Author Of 3 Presentations
P0050 - Comparative transcriptomics of multiple sclerosis vs. viral infections, including SARS-CoV-2 (ID 1045)
Abstract
Background
There are accumulating evidence in the literature that viral infections provide an environmental trigger for the onset of multiple sclerosis (MS) in genetically susceptible individuals. Furthermore, viral infections may contribute to the progression of disability in MS, triggering relapses and promoting neurodgeneration. There are multiple studies assessing the effect of viral infections both in vitro and ex vivo. No study to date has performed a head to head comparison of transcriptomic modulations between MS and viral infections. Furthermore, no study to date has performed these comparisons with the novel coronavirus, SARS-CoV-2, whose neurotropism potential is still under scrutiny.
Objectives
The purpose of this study is to discover common pathways between multiple sclerosis and viral infections, including SARS-CoV-2, on a transcriptomic and functional level.
Methods
The Gene Expression Omnibus (GEO) database was inquired using a query containing the keywords “Virus”, “Multiple Sclerosis”, “Infection”. Included studies involved ex vivo samples of peripheral blood mononuclear cells (PBMCs) following a case – control design. For SARS-CoV-2, a gene signature extracted from a recent infection translatomics experiment (Bojkova et al, 2020) was used in over-representation analyses, and subsequently comapred with the signatures extracted from the MS datasets.
Results
The initial search retrieved 35 studies. Applying the predetermined inclusion criteria, 2 MS vs Healthy Controls (HC) studies and 3 studies of viral infection vs. HC (Dengue, SARS Coronavirus and Rotavirus infections). Multiple common, differentially expressed genes (DEGs) and associated significantly enriched pathways emerged between the MS vs viral infection subgroups. The “Epstein Barr infection” pathway was salient among MS-related viral infection pathways (False Discovery Rate (FDR) <0.05). Furthermore, comparative transcriptomics revealed 4 common gene signatures of 80 to 150 genes, associated with nuclear transport, neuroactive peptide binding and the spliceosome (FDR<0.0001). Comparisons between the MS datasets and the SARS-CoV-2 - host interactome revealed overlapping perturbations in pathways associated with neurodegeneration and mRNA surveillance pathways (FDR<0.05). Notably, a confirmatory analysis of the SARS-CoV-2 interactome with Enrichr, comapring said interactome with disease-control experiments in the Gene Expression Omnibus (GEO) databases revealed relapsing remitting MS among diseases with overlapping gene signatures (FDR<0.05).
Conclusions
Ours is the first study to directly compare viral infection mechanisms with the molecular pathophysiology of MS in a transcriptomic level. Our results indicate a “response to infection” phenotype in MS PBMCs, associated with alternative splicing and disruptions of transcriptional surveillance.
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.
P0352 - Lymphocyte Subtypes Repopulation Pattern and Secondary Autoimmunity in patients with RRMS treated with Alemtuzumab in a Real World setting (ID 1112)
Abstract
Background
Alemtuzumab is a humanized monoclonal antibody targeting CD52 expressing T and B lymphocytes used as a second line treatment for patients with highly active Relapsing Remitting Multiple Sclerosis (RRMS). Treatment with alemtuzumab has been associated with increased incidence of secondary auto-immune adverse events. Although the exact underlying mechanisms remain unclear, it has been hypothesized that secondary auto-immunity is a result of the fast / excessive repopulation of autoreactive CD19 lymphocytes following their initial depletion.
Objectives
To investigate the potential association of peripheral lymphocyte subtypes kinetics following treatment with Αlemtuzumab with auto-immune adverse events as well as with disease activity and disease progression in patients with RRMS, in a real-world setting.
Methods
Α retrospective analysis of data from a series of 33 patients that received two courses of treatment and completed at least 24 months of follow up was performed. Primary endpoints included incidence of new or exacerbation of preexisting auto-immunities, disease activity and disease progression in association with lymphocyte depletion and repopulation patterns. Lymphocyte subpopulations (CD4+/CD8+ T cells, CD19+ B cells total and memory, CD56 NK cells) were measured using flow cytometry at baseline and at months one, three, six and twelve after each treatment course. Patients were assessed clinically and with MRI every six months throughout the 2-year follow-up period. Statistical analysis included generalized linear models for repeated measures.
Results
Overall, 17 adverse events of autoimmune origin and 2 cases of exacerbation of previously existing auto-immunities were observed. Lymphocyte repopulation patterns did not show significant differences in association with incidence of auto-immune reactions. Repopulation kinetics were also unrelated to any other primary outcome investigated in this study.
Conclusions
Our findings suggest that lymphocytes repopulation patterns do not have a predictive value of the incidence of secondary auto-immunity, as well as the activity and the progression of the disease, following treatment with Alemtuzumab. The mechanisms behind the differentiation among patients in regards to autoimmune reactions may lie in more specific lymphocyte subpopulations that have not been included in this study or in deeper molecular paths mediated by specific cytokines. Further study is required in this field.