Nou mètode per tractar els brots d'esclerosi múltiple

Investigadors del Servei de Neurologia de l'Hospital Germans Trias i Pujol de Badalona han elaborat un nou protocol per tractar els brots d'esclerosi múltiple. Aquest protocol classifica els brots en lleus, moderats o greus, segons la puntuació obtinguda en l'escala de discapacitat EDSS, a fi de no tractar els brots lleus i tractar únicament els moderats o greus. A més, aquest treball ha mostrat que tractar els pacients amb les dosis altes habituals de metilprednisolona però per via oral en lloc de per via intravenosa, suposa una millora per a la qualitat de vida del pacient i un estalvi per al sistema sanitari i laboral, contribuint per tant a la seva sostenibilitat.Investigadores del Servicio de Neurología del Hospital Germans Trias i Pujol de Badalona han elaborado un nuevo protocolo para tratar los brotes de esclerosis múltiple. Este protocolo clasifica los brotes en leves, moderados o graves, según la puntuación obtenida en la escala de discapacidad EDSS, con el objetivo de no tratar los brotes leves y tratar únicamente los moderados o graves. Además, este trabajo ha mostrado que tratar a los pacientes con las dosis altas habituales de metilprednisolona pero por vía oral en vez de por vía intravenosa, supone una mejora para la calidad de vida del paciente y un ahorro para el sistema sanitario y laboral contribuyendo por tanto a su sostenibilidad.Researchers at the Department of Neurology of the Germans Trias i Pujol Hospital in Badalona have developed a new protocol to treat relapses of multiple sclerosis. This protocol classifies the intensity of relapses as mild, moderate or severe, according to their score on the EDSS disability scale, in order to avoid treating mild relapses and concentrate only on the moderate or severe ones. Patients are given the usual high doses of methylprednisolone, but orally instead of intravenously, which is favourable to their quality of life, and means greater sustainability through lower financial and labour costs

Megadosis de metilprednisolona oral frente a intravenosa para el brote de esclerosis múltiple : comparación de la eficacia clínica y radiológica /

La majoria de pacients amb esclerosi múltiple (EM), patiran, sobretot al principi de la seva malaltia, episodis subaguts de dèficit neurològic (brots), dels que es recuperaran en major o menor mesura. Minimitzar el risc de patir un brot és el fonament en el qual es basen les teràpies actuals per a l'EM, si bé cap de les disponibles és capaç d'evitar-lo completament, per la qual cosa, el tractament adequat del brot, que persegueix escurçar la seva durada y millorar la seva recuperació, continua essent una de les bases de l' atenció als pacients amb EM.Disposem d' una molt abundant literatura mèdica i de guies terapèutiques sobre els tractaments que modi-fiquen l' evolució natural de la malaltia, però molt poca sobre quin és el millor tractament pel brot una vega-da s'ha produït. Existeix acord en que cal tractar amb corticoides, però no hi ha consens sobre els brots que s'han de tractar, els corticoides a utilitzar, per quina via, en quina dosi ni durant quant de temps, ni tampoc amb quin període temporal pel que fa a la finestra terapèutica. En aquesta Tesi Doctoral s' ha revisat la literatura mèdica relacionada amb la fisiopatologia del brot d' EM, les pautes de tractament que s' apliquen i com actuen aquests tractaments, i s' hi exposen els resultats de l' assaig doble cec i aleatoritzat, realitzat amb l' objectiu de comprovar la hipòtesi que una dosi bio-equivalent de metilprednisolona (MP) administrada per via oral no ha d' ésser inferior, ni clínica ni radiològicament, a l' administrada per via intravenosa pel tractament del brot d'EM.Els resultats evidencien que no hi ha relació d' inferioritat de la via oral en relació a la intravenosa i que es manté el mateix nivell de seguretat i tolerància. Això ja constitueix en si mateix un benefici per a la qualitat de vida del pacient, però també suposa un estalvi pel sistema sanitari i laboral. Concloem que no sembla justificat continuar tractant el brot d' EM per via intravenosa i creiem haver contri-buït amb aquest treball a canviar el paradigma del tractament del brot de EM.La mayoría de los pacientes con esclerosis múltiple (EM) sufrirán, sobretodo al principio de su enfermedad, episodios subagudos de déficit neurológico (brotes), de los que se recuperarán en mayor o menor medida. Minimizar el riesgo de padecer un brote es el pilar en el que se basan las terapias actuales para la EM, pero ninguna de las disponibles es capaz de evitarlo por completo, por lo que el tratamiento adecuado del brote, que persigue acortar su duración y mejorar su recuperación, sigue siendo una piedra angular en la atención a los pacientes con EM.Disponemos de abundantísima literatura médica y guías terapéuticas sobre los tratamientos que modifican la evolución natural de la enfermedad, pero muy poca sobre cual es el mejor tratamiento para el brote una vez que se produce. Existe acuerdo en que hay que tratar con corticoides, pero no hay consenso acerca de qué brotes tratar, qué corticoide utilizar, por qué vía, a qué dosis, por cuanto tiempo y con cuanto periodo de ventana terapéutica. En esta Tesis Doctoral se ha revisado la literatura médica relacionada con la fisiopatología del brote de EM, las pautas de tratamiento que se aplican y cómo actúan estos tratamientos, y se exponen los resultados del ensayo clínico multicéntrico, doble cegado y aleatorizado, que se ha realizado con el objeto de comprobar la hipótesis de que una dosis bioequivalente de metilprednisolona (MP) administrada por vía oral no debe de ser inferior, ni clínica ni radiológicamente, a la administrada por vía intravenosa para el tratamiento del brote de EM .Los resultados evidencian que no hay relación de inferioridad de la vía oral en relación a la intravenosa y que se mantiene el mismo nivel de seguridad y tolerancia. Esto en si mismo ya es un claro beneficio para la calidad de vida del paciente, pero además supone un ahorro para el sistema sanitario y laboral. Concluimos que no parece justificado seguir tratando el brote de EM con MP por vía intravenosa y creemos haber con-tribuido con este trabajo a cambiar el paradigma del tratamiento del brote de EM.Most patients with multiple sclerosis (MS) experience relapses, especially in the initial phases of the disease. The relapses are subacute episodes of neurological deficit with variable recovery. Current MS therapies are based on minimizing the risk of relapses, but none have been able to completely prevent them. Treating relapses, shortening their duration, and promoting recovery remain essential aspects in the care of patients with MS. The literature contains extensive guidelines regarding treatments to modify the natural history of MS, but there are few references about the best treatment for exacerbations. The experts agree that MS relapses should be treated with steroids, but there is no consensus regarding which steroid is optimal for this purpose, the most effective dose, or how long treatment should last. This thesis contains a review of the literature related to the pathophysiology of MS relapse, the guidelines that are applied for relapses, and the mechanisms of action of the treatments used. We report the results of a multi-center, double-blind, randomized clinical trial performed to test the hypothesis that a bioequivalent high dose of methylprednisolone (MP) administered orally, should not be inferior clinically or radiologically to intravenous MP for the treatment of MS relapses. The results show that the oral route is not inferior to the intravenous route for this purpose, and that the safety and tolerability of both administration routes are equal. These findings imply a great benefit for the patients' quality of life, in addition to healthcare- and work-related savings. We conclude that treatment of MS exacerbations with intravenous MP may not be justified. It is our hope that the results of this study will contribute to changing the treatment paradigm of MS relapses

Recommendations for the Diagnosis and Treatment of Multiple Sclerosis Relapses

Metilprednisolona; Esclerosi múltiple; RecaigudaMetilprednisolona; Esclerosis múltiple; RecaídaMethylprednisolone; Multiple sclerosis; RelapseMinimizing the risk of relapse is essential in multiple sclerosis (MS). As none of the treatments currently available are capable of completely preventing relapses, treatment of these episodes remains a cornerstone of MS care. The objective of this manuscript is to reduce uncertainty and improve quality of care of this neurological process. This article addresses definitions of key concepts, recommendations for clinical examination, classification criteria, magnetic resonance imaging, biomarkers, and specific therapeutic counsels including special populations such as pregnant and breastfeeding women, and children. An algorithm for treating MS relapses is also provided.This research was funded by NOVARTIS FARMACÉUTICA, SA, for the two expert panel meetings held and the recording and transcription of the content of the first meeting performed by the contract research organization, Dynamic

Vitamin D3-Induced Tolerogenic Dendritic Cells Modulate the Transcriptomic Profile of T CD4 + Cells Towards a Functional Hyporesponsiveness

The use of autologous tolerogenic dendritic cells (tolDC) has become a promising alternative for the treatment of autoimmune diseases. Among the different strategies available, the use of vitamin D3 for the generation of tolDC (vitD3-tolDC) constitutes one of the most robust approaches due to their immune regulatory properties, which are currently being tested in clinical trials. However, the mechanisms that vitD3-tolDC trigger for the induction of tolerance remain elusive. For this reason, we performed a full phenotypical, functional, and transcriptomic characterization of T cells upon their interaction with autologous, antigen-specific vitD3-tolDC. We observed a strong antigen-specific reduction of T cell proliferation, combined with a decrease in the relative prevalence of T1 subpopulations and IFN- γ production. The analysis of the transcriptomic profile of T CD4 + cells evidenced a significant down-modulation of genes involved in cell cycle and cell response to mainly pro-inflammatory immune-related stimuli, highlighting the role of JUNB gene as a potential biomarker of these processes. Consequently, our results show the induction of a strong antigen-specific hyporesponsiveness combined with a reduction on the T1 immune profile of T cells upon their interaction with vitD3-tolDC, which manifests the regulatory properties of these cells and, therefore, their therapeutic potential in the clinic. https://doi.org/10.13039/5011000033295https://doi.org/10.13039/5011000033293https://doi.org/10.13039/5011000033296https://doi.org/10.13039/501100003329 https://doi.org/10.13039/501100003329_https://doi.org/10.13039/501100003329_https://doi.org/10.13039/501100003329 https://doi.org/10.13039/50110000332

Adherencia a los tratamientos inmunomoduladores en los pacientes con esclerosis múltiple remitente recurrente. Propuestas para mejorar el cumplimiento

L'adherència a immunomoduladors en esclerosi múltiple és d'interès. OBJECTIU: Elaborar eines per millorar l'adherència MÈTODE: Reunió amb investigadors per avaluar els factors associats amb la no-adherència als immunomoduladors. RESULTATS: Es van acordar les recomanacions per neuròlegs i pacients i els qüestionaris a passar a l'inici del tractament i durant el seguiment per identificar els pacients probablement no adherents CONCLUSIÓ: L'adherència es considera essencial. Els professionals sanitaris han de verificar i utilizar estratègies per afavorirla. Donar informació adequada i utilitzar mètodes d'identificació de l'adherència és la clau de l'èxit.La adherencia a inmunomoduladores en esclerosis múltiple es de interés. OBJETIVO: Elaborar herramientas para mejorar la adherencia MÉTODO: Reunión con investigadores para evaluar los factores asociados con la no-adherencia a los inmunomoduladores. RESULTADOS: Se acordaron las recomendaciones para neurólogos y pacientes y los cuestionarios a pasar al inicio del tratamiento y durante el seguimiento para identificar a los pacientes probablemente no adherentes CONCLUSIÓN: La adherencia se considera esencial. Los profesionales sanitarios deben verificarla y usar estrategias para favorecerla. Dar información adecuada y utilizar métodos de identificación de la adherencia es la clave del éxito

Regulatory role of vitamin D in T-cell reactivity against myelin peptides in relapsing-remitting multiple sclerosis patients

Background: Low levels of plasma 25-hydroxyvitaminD (25(OH)D) are associated with a higher incidence of multiple sclerosis (MS) due to the immune suppressive properties of vitamin D. The aim of this study was to determine the correlation between plasma 25(OH)D concentrations and clinical and immunological variables in a cohort of multiple sclerosis patients. Methods: Plasma 25(OH)D concentrations were evaluated in summer and winter in 15 primary progressive MS (PPMS) patients, 40 relapsing- remitting MS (RRMS) patients and 40 controls (HC). Protocol variables included demographic and clinical data, radiological findings and immunological variables (oligoclonal bands, HLADR15 and T-lymphocyte proliferation to a definite mix of 7 myelin peptides). Results: During the winter, plasma concentrations were significantly lower in RRMS patients compared to HC, whereas no differences were found in summer. No relationships were found between plasma 25(OH)D concentrations and clinical or radiological variables. RRMS patients with a positive T-cell proliferation to a mix of myelin peptides (n = 31) had lower 25(OH)D concentrations. Conclusions: 25(OH)D is an immunomodulatory molecule that might have a regulatory role in T-cell proliferation to myelin peptides in RRMS patients

Comparative transcriptomic profile of tolerogenic dendritic cells differentiated with vitamin D3, dexamethasone and rapamycin

Tolerogenic dendritic cell (tolDC)-based therapies have become a promising approach for the treatment of autoimmune diseases by their potential ability to restore immune tolerance in an antigen-specific manner. However, the broad variety of protocols used to generate tolDC in vitro and their functional and phenotypical heterogeneity are evidencing the need to find robust biomarkers as a key point towards their translation into the clinic, as well as better understanding the mechanisms involved in the induction of immune tolerance. With that aim, in this study we have compared the transcriptomic profile of tolDC induced with either vitamin D3 (vitD3-tolDC), dexamethasone (dexa-tolDC) or rapamycin (rapa-tolDC) through a microarray analysis in 5 healthy donors. The results evidenced that common differentially expressed genes could not be found for the three different tolDC protocols. However, individually, CYP24A1, MUCL1 and MAP7 for vitD3-tolDC; CD163, CCL18, C1QB and C1QC for dexa-tolDC; and CNGA1 and CYP7B1 for rapa-tolDC, constituted good candidate biomarkers for each respective cellular product. In addition, a further gene set enrichment analysis of the data revealed that dexa-tolDC and vitD3-tolDC share several immune regulatory and anti-inflammatory pathways, while rapa-tolDC seem to be playing a totally different role towards tolerance induction through a strong immunosuppression of their cellular processes

MAP7 and MUCL1 are biomarkers of Vitamin D3-induced tolerogenic dendritic cells in multiple sclerosis patients

The administration of autologous tolerogenic dendritic cells (tolDC) has become a promising alternative for the treatment of autoimmune diseases, such as multiple sclerosis (MS). Specifically, the use of vitamin D3 for the generation of tolDC (vitD3-tolDC) constitutes one of the most widely studied approaches, as it has evidenced significant immune regulatory properties, both in vitro and in vivo. In this article, we generated human vitD3-tolDC from monocytes from healthy donors and MS patients, characterized in both cases by a semi-mature phenotype, secretion of IL-10 and inhibition of allogeneic lymphocyte proliferation. Additionally, we studied their transcriptomic profile and selected a number of differentially expressed genes compared to control mature and immature dendritic cells for their analysis. Among them, qPCR results validated CYP24A1, MAP7 and MUCL1 genes as biomarkers of vitD3-tolDC in both healthy donors and MS patients. Furthermore, we constructed a network of protein interactions based on the literature, which manifested that MAP7 and MUCL1 genes are both closely connected between them and involved in immune-related functions. In conclusion, this study evidences that MAP7 and MUCL1 constitute robust and potentially functional biomarkers of the generation of vitD3-tolDC, opening the window for their use as quality controls in clinical trials for MS

Cryopreserved vitamin D3-tolerogenic dendritic cells pulsed with autoantigens as a potential therapy for multiple sclerosis patients

Altres ajuts: Cost Action BM1305BACKGROUND: Tolerogenic dendritic cells (tolDC) have been postulated as a potent immunoregulatory therapy for autoimmune diseases such as multiple sclerosis (MS). In a previous study, we demonstrated that the administration of antigen-specific vitamin D3 (vitD3) tolDC in mice showing clinical signs of experimental autoimmune encephalomyelitis (EAE; the animal model of MS) resulted in abrogation of disease progression. With the purpose to translate this beneficial therapy to the clinics, we have investigated the effectivity of vitD3-frozen antigen-specific tolDC pulsed with myelin oligodendrocyte glycoprotein 40-55 peptide (f-tolDC-MOG) since it would reduce the cost, functional variability and number of leukapheresis to perform to the patients. METHODS: Mice showing EAE clinical signs were treated with repetitive doses of f-tolDC-MOG. Tolerogenic mechanisms induced by the therapy were analysed by flow cytometry and T cell proliferation assays. RESULTS: Treatment with f-tolDC-MOG was effective in ameliorating clinical signs of mice with EAE, inhibiting antigen-specific reactivity and inducing Treg. In addition, the long-term treatment was well tolerated and leading to a prolonged maintenance of tolerogenicity mediated by induction of Breg, reduction of NK cells and activation of immunoregulatory NKT cells. CONCLUSIONS: The outcomes of this study show that the use of antigen-specific f-tolDC promotes multiple and potent tolerogenic mechanisms. Moreover, these cells can be kept frozen maintaining their tolerogenic properties, which is a relevant step for their translation to the clinic. Altogether, vitD3 f-tolDC-MOG is a potential strategy to arrest the autoimmune destruction in MS patients

Seroprevalence of SARS-CoV-2 in a Cohort of Patients with Multiple Sclerosis under Disease-Modifying Therapies

Background: Disease-modifying therapies (DMTs) used to treat multiple sclerosis (MS) alter the immune system and therefore increase the risk of infection. There is growing concern about the impact of COVID-19 on patients with MS (pwMS), especially those treated with DMTs. Methods: This is a single-center prospective observational study based on data from the Esclerosis Múltiple y COVID-19 (EMCOVID-19) study. Demographic characteristics, MS history, laboratory data and SARS-CoV-2 serology, and symptoms of COVID-19 in pwMS treated with any DTM were extracted. The relationship among demographics, MS status, DMT, and COVID-19 was evaluated. Results: A total of 259 pwMS were included. The administration of interferon was significantly associated with the presence of SARS-CoV-2 antibodies (26.4% vs. 10.7%, p = 0.006). Although patients taking interferon were significantly older (49.1 vs. 43.5, p = 0.003), the association of interferon with the presence of SARS-CoV-2 antibodies was still significant in the multivariate analysis (OR 2.99 (1.38; 6.36), p = 0.006). Conclusions: According to our data, pwMS present a higher risk of COVID-19 infection compared with results obtained from the general population. There is no evidence of a worse COVID-19 outcome in pwMS. DMTs did not significantly change the frequency of COVID-19, except for interferon; however, these findings must be interpreted with caution given the small sample of pwMS taking each DMT