Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that affects the central nervous system. MS is more prevalent in women and is estimated to affect some 2.3 million people across the world. There is unequivocal genetic susceptibility in MS. The most consistent genetic determinant identified is the major histocompatibility complex (MHC). The haplotypes more strongly related to susceptibility and protection for MS are HLA-DR2 and HLA-DR11, respectively. Some genes outside the MHC, such as IL2RA, IL7R and TNFRSF1A, have also been related to MS. There is a latitudinal gradient of MS prevalence, probably due to environmental factors on the genetic susceptibility. The most important MS risk factors are seropositivity against Epstein–Barr virus, infectious mononucleosis, and smoking. Other factors such as vitamin D or parasitic infections require further investigation. The clinical manifestations of relapsing forms of MS in initial stages are related to demyelination of the susceptible structures such as the optic nerves or spinal cord. In established MS, the clinical symptoms are related to the multisystemic affectation and neurodegeneration such as cognitive impairment or sphincter disorders. An unmet need exists for highly effective medications with low risk for deep immunosuppression and for the symptomatic relief of MS.

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Background and objectiveDimethyl fumarate (DMF) is an immunomodulatory drug approved for the therapy of multiple sclerosis (MS). The identification of response biomarkers to DMF is a necessity in the clinical practice. With this aim, we studied the immunophenotypic and transcriptomic changes produced by DMF in peripheral blood mononuclear cells (PBMCs) and its association with clinical response.Material and methodsPBMCs were obtained from 22 RRMS patients at baseline and 12 months of DMF treatment. Lymphocyte and monocyte subsets, and gene expression were assessed by flow cytometry and next-generation RNA sequencing, respectively. Clinical response was evaluated using the composite measure “no evidence of disease activity” NEDA-3 or “evidence of disease activity” EDA-3 at 2 years, classifying patients into responders (n=15) or non-responders (n=7), respectively.ResultsIn the whole cohort, DMF produced a decrease in effector (TEM) and central (TCM) memory T cells in both the CD4+ and CD8+ compartments, followed by an increase in CD4+ naïve T cells. Responder patients presented a greater decrease in TEM lymphocytes. In addition, responder patients showed an increase in NK cells and were resistant to the decrease in the intermediate monocytes shown by non-responders. Responder patients also presented differences in 3 subpopulations (NK bright, NK dim and CD8 TCM) at baseline and 4 subpopulations (intermediate monocytes, regulatory T cells, CD4 TCM and CD4 TEMRA) at 12 months. DMF induced a mild transcriptional effect, with only 328 differentially expressed genes (DEGs) after 12 months of treatment. The overall effect was a downregulation of pro-inflammatory genes, chemokines, and activators of the NF-kB pathway. At baseline, no DEGs were found between responders and non-responders. During DMF treatment a differential transcriptomic response was observed, with responders presenting a higher number of DEGs (902 genes) compared to non-responders (189 genes).ConclusionsResponder patients to DMF exhibit differences in monocyte and lymphocyte subpopulations and a distinguishable transcriptomic response compared to non-responders that should be further studied for the validation of biomarkers of treatment response to DMF.

Introducción El ictus isquémico puede ser una complicación grave en los pacientes con infección por SARS-CoV-2. Estudiar y caracterizar los diferentes subtipos etiológicos, las características clínicas y el pronóstico funcional podrá resultar útil en la selección de pacientes para un manejo y tratamiento óptimos. Métodos La recogida de variables se hizo de forma retrospectiva en pacientes consecutivos con infección por COVID-19 que desarrollaron un episodio de isquemia cerebral focal (entre el 1 de Marzo 1, 2020, y el 19 de Abril, 2020). Se llevó a cabo en un hospital universitario de tercer nivel en la Comunidad de Madrid. (España). Resultados Durante el período de estudio 1594 pacientes fueron diagnosticados de infección por COVID 19. Identificamos 22 pacientes con ictus isquémico (1.38%), de estos no cumplieron los criterios de inclusión 6. Un total de 16 pacientes con isquemia cerebral focal constituyeron la serie del estudio (15 con ictus isquémico y 1 con accidente isquémico transitorio). En la valoración basal en el National Institutes of Health Stroke Scale (NIHSS) la mediana fue de 9 (Rango Intercuartil RIQ: 16), la edad media fue de 73 años (DE ± 12.8). 12 pacientes fueros varones (75%). El tiempo desde los síntomas de COVID-19 hasta el ictus fue de 13 días. Se encontró oclusión de gran vaso en 12 pacientes (75%). El dímero –D estuvo elevado en el 87.5% y la proteína C reactiva en el 81.2% de los casos. La etiología más frecuente del ictus isquémico fue la aterotrombosis (9 pacientes, 56.3%) con un subtipo predominante que fue el trombo endoluminal sobre placa de ateroma (5 pacientes, 31.2%), 4 de ellos en la arteria carótida interna y uno de ellos en el arco aórtico. La mortalidad en nuestra serie fue del 44% (7 de 16 pacientes). Conclusiones En los pacientes con ictus y COVID-19 la etiología más frecuente fue la aterotrombótica con una elevada frecuencia de trombo endoluminal sobre placa de ateroma (31.2% de los pacientes). Nuestros hallazgos clínicos y de laboratorio apoyan la coagulopatía asociada a COVID-19 como un mecanismo etiopatogénico relevante en el ictus isquémico en este contexto.

The endocannabinoid system (ECS), a signalling network with immunomodulatory properties, is a potential therapeutic target in multiple sclerosis (MS). Dimethyl fumarate (DMF) is an approved drug for MS whose mechanism of action has not been fully elucidated; the possibility exists that its therapeutic effects could imply the ECS. With the aim of studying if DMF can modulate the ECS, the endocannabinoids 2-arachidonoylglycerol (2-AG), anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) were determined by liquid chromatography-mass spectrometry in peripheral blood mononuclear cells from 21 healthy donors (HD) and 32 MS patients at baseline and after 12 and 24 months of DMF treatment. MS patients presented lower levels of 2-AG and PEA compared to HD. 2-AG increased at 24 months, reaching HD levels. AEA and PEA remained stable at 12 and 24 months. OEA increased at 12 months and returned to initial levels at 24 months. Patients who achieved no evidence of disease activity (NEDA3) presented the same modulation over time as EDA3 patients. PEA was modulated differentially between females and males. Our results show that the ECS is dysregulated in MS patients. The increase in 2-AG and OEA during DMF treatment suggests a possible role of DMF in ECS modulation.