Dual role of peripheral B cells in multiple sclerosis: emerging remote players in demyelination and novel diagnostic biomarkers.

Introduction: Multiple sclerosis is an inflammatory and demyelinating disease caused by a pathogenic immune response against the myelin sheath surfaces of oligodendrocytes. The demyelination has been classically associated with pathogenic B cells residing in the central nervous system that release autoreactive antibodies against myelin. The aim of the present study was to investigate whether extracellular vesicles (EVs) mediate delivery of myelin autoreactive antibodies from peripheral B cells against oligodendrocytes in multiple sclerosis (MS) and to analyze whether these EVs could mediate demyelination in vitro. We also studied the role of these EV-derived myelin antibodies as a diagnostic biomarker in MS. Methods: This is a prospective, observational, and single-center study that includes patients with MS and two control groups: patients with non-immune white matter lesions and healthy controls. We isolated B-cell-derived EVs from the blood and cerebrospinal fluid (CSF) and analyzed their myelin antibody content. We also studied whether antibody-loaded EVs reach oligodendrocytes in patients with MS and the effect on demyelination of B-cell-derived EVs containing antibodies in vitro. Results: This study enrolled 136 MS patients, 23 white matter lesions controls, and 39 healthy controls. We found autoreactive myelin antibodies in EVs that were released by peripheral B cells, but not by populations of B cells resident in CSF. We also identified a cut-off of 3.95 ng/mL of myelin basic protein autoantibodies in EVs from peripheral B cells, with 95.2% sensitivity and 88.2% specificity, which allows us to differentiate MS patients from healthy controls. EV-derived myelin antibodies were also detected in the oligodendrocytes of MS patients. Myelin antibody-loaded EVs from B cells induced myelin markers decrease of oligodendrocytes in vitro. Discussion: Peripheral reactive immune cells could contribute remotely to MS pathogenesis by delivering myelin antibodies to oligodendrocytes. EV-derived myelin antibodies could play a role as diagnostic biomarker in MS.

Long-Term Anticoagulation in Secondary Ischemic Stroke Prevention: The Prospective Multicenter RESTAIC Registry.

Background and Objective: Oral anticoagulation (OAC) for secondary stroke prevention is recommended in atrial fibrillation (AF) and other sources of cardioembolic stroke. Our objectives were to explore the differences in ischemic and hemorrhagic events when using OAC for secondary stroke prevention according to the type of anticoagulant treatment and to analyze the number and reasons for OAC switches during long-term follow-up. Methods: Ischemic stroke (IS) patients who were discharged on OAC for secondary stroke prevention from January 2014 to October 2017 were recruited in a prospective, multicenter, hospital-based registry. Follow-up at 3 months was scheduled at the outpatient clinic with subsequent annual phone interviews for 3 years. Patients were classified into three study groups according to OAC at discharge: Vitamin K antagonist (VKA), Factor Xa inhibitor (FXa), or direct thrombin inhibitor (DTI). We compared stroke recurrences, intracranial hemorrhage, major bleeding, and all-cause mortality during the follow-up. We recorded any switches in OAC and the main reasons for the change. Results: A total of 241 patients were included. An anticoagulant was indicated in the presence of a source of cardioembolic stroke in 240 patients (99.6%) and lupus plus antiphospholipid syndrome in one patient. Up to 86 patients (35.6%) were on OAC before the index stroke; in 71 (82.5%) of them, this was VKA. At hospital discharge, 105 were treated with FXa (43.8%), 96 with VKA (39.6%), and 40 with DTI (16.6%). The cumulative incidences at 3 years were 17% for stroke recurrence, 1.6% for intracranial hemorrhage, 4.9% for major hemorrhage, and 22.8% for all-cause mortality, with no differences among the OAC groups in any outcomes. During the follow-up, 40 OAC switches were recorded (63% of them to FXa), mostly due to stroke recurrence. Conclusion: Long-term OAC in secondary stroke prevention is associated with a lower frequency of bleeding complications than stroke recurrences. No differences between anticoagulant drugs were found in any of the analyzed outcomes. The main cause for OAC switch during follow-up was stroke recurrence.

A tool to identify patients with embolic stroke of undetermined source at high recurrence risk.

OBJECTIVE: A tool to stratify the risk of stroke recurrence in patients with embolic stroke of undetermined source (ESUS) could be useful in research and clinical practice. We aimed to determine whether a score can be developed and externally validated for the identification of patients with ESUS at high risk for stroke recurrence. METHODS: We pooled the data of all consecutive patients with ESUS from 11 prospective stroke registries. We performed multivariable Cox regression analysis to identify predictors of stroke recurrence. Based on the coefficient of each covariate of the fitted multivariable model, we generated an integer-based point scoring system. We validated the score externally assessing its discrimination and calibration. RESULTS: In 3 registries (884 patients) that were used as the derivation cohort, age, leukoaraiosis, and multiterritorial infarct were identified as independent predictors of stroke recurrence and were included in the final score, which assigns 1 point per every decade after 35 years of age, 2 points for leukoaraiosis, and 3 points for multiterritorial infarcts (acute or old nonlacunar). The rate of stroke recurrence was 2.1 per 100 patient-years (95% confidence interval [CI] 1.44-3.06) in patients with a score of 0-4 (low risk), 3.74 (95% CI 2.77-5.04) in patients with a score of 5-6 (intermediate risk), and 8.23 (95% CI 5.99-11.3) in patients with a score of 7-12 (high risk). Compared to low-risk patients, the risk of stroke recurrence was significantly higher in intermediate-risk (hazard ratio [HR] 1.78, 95% CI 1.1-2.88) and high-risk patients (HR 4.67, 95% CI 2.83-7.7). The score was well-calibrated in both derivation and external validation cohorts (8 registries, 820 patients) (Hosmer-Lemeshow test χ2: 12.1 [p = 0.357] and χ2: 21.7 [p = 0.753], respectively). The area under the curve of the score was 0.63 (95% CI 0.58-0.68) and 0.60 (95% CI 0.54-0.66), respectively. CONCLUSIONS: The proposed score can assist in the identification of patients with ESUS at high risk for stroke recurrence.