleting therapies in MS (i.e. ofatumumab, ocrelizumab, rituximab, ublituximab, cladribine) and investigating a possible role in the incidence of headache in MS patients. PRISMA guidelines for systematic reviews were applied. Risk of bias was evaluated using the Cochrane Risk of Bias tool. Relative risk (RR) and confidence intervals (CI) were calculated.
Results
In total, 9 randomized-control trials with 3785 patients were included in this study. The overall pooled relative risk of headaches in MS patients receiving B-cell depleting therapies was estimated to 1.12; p=0.15 (95% CI: 0.96 – 1.30; I2=9.32%; Q=7.42 [p=0.49]). Subgroup analysis of the studies in which cladribine was given as B-cell targeted therapy, showed a statistically significant higher increased risk of headache with a risk ratio of 1.19; p=0.04 (95% CI 1.01 – 1.42; I2=0%; Q=1.07 [p=0.59]).
Conclusions
B-cell targeted MS therapies do not correlate with increased incidence of headache as an adverse effect, even though a trend is shown. Further sub-analysis revealed that cladribine alone is associated with increased incidence of headache. More research is needed to elucidate the pathogenetic mechanism of headache induction, as well as, to identify headache prevention strategies.
P0760 - Tumefactive demyelination following rituximab in an anti-MOG positive NMOSD patient: evidence of T-cell and NK-cell involvement (ID 1001)
Abstract
Background
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.
Objectives
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.
Methods
We performed flow cytometric immunophenotypic analysis of peripheral blood mononuclear cells during exacerbation.
Results
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).
Conclusions
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.