Gadolinium-enhanced brain lesions in multiple sclerosis relapse.

OBJECTIVE: To study the clinico-radiological paradox in multiple sclerosis (MS) relapse by analyzing the number and location of gadolinium-enhanced (Gd+) lesions on brain MRI before methylprednisolone (MP) treatment. METHODS: We analyzed brain MRI from 90 relapsed MS patients in two Phase IV multicenter double-blind randomized clinical trials that showed the noninferiority of different routes and doses of MP administration. A 1.5- or 3-T brain MRI was performed at baseline before MP treatment and within 15 days of symptom onset. The number and location of Gd+ lesions were analyzed. Associations were studied using univariate analysis. RESULTS: Sixty-two percent of patients had at least 1 Gd+ brain lesion; the median number was 1 (interquartile range 0-4), and 41% of patients had 2 or more lesions. The most frequent location of Gd+ lesions was subcortical (41.4%). Gd+ brain lesions were found in 71.4% of patients with brainstem-cerebellum symptoms, 57.1% with spinal cord symptoms and 55.5% with optic neuritis (ON). Thirty percent of patients with brain symptoms did not have Gd+ lesions, and only 43.6% of patients had symptomatic Gd+ lesions. The univariate analysis showed a negative correlation between age and the number of Gd+ lesions (p=0.002). CONCLUSION: Most patients with relapse showed several Gd+ lesions on brain MRI, even when the clinical manifestation was outside of the brain. Our findings illustrate the clinico-radiological paradox in MS relapse and support the value of brain MRI in this scenario.

Gadolinium-enhanced brain lesions in multiple sclerosis relapse / Lesiones cerebrales captantes de gadolinio en el brote de los pacientes con esclerosis múltiple

Objective: To study the clinico-radiological paradox in multiple sclerosis (MS) relapse by analyzing the number and location of gadolinium-enhanced (Gd+) lesions on brain MRI before methylprednisolone (MP) treatment. Methods: We analyzed brain MRI from 90 relapsed MS patients in two Phase IV multicenter double-blind randomized clinical trials that showed the noninferiority of different routes and doses of MP administration. A 1.5- or 3-T brain MRI was performed at baseline before MP treatment and within 15 days of symptom onset. The number and location of Gd+ lesions were analyzed. Associations were studied using univariate analysis. Results: Sixty-two percent of patients had at least 1 Gd+ brain lesion; the median number was 1 (interquartile range 0–4), and 41% of patients had 2 or more lesions. The most frequent location of Gd+ lesions was subcortical (41.4%). Gd+ brain lesions were found in 71.4% of patients with brainstem-cerebellum symptoms, 57.1% with spinal cord symptoms and 55.5% with optic neuritis (ON). Thirty percent of patients with brain symptoms did not have Gd+ lesions, and only 43.6% of patients had symptomatic Gd+ lesions. The univariate analysis showed a negative correlation between age and the number of Gd+ lesions (p = 0.002). Conclusion: Most patients with relapse showed several Gd+ lesions on brain MRI, even when the clinical manifestation was outside of the brain. Our findings illustrate the clinico-radiological paradox in MS relapse and support the value of brain MRI in this scenario. (AU)

Objetivo: Estudiar la paradoja clínico-radiológica en el brote de la esclerosis múltiple (EM) mediante el análisis de lesiones captantes de gadolinio (Gd+) en la RM cerebral antes del tratamiento con metilprednisolona (MP). Métodos: Analizamos la RM cerebral basal de 90 pacientes con EM en brote de 2 ensayos clínicos aleatorizados multicéntricos fase IV que demostraron la no inferioridad de diferentes vías y dosis de MP, realizadas antes del tratamiento con MP y en los 15 días siguientes a la aparición de los síntomas. Se analizaron el número y la localización de las lesiones Gd+. Se estudiaron las asociaciones mediante análisis univariado. Resultados: El 62% de los pacientes tenía al menos una lesión Gd+ cerebral y el 41% de los pacientes tenía 2 o más lesiones. La localización más frecuente fue la subcortical (41,4%). Se encontraron lesiones Gd+ cerebrales en el 71,4% de los pacientes con síntomas de tronco cerebral o cerebelo, en el 57,1% con síntomas medulares y en el 55,5% con neuritis óptica. El 30% de los pacientes con síntomas cerebrales no tenían lesiones Gd+ y sólo el 4,.6% de los pacientes tenían lesiones Gd+ sintomáticas. El análisis univariante mostró una correlación negativa entre la edad y el número de lesiones Gd+ (p = 0,002). Conclusiones: La mayoría de los pacientes en brote mostraron varias lesiones Gd+ en la RM cerebral, incluso cuando la manifestación clínica fue medular u óptica. Nuestros hallazgos ilustran la paradoja clínico-radiológica en el brote de la EM y apoyan el valor de la RM cerebral en este escenario. (AU)

Paving the way towards an effective treatment for multiple sclerosis: advances in cell therapy.

Multiple sclerosis (MS) is a leading cause of chronic neurological disability in young to middle-aged adults, affecting ~2.5 million people worldwide. Currently, most therapeutics for MS are systemic immunosuppressive or immunomodulatory drugs, but these drugs are unable to halt or reverse the disease and have the potential to cause serious adverse events. Hence, there is an urgent need for the development of next-generation treatments that, alone or in combination, stop the undesired autoimmune response and contribute to the restoration of homeostasis. This review analyzes current MS treatments as well as different cell-based therapies that have been proposed to restore homeostasis in MS patients (tolerogenic dendritic cells, regulatory T cells, mesenchymal stem cells, and vaccination with T cells). Data collected from preclinical studies performed in the experimental autoimmune encephalomyelitis (EAE) model of MS in animals, in vitro cultures of cells from MS patients and the initial results of phase I/II clinical trials are analyzed to better understand which parameters are relevant for obtaining an efficient cell-based therapy for MS.

Anti-inflammatory disease-modifying treatment and disability progression in primary progressive multiple sclerosis: a cohort study.

BACKGROUND AND PURPOSE: Treatment options in primary progressive multiple sclerosis (PPMS) are scarce and, with the exception of ocrelizumab, anti-inflammatory agents have failed to show efficacy in ameliorating disability progression. The aim of this study was to investigate a potential effect of anti-inflammatory disease-modifying treatment on disability outcomes in PPMS. METHODS: Using MSBase, a large, international, observational database, we identified patients with PPMS who were either never treated or treated with a disease-modifying agent. Propensity score matching was used to select subpopulations with similar baseline characteristics. Expanded Disability Status Scale (EDSS) outcomes were compared with an intention-to-treat and an as-treated approach in paired, pairwise-censored analyses. RESULTS: Of the 1284 included patients, 533 were matched (treated, n = 195; untreated n = 338). Median on-study pairwise-censored follow-up was 3.4 years (quartiles 1.2-5.5). No difference in the hazard of experiencing 3-month confirmed EDSS progression events was observed between the groups [hazard ratio (HR), 1.0; 95% confidence interval (CI), 0.6-1.7, P = 0.87]. We did not find significant differences in the hazards of confirmed EDSS improvement (HR, 1.0; 95% CI, 0.6-1.6, P = 0.91) or reaching a confirmed EDSS step ≥7 (HR, 1.1; 95% CI, 0.7-1.6, P = 0.69). CONCLUSION: Our pooled analysis of disease-modifying agents suggests that these therapies have no substantial effect on short- to medium-term disability outcomes in PPMS.

Comparison of two high doses of oral methylprednisolone for multiple sclerosis relapses: a pilot, multicentre, randomized, double-blind, non-inferiority trial.

BACKGROUND AND PURPOSE: Oral or intravenous methylprednisolone (≥500 mg/day for 5 days) is recommended for multiple sclerosis (MS) relapses. Nonetheless, the optimal dose remains uncertain. We compared clinical and radiological effectiveness, safety and quality of life (QoL) of oral methylprednisolone [1250 mg/day (standard high dose)] versus 625 mg/day (lesser high dose), both for 3 days] in MS relapses. METHODS: A total of 49 patients with moderate to severe MS relapse within the previous 15 days were randomized in a pilot, double-blind, multicentre, non-inferiority trial (ClinicalTrial.gov, NCT01986998). The primary endpoint was non-inferiority of the lesser high dose by Expanded Disability Status Scale (EDSS) score improvement on day 30 (non-inferiority margin, 1 point). The secondary endpoints were EDSS score change on days 7 and 90, changes in T1 gadolinium-enhanced and new/enlarged T2 lesions on days 7 and 30, and safety and QoL results. RESULTS: The primary outcome was achieved [mean (95% confidence interval) EDSS score difference, -0.26 (-0.7 to 0.18) at 30 days (P = 0.246)]. The standard high dose yielded a superior EDSS score improvement on day 7 (P = 0.028). No differences were observed in EDSS score on day 90 (P = 0.352) or in the number of T1 gadolinium-enhanced or new/enlarged T2 lesions on day 7 (P = 0.401, 0.347) or day 30 (P = 0.349, 0.529). Safety and QoL were good at both doses. CONCLUSIONS: A lesser high-dose oral methylprednisolone regimen may not be inferior to the standard high dose in terms of clinical and radiological response.

Hepatitis tóxica tras tratamiento concomitante con interferón beta y aloe vera en un paciente con esclerosis múltiple: a propósito de un caso / Toxic hepatitis after concomitant interferon beta and aloe vera treatment in a patient with multiple sclerosis: A case report

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Mielitis. Diferencias entre esclerosis múltiple y otras etiologías / Myelitis: Differences between multiple sclerosis and other aetiologies

Introducción: Un primer brote de mielitis puede ocurrir en el contexto de enfermedades desmielinizantes, inflamatorias sistémicas o infecciosas. Nuestro objetivo fue analizar las diferencias entre mielitis asociadas a esclerosis múltiple (EM) y mielitis por otras etiologías. Métodos: Análisis retrospectivo, unicéntrico, de pacientes con primer brote de mielitis (2000-2013). Se analizaron variables demográficas, etiológicas, clínicas, radiológicas y pronósticas, y se compararon entre mielitis por EM y mielitis por otras etiologías. Resultados: Se incluyó un total de 91 pacientes. Tiempo medio de seguimiento: 7 años. Diagnósticos: EM 57 (63%), mielitis transversa idiopática 22 (24%), asociada a enfermedades sistémicas 6 (7%), otros diagnósticos (6%). Mielitis por EM: menor edad de inicio (35 ± 11 vs .41 ± 13; p = 0,02), mayor afectación esfinteriana (40,4 vs. 27,3%; p = 0,05), mayor afectación multifocal en la RM medular (77,2 vs. 26,5%; p = 0,001), menor extensión de la lesión (segmentos vertebrales 2,4 vs. 1,4; p = 0,001), localización cervical (82,5 vs. 64,7%; p = 0,05) y localización posterior (89,5 vs. 41,2%; p = 0,001). Mielitis por otras etiologías: mayor localización anterior (47,1 vs. 24,6%; p = 0,02) y centromedular (47,1 vs. 14,1%; p = 0,001) y mejor recuperación al año (EDSS 2,0 vs. 1,5; p = 0,01). Análisis multivariante: la afectación multifocal medular (OR 9,38; IC 95%: 2,04-43,1) y del cordón posterior (OR 2,16; IC 95%: 2,04-2,67) se asociaron de forma independiente al diagnóstico de EM. Conclusiones: Un alto porcentaje de pacientes con un primer brote de mielitis serán diagnosticados de EM. La presencia de lesiones medulares multifocales y en el cordón posterior se asocian de forma significativa a este diagnóstico

Background: Myelitis can appear as an initial symptom in the context of demyelinating diseases, systemic inflammatory diseases, and infectious diseases. We aim to analyse the differences between myelitis associated with multiple sclerosis (MS) and myelitis resulting from other aetiologies. Methods: Single-centre, retrospective analysis of patients with initial myelitis (2000-2013). Demographic, aetiological, clinical, radiological and prognostic variables were analysed and compared between patients with myelitis from MS and those with myelitis due to other aetiologies. Results: We included 91 patients; mean follow-up was 7 years. Diagnoses were as follows: MS 57 (63%), idiopathic transverse myelitis 22 (24%), associated systemic diseases 6 (7%), and other diagnoses (6%). Myelitis due to MS was associated with younger age of onset (35 ± 11 vs. 41 ± 13; P = .02), more pronounced sphincter involvement (40.4 vs. 27.3%; P=.05), greater multifocal involvement in spinal MRI (77.2 vs. 26.5%; P=.001), shorter lesion extension (2.4 vs. 1.4 vertebral segments; P=.001), cervical location (82.5 vs. 64.7%; P=.05) and posterior location (89.5 vs. 41.2%; P=.001). Myelitis due to other aetiologies more frequently showed anterior location (47.1 vs. 24.6%; P=.02), and central cord involvement (47.1 vs. 14.1%; P=.001), with better recovery at one year of follow up (EDSS 2.0 vs. 1.5;P=.01). Multivariate analysis showed that multifocal spinal cord involvement (OR 9.38, 95% CI: 2.04-43.1) and posterior cord involvement (OR 2.16, 95% CI: 2.04-2.67) were independently associated with the diagnosis of MS. Conclusions: A high percentage of patients with an initial myelitis event will be diagnosed with MS. The presence of multifocal and posterior spinal cord lesions was significantly associated with the diagnosis of MS

Myelitis: Differences between multiple sclerosis and other aetiologies.

BACKGROUND: Myelitis can appear as an initial symptom in the context of demyelinating diseases, systemic inflammatory diseases, and infectious diseases. We aim to analyse the differences between myelitis associated with multiple sclerosis (MS) and myelitis resulting from other aetiologies. METHODS: Single-centre, retrospective analysis of patients with initial myelitis (2000-2013). Demographic, aetiological, clinical, radiological and prognostic variables were analysed and compared between patients with myelitis from MS and those with myelitis due to other aetiologies. RESULTS: We included 91 patients; mean follow-up was 7 years. Diagnoses were as follows: MS 57 (63%), idiopathic transverse myelitis 22 (24%), associated systemic diseases 6 (7%), and other diagnoses (6%). Myelitis due to MS was associated with younger age of onset (35 ± 11 vs. 41 ± 13; P = .02), more pronounced sphincter involvement (40.4 vs. 27.3%; P=.05), greater multifocal involvement in spinal MRI (77.2 vs. 26.5%; P=.001), shorter lesion extension (2.4 vs. 1.4 vertebral segments; P=.001), cervical location (82.5 vs. 64.7%; P=.05) and posterior location (89.5 vs. 41.2%; P=.001). Myelitis due to other aetiologies more frequently showed anterior location (47.1 vs. 24.6%; P=.02), and central cord involvement (47.1 vs. 14.1%; P=.001), with better recovery at one year of follow up (EDSS 2.0 vs. 1.5; P=.01). Multivariate analysis showed that multifocal spinal cord involvement (OR 9.38, 95% CI: 2.04-43.1) and posterior cord involvement (OR 2.16, 95% CI: 2.04-2.67) were independently associated with the diagnosis of MS. CONCLUSIONS: A high percentage of patients with an initial myelitis event will be diagnosed with MS. The presence of multifocal and posterior spinal cord lesions was significantly associated with the diagnosis of MS.

Similar biological effect of high-dose oral versus intravenous methylprednisolone in multiple sclerosis relapses.

UNLABELLED: Our aim was to investigate differences in immune mechanisms in multiple sclerosis (MS) relapse, after high-dose oral methylprednisolone (oMP) or intravenous methylprednisolone (ivMP). We measured serum cytokines (IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α and IFN-γ) in 39 of 49 MS patients with moderate-severe relapse, whom were treated with ivMP or oMP in a placebo-controlled, non-inferiority clinical trial. We assessed these cytokine levels at baseline and at 1 and 4 weeks post-treatment. The cytokine levels between oMP and ivMP were similar at any time. Proinflammatory cytokines (IL-6 and IFN-γ) were significantly decreased in both groups at week 1 (p = 0.05 / p = 0.03) and at week 4 (p = 0.04 / p = 0.05). This study provides further confirmatory evidence that oMP is not inferior to ivMP. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00753792.

A randomized clinical trial of oral versus intravenous methylprednisolone for relapse of MS.

BACKGROUND: Steroids improve multiple sclerosis (MS) relapses but therapeutic window and dose, frequency and administration route remain uncertain. OBJECTIVE: The objective of this paper is to compare the clinical and radiologic efficacy, tolerability and safety of intravenous methylprednisolone (ivMP) vs oral methylprednisolone (oMP), at equivalent high doses, for MS relapse. METHODS: Forty-nine patients with moderate or severe relapse within the previous 15 days were randomized in a double-blind, noninferiority, multicenter trial to receive ivMP or oMP and their matching placebos. Expanded Disability Status Scale (EDSS) scores were determined at baseline and weeks 1, 4 and 12. Brain MRI were assessed at baseline and at weeks 1 and 4. Primary endpoint was a noninferiority assessment of EDSS improvement at four weeks (noninferiority margin of one point), with further key efficacy assessments of number and volume of T1 gadolinium-enhancing (Gd+), and new or enlarged T2 lesions at four weeks' post-treatment initiation. Secondary outcomes were safety and tolerability. RESULTS: The study achieved the main outcome of noninferiority at four weeks for improved EDSS score. No differences were found between ivMP and oMP in the number of Gd+ lesions (0 (0-1) vs 0 (0-0.5), p = 0.630), volume of Gd+ lesions (0 (0-88.0) vs 0 (0-32.9) mm(3), p = 0.735), or new or enlarged T2 lesions (0 (0-194) vs 0 (0-123), p = 0.769). MP was well tolerated, and no serious adverse events were reported. CONCLUSIONS: This study provides confirmatory evidence that oMP is not inferior to ivMP in reducing EDSS, similar in MRI lesions at four weeks for MS relapses and is equally well tolerated and safe. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00753792.

[HLA-DRB1 typing in Caucasians patients with neuromyelitis optica]. / HLA-DRB1 en pacientes caucasicos con neuromielitis optica.

INTRODUCTION: The existence of antibodies to aquaporin-4 (AQP-4-ab) has identified neuromyelitis optica (NMO) and multiple sclerosis (MS) as different diseases. Although HLA-DRB1 alleles contribute to MS risk, recent studies suggest that HLA back-ground differs between patients with NMO or MS in non-Caucasians populations. Our study was aimed to analyze HLA-DRB1 distribution in Caucasians NMO patients. SUBJECTS AND METHODS: We recruited a cohort of 22 NMO patients (73% were AQP-4-ab positive), 228 MS patients and 225 healthy controls from Spain and we genotyped the HLA-DRB1 locus. Then, we performed a pool analysis using reported data from 45 NMO patients (53% were AQP-4-ab positive), 156 MS patients and 310 healthy controls from Caucasian French population. RESULTS: In the Spanish cohort, NMO was associated with increased frequency of DRB1*10 allele compared with MS (odds ratio, OR = 15.1; 95% confidence interval, 95% CI = 3.26-69.84; p = 0.012). In the pooled analysis, by comparison with healthy controls, NMO was associated with increased frequency of DRB1*03 allele (OR = 2.27; 95% CI = 1.44-3.58; p < 0.0008) which was related to AQP-4-ab seropositivity (OR = 2.74; 95% CI = 1.58-4.77; p < 0.0008). By contrast, MS was associated with increased frequency of DRB1*15 allele (OR = 2.09; 95% CI = 1.62-2.68; p < 0.0008) and decreased frequency of DRB1*07 allele (OR = 0.58; 95% CI = 0.44-0.78; p < 0.0008). CONCLUSIONS: Caucasian patients with NMO and MS have a different HLA-DRB1 allelic distribution. DRB1*03 allele seems to contribute to NMO seropositivity. Multicenter collaborative efforts are needed to adequately address the genetic contribution to NMO susceptibility.

Specific T-cell proliferation to myelin peptides in relapsing-remitting multiple sclerosis.

BACKGROUND: The identification of major immunogenic peptides in multiple sclerosis (MS) is of great importance for the development of antigen-specific therapies. Cellular reactivity against a selected mix of seven myelin peptides was evaluated in vitro. The evolution of this reactivity over time and its correlation with clinical variables was also analysed. MATERIAL AND METHODS: Forty-two patients with MS, 15 with other demyelinating diseases and 40 healthy donors (HD) were studied. Cell proliferation was measured by 3[H] thymidine incorporation into samples obtained at 0, 3, 6 and 12months of MS patient follow-up. RESULTS: A positive reaction to the peptide mix was detected in 31 of the 42 patients (74%), 12 of the 40 HD (30%) and 6 of the 15 (40%) patients with other demyelinating diseases. Patients with positive proliferation had greater disability (EDSS score, 3 [1-5.5] vs. 1.0[1-2], P=0.021), higher number of relapses (7±4.1 vs. 3±1.2, P<0.001) and shorter time since the last relapse (9±7.5 vs. 32±12.3months, P=0.036). After 12months of follow-up, cell reactivity was maintained in 33 patients (78%). CONCLUSION: A high percentage of patients exhibit a significant and maintained reactivity to myelin peptides over time. Therefore, this mix may be useful as a source of antigen in the development of protocols aimed at inducing specific tolerance in MS.

Comparative study of clinical grade human tolerogenic dendritic cells.

BACKGROUND: The use of tolerogenic DCs is a promising therapeutic strategy for transplantation and autoimmune disorders. Immunomodulatory DCs are primarily generated from monocytes (MDDCs) for in vitro experiments following protocols that fail to fulfil the strict regulatory rules of clinically applicable products. Here, we compared the efficacy of three different tolerance-inducing agents, dexamethasone, rapamycin and vitamin D3, on DC biology using GMP (Good Manufacturing Practice) or clinical grade reagents with the aim of defining their use for human cell therapy. METHODS: Tolerogenic MDDCs were generated by adding tolerogenic agents prior to the induction of maturation using TNF-α, IL-ß and PGE2. We evaluated the effects of each agent on viability, efficiency of differentiation, phenotype, cytokine secretion and stability, the stimulatory capacity of tol-DCs and the T-cell profiles induced. RESULTS: Differences relevant to therapeutic applicability were observed with the cellular products that were obtained. VitD3-induced tol-DCs exhibited a slightly reduced viability and yield compared to Dexa-and Rapa-tol-DCs. Phenotypically, while Dexa-and VitD3-tol-DCs were similar to immature DCs, Rapa-tol-DCs were not distinguishable from mature DCs. In addition, only Dexa-and moderately VitD3-tol-DCs exhibited IL-10 production. Interestingly, in all cases, the cytokine secretion profiles of tol-DCs were not modified by a subsequent TLR stimulation with LPS, indicating that all products had stable phenotypes. Functionally, clearly reduced alloantigen T cell proliferation was induced by tol-DCs obtained using any of these agent. Also, total interferon-gamma (IFN-γ) secretion by T cells stimulated with allogeneic tol-DCs was reduced in all three cases, but only T cells co-cultured with Rapa-tol-DCs showed impaired intracellular IFN-γ production. In addition, Rapa-DCs promoted CD4+ CD127 low/negative CD25high and Foxp3+ T cells. CONCLUSIONS: Our results demonstrate contrasting influences of different clinical-grade pharmacological agents on human tol-DC generation. This should be taken into account for decisions on the use of a specific agent for the appropriate cellular therapy in the context of a particular disease.