MHC2TA mRNA levels and human herpesvirus 6 in multiple sclerosis patients treated with interferon beta along two-year follow-up.

BACKGROUND: In previous studies we found that MHC2TA +1614 genotype frequency was very different when MS patients with and without human herpesvirus 6 (HHV-6) in serum samples were compared; a different clinical behavior was also described. The purpose of the study was: 1. To evaluate if MHC2TA expression in MS patients was influenced by interferon beta (IFN-beta) treatment. 2. To study MHC2TA expression in MS patients with and without minor allele C. 3. To analyze the relation between MHC2TA mRNA levels and HHV-6 active infection in MS patients. METHODS: Blood and serum samples of 154 MS patients were collected in five programmed visits: basal (prior to beginning IFN-beta treatment), six, twelve, eighteen and twenty-four months later. HHV-6 in serum and MHC2TA mRNA levels were evaluated by PCR and RT-PCR, respectively. Neutralizing antibodies (NAbs) against IFN-beta were analyzed by the cytopathic effect assay. RESULTS: We found that MHC2TA mRNA levels were significantly lower among MS patients with HHV-6 active infection at the basal visit (without treatment) than in those MS patients without HHV-6 active infection at the basal visit (p = 0.012); in all the positive samples we only found variant A. Furthermore, 58/99 (58.6%) MS patients without HHV-6 along the five programmed visits and an increase of MHC2TA expression after two-years of IFN-beta treatment were clinical responders vs. 5/21 (23.8%) among those MS patients with HHV-6 and a decrease of MHC2TA mRNA levels along the two-years with IFN-beta treatment (p = 0.004); no differences were found between patients with and without NAbs. CONCLUSIONS: MHC2TA mRNA levels could be decreased by the active replication of HHV-6; the absence of HHV-6 in serum and the increase of MHC2TA expression could be further studied as markers of good clinical response to IFN-beta treatment.

CD46 in a Spanish cohort of multiple sclerosis patients: genetics, mRNA expression and response to interferon-beta treatment.

BACKGROUND: In a prior study of our group we found an up-regulation of CD46 expression in a cohort of Spanish multiple sclerosis (MS) patients. OBJECTIVE: To evaluate the potential role of CD46 in the response to interferon-beta treatment in MS patients through the analysis of five tagging single nucleotide polymorphisms (SNPs) and measurement of mRNA. METHODS: A total of 406 MS patients and 513 control patients were analysed for five SNPs at the CD46 locus. Furthermore, 163 MS patients and 163 matched control patients were analysed by RT-PCR for the CD46 mRNA expression in three blood samples (basal, and at 6 and 12 months of interferon-beta treatment) collected in the course of a 1-year follow-up. RESULTS: Two genotypes of rs2724385 polymorphism (AT and TT) could be markers of response to interferon-beta therapy in MS patients (p=0.007 and p=0.006, respectively). Furthermore, the frequency of interferon-beta responders was 44.4% (32/72) in MS patients with an increased CD46 mRNA expression, vs. 65.9% (60/91) in patients with a decreased CD46 mRNA expression (p=0.006). CONCLUSION: The present study shows that CD46 could be associated with the response to interferon-beta therapy; however, the genetic results should be replicated in an independent cohort and further studies are needed to confirm the role of CD46.

IFNbeta-1a therapy for multiple sclerosis expands regulatory CD8+ T cells and decreases memory CD8+ subset: a longitudinal 1-year study.

The beneficial effects of interferon beta-1a (IFNbeta-1a) in multiple sclerosis (MS) remain only partially understood. CD8(+) T cells are key cells in MS pathogenesis that contribute to axonal damage in MS, whereas CD4(+) regulatory T cells (T(Reg)) and CD8(+) regulatory/suppressor T cells (Ts) play an important role in protecting against subsequent MS activity. We analysed ex vivo changes on T(Reg) and on the different subsets of CD4(+) and CD8(+) T lymphocytes, before IFNbeta-1a (Rebif) therapy and at 3, 6, and 12 months after treatment, in 23 MS patients and in 26 healthy controls. IFNbeta-1a significantly increased the proportions of CD4(+) T(Reg) and regulatory CD8(+) T cells (Tr). Memory CD8(+) T cells were significantly decreased after 1 year of treatment, maybe reflecting down-regulation of abnormally persistent systemic activation in MS patients. After 1 year of IFNbeta-1a, a direct correlation was observed between plasmacytoid dendritic cells and effector CD8(+) T cells.

IFIH1-GCA-KCNH7 locus: influence on multiple sclerosis risk.

A recent genome-wide scan of nonsynonymous SNPs and ulterior validation in case-control and family analyses evidenced a susceptibility locus for type 1 diabetes (T1D) on chromosome 2q24.3. We aimed at testing the effect of this locus in other autoimmune diseases with complex genetic background, such as multiple sclerosis (MS). Four SNPs along the locus, rs13422767, rs2111485, rs1990760 and rs2068330, were genotyped using TaqMan MGB chemistry in 311 T1D and 412 MS patients and 535 ethnically matched healthy controls. The previously reported association of this locus was found for the first time in MS (rs2068330, G vs C: P=0.001; OR (95% CI)=0.73 (0.6-0.88)) and a trend for replication was observed in our Spanish diabetic cohort. Therefore, genes included in this locus - IFIH1 interferon induced helicase, GCA grancalcin or the potassium channel KCNH7 - are potential candidates implicated in the pathogenesis of these autoimmune diseases, although strong linkage disequilibrium in the region hampered further localization of the etiologic gene.

TLR4 haplotypes in multiple sclerosis: a case-control study in the Spanish population.

Our aim in the present study is to evaluate the variation present in the TLR4 gene and its relationship with multiple sclerosis susceptibility in the Spanish population. Three hundred and sixty-two multiple sclerosis patients and 467 healthy controls from the Spanish population were included in the present study. Twelve single nucleotide polymorphisms (SNPs) were selected, and analyzed by the TaqMan technique. No statistically significant differences for any polymorphism or haplotypes were observed when patients were compared with controls. In conclusion, TLR4 does not play a major role in the predisposition to suffer from multiple sclerosis in our population.

FcRL3 and multiple sclerosis pathogenesis: role in autoimmunity?

BACKGROUND AND AIMS: A functional promoter polymorphism in the FcRL3 gene, -169 T/C, has been shown to regulate gene expression and to play a role in several autoimmune diseases. We aimed at testing for the first time whether this gene was involved in multiple sclerosis (MS) pathogenesis. METHODS: Case-control study performed with 400 Spanish MS patients and 508 healthy subjects. Genotyping of -169 T/C and -110 G/A was ascertained by using TaqMan MGB chemistry following manufacturer suggestions (Applied Biosystems, CA, USA). RESULTS: As previously seen for other autoimmune diseases, a significant difference was observed in the distribution of -169 T/C FcRL3 genotypes between MS patients and healthy controls (p = 0.03; chi(2) = 6.99). The -169 T allele, recently associated with increased susceptibility to Addison's disease, showed a parallel effect in MS [(TT+TC) vs. CC: p = 0.013; OR = 1.55 (1.08-2.54)]. CONCLUSIONS: An increased susceptibility associated to the -169 T allele was found when MS patients and controls were compared, supporting the role of the FcRL3 locus in MS predisposition and therefore extending the evidence of its general influence on autoimmunity.

Interferon beta-1a therapy enhances CD4+ regulatory T-cell function: an ex vivo and in vitro longitudinal study in relapsing-remitting multiple sclerosis.

Interferon beta-1a (IFNâ-1a) has demonstrated efficacy in multiple sclerosis (MS), although its mechanism of action remains only partly understood. We evaluated the ex vivo and in vitro effects of IFNâ-1a (Rebif) on regulatory T-cell (T(Reg)) function in 22 relapsing-remitting MS patients and 16 healthy controls. T(Reg) function was significantly enhanced after 3 and 6 months of IFNbeta-1a therapy. Furthermore, there was a trend towards increasing proportions of total CD4(+)CD25(+) and CD4(+)CD25(+)GITR(+) T(Reg) after 6 months of IFNbeta-1a therapy when compared with baseline. In conclusion, IFNbeta-1a therapy enhances T(Reg) function, and this may be relevant in the inflammatory environment of MS lesions.

Environment-gene interaction in multiple sclerosis: human herpesvirus 6 and MHC2TA.

Multiple sclerosis (MS) is an inflammatory disorder affecting the central nervous system, in which both genetic and environmental factors interact. Among these environmental contributors, herpesvirus has been proposed as an important etiologic factor. CIITA is a transcription factor controlling the expression of MHC class II genes, the main genetic determinants of MS susceptibility. This gene has been described as a target of the immunoevasive strategies, and it is therefore an attractive candidate gene to be at the genetic-viral crossroads. Two polymorphisms in MHC2TA gene (rs4,774G/C and rs3,087,456A/G) were studied in two groups: one in 22 multiple sclerosis patients with active human herpes virus 6 (HHV-6A) replication (HHV-6A-positive), and the other of 77 patients with no detectable HHV-6A active infection (HHV-6A-negative); a Spanish healthy control group (n = 520) was also included as external control. An association of the rs4,774C allele with the HHV-6A-positive group was found when compared with the HHV-6A-negative (47.7% vs 18.8%, p = 0.0001; odds ratio = 3.94) and also with the control group (47.7% vs 25.5%, p = 0.001, odds ratio = 2.67). No significant differences were observed between HHV-6A-negative subjects and healthy controls. Our data suggest that a strong gene-environment interaction occurs between HHV-6A active replication and MHC2TA rs4,774C or another polymorphism in tight linkage disequilibrium with it. Besides, this report indicates that when patients are grouped based upon a well-defined molecular event, complex diseases may reveal themselves as being constituted by distinct entities in which some genes may have a strong influence.

Human herpesvirus 6 and multiple sclerosis: a one-year follow-up study.

BACKGROUND: This study was undertaken in order to investigate the possible relation of HHV-6 and EBV in relapsing-remitting MS (RRMS). MATERIALS AND METHODS: A one-year follow up study was performed analysing peripheral blood mononuclear cells and serum samples of 57 patients with RRMS and 57 healthy blood donors (HBD) by a quantitative real time PCR, to detect HHV-6 and EBV. Clinical data (starting age and EDSS increase) were collected. RESULTS: We did not find any statistically significant difference for EBV between RRMS patients and HBD. Regarding HHV-6: i) There was a higher prevalence of HHV-6 in RRMS patients than in controls: 80.7% versus 29.8% respectively. ii) HHV-6 active replication seems to be related to exacerbations. iii) Only variant A was detected among RRMS patients with HHV-6 active replication. iv) Although some difference was found when we compared clinical data in RRMS patients with and without HHV-6 active replication, the results did not reach statistical significance. CONCLUSIONS: A higher HHV-6A frequency of active infection (reactivation or new infection) would lead to a more frequent exposure of HHV-6A antigens to the immune system of RRMS patients; this active replication of HHV-6A seems to be specifically related with the exacerbations in a subset of RRMS patients.

Clinical parameters and HHV-6 active replication in relapsing-remitting multiple sclerosis patients.

BACKGROUND: Although the etiology of multiple sclerosis (MS) remains uncertain, clinical, epidemiological, and laboratory findings suggest that environmental factors may be involved in the disease. OBJECTIVE: This study was undertaken in order to investigate the possible relation of human herpesvirus-6 (HHV-6) in relapsing-remitting MS (RRMS). STUDY DESIGN: A one-year follow-up study was performed analyzing serum samples of 63 patients with RRMS and 63 healthy blood donors (HBD) by a quantitative real time PCR, to measure HHV-6 prevalence and viral load. Clinical data (starting age and EDSS increase) were collected. RESULTS: (i) We found 25.4% of RRMS patients with at least one positive serum sample along the one year follow-up. (ii) 19.1% of RRMS samples in relapse had HHV-6 active infection vs. 7.9% of RRMS samples in remission. (iii) We only found variant A. (iv) RRMS patients with HHV-6 active replication initiated the disease 1.9 years earlier, and they had a higher EDSS increase. CONCLUSIONS: A higher HHV-6A frequency of active infection seems to be related with the exacerbations in a subset of RRMS patients. Regarding the relationship between HHV-6A active infection and the clinical data in RRMS patients, further investigations are needed.

Role of interleukin 4 in Spanish multiple sclerosis patients.

Interleukin 4 is a Th2 cytokine with potent anti-inflammatory properties. Protection from autoimmune encephalomyelitis and multiple sclerosis has been achieved with IL-4 therapy and IL-4 deficient mice developed a more severe form of clinical disease. Four polymorphisms within the IL-4 gene are in strong linkage disequilibrium, including one in the promoter at -590, which controls transcriptional activity. An MS protective role for the heterozygous genotype was confirmed in Spain (exon-1+33 C/T: p=0.003, OR [CI]=0.57 [0.38-0.84]), probably indicative of an MS protection haplotype at 5q31 locus. No difference among MS clinical forms or age at onset was detected.

Early B-cell Factor gene association with multiple sclerosis in the Spanish population.

BACKGROUND: The etiology of multiple sclerosis (MS) is at present not fully elucidated, although it is considered to result from the interaction of environmental and genetic susceptibility factors. In this work we aimed at testing the Early B-cell Factor (EBF1) gene as a functional and positional candidate risk factor for this neurological disease. Axonal damage is a hallmark for multiple sclerosis clinical disability and EBF plays an evolutionarily conserved role in the expression of proteins essential for axonal pathfinding. Failure of B-cell differentiation was found in EBF-deficient mice and involvement of B-lymphocytes in MS has been suggested from their presence in cerebrospinal fluid and lesions of patients. METHODS: The role of the EBF1 gene in multiple sclerosis susceptibility was analyzed by performing a case-control study with 356 multiple sclerosis patients and 540 ethnically matched controls comparing the EBF1 polymorphism rs1368297 and the microsatellite D5S2038. RESULTS: Significant association of an EBF1-intronic polymorphism (rs1368297, A vs. T: p = 0.02; OR = 1.26 and AA vs. [TA+TT]: p = 0.02; OR = 1.39) was discovered. This association was even stronger after stratification for the well-established risk factor of multiple sclerosis in the Major Histocompatibility Complex, DRB1*1501 (AA vs. [TA+TT]: p = 0.005; OR = 1.78). A trend for association in the case-control study of another EBF1 marker, the allele 5 of the very informative microsatellite D5S2038, was corroborated by Transmission Disequilibrium Test of 53 trios (p = 0.03). CONCLUSION: Our data support EBF1 gene association with MS pathogenesis in the Spanish white population. Two genetic markers within the EBF1 gene have been found associated with this neurological disease, indicative either of their causative role or that of some other polymorphism in linkage disequilibrium with them.

Relapsing-remitting multiple sclerosis and human herpesvirus 6 active infection.

BACKGROUND: Recent studies have focused on the relationship between human herpesvirus 6 (HHV-6) and multiple sclerosis (MS). OBJECTIVE: To analyze HHV-6 messenger RNA expression in patients with relapsing-remitting (RR) MS vs healthy blood donors (HBDs). DESIGN: One hundred fifty-four subjects were enrolled in the study: 105 patients with RRMS (32 in relapse) and 49 HBDs. Total DNA and messenger RNA were extracted from serum and blood samples, respectively, and analyzed by quantitative real-time reverse transcription-polymerase chain reaction for the detection of 3 HHV-6 immediate-early genes (U16/U17,U89/U90, and U94) and both HHV-6 variants (HHV-6A and HHV-6B). RESULTS: Active HHV-6 infection was detected in 16% of patients with RRMS vs 0% of HBDs (P = .003). Seven patients with RRMS with exacerbation had HHV-6 active replication, and the virus remained latent in only 1 of them. We did not find any statistically significant difference between HHV-6 active or latent infection for patients in remission (P = .12). Among patients with RRMS with HHV-6 active replication, viral load was higher when they experienced an acute attack than when in remission (P = .04). In those patients with RRMS who had an active infection only, HHV-6A was found. Cell-free HHV-6 DNA detected in serum samples confirmed the results. CONCLUSIONS: The results show that a subset of patients with RRMS experience HHV-6 active infection, and there likely is an association between the viral active replication and relapses; therefore, HHV-6 active infection may imply a greater risk of exacerbations in a subgroup of patients with RRMS.

Active human herpesvirus 6 infection in patients with multiple sclerosis.

CONTEXT: Human herpesvirus 6 (HHV-6) has been linked with multiple sclerosis (MS). OBJECTIVES: To determine HHV-6 viral load in patients with MS, and to analyze separately its 2 variants, HHV-6A and HHV-6B. PATIENTS AND METHODS: We analyzed 149 blood and serum samples; 103 were from patients with relapsing-remitting MS (33 during an MS relapse and 70 during remission), and 46 were from healthy blood donors. To determine whether the HHV-6 genome and its variants were present, we analyzed viral DNA using quantitative real-time polymerase chain reaction, which has a sensitivity of 1 copy. RESULTS: We found HHV-6 DNA in the peripheral blood mononuclear cells of 53.4% of patients and 30.4% of healthy blood donors; HHV-6A was found in 20.4% of patients and 4.4% of controls, and HHV-6B was found in 33.0% vs 26.1%, respectively. Mean viral load in both groups was 7.4 copies of HHV-6 per microgram of DNA (range, 1-15 copies). Analysis of serum samples showed that none of the healthy blood donors were positive for HHV-6, although 14.6% of patients were positive for the virus, specifically the HHV-6A variant. There was no difference between patients during remission or relapse. Mean viral load was 26.3 copies/microg microgram of DNA (range, 1-86 copies). CONCLUSIONS: Despite the low viral load and the lack of clinical correlation, and given the biological characteristics of the virus, our results suggest that there was active HHV-6A infection in 14.6% of patients with MS. Further quantitative real-time polymerase chain reaction studies will help us understand the clinical significance of such a low viral load.

Interleukin-10 polymorphisms in Spanish multiple sclerosis patients.

Interleukin-10 (IL-10) is an anti-inflammatory cytokine that may be an important regulator in multiple sclerosis (MS) pathogenesis. IL-10 gene contains three single nucleotide polymorphisms (SNPs) and two polymorphic microsatellites in the 5'-flanking region. Our aim was to ascertain if any of these polymorphic markers is associated or linked to MS among Spanish patients. We have genotyped 300 patients and 357 ethnically matched controls for the microsatellites, and most of them also for the promoter SNPs. We included in this study the parents of 63 patients in order to perform a TDT analysis as well. IL-10G12 allele was significantly increased in MS patients (17% versus 11% in controls; p=0.004; p(c)<0.05). No other allele showed a significant difference between patients and controls, and the TDT analysis yielded negative results. The data indicate that IL-10 is not a major susceptibility locus in MS, but in our population it might, however, have a minor role.

Anti-JCV antibodies detection and JCV DNA levels in PBMC, serum and urine in a cohort of Spanish Multiple Sclerosis patients treated with natalizumab.

One of the most effective multiple sclerosis (MS) treatment is natalizumab. Nevertheless, it has been associated with an increased risk of progressive multifocal leukoencephalopathy (PML) caused by the JC virus (JCV). Our main objective was to assess the utility of testing JCV-DNA, apart from anti-JCV antibodies, to determine which natalizumab-treated MS patients has been previously in contact with the virus. For this purpose, 138 MS natalizumab/non-natalizumab treated patients participated in several studies. Cross-sectional study (CS): association of several epidemiological variables with anti-JCV antibodies and JCV-DNA levels in PBMC/serum/urine. First longitudinal study (A): evaluation of JCV-DNA prevalence in urine throughout the treatment. Second longitudinal study (B): simultaneous assessment of antibodies and viral DNA levels in PBMC/serum/urine at two time points. CS: The seropositivity rate for anti-JCV antibodies (62.3 %) and JCV prevalence in urine (59.4 %) were similar; although 26 % of our population was positive only using one of the two techniques. A: The viral prevalence in urine seemed to increase between the baseline visit and the others (Baseline-Visit/V18months, p = 0.006). B: Our rate of positive antibody seroconversion was 36 %. Nearly all patients with detectable JCV-DNA levels in PBMC excreted the virus intermittently in urine; while our PML case, positive in PBMC and serum samples 2 month before the PML, excreted JCV permanently. In conclusion, the determination of JCV DNA levels in urine could be complementary to anti-JCV antibodies for identifying MS patients who has been infected by the JCV. Further research would be necessary to understand the different JCV excretion profiles in urine.

The DNA copy number of human endogenous retrovirus-W (MSRV-type) is increased in multiple sclerosis patients and is influenced by gender and disease severity.

BACKGROUND: Multiple sclerosis is an autoimmune disease more prevalent in women than in men. Multiple Sclerosis Associated Retrovirus element (MSRV) is a member of type-W endogenous retrovirus family (HERV-W), known to be associated to MS. Most HERVs are unable to replicate but MSRV expression associated with reverse-transcriptase activity in MS would explain reported DNA copy number increase in MS patients. A potential link between HERV-W copies on chromosome X and gender differential prevalence has been suggested. The present study addresses MSRV-type DNA load in relation with the gender differences and clinical status in MS and healthy controls. RESULTS: 178 MS patients (62.9% women) and 124 controls (56.5% women) were included. MSRV env load (copies/pg of DNA) was analyzed by real time qPCR with specific primers and probe for its env gene, in DNA from peripheral blood mononuclear cells (PBMCs). MSRV load was more elevated in MS patients than in controls (p = 4.15e-7). MS women presented higher MSRV load than control women (p = 0.009) and MS men also had higher load than control men (p = 2.77e-6). Besides, women had higher levels than men, both among patients (p = 0.007) and controls (p = 1.24e-6). Concordantly, EDSS and MSSS scores were higher among female patients with an elevated MSRV load (p = 0.03 and p = 0.04, respectively). CONCLUSIONS: MSRV increases its copy number in PBMC of MS patients and particularly in women with high clinical scores. This may explain causes underlying the higher prevalence of MS in women. The association with the clinical severity calls for further investigations on MSRV load in PBMCs as a biomarker for MS.

Review of the novelties presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (I).

The most relevant data presented at the 28th edition of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held in October 2012 in France, have been summarized in the fifth edition of the Post-ECTRIMS Expert Meeting held in Madrid in October 2012. The present review summarizes the views and results of the meeting and is being published in three parts. This first part of the Post-ECTRIMS review addresses the incidence and prevalence of multiple sclerosis (MS), which has increased at the global level, largely due to the increased incidence in women because the risk of developing the disease is increased in females, with minimal concurrent effect on the progression of MS. Sexual dimorphism is evident in MS, and all evidence points to an interaction between hormonal, genetic, and environmental factors. The paediatric population represents an ideal group to study susceptibility factors to the disease, which is why collaborative studies designed to increase the patient samples are being considered, given its low prevalence. In this review, inflammatory and neurodegenerative phenomena involved in the pathogenesis of the disease and that have a cause-and-effect or shared relationship with the disease are being discussed. Current hypotheses suggest a phenomenon of compartmentalization, presumably inaccessible to current immunomodulatory therapy. Among the possible mechanisms involved in these processes of inflammation and demyelination, the role of Th17 cells, mitochondrial dysfunction, early disruption of astrocytic processes, and chronic hypoxia are discussed.

TITLE: Revision de las novedades presentadas en el XXVIII Congreso del Comite Europeo para el Tratamiento e Investigacion en Esclerosis Multiple (ECTRIMS) (I).Los datos mas relevantes presentados en la XXVIII edicion del Congreso del Comite Europeo para el Tratamiento e Investigacion en Esclerosis Multiple (ECTRIMS), celebrado en octubre de 2012 en Francia, se han resumido en la quinta edicion de la Reunion de Expertos Post-ECTRIMS celebrada en Madrid en octubre de 2012, fruto de la cual nace esta revision, que se publica en tres partes. Esta primera parte de la revision Post-ECTRIMS aborda la incidencia y prevalencia de la esclerosis multiple (EM), que, en el ambito mundial, ha aumentado a expensas de las mujeres, ya que el sexo femenino aumenta el riesgo de desarrollar la enfermedad, aunque no afecta de forma negativa a su evolucion. El dimorfismo sexual en la EM es evidente, y todo apunta a una interaccion entre factores hormonales, geneticos y medioambientales. La poblacion pediatrica representa un grupo idoneo para el estudio de factores de susceptibilidad a la enfermedad, razon por la que se estan planteando estudios colaborativos ideados para aumentar la muestra de pacientes, dada su baja prevalencia. En esta revision se discute sobre los fenomenos inflamatorios y de neurodegeneracion que intervienen en la patogenia de la enfermedad, y que probablemente esten relacionados, bien de forma compartida o como causa efecto. Las hipotesis actuales apuntan a un fenomeno de compartimentacion presumiblemente inaccesible a la terapia inmunomoduladora actual. Entre los posibles mecanismos involucrados en estos procesos de inflamacion y desmielinizacion se discute el papel de las celulas Th17, disfuncion mitocondrial, disrupcion precoz de procesos astrocitarios e hipoxia cronica.

Review of the novelties presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (III).

The most significant data presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held in France in October 2012, have been summarised in the fifth edition of the Post-ECTRIMS Experts Meeting, held in Madrid in October 2012. This led to the drafting of this review, which has been published in three parts. This third part of the Post-ECTRIMS review presents the findings from the latest studies conducted with disease-modifying treatments, more specifically with glatiramer acetate, laquinimod, ponesimod, BG-12, teriflunomide, daclizumab, natalizumab and secukinumab (AIN457). Likewise, we also address the reasons that justify the search for innovative treatments for multiple sclerosis, with antigen-specific therapy, cell therapy and therapy aimed at promoting remyelination being highlighted among other future therapeutic strategies. Access to new pharmacological agents and the complexity of the therapy of multiple sclerosis in the future will require new design strategies and directions in clinical trials, including the use of surrogate markers, new statistical applications, superiority, inferiority or equivalence clinical trials and adaptable designs.

TITLE: Revision de las novedades presentadas en el XXVIII Congreso del Comite Europeo para el Tratamiento e Investigacion en Esclerosis Multiple (ECTRIMS) (III).Los datos mas relevantes presentados en la XXVIII edicion del Congreso del Comite Europeo para el Tratamiento e Investigacion en Esclerosis Multiple (ECTRIMS), celebrado en octubre de 2012 en Francia, han sido resumidos en la quinta edicion de la Reunion de Expertos Post-ECTRIMS celebrada en Madrid en octubre de 2012, fruto de la cual nace esta revision que se publica en tres partes. Esta tercera parte de la revision Post-ECTRIMS expone los resultados de los ultimos estudios realizados con los tratamientos modificadores de la enfermedad, concretamente con acetato de glatiramero, laquinimod, ponesimod, BG-12, teriflunomida, daclizumab, natalizumab y secukinumab (AIN457). Asimismo, se abordan las razones que justifican la busqueda de tratamientos innovadores para la esclerosis multiple, destacando la terapia antigenoespecifica, la terapia celular y la terapia dirigida a promover la remielinizacion entre las futuras estrategias terapeuticas. La disponibilidad de nuevos farmacos y la complejidad de la futura terapia de la esclerosis multiple necesitan nuevas direcciones y estrategias de diseño en los ensayos clinicos, entre ellas el uso de marcadores subrogados, nuevas aplicaciones estadisticas, ensayos clinicos de superioridad, inferioridad o equivalencia, y diseños adaptables.

Review of the novelties presented at the 27th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (II).

The new insights presented at the 5th Joint Triennial Congress of the European and Americas Committees on Treatment and Research in Multiple Sclerosis (ECTRIMS and ACTRIMS) held in Amsterdam, the Netherlands, 19-22 October 2011, have been summarized at the fourth edition of Post-ECTRIMS meeting held in Madrid in November 2011. Regional grey-matter atrophy is more sensitive to cognitive impairment than global grey-matter atrophy measures. In patients with clinically isolated syndrome cognitive impairment does not predict conversion to multiple sclerosis (MS) after 5-years of follow-up. Focusing on central nervous system plasticity and functional reorganization in MS, an early intervention can improve clinical aspects and enhances brain plasticity. Preservation of a potential for plasticity provides a rationale for rehabilitation interventions even in later stages of disease. Therapeutical strategies have focused on stem cell-mediated remyelination and immunomodulation functions, on cellular infiltration into the brain, and on new ways for immuno-modulation for the development of future therapies in MS. Encouraging findings from clinical trials with current and emerging disease-modifying therapy being developed was also a key theme at this edition. Positive results have been reported for rituximab, ocrelizumab, ofatumumab, daclizumab, alemtuzumab, teriflunomide, BG-12, and laquinimod, including a favorable safety profile. Since armamentarium for the treatment of MS is fast increasing, concerns exist about the risk of severe adverse events with their use. This aspect reinforces the importance of disease registries as a proactive tool for monitoring drug safety in the post-approval setting.