Serum biomarker levels predict disability progression in patients with primary progressive multiple sclerosis.

BACKGROUND: We aimed to investigate the potential of serum biomarker levels to predict disability progression in a multicentric real-world cohort of patients with primary progressive multiple sclerosis (PPMS). METHODS: A total of 141 patients with PPMS from 18 European MS centres were included. Disability progression was investigated using change in Expanded Disability Status Scale (EDSS) score over three time intervals: baseline to 2 years, 6 years and to the last follow-up. Serum levels of neurofilament light chain (sNfL), glial fibrillar acidic protein (sGFAP) and chitinase 3-like 1 (sCHI3L1) were measured using single-molecule array assays at baseline. Correlations between biomarker levels, and between biomarkers and age were quantified using Spearman's r. Univariable and multivariable linear models were performed to assess associations between biomarker levels and EDSS change over the different time periods. RESULTS: Median (IQR) age of patients was 52.9 (46.4-58.5) years, and 58 (41.1%) were men. Median follow-up time was 9.1 (7.0-12.6) years. Only 8 (5.7%) patients received treatment during follow-up. sNfL and sGFAP levels were moderately correlated (r=0.43) and both weakly correlated with sCHI3L1 levels (r=0.19 and r=0.17, respectively). In multivariable analyses, levels of the three biomarkers were associated with EDSS changes across all time periods. However, when analysis was restricted to non-inflammatory patients according to clinical and radiological parameters (n=64), only sCHI3L1 levels remained associated with future EDSS change. CONCLUSIONS: Levels of sNfL, sGFAP and sCHI3L1 are prognostic biomarkers associated with disability progression in patients with PPMS, being CHI3L1 findings less dependent on the inflammatory component associated with disease progression.

Effectiveness and Safety of Teriflunomide in Relapsing-Remitting Multiple Sclerosis and Improvements in Quality of Life: Results from the Real-World TERICARE Study.

INTRODUCTION: Teriflunomide is a once-daily oral immunomodulator approved for relapsing forms of multiple sclerosis (MS) or relapsing-remitting multiple sclerosis (RRMS; depending on the local label), based on extensive evidence from clinical trials and a real-world setting on efficacy, tolerability and patient-reported benefits. The TERICARE study assessed the impact of teriflunomide treatment over 2 years on health-related quality of life (HRQoL) and some of the most common and disabling symptoms of MS, such as fatigue and depression. METHODS: This prospective observational study in Spain included RRMS patients treated with teriflunomide for ≤ 4 weeks. The following patient-reported outcomes (PROs) were collected at baseline and every 6 months for 2 years: the 29-item Multiple Sclerosis Impact Scale version 2 (MSIS-29), the 21-item Modified Fatigue Impact Scale (MFIS-21), the Beck Depression Inventory (BDI-II), the Short Form (SF)-Qualiveen and the Treatment Satisfaction Questionnaire for Medication v1.4 (TSQM). Annualised relapse rate (ARR), disability progression according to the Expanded Disability Status Scale (EDSS), and no evidence of disease activity (NEDA-3) were also assessed. RESULTS: A total of 325 patients were analysed. Patients had a mean (SD) age of 43.2 years (10.4), a mean baseline EDSS score of 1.75 (1.5), a mean number of relapses in the past 2 years of 1.5 (0.7), and 64% had received prior disease-modifying therapy (DMT). Patients showed significant improvements in the psychological domain of MSIS-29 from 35.9 (26.6) at baseline to 29.4 (25.5) at 18 months (p = 0.004) and 29.0 (24.6) at 24 months (p = 0.002). Levels of fatigue and depression were also reduced. After 2 years of treatment with teriflunomide, ARR was reduced to 0.17 (95% CI 0.14-0.21) from the baseline of 0.42 (95% CI 0.38-0.48), representing a 60.1% reduction. Mean EDSS scores remained stable during the study, and 79.9% of patients showed no disability progression. 54.7% of patients achieved NEDA-3 in the first 12 months, which increased to 61.4% during months 12-24. Patients reported increased satisfaction with treatment over the course of the study, regardless of whether they were DMT naive or not. CONCLUSION: Teriflunomide improves psychological aspects of HRQoL and maintains low levels of fatigue and depression. Treatment with teriflunomide over 2 years is effective in reducing ARR and disability progression.

Effect of resistance exercise training on plasma neurofilaments in multiple sclerosis: a proof of concept for future designs.

Multiple sclerosis (MS) is a dysimmune and neurodegenerative disease of the central nervous system that continues to be one of the main causes of non-traumatic disability in young people despite the recent availability of highly effective drugs. Exercise-based interventions seem to have a positive impact on the course of the disease although pathophysiological mechanisms responsible for this benefit remain unclear. This is a longitudinal study to examine the effects of a short-term training program on neurofilament plasma levels, a biomarker of axonal destruction, measured using the ultrasensitive single molecule array (SiMoA). Eleven patients completed a 6-week supervised resistance-training program of 18 sessions that consisted of 3 sets of 8-10 repetitions of 7 exercises. Median plasma neurofilament levels significantly decreased from baseline (6.61 pg/ml) to 1 week after training intervention (4.44 pg/ml), and this effect was maintained after 4 weeks of detraining (4.38 pg/ml). These results suggest a neuroprotective effect of resistance training in this population and encourage us to investigate further the beneficial impact of physical exercise and to emphasize the importance of lifestyle in MS.

Frequency and Characterization of Movement Disorders in Anti-IgLON5 Disease.

OBJECTIVE: Anti-IgLON5 disease is a recently described neurological disease that shares features of autoimmunity and neurodegeneration. Abnormal movements appear to be frequent and important but have not been characterized and are under-reported. Here we describe the frequency and types of movement disorders in a series of consecutive patients with this disease. METHODS: In this retrospective, observational study, the presence and phenomenology of movement disorders were assessed with a standardized clinical questionnaire. Available videos were centrally reviewed by three experts in movement disorders. RESULTS: Seventy two patients were included. In 41 (57%) the main reason for initial consultation was difficulty walking along with one or several concurrent movement disorders. At the time of anti-IgLON5 diagnosis, 63 (87%) patients had at least one movement disorder with a median of three per patient. The most frequent abnormal movements were gait and balance disturbances (52 patients, 72%), chorea (24, 33%), bradykinesia (20, 28%), dystonia (19, 26%), abnormal body postures or rigidity (18, 25%), and tremor (15, 21%). Other hyperkinetic movements (myoclonus, akathisia, myorhythmia, myokymia, or abdominal dyskinesias) occurred in 26 (36%) patients. The craniofacial region was one of the most frequently affected by multiple concurrent movement disorders (23 patients, 32%) including dystonia (13), myorhythmia (6), chorea (4) or myokymia (4). Considering any body region, the most frequent combination of multiple movement disorders consisted of gait instability or ataxia associated with craniofacial dyskinesias or generalized chorea observed in 31(43%) of patients. In addition to abnormal movements, 87% of patients had sleep alterations, 74% bulbar dysfunction, and 53% cognitive impairment. Fifty-five (76%) patients were treated with immunotherapy, resulting in important and sustained improvement of the movement disorders in only seven (13%) cases. CONCLUSIONS: Movement disorders are a frequent and leading cause of initial neurological consultation in patients with anti-IgLON5 disease. Although multiple types of abnormal movements can occur, the most prevalent are disorders of gait, generalized chorea, and dystonia and other dyskinesias that frequently affect craniofacial muscles. Overall, anti-IgLON5 disease should be considered in patients with multiple movement disorders, particularly if they occur in association with sleep alterations, bulbar dysfunction, or cognitive impairment.

OCT Variability Prevents Their Use as Robust Biomarkers in Multiple Sclerosis.

OBJECTIVE: To evaluate the agreement between the peripapillary retinal nerve fiber layer (pRNFL) and foveal thickness (FT) measurements among three different spectral domain-optical coherence tomography (SD-OCT) instruments in a sample of multiple sclerosis (MS) patients and a healthy age-matched control group. METHODS: An observational cross-sectional study with three groups: healthy subjects and MS patients w/w a previous clinical diagnosis of optic neuritis (ON) was conducted. The pRNFL and FT were measured using three different SD-OCT instruments (OCT PRIMUS 200 and OCT CIRRUS 500 SD-OCT [Carl Zeiss Meditec] and OCT 3D 2000 [Topcon]). RESULTS: Twenty eyes from 10 healthy subjects matched in age with MS patients without a previous history of eye disease and 62 MS eyes from 31 MS patients (29 eyes without history of ON and 33 eyes with history of ON) were enrolled. Healthy subjects and MS patients without ON did not show differences between the pRNFL and FT thickness (P>0.99) with any of the instruments. However, MS eyes with a previous episode of ON showed thinner pRNFL and FT (P<0.01). PRIMUS and CIRRUS OCT showed better agreement of the pRNLF and FT in both healthy and MS eyes. However, 3D OCT showed less agreement in the pRNFL measurement with CIRRUS in both healthy and MS eyes. INTERPRETATION: Although OCT is a valuable technology to improve MS patient assessment, differences between devices must be taken into account. It is necessary to create an international group that standardizes the measurement conditions and above all that provides reference bases for normal subjects.

A Pilot Study to Explore Patient Satisfaction With a Virtual Rehabilitation Program in Multiple Sclerosis: The RehabVR Study Protocol.

Background: Virtual reality (VR) has emerged as a promising treatment approach in rehabilitation for patients with multiple sclerosis (MS) due to its potential to increase patient motivation and rehabilitation adherence. One of the key features for rehabilitation adherence is patient satisfaction with the VR rehabilitation (VRR) program, and information on user satisfaction and not only effectiveness is required to systematically include VRR in routine clinical practice. Given that information on patient satisfaction with VRR is scarce, the primary objective of this study is to assess long-term patient satisfaction with a novel VRR program. This program has been specifically designed for MS patients by a multidisciplinary team of specialists, based on an effective conventional rehabilitation (CR) program. Secondarily, discomfort with VRR will be evaluated, and therapy adherence and changes in a variety of domains typically affected by MS will be compared between patients receiving VRR and patients receiving CR. Methods: In this prospective single-center 6-months follow-up study, 32 and 16 MS patients will receive VRR or CR, respectively. Patients will attend twice weekly rehabilitation sessions on site during 4 weeks, and they will continue with rehabilitation at home for five additional months. Satisfaction, assessed by the User Satisfaction Evaluation Questionnaire (USEQ), at 6 months of the VRR program initiation will be the primary outcome. Secondary outcomes include adherence, disability, spasms and spasticity, balance, fatigue, activities of daily living (ADLs), depression, anxiety, work status, cognition, demographic, and clinical characteristics (in the VRR and CR groups), and discomfort (in the VRR group). Outcome measures will be assessed at baseline, and at 1 and 6 months of rehabilitation initiation. Discussion: The study is intended to provide a better understanding of long-term patient satisfaction with a VRR program specifically designed for MS patients. Additionally, the study will provide information on long-term adherence, changes in motor symptoms, cognitive functions and patient-reported outcomes after the rehabilitation program. The results from this study will help to gather valuable knowledge on the use of rehabilitation with a new VR tool in MS patients.

XII Reunión Post-ECTRIMS: revisión de las novedades presentadas en el Congreso ECTRIMS 2019 (II) / 12th Post-ECTRIMS Meeting: review of the novelties from the 2019 ECTRIMS Congress (II)

INTRODUCCIÓN: Como cada año, tras la celebración del Congreso del ECTRIMS, reconocidos neurólogos españoles expertos en esclerosis múltiple expusieron en la Reunión Post-ECTRIMS las principales novedades en investigación en este ámbito. OBJETIVO: Sintetizar el contenido presentado en la XII edición de la Reunión Post-ECTRIMS, que tuvo lugar en septiembre de 2019 en Sevilla y que se presenta en dos partes. DESARROLLO: En esta segunda parte, se exponen las evidencias más recientes sobre el uso de tratamientos modificadores de la enfermedad durante el embarazo. Se detallan los resultados de ensayos clínicos en fase 3 en los que se ha evaluado la eficacia y la seguridad de dos potenciales tratamientos modificadores de la enfermedad para la esclerosis múltiple remitente recurrente: ponesimod y ofatumumab. Para las formas progresivas, se revisan los tratamientos modificadores de la enfermedad disponibles y en investigación. En el ámbito de las terapias con células madre, se incluyen los resultados del único ensayo clínico hasta la fecha que compara a pacientes con esclerosis múltiple remitente recurrente tratados con trasplante autólogo de células madre hematopoyéticas y a los tratados con tratamientos modificadores de la enfermedad. No hay grandes novedades sobre tratamientos sintomáticos, aunque la Academia Europea de Neurología ha publicado una guía sobre cuidados paliativos. Se revisan las distintas fuentes de información que recogen datos de farmacovigilancia en el entorno poscomercialización. CONCLUSIONES: Los pacientes diagnosticados en los últimos años tienden a tener una menor gravedad de la esclerosis múltiple, probablemente debido al diagnóstico desde sus estadios más leves y al continuo aumento de tratamientos disponibles

INTRODUCTION: Like every year, after the ECTRIMS Congress, renowned Spanish neurologists who are experts in multiple sclerosis presented the main novelties in research in this field at the Post-ECTRIMS Meeting. AIM: To summarise the content presented at the 12th edition of the Post-ECTRIMS Meeting, which took place in September 2019 in Sevilla and is presented in two parts. DEVELOPMENT. In this second part, the most recent evidence on the use of disease-modifying treatments during pregnancy is presented. Details are provided concerning the results of phase 3 clinical trials conducted to evaluate the efficacy and safety of two potential disease-modifying treatments for relapsing-remitting multiple sclerosis: ponesimod and ofatumumab. For the progressive forms, both available disease modifying treatments and others still in the research phase are reviewed. In the field of stem cell therapies, the article includes the results of the only clinical trial carried out to date comparing patients with relapsing-remitting multiple sclerosis treated with autologous haematopoietic stem cell transplantation and those treated with disease-modifying therapies. There are no important developments as regards symptomatic treatments, although the European Academy of Neurology has published a guide on palliative care. The various sources of information that collect pharmacovigilance data in the post-marketing setting are reviewed. CONCLUSIONS:l Patients diagnosed in recent years tend to have less severe multiple sclerosis, probably due to the fact that it is diagnosed in its milder stages together with the steady increase in the number of treatments available

XII Reunión Post-ECTRIMS: revisión de las novedades presentadas en el Congreso ECTRIMS 2019 (I) / 12th Post-ECTRIMS Meeting: review of the novelties from the 2019 ECTRIMS Congress (I)

INTRODUCCIÓN: Como cada año, tras la celebración del Congreso ECTRIMS, reconocidos neurólogos españoles expertos en esclerosis múltiple expusieron en la Reunión Post-ECTRIMS las principales novedades en investigación en este ámbito. OBJETIVO: Sintetizar el contenido presentado en la XII edición de la Reunión Post-ECTRIMS, que tuvo lugar en septiembre de 2019 en Sevilla y que se presenta en dos partes. DESARROLLO: Esta primera parte aborda los últimos estudios sobre el déficit de vitamina D y las discrepancias existentes acerca de su tratamiento. Los avances en epigenética realizados permiten presentar esta aproximación como un posible biomarcador de la esclerosis múltiple. Se explica el creciente protagonismo de las técnicas de imagen para detectar la atrofia y otros fenómenos que acontecen durante la enfermedad, como los cambios en la concentración de hierro o los procesos de remielinización, que nos permiten ganar comprensión sobre los mecanismos de la patología cortical, y sobre la dimensionalidad de la neurodegeneración durante su evolución. Se discuten los hallazgos relacionados con los mecanismos inmunológicos y los avances realizados en las potenciales terapias específicas del antígeno. Se presentan los últimos estudios sobre la evaluación del deterioro cognitivo y su rehabilitación, que cobran cada vez más importancia por la alta prevalencia de estas alteraciones y por la ausencia de su evaluación sistemática en la práctica clínica. Por último, se exponen las necesidades sociosanitarias no cubiertas de los pacientes de esclerosis múltiple en nuestro país, poniendo el acento en los déficits actuales del sistema de protección social

INTRODUCTION. Like every year, after the ECTRIMS Congress, renowned Spanish neurologists who are experts in multiple sclerosis presented the main novelties in research in this field at the Post-ECTRIMS Meeting. AIM. To summarise the content presented at the 12th edition of the Post-ECTRIMS Meeting, which took place in September 2019 in Sevilla and is presented in two parts. DEVELOPMENT. This first part addresses the latest studies on vitamin D deficiency and the discrepancies that currently exist regarding its treatment. The advances made in epigenetics allow us to present this approach as a possible biomarker of multiple sclerosis. An account is provided to explain the growing importance of imaging techniques to detect atrophy and other phenomena that occur during the disease, such as changes in iron concentration or remyelination processes, which allow us to further our understanding of the mechanisms of cortical pathology, and the dimensionality of neurodegeneration during its course. Findings related to immunological mechanisms and advances in potential antigen-specific therapies are discussed. The contribution presents the latest studies on the assessment of cognitive impairment and its rehabilitation, which are becoming increasingly important due to the high prevalence of these disorders and the absence of their systematic assessment in clinical practice. Finally, the unmet social and health needs of multiple sclerosis patients in our country are presented, with emphasis on the current deficits in the system of social protection

Revisión de las novedades presentadas en el Congreso ECTRIMS 2018: XI Reunión Post-ECTRIMS (II) / Review of the novelties presented at the 2018 ECTRIMS Congress: 11th Post-ECTRIMS Meeting (II)

La reunión Post-ECTRIMS se celebró por undécimo año consecutivo el pasado octubre de 2018 en Madrid, con el objetivo de analizar los avances en esclerosis múltiple destacados en el último congreso anual ECTRIMS. Fruto de esta reunión, formada por los líderes de opinión en esclerosis múltiple de ámbito nacional, se presentan dos artículos de revisión. En esta segunda parte, se incluye el creciente número de evidencias que confirman la seguridad de la exposición a los tratamientos modificadores de la enfermedad en mujeres que planifican un embarazo, y el efecto beneficioso de la lactancia, siempre y cuando la enfermedad no esté muy activa. Se abordan los datos que muestran cómo la aplicación de los criterios de McDonald de 2017 en población pediátrica ha mejorado considerablemente el diagnóstico en comparación con los criterios anteriores. En cuanto a la esclerosis múltiple progresiva, los resultados de los fármacos neuroprotectores son poco concluyentes, pero se proponen biomarcadores para mejorar la evaluación de la respuesta terapéutica. Los estudios sobre tratamientos de reparación de la mielina sugieren que la remielinización en la esclerosis múltiple es posible. De igual manera, se exponen indicios favorables sobre el trasplante de células madre hematopoyéticas, siempre que se seleccione adecuadamente a los pacientes. Por otro lado, se revisan las similitudes y diferencias de las recomendaciones de las nuevas guías de práctica clínica publicadas. Por último, los resultados positivos de la rehabilitación cognitiva y motora con el uso de las nuevas tecnologías vaticinan la incorporación sistemática de estas herramientas en el tratamiento de la enfermedad en un futuro próximo

The Post-ECTRIMS Meeting was held for the eleventh consecutive year in October 2018 in Madrid, with the aim of analysing the advances made in multiple sclerosis that were highlighted at the latest ECTRIMS annual congress. Based on the issues discussed at this meeting, attended by the nation’s foremost opinion leaders on multiple sclerosis, two review articles are presented. This second part includes the growing body of evidence confirming the safety of exposure to disease-modifying treatments in women planning a pregnancy, and the beneficial effect of breastfeeding, provided that the disease is not very active. It addresses data showing how the application of the 2017 McDonald criteria in the paediatric population has significantly improved diagnosis compared to the previous criteria. With regard to progressive multiple sclerosis, the results of neuroprotective drugs are inconclusive, but biomarkers are proposed to improve the evaluation of the therapeutic response. Studies on myelin repair treatments suggest that remyelination in multiple sclerosis is possible. Likewise, there are favourable indications for haematopoietic stem cell transplantation, provided that patients are selected appropriately. On the other hand, we also conduct a review of the similarities and differences of the recommendations in the new clinical practice guidelines. Finally, the positive results of cognitive and motor rehabilitation with the use of new technologies point to the systematic incorporation of these tools in the treatment of the disease in the near future

CLIPPERS and its mimics: evaluation of new criteria for the diagnosis of CLIPPERS.

OBJECTIVE: To evaluate the accuracy of the recently proposed diagnostic criteria for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). METHODS: We enrolled 42 patients with hindbrain punctate and/or linear enhancements (<3 mm in diameter) and tested the CLIPPERS criteria. RESULTS: After a median follow-up of 50 months (IQR 25-82), 13 out of 42 patients were CLIPPERS-mimics: systemic and central nervous system lymphomas (n=7), primary central nervous system angiitis (n=4) and autoimmune gliopathies (n=2). The sensitivity and specificity of the CLIPPERS criteria were 93% and 69%, respectively. Nodular enhancement ( ≥ 3 mm in diameter), considered as a red flag in CLIPPERS criteria, was present in 4 out of 13 CLIPPERS-mimics but also in 2 out of 29 patients with CLIPPERS, explaining the lack of sensitivity. Four out of 13 CLIPPERS-mimics who initially met the CLIPPERS criteria displayed red flags at the second attack with a median time of 5.5 months (min 3, max 18), explaining the lack of specificity. One of these four patients had antimyelin oligodendrocyte glycoprotein antibodies, and the three remaining patients relapsed despite a daily dose of prednisone/prednisolone ≥ 30 mg and a biopsy targeting atypical enhancing lesions revealed a lymphoma. CONCLUSIONS: Our study highlights that (1) nodular enhancement should be considered more as an unusual finding than a red flag excluding the diagnosis of CLIPPERS; (2) red flags may occur up to 18 months after disease onset; (3) as opposed to CLIPPERS-mimics, no relapse occurs when the daily dose of prednisone/prednisolone is ≥ 30 mg; and (4) brain biopsy should target an atypical enhancing lesion when non-invasive investigations remain inconclusive.

Revisión de las novedades presentadas en el congreso ECTRIMS 2018: XI Reunión Post-ECTRIMS (I) / Review of the novelties presented at the 2018 ECTRIMS Congress: 11th Post-ECTRIMS Meeting (I)

La reunión Post-ECTRIMS es un encuentro emblemático en España que persigue revisar y difundir los principales avances en esclerosis múltiple presentados en el congreso anual ECTRIMS. En octubre de 2018, la reunión Post-ECTRIMS celebró en Madrid su undécima edición, contando con los mayores expertos de ámbito nacional en esclerosis múltiple. Como resultado de esta reunión, se presentan dos artículos donde se recogen las novedades más destacadas en la misma. En esta primera parte se incluyen los últimos resultados sobre la influencia de los factores de riesgo modificables y no modificables en la esclerosis múltiple, destacando los progresos realizados en el ámbito genético, donde el descubrimiento de genes asociados a la esclerosis múltiple ha aumentado exponencialmente. Se aborda la complejidad del sistema inmune y se realizan algunas aportaciones sobre los mecanismos de autoinmunidad, en los que se observan relaciones bidireccionales entre las células inmunes y las células residentes del sistema nervioso central, como la microglía y los astrocitos. Los biomarcadores, tanto en suero y líquido cefalorraquídeo como de imagen, ganan cada vez más atención por su papel actual, y sobre todo potencial, en el diagnóstico y pronóstico de la enfermedad y en la evaluación de la eficacia de los tratamientos. Por último, se presentan las observaciones realizadas respecto a los cambios en la conectividad estructural y funcional en los pacientes y su relación con las alteraciones clínicas

The Post-ECTRIMS Meeting is an emblematic event in Spain which seeks to review and disseminate the main advances in multiple sclerosis presented at the ECTRIMS annual congress. In October 2018, the eleventh Post-ECTRIMS meeting was held in Madrid and was attended by the country’s leading experts in multiple sclerosis. As a result of this meeting, we present two articles which outline the most interesting novelties discussed there. This first part includes the latest results obtained regarding the influence of modifiable and non-modifiable risk factors in multiple sclerosis, with emphasis on the progress made in the field of genetics, where the discovery of genes associated with multiple sclerosis has increased exponentially. The complexity of the immune system is addressed and some contributions are made on autoimmunity mechanisms, in which bidirectional relations are observed between immune cells and cells residing in the central nervous system, such as microglial cells and astrocytes. Biomarkers, both in serum and cerebrospinal fluid as well as in imaging, are gaining more and more attention due to their current and, above all, potential role in the diagnosis and prognosis of the disease and in the evaluation of the efficacy of treatments. Finally, the observations made regarding changes in structural and functional connectivity in patients and their relationship with clinical alterations are presented

Immune tolerance in multiple sclerosis and neuromyelitis optica with peptide-loaded tolerogenic dendritic cells in a phase 1b trial.

There are adaptive T-cell and antibody autoimmune responses to myelin-derived peptides in multiple sclerosis (MS) and to aquaporin-4 (AQP4) in neuromyelitis optica spectrum disorders (NMOSDs). Strategies aimed at antigen-specific tolerance to these autoantigens are thus indicated for these diseases. One approach involves induction of tolerance with engineered dendritic cells (tolDCs) loaded with specific antigens. We conducted an in-human phase 1b clinical trial testing increasing concentrations of autologous tolDCs loaded with peptides from various myelin proteins and from AQP4. We tested this approach in 12 patients, 8 with MS and 4 with NMOSD. The primary end point was the safety and tolerability, while secondary end points were clinical outcomes (relapses and disability), imaging (MRI and optical coherence tomography), and immunological responses. Therapy with tolDCs was well tolerated, without serious adverse events and with no therapy-related reactions. Patients remained stable clinically in terms of relapse, disability, and in various measurements using imaging. We observed a significant increase in the production of IL-10 levels in PBMCs stimulated with the peptides as well as an increase in the frequency of a regulatory T cell, known as Tr1, by week 12 of follow-up. In this phase 1b trial, we concluded that the i.v. administration of peptide-loaded dendritic cells is safe and feasible. Elicitation of specific IL-10 production by peptide-specific T cells in MS and NMOSD patients indicates that a key element in antigen specific tolerance is activated with this approach. The results warrant further clinical testing in larger trials.

Revisión de las novedades del Congreso ECTRIMS 2017, presentadas en la X Reunión Post-ECTRIMS (II) / Review of the novelties from the 2017 ECTRIMS Congress, presented at the 10th Post-ECTRIMS Meeting (II)

La reunión Post-ECTRIMS es una reunión emblemática en el ámbito de la esclerosis múltiple en España, con el claro objetivo de analizar, de la mano de reconocidos neurólogos especialistas nacionales, los principales avances en esclerosis múltiple y revisar los temas más importantes del congreso ECTRIMS. En noviembre de 2017, la reunión Post-ECTRIMS celebro su décima edición, y se ha consolidado como un importante foro de encuentro de expertos en nuestro país para favorecer la comunicación, establecer sinergias, y promover y potenciar la investigación para mejorar, en última instancia, el pronóstico y la calidad de vida de los pacientes con esclerosis múltiple. En esta segunda parte se abordan las diferentes estrategias para el manejo de los pacientes con enfermedad avanzada y la seguridad de la terapia en esclerosis múltiple, y se resaltan las áreas que requieren una mayor evidencia científica y clínica. La esclerosis múltiple en la población pediátrica y el envejecimiento en la enfermedad cobran especial importancia en esta edición, remarcando la necesidad del desarrollo de estudios colaborativos y de una mayor concienciación de los especialistas en la detección y el manejo de las comorbilidades en la esclerosis múltiple

The Post-ECTRIMS Meeting is an emblematic event in the field of multiple sclerosis in Spain. Its chief aim is bring together the country’s leading specialist neurologists to analyse the main advances made in multiple sclerosis and to review the most important topics addressed at the ECTRIMS Congress. The tenth Post-ECTRIMS Meeting was held in November 2017. Over the years this event has firmly established itself as an important meeting point where experts from all over the country get together to foster communication, establish synergies and promote and enhance research ultimately aimed at improving the prognosis and quality of life of patients with multiple sclerosis. This second part addresses the different strategies for the management of patients in advanced stages of the disease and the safety of therapy in multiple sclerosis. Likewise, attention is also drawn to the areas that require further scientific and clinical evidence. In this edition, particular importance is given to multiple sclerosis in the paediatric population and ageing in the disease. At the same time emphasis is placed on the need to conduct collaborative studies and to foster greater awareness among specialists regarding the detection and management of the comorbidities in multiple sclerosis

Revisión de las novedades del Congreso ECTRIMS 2017, presentadas en la X Reunión Post-ECTRIMS (I) / Review of the novelties from the 2017 ECTRIMS Congress, presented at the 10th Post-ECTRIMS Meeting (I)

La reunión Post-ECTRIMS es una reunión emblemática en el ámbito de la esclerosis múltiple en España, con el claro objetivo de analizar, de la mano de reconocidos neurólogos especialistas nacionales, los principales avances en esclerosis múltiple y revisar los temas más importantes del congreso ECTRIMS. En noviembre de 2017, la reunión Post-ECTRIMS celebró su décima edición, y se ha consolidado como un importante foro de encuentro de expertos en nuestro país para favorecer la comunicación, establecer sinergias, y promover y potenciar la investigación para mejorar, en última instancia, el pronóstico y la calidad de vida de los pacientes con esclerosis múltiple. En esta primera parte se avanza la publicación de las nuevas guías clínicas europea y americana para el uso de los tratamientos modificadores de la enfermedad, y los nuevos criterios diagnósticos. Se discuten las estrategias para el seguimiento de los pacientes tratados con terapias modificadoras de la enfermedad, se revisan la atrofia cerebral y los biomarcadores de neurodegeneración y neuroinflamación, y se analiza el papel de la neuroglía en la patogenia y el tratamiento. Se hace un recorrido por la historia natural de la enfermedad, con la evidencia que aportan los registros, y nos adelantamos al futuro gracias a los avances en genética e inmunología

The Post-ECTRIMS Meeting is an emblematic event in the field of multiple sclerosis in Spain. Its chief aim is bring together the country’s leading specialist neurologists to analyse the main advances made in multiple sclerosis and to review the most important topics addressed at the ECTRIMS Congress. The tenth Post-ECTRIMS Meeting was held in November 2017. Over the years this event has firmly established itself as an important meeting point where experts from all over the country get together to foster communication, establish synergies and promote and enhance research ultimately aimed at improving the prognosis and quality of life of patients with multiple sclerosis. This first part reports on the publication of the new European and American clinical guidelines on the use of disease-modifying treatments and the new diagnostic criteria. It also discusses the strategies for following up patients treated with disease-modifying therapies, reviews cerebral atrophy and biomarkers of neurodegeneration and neuroinflammation, and analyses the role of neuroglia in pathogenesis and treatment. The study examines the natural history of the disease, with the evidence provided by registers, and we anticipate the future thanks to the progress being made in genetics and immunology

Ocrelizumab: eficacia y seguridad en la esclerosis múltiple / Ocrelizumab: its efficacy and safety in multiple sclerosis

Introducción. El ocrelizumab es un anticuerpo monoclonal humanizado contra el antígeno CD20 de las células B. Ha sido aprobado recientemente por las agencias sanitarias estadounidense (Food and Drug Administration) y europea (European Medicines Agency) para el tratamiento de la esclerosis múltiple (EM), y supone el primer fármaco comercializado tanto para la EM remitente recurrente (EMRR) como para la EM primariamente progresiva (EMPP). Los ensayos clínicos, tanto para formas recurrentes (OPERA I/II) como para las formas progresivas de la enfermedad (ORATORIO), han demostrado su eficacia. El objetivo de esta revisión es abordar los principales aspectos de eficacia y seguridad del ocrelizumab en la EM. Desarrollo. Se ha realizado una revisión bibliográfica a través de PubMed de trabajos publicados en el congreso ECTRIMS 2017 y de estudios activos en ClinicalTrials. Con el fin de evaluar la eficacia y seguridad del ocrelizumab en la EM, se han revisado ensayos clínicos aleatorizados, así como sus estudios de extensión y de seguimiento, y se ha incluido información sobre seguridad de los programas de monitorización de la Food and Drug Administration y la European Medicines Agency. Conclusiones. El ocrelizumab es el primer fármaco que ha demostrado poder frenar de forma significativa la progresión de la discapacidad en 12 y 24 semanas en pacientes con EMPP. Es también eficaz en el control de la actividad clínica y radiológica en pacientes con formas de EMRR, y su aprobación e indicación engloban ambos fenotipos de la enfermedad. Hasta ahora, el perfil de seguridad del ocrelizumab se ajusta a lo observado en los ensayos clínicos, sin alertas inesperadas

Introduction. Ocrelizumab is a humanised monoclonal antibody that targets the CD20 antigen on B cells. It has recently been approved by the US (Food and Drug Administration) and European health agencies (European Medicines Agency) for the treatment of multiple sclerosis (MS) and is the first drug marketed for both relapsing-remitting MS (RRMS) and primary progressive MS (PPMS). The clinical trials conducted for both the relapsing forms (OPERA I/II) and the progressive forms of the disease (ORATORIO) have demonstrated its efficacy. The aim of this review is to address the main aspects of the efficacy and safety of ocrelizumab in MS. Development. Using PubMed, a literature review was conducted of studies published at the ECTRIMS 2017 Congress and of active studies in ClinicalTrials. In order to evaluate the efficacy and safety of ocrelizumab in MS, both randomised clinical trials and their extension and follow-up studies were reviewed, and information about its safety obtained from monitoring programmes of the Food and Drug Administration and European Medicines Agency was included. Conclusions. Ocrelizumab is the first drug that has been shown to be able to significantly slow disability progression at 12 and 24 weeks in patients with PPMS. It is also effective in controlling clinical and radiological activity in patients with RRMS forms, and it is approved and indicated for both phenotypes of the disease. To date, the safety profile of ocrelizumab matches that observed in clinical trials, without any unexpected alerts

Clinical manifestations of the anti-IgLON5 disease.

OBJECTIVE: To report the presentation, main syndromes, human leukocyte antigen (HLA) association, and immunoglobulin G (IgG) subclass in the anti-IgLON5 disease: a disorder with parasomnias, sleep apnea, and IgLON5 antibodies. METHODS: This was a retrospective clinical analysis of 22 patients. The IgG subclass was determined using reported techniques. RESULTS: Patients' median age was 64 years (range 46-83). Symptoms that led to initial consultation included sleep problems (8 patients; 36%), gait abnormalities (8; 36%), bulbar dysfunction (3; 14%), chorea (2; 9%), and cognitive decline (1; 5%). By the time of diagnosis of the disorder, 4 syndromes were identified: (1) a sleep disorder with parasomnia and sleep breathing difficulty in 8 (36%) patients; (2) a bulbar syndrome including dysphagia, sialorrhea, stridor, or acute respiratory insufficiency in 6 (27%); (3) a syndrome resembling progressive supranuclear palsy (PSP-like) in 5 (23%); and (4) cognitive decline with or without chorea in 3 (14%). All patients eventually developed parasomnia, sleep apnea, insomnia, or excessive daytime sleepiness. HLA-DRB1*10:01 and HLA-DQB1*05:01 were positive in 13/15 (87%) patients; the DRB1*10:01 allele was 36 times more prevalent than in the general population. Among 16 patients with paired serum and CSF samples, 14 had IgLON5 antibodies in both, and 2 only in serum (both had a PSP-like syndrome). Twenty of 21 patients had IgG1 and IgG4 antibodies; the latter predominated in 16. CONCLUSIONS: Patients with IgLON5 antibodies develop a characteristic sleep disorder preceded or accompanied by bulbar symptoms, gait abnormalities, oculomotor problems, and, less frequently, cognitive decline. IgG4 subclass antibodies predominate over IgG1; we confirm a strong association with the HLA-DRB1*10:01 allele.

Clinical spectrum associated with MOG autoimmunity in adults: significance of sharing rodent MOG epitopes.

The aim of this study was to report the clinical spectrum associated with antibodies to myelin oligodendrocyte glycoprotein (MOG) in adult patients, and to assess whether phenotypic variants are dependent on recognition of rodent MOG epitopes. We retrospectively analyzed the features, course and outcome of 56 patients whose samples were investigated by brain tissue immunohistochemistry and cell-based assays using human and rodent MOG. The median age at symptom onset was 37 years (range 18-70); 35 patients (63 %) were female. After a median follow-up of 43 months (range 4-554), only 14 patients (25 %) developed a neuromyelitis optica spectrum disorder (NMOSD), 27 patients (47 %) retained the initial diagnosis of isolated optic neuritis, 7 (12 %) of longitudinally extensive transverse myelitis, and 2 (4 %) of acute disseminated encephalomyelitis; 6 patients (11 %) developed atypical demyelinating syndromes (4 had relapsing episodes of short myelitis lesions which in one occurred with optic neuritis; 1 had relapsing brainstem symptoms, and 1 relapsing demyelinating encephalomyelitis). The course was frequently associated with relapses (71 %) and good outcome. Twenty-seven patients (49 %) had antibodies that recognized rodent MOG epitopes, and 9 of them (16 %) showed a myelin staining pattern in rodent tissue. Only the myelin staining pattern was linked to NMOSD (p = 0.005). In conclusion, MOG autoimmunity in adult patients associates with a clinical spectrum wider than the one expected for patients with suspected NMOSD and overall good outcome. Antibodies to rodent MOG epitopes do not associate with any phenotypic variant.

Improvement of fatigue in multiple sclerosis by physical exercise is associated to modulation of systemic interferon response.

Mechanisms underlying multiple sclerosis (MS) fatigue and the causes of the beneficial effect of exercise on this symptom are not clarified. Our aim was to evaluate gene expression profiles in MS patients who improved their fatigue status after an exercise program and to compare them with healthy controls (HC). Gene expression in whole blood was profiled at baseline in 7 HC and also in 7 fatigued-MS patients. Patients underwent an exercise program for 6 months, and their fatigue status and gene expression profiles were again analyzed. MS patients showed a significant activation of genes participating in the systemic interferon response in comparison with HC that disappeared at the end of the program. Our results provide a biological basis for the observed benefit of exercise in MS.

Revisión de las novedades presentadas en el XXVIII Congreso del Comité Europeo para el Tratamiento e Investigación en Esclerosis Múltiple (ECTRIMS) (III) / Review of the novelties presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (III)

Los datos más relevantes presentados en la XXVIII edición del Congreso del Comité Europeo para el Tratamiento e Investigación en Esclerosis Múltiple (ECTRIMS), celebrado en octubre de 2012 en Francia, han sido resumidos en la quinta edición de la Reunión de Expertos Post-ECTRIMS celebrada en Madrid en octubre de 2012, fruto de la cual nace esta revisión que se publica en tres partes. Esta tercera parte de la revisión Post-ECTRIMS expone los resultados de los últimos 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 búsqueda de tratamientos innovadores para la esclerosis múltiple, destacando la terapia antigenoespecífica, la terapia celular y la terapia dirigida a promover la remielinización entre las futuras estrategias terapéuticas. La disponibilidad de nuevos fármacos y la complejidad de la futura terapia de la esclerosis múltiple necesitan nuevas direcciones y estrategias de diseño en los ensayos clínicos, entre ellas el uso de marcadores subrogados, nuevasaplicaciones estadísticas, ensayos clínicos de superioridad, inferioridad o equivalencia, y diseños adaptables (AU)

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 conductedwith 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 (AU)

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.