Indicadores precoces de respuesta al tratamiento con interferón en pacientes con esclerosis múltiple /

Introducción: el tratamiento con interferón β sigue siendo la terapia inmunomoduladora más extendida en el tratamiento de la esclerosis múltiple remitente-recurrente si bien su eficacia es parcial. En ausencia de un biomarcador específico de respuesta, identificar precozmente a los pacientes que presentan un fallo terapéutico o una respuesta parcial es fundamental para plantear alternativas terapéuticas. Objetivo: estudiar la utilidad de la Multiple Sclerosis Functional Composite para evaluar el acumulo precoz de discapacidad, así como el valor de otras variables clínicas y de RM recogidas en el primer año de tratamiento para predecir la evolución en los 24 meses siguientes. Métodos: se diseñó un estudio prospectivo en pacientes con esclerosis múltiple remitente-recurrente que iniciaban tratamiento con interferón beta. Se realizó una valoración clínica (EDSS, MSFC, tasa de brotes) y por RM, al inicio y tras los 12 primeros meses de tratamiento. Durante los siguientes 24 meses se evaluó la presencia de actividad de la enfermedad (brotes o progresión) para definir el fallo terapéutico a largo plazo. Resultados: se incluyeron 165 pacientes, 127 en el subestudio con RM. El modelo de regresión logística demostró que sólo los parámetros de RM (presencia de más de 2 lesiones activas, OR 2.3, IC 95% 1.0-5.2) y las variables compuestas (Río Score ≥2, OR 4.8 IC 95% 1.6-1.4) eran capaces de identificar a los pacientes con riesgo de presentar una enfermedad activa tras el primer año de tratamiento con interferón. Conclusión: en pacientes con EMRR que inician tratamiento con interferón beta, la combinación de medidas de actividad clínica y por RM tras los 12 primeros meses, podría permitir identificar a aquellos que se beneficiarían de un cambio precoz de tratamiento.Introduction: treatment with interferon β remains the most widespread immunomodulatory therapy in the treatment of relapsing-remitting multiple sclerosis, although its efficacy is partial. In the absence of a specific biomarker of response, early identification of patients with treatment failure or a partial response is critical to defining therapeutic strategies. Objective: To study the usefulness of the Multiple Sclerosis Functional Composite to evaluate the early accumulation of disability, as well as the value of other clinical and MRI variables in the first year of treatment to predict the evolution in the following 24 months. Methods: A prospective study was designed in patients with relapsing-remitting multiple sclerosis starting treatment with interferon beta. Clinical assessment (EDSS, MSFC, relapse rate) and MRI study at baseline and after 12 months of treatment were performed. During the next 24 months the presence of disease activity (relapses or progression) was evaluated to define the long term treatment failure. Results: 165 patients, 127 in the MRI substudy, were included. The logistic regression model showed that only RM parameters (presence of more than 2 active lesions, OR 2.3, 95% CI 1.0-5.2) and composite variables (Río Score ≥2, OR 4.8 95% CI 1.6-1.4) were able to identify patients at risk of developing active disease after the first year of treatment with interferon. Conclusion: In patients with RRMS starting treatment with beta interferon, the combination of measures of disease activity and the presence of new active lesions, may have a prognostic value to identify patients who benefits from early treatment change

Circulating EZH2-positive T cells are decreased in multiple sclerosis patients

BACKGROUND: Recent studies in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS), suggest an involvement of the histone methyltransferase enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) in important processes such as cell adhesion and migration. METHODS: Here, we aimed to expand these initial observations by investigating the role of EZH2 in MS. mRNA expression levels for EZH2 were measured by real-time PCR in peripheral blood mononuclear cells (PBMC) from 121 MS patients (62 untreated and 59 receiving treatment) and 24 healthy controls. RESULTS: EZH2 expression levels were decreased in PBMC from untreated patients compared to that from controls, and treatment significantly upregulated EZH2 expression. Expression of miR-124 was increased in MS patients compared to controls. Blood immunophenotyping revealed EZH2 expression mostly restricted to CD4+ and CD8+ T cells, and circulating EZH2+ CD4+ and CD8+ T cells were decreased in untreated MS patients compared to controls. CD8+ T cells expressing EZH2 exhibited a predominant central memory phenotype, whereas EZH2+ CD4+ T cells were of effector memory nature, and both T cell subsets produced TNF-α. EZH2+ T cells were enriched in the cerebrospinal fluid compartment compared to blood and were found in chronic active lesions from MS patients. EZH2 inhibition and microarray analysis in PBMC was associated with significant downregulation of key T cell adhesion molecules. CONCLUSION: These findings suggest a role of EZH2 in the migration of T cells in MS patients. The observation of TNF-α expression by CD4+ and CD8+ T cells expressing EZH2 warrants additional studies to explore more in depth the pathogenic potential of EZH2+-positive cells in MS

Risk Acceptance in Multiple Sclerosis Patients on Natalizumab Treatment

Objective: We aimed to investigate the ability of natalizumab (NTZ)-treated patients to assume treatment-associated risks and the factors involved in such risk acceptance.Methods: From a total of 185 patients, 114 patients on NTZ as of July 2011 carried out a comprehensive survey. We obtained disease severity perception scores, personality traits' scores, and risk-acceptance scores (RAS) so that higher RAS indicated higher risk acceptance. We recorded JC virus status (JCV+/-), prior immunosuppression, NTZ treatment duration, and clinical characteristics. NTZ patients were split into subgroups (A-E), depending on their individual PML risk. Some 22 MS patients on first-line drugs (DMD) acted as controls.Results: No differences between treatment groups were observed in disease severity perception and personality traits. RAS were higher in NTZ than in DMD patients (p<0.01). Perception of the own disease as a more severe condition tended to predict higher RAS (p=0.07). Higher neuroticism scores predicted higher RAS in the NTZ group as a whole (p=0.04), and in high PML-risk subgroups (A-B) (p=0.02). in low PML-risk subgroups (C-E), higher RAS were associated with a JCV+ status (p=0.01). Neither disability scores nor pre-treatment relapse rate predicted RAS in either group.Conclusions: Risk acceptance is a multifactorial phenomenon, which might be partly explained by an adaptive process, in light of the higher risk acceptance amongst NTZ-treated patients and, especially, amongst those who are JCV seropositive but still have low PML risk, but which seems also intimately related to personality traits.Bayer Health CareMerck SeronoTEVAVall dHebron Univ Hosp, Dept Neurol Neuroimmunol, Multiple Sclerosis Ctr Catalonia Cemcat, Barcelona, SpainUniversidade Federal de São Paulo, Dept Neurol & Neurosurg, São Paulo, BrazilUniv Hosp Principe de Asturias, Dept Neurol, Madrid, SpainUniversidade Federal de São Paulo, Dept Neurol & Neurosurg, São Paulo, BrazilWeb of Scienc

Lesion topographies in multiple sclerosis diagnosis

To assess the contributions of cortico-juxtacortical and corpus callosum lesions to multiple sclerosis diagnosis and to compare the value of ≥1 vs ≥3 periventricular lesions in clinically isolated syndromes (CIS). Step 1: We evaluated lesion topography classifications in 657 patients with CIS with stepwise Cox proportional hazards regression models considering second attack as the outcome. Step 2: We established 2 dissemination in space (DIS) versions according to the periventricular lesion cutoffs of ≥1 and ≥3 and assessed their performance at 10 years with second attack as the outcome, first individually and then combined with dissemination in time (DIT) in all cases (n = 326), by age, and by CIS topography. Step 1: The models (hazard ratios [95% confidence interval]) favored ≥1 over ≥3 periventricular lesions (2.5 [1.7-3.6]) and cortico-juxtacortical over juxtacortical lesions (1.4 [1.0-1.8]). Callosal lesions were not selected. Step 2: DIS specificity with ≥1 periventricular lesions was slightly lower than with ≥3 (59.1 vs 61.4) and the same after adding DIT (88.6). Regarding age, ≥3 periventricular lesions improved DIS specificity over ≥1 lesions in the 40-49 years of age bracket (66.7 vs 58.3). This difference disappeared when adding DIT (83.3). Optic neuritis had a similar pattern when evaluating CIS topographies. Our results comply with the Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) consensus recommendation of combining cortical and juxtacortical lesions into a single term when possible. Concerning periventricular lesions, maintaining the current ≥1 cutoff in the McDonald criteria does not compromise specificity in typical CIS cases, but attention should be paid to older patients or optic neuritis cases

Analysis of prognostic factors associated with longitudinally extensive transverse myelitis

Abstract Objective: The aim of this study is to report the clinical profile and outcome of longitudinally extensive transverse myelitis (LETM). Methods: We prospectively studied adult patients who presented with LETM from January 2008 to December 2011. Information on demographic, clinical course, magnetic resonance imaging (MRI) and outcome was collected. HLA-DRB1 genotype was compared with those of 225 normal controls and patients with MS (228) and neuromyelitis optica (NMO) (22). Results: In total, 23 patients (16 female) with a median age of 44.5 years (range: 20–77 years) were included. Most (74%) had moderate–severe disability at nadir (48% non-ambulatory), normal/non-multiple sclerosis (MS) brain MRI (96%) and a median MRI cord lesion of 5 vertebral segments (range: 3–19). Laboratory analysis showed cerebrospinal fluid pleocytosis (45%), NMO-IgG (9%), antinuclear antibodies (70%), and genotype HLA-DRB1*13 (57%). The frequency of DRB1*13 genotype was higher compared with controls (p=0.002), MS (p=0.001) and NMO (p= 0.003) patients. After a median follow-up of 32 months, one patient converted to MS, two had relapsing LETM with NMO-IgG, and 20 remained as idiopathic with recurrences in four (20%). Twelve (52%) patients recovered with minimal disability (Expanded Disability Status Scale (EDSS) <2.5) and three (13%) remained wheelchair dependent. Disability at nadir was associated with the final outcome and extension of the spinal cord lesion with risk of recurrence. Recurrence was not associated with worse outcome. Conclusions: Inflammatory LETM is mostly idiopathic with a good outcome. It includes a relatively homogenous group of patients with an overrepresentation of the HLA-DRB1*13 genotype. EDSS at nadir is a predictor of the final outcome and extension of the myelitis of the recurrence risk

Association of Early Progression Independent of Relapse Activity With Long-term Disability After a First Demyelinating Event in Multiple Sclerosis

This cohort study investigates the long-term outcomes of patients who develop progression independent of relapse activity after a first demyelinating event in multiple sclerosis. What are the long-term outcomes of patients developing progression independent of relapse activity (PIRA) after a first demyelinating event in multiple sclerosis? In this longitudinal cohort study including 1128 patients with a first demyelinating event in multiple sclerosis, presenting with PIRA was associated with significantly shorter times to developing severe disability compared with not presenting with PIRA. Patients presenting with PIRA within the first 5 years of multiple sclerosis had a significantly 26-fold greater risk of developing severe disability than patients whose first PIRA appeared late in the disease. Results suggest that presenting with PIRA after a first demyelinating event in multiple sclerosis is an ominous prognosis, especially if it occurs early in the disease course. Progression independent of relapse activity (PIRA) is the main event responsible for irreversible disability accumulation in relapsing multiple sclerosis (MS). To investigate clinical and neuroimaging predictors of PIRA at the time of the first demyelinating attack and factors associated with long-term clinical outcomes of people who present with PIRA. This cohort study, conducted from January 1, 1994, to July 31, 2021, included patients with a first demyelinating attack from multiple sclerosis; patients were recruited from 1 study center in Spain. Patients were excluded if they refused to participate, had alternative diagnoses, did not meet protocol requirements, had inconsistent demographic information, or had less than 3 clinical assessments. Exposures included (1) clinical and neuroimaging features at the first demyelinating attack and (2) presenting PIRA, ie, confirmed disability accumulation (CDA) in a free-relapse period at any time after symptom onset, within (vs after) the first 5 years of the disease (ie, early/late PIRA), and in the presence (vs absence) of new T2 lesions in the previous 2 years (ie, active/nonactive PIRA). Expanded Disability Status Scale (EDSS) yearly increase rates since the first attack and adjusted hazard ratios (HRs) for predictors of time to PIRA and time to EDSS 6.0. Of the 1128 patients (mean [SD] age, 32.1 [8.3] years; 781 female individuals [69.2%]) included in the study, 277 (25%) developed 1 or more PIRA events at a median (IQR) follow-up time of 7.2 (4.6-12.4) years (for first PIRA). Of all patients with PIRA, 86 of 277 (31%) developed early PIRA, and 73 of 144 (51%) developed active PIRA. Patients with PIRA were slightly older, had more brain lesions, and were more likely to have oligoclonal bands than those without PIRA. Older age at the first attack was the only predictor of PIRA (HR, 1.43; 95% CI, 1.23-1.65; P <.001 for each older decade). Patients with PIRA had steeper EDSS yearly increase rates (0.18; 95% CI, 0.16-0.20 vs 0.04; 95% CI, 0.02-0.05; P < .001) and an 8-fold greater risk of reaching EDSS 6.0 (HR, 7.93; 95% CI, 2.25-27.96; P = .001) than those without PIRA. Early PIRA had steeper EDSS yearly increase rates than late PIRA (0.31; 95% CI, 0.26-0.35 vs 0.13; 95% CI, 0.10-0.16; P < .001) and a 26-fold greater risk of reaching EDSS 6.0 from the first attack (HR, 26.21; 95% CI, 2.26-303.95; P = .009). Results of this cohort study suggest that for patients with multiple sclerosis, presenting with PIRA after a first demyelinating event was not uncommon and suggests an unfavorable long-term prognosis, especially if it occurs early in the disease course

Menarche, pregnancies, and breastfeeding do not modify long-term prognosis in multiple sclerosis

ObjectiveTo investigate the effect of menarche, pregnancies, and breastfeeding on the risk of developing multiple sclerosis (MS) and disability accrual using a multivariate approach based on a large prospective cohort of patients with clinically isolated syndrome (CIS).MethodsA cross-sectional survey of the reproductive information of female participants in a CIS cohort was performed. We examined the relationship of age at menarche with the risk of clinically definite MS (CDMS), McDonald 2010 MS, and Expanded Disability Status Scale (EDSS) 3.0 and 6.0. The effect of pregnancy (before and after CIS) and breastfeeding in the risk of CDMS, McDonald 2010 MS, and EDSS 3.0 was also examined. Univariate and multivariate analyses were performed and findings were confirmed using sensitivity analyses and a propensity score model.ResultsThe data of 501 female participants were collected. Age at menarche did not correlate with age at CIS and was not associated with the risk of CDMS or EDSS 3.0 or 6.0. Pregnancy before CIS was protective for CDMS in the univariate analysis, but the effect was lost in the multivariate model and did not modify the risk of EDSS 3.0. Pregnancy after CIS was protective for both outcomes in univariate and multivariate analyses when pregnancy was considered a baseline variable, but the protective effect disappeared when analyzed as a time-dependent event. Breastfeeding did not modify the risk for the 3 outcomes.ConclusionsThese results demonstrate that menarche, pregnancies, and breastfeeding did not substantially modify the risk of CDMS or disability accrual using a multivariable and time-dependent approach

Deciphering multiple sclerosis disability with deep learning attention maps on clinical MRI

The application of convolutional neural networks (CNNs) to MRI data has emerged as a promising approach to achieving unprecedented levels of accuracy when predicting the course of neurological conditions, including multiple sclerosis, by means of extracting image features not detectable through conventional methods. Additionally, the study of CNN-derived attention maps, which indicate the most relevant anatomical features for CNN-based decisions, has the potential to uncover key disease mechanisms leading to disability accumulation. From a cohort of patients prospectively followed up after a first demyelinating attack, we selected those with T1-weighted and T2-FLAIR brain MRI sequences available for image analysis and a clinical assessment performed within the following six months (N = 319). Patients were divided into two groups according to expanded disability status scale (EDSS) score: ≥3.0 and < 3.0. A 3D-CNN model predicted the class using whole-brain MRI scans as input. A comparison with a logistic regression (LR) model using volumetric measurements as explanatory variables and a validation of the CNN model on an independent dataset with similar characteristics (N = 440) were also performed. The layer-wise relevance propagation method was used to obtain individual attention maps. The CNN model achieved a mean accuracy of 79% and proved to be superior to the equivalent LR-model (77%). Additionally, the model was successfully validated in the independent external cohort without any re-training (accuracy = 71%). Attention-map analyses revealed the predominant role of frontotemporal cortex and cerebellum for CNN decisions, suggesting that the mechanisms leading to disability accrual exceed the mere presence of brain lesions or atrophy and probably involve how damage is distributed in the central nervous system

Neurofilament light chain level is a weak risk factor for the development of MS

Altres ajuts: T Jens Kuhle was supported by an ECTRIMS Research Fellowship Programme and by the Forschungsfonds of the University of Basel, Switzerland.To determine the prognostic value of selected biomarkers in clinically isolated syndromes (CIS) for conversion to multiple sclerosis (MS) and disability accrual. Data were acquired from 2 CIS cohorts. The screening phase evaluated patients developing clinically definite MS (CIS-CDMS) and patients who remained as CIS during a 2-year minimum follow-up (CIS-CIS). We determined levels of neurofascin, semaphorin 3A, fetuin A, glial fibrillary acidic protein, and neurofilament light (NfL) and heavy chains in CSF (estimated mean [95% confidence interval; CI]). We evaluated associations between biomarker levels, conversion, disability, and magnetic resonance parameters. In the replication phase, we determined NfL levels (n = 155) using a 900 ng/L cutoff. Primary endpoints in uni- and multivariate analyses were CDMS and 2010 McDonald MS. The only biomarker showing significant differences in the screening was NfL (CIS-CDMS 1,553.1 [1,208.7-1,897.5] ng/L and CIS-CIS 499.0 [168.8-829.2] ng/L, p < 0.0001). The strongest associations were with brain parenchymal fraction change (r = −0.892) and percentage brain volume change (r = −0.842) at 5 years. NfL did not correlate with disability. In the replication phase, more NfL-positive patients, according to the cutoff, evolved to MS. Every 100-ng/L increase in NfL predicted CDMS (hazard ratio [HR] = 1.009, 95% CI 1.005-1.014) and McDonald MS (HR = 1.009, 95% CI 1.005-1.013), remaining significant for CDMS in the multivariate analysis (adjusted HR = 1.005, 95% CI 1.000-1.011). This risk was lower than the presence of oligoclonal bands or T2 lesions. NfL is a weak independent risk factor for MS. Its role as an axonal damage biomarker may be more relevant as suggested by its association with medium-term brain volume changes

Indicadores precoces de respuesta al tratamiento con interferón en pacientes con esclerosis múltiple

Introducción: el tratamiento con interferón β sigue siendo la terapia inmunomoduladora más extendida en el tratamiento de la esclerosis múltiple remitente-recurrente si bien su eficacia es parcial. En ausencia de un biomarcador específico de respuesta, identificar precozmente a los pacientes que presentan un fallo terapéutico o una respuesta parcial es fundamental para plantear alternativas terapéuticas. Objetivo: estudiar la utilidad de la Multiple Sclerosis Functional Composite para evaluar el acumulo precoz de discapacidad, así como el valor de otras variables clínicas y de RM recogidas en el primer año de tratamiento para predecir la evolución en los 24 meses siguientes. Métodos: se diseñó un estudio prospectivo en pacientes con esclerosis múltiple remitente-recurrente que iniciaban tratamiento con interferón beta. Se realizó una valoración clínica (EDSS, MSFC, tasa de brotes) y por RM, al inicio y tras los 12 primeros meses de tratamiento. Durante los siguientes 24 meses se evaluó la presencia de actividad de la enfermedad (brotes o progresión) para definir el fallo terapéutico a largo plazo. Resultados: se incluyeron 165 pacientes, 127 en el subestudio con RM. El modelo de regresión logística demostró que sólo los parámetros de RM (presencia de más de 2 lesiones activas, OR 2.3, IC 95% 1.0-5.2) y las variables compuestas (Río Score ≥2, OR 4.8 IC 95% 1.6-1.4) eran capaces de identificar a los pacientes con riesgo de presentar una enfermedad activa tras el primer año de tratamiento con interferón. Conclusión: en pacientes con EMRR que inician tratamiento con interferón beta, la combinación de medidas de actividad clínica y por RM tras los 12 primeros meses, podría permitir identificar a aquellos que se beneficiarían de un cambio precoz de tratamiento.Introduction: treatment with interferon β remains the most widespread immunomodulatory therapy in the treatment of relapsing-remitting multiple sclerosis, although its efficacy is partial. In the absence of a specific biomarker of response, early identification of patients with treatment failure or a partial response is critical to defining therapeutic strategies. Objective: To study the usefulness of the Multiple Sclerosis Functional Composite to evaluate the early accumulation of disability, as well as the value of other clinical and MRI variables in the first year of treatment to predict the evolution in the following 24 months. Methods: A prospective study was designed in patients with relapsing-remitting multiple sclerosis starting treatment with interferon beta. Clinical assessment (EDSS, MSFC, relapse rate) and MRI study at baseline and after 12 months of treatment were performed. During the next 24 months the presence of disease activity (relapses or progression) was evaluated to define the long term treatment failure. Results: 165 patients, 127 in the MRI substudy, were included. The logistic regression model showed that only RM parameters (presence of more than 2 active lesions, OR 2.3, 95% CI 1.0-5.2) and composite variables (Río Score ≥2, OR 4.8 95% CI 1.6-1.4) were able to identify patients at risk of developing active disease after the first year of treatment with interferon. Conclusion: In patients with RRMS starting treatment with beta interferon, the combination of measures of disease activity and the presence of new active lesions, may have a prognostic value to identify patients who benefits from early treatment change