Smoking at time of CIS increases the risk of clinically definite multiple sclerosis

Background: Cigarette smoking is a modifiable risk factor that influences the disease course of patients with multiple sclerosis (MS). However, in patients with a clinically isolated syndrome (CIS), there are conflicting results about the association between smoking and the risk of a subsequent MS diagnosis. The aim of this study was to determine the risk of clinically definite MS (CDMS) in smoking and non-smoking patients at time of a first demyelinating event. Methods: Two hundred and fifty patients, aged 18–50 years, were included in our prospective CIS cohort. At time of the first neurological symptoms, patients completed a questionnaire about smoking habits. Cox regression analyses were performed to calculate univariate and multivariate hazard ratios for CDMS diagnosis in smoking and non-smoking CIS patients. Results: One hundred and fourteen (46%) CIS patients were diagnosed with CDMS during a mean follow-up of 58 months. In total, 79 (32%) patients smoked at time of CIS. Sixty-seven % of the smoking CIS patients were diagnosed with CDMS during follow-up compared to 36% of the non-smoking CIS patients (p < 0.001). Smoking at time of CIS was an independent predictor for CDMS diagnosis (HR 2.3; p = 0.002). Non-smoking CIS patients who had a history of smoking did not have a higher risk for CDMS than those who had never smoked. Conclusions: Smoking at time of CIS was an independent risk factor for a future CDMS diagnosis. This is an additional argument to quit smoking at time of the first attack of suspected MS

The association of Epstein-Barr virus infection with CXCR3+ B-cell development in multiple sclerosis: impact of immunotherapies

Epstein–Barr virus (EBV) infection of B cells is associated with increased multiple sclerosis (MS) susceptibility. Recently, we found that CXCR3-expressing B cells preferentially infiltrate the CNS of MS patients. In chronic virus-infected mice, these types of B cells are sustained and show increased antiviral responsiveness. How EBV persistence in B cells influences their development remains unclear. First, we analyzed ex vivo B-cell subsets from MS patients who received autologous bone marrow transplantation (n = 9), which is often accompanied by EBV reactivation. The frequencies of nonclass-switched and class-switched memory B cells were reduced at 3–7 months, while only class-switched B cells returned back to baseline at 24–36 months posttransplantation. At these time points, EBV DNA load positively correlated to the frequency of CXCR3+

Induction of brain-infiltrating T-bet–expressing B cells in multiple sclerosis

Objective: Results from anti-CD20 therapies demonstrate that B- and T-cell interaction is a major driver of multiple sclerosis (MS). The local presence of B-cell follicle-like structures and oligoclonal bands in MS patients indicates that certain B cells infiltrate the central nervous system (CNS) to mediate pathology. Which peripheral triggers underlie the development of CNS-infiltrating B cells is not fully understood. Methods: Ex vivo flow cytometry was used to assess chemokine receptor profiles of B cells in blood, cerebrospinal fluid, meningeal, and brain tissues of MS patients (n = 10). Similar analyses were performed for distinct memory subsets in the blood of untreated and natalizumab-treated MS patients (n = 38). To assess T-bet(CXCR3)+ B-cell differentiation, we cultured B cells from MS patients (n = 21) and healthy individuals (n = 34) under T helper 1- and TLR9-inducing conditions. Their CNS transmigration capacity was confirmed using brain endothelial monolayers. Results: CXC chemokine receptor 3 (CXCR3)-expressing B cells were enriched in different CNS compartments of MS patients. Treatment with the clinically effective drug natalizumab prevented the recruitment of CXCR3high IgG1+ subsets, corresponding to their increased ability to cross CNS barriers in vitro. Blocking of interferon-γ (IFNγ) reduced the transmigration potential and antigen-presenting function of these cells. IFNγ-induced B cells from MS patients showed increased T-bet expression and plasmablast development. Additional TLR9 triggering further upregulated T-bet and CXCR3, and was essential for IgG1 switching. Interpretation: This study demonstrates that T-bethigh IgG1+ B cells are triggered by IFNγ and TLR9 signals, likely contributing to enhanced CXCR3-mediated recruitment and local reactivity in the CNS of MS patients. ANN NEUROL 2019

Infliximab treatment in pathology-confirmed neurosarcoidosis

OBJECTIVE: To assess the efficacy and risks of treatment with infliximab (anti-tumor necrosis factor alpha) in pathology-confirmed neurosarcoidosis. METHODS: In a retrospective study in 2 tertiary referral centers in the Netherlands, we analyzed clinical characteristics, complications, and outcome of patients with neurosarcoidosis treated with infliximab. RESULTS: Twenty-eight patients were identified with a mean age of 42 years. Neurosarcoidosis presented with a cerebral parenchymal localization in 16 (59%), pituitary gland/hypothalamic sarcoidosis in 15 (54%), peripheral nerve involvement in 12 (43%), and chronic meningitis in 11 patients (41%). Initial treatment response after the start of infliximab was complete remission in 6 (21%) and improvement in 14 (50%), whereas 7 patients had stable disease (25%), and 1 (4%) deteriorated and died. At the end of follow-up, with a median of 32 months, 5 patients (18%) had died, and 2 (40%) were using infliximab at the time of death. Tapering or discontinuation of corticosteroids without a relapse was achieved in 19 of 28 patients (68%). In patients with decreasing dosing or discontinuation of infliximab, a relapse occurred in 5 of 19 patients (26%). Complications of infliximab were reported in 10 of 28 patients (36%) and mainly consisted of infections in 8 (29%). CONCLUSION: Infliximab is an effective treatment in neurosarcoidosis leading to remission or improvement in 70%. The mortality rate in infliximab-treated patients was substantial, indicating the severity of disease and treatment-associated complications. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in people with pathology-confirmed neurosarcoidosis, infliximab is beneficial

Intermittent versus continuous esketamine infusions for long-term pain modulation in complex regional pain syndrome: protocol of a randomized controlled non-inferiority study (KetCRPS-2)

Background: Complex regional pain syndrome (CRPS) is a chronic pain condition of an extremity. While achieving pain relief in CRPS is challenging, esketamine infusions can accomplish pain relief for several weeks post-infusion in a subgroup of CRPS patients. Unfortunately, CRPS esketamine protocols are very heterogeneous in advice on dosage, administration and treatment setting. Currently, no trials are available that study differences between intermittent and continuous esketamine infusions for CRPS. With the current situation of bed shortages, it is difficult to admit patients for several consecutive days for inpatient esketamine treatments. In this study, we investigate whether 6 intermittent outpatient esketamine treatments are not inferior to a continuous 6-day inpatient esketamine treatment in establishing pain relief. In addition, several secondary study parameters will be assessed in order to investigate mechanisms responsible for pain relief by esketamine infusions. Furthermore, the cost-effectiveness will be analyzed. Methods: In this RCT, the primary objective is to demonstrate that an intermittent esketamine dosing regimen is non-inferior to a continuous esketamine dosing regimen at 3 months follow-up. We will include 60 adult CRPS patients. The inpatient treatment group receives a continuous intravenous esketamine infusion for 6 consecutive days. The outpatient treatment group receives a 6-hour intravenous esketamine infusion every 2 weeks for 3 months. Esketamine dose will be individually tailored and is started at 0.05 mg/kg/h and can be increased to a maximum of 0.2 mg/kg/h. Each patient will be followed for 6 months. The primary study parameter is perceived pain intensity, measured by an 11-point Numerical Rating Scale. Secondary study parameters are conditioned pain modulation, quantitative sensory testing, adverse events, thermography, blood inflammatory parameter, questionnaires about functionality, quality of life and mood and costs per patient. Discussion: If our study reveals non-inferiority between intermittent and continuous esketamine infusions, these findings can be beneficial to increase the availability and flexibility of esketamine infusions through outpatient treatments. Furthermore, the costs of outpatient esketamine infusions could be lower than inpatient esketamine infusions. In addition, secondary parameters may predict response to esketamine treatment. Trial registration: ClinicalTrials.gov Identifier NCT05212571, date of registration 01-28-2022. Protocol version: Version 3, February 2022

The association of Epstein-Barr virus infection with CXCR3+ B-cell development in multiple sclerosis impact of immunotherapies

Epstein-Barr virus (EBV) infection of B cells is associated with increased multiple sclerosis (MS) susceptibility. Recently, we found that CXCR3-expressing B cells preferentially infiltrate the central nervous system of MS patients. In chronic virus-infected mice, these types of B cells are sustained and show increased antiviral responsiveness. How EBV persistence in B cells influences their development remains unclear. First, we analyzed ex vivo B-cell subsets from MS patients who received autologous bone marrow transplantation (n=9), which is often accompanied by EBV reactivation. The frequencies of non-class-switched and class-switched memory B cells were reduced at 3-7 months, while only class-switched B cells returned back to baseline at 24-36 months post-transplantation. At these time points, EBV DNA load positively correlated to the frequency of CXCR3+ , and not CXCR4+ or CXCR5+ , class-switched B cells. Second, for CXCR3+ memory B cells trapped within the blood of MS patients treated with natalizumab (anti-VLA-4 antibody n=15), latent EBV infection corresponded to enhanced in vitro formation of anti-EBNA1 IgG-secreting plasma cells under germinal center-like conditions. These findings imply that EBV persistence in B cells potentiates brain-homing and antibody-producing CXCR3+ subsets in MS. This article is protected by copyright. All rights reserved

Brain-homing CD4+ T cells display glucocorticoid-resistant features in MS

OBJECTIVE: To study whether glucocorticoid (GC) resistance delineates disease-relevant T helper (Th) subsets that home to the CNS of patients with early MS. METHODS: The expression of key determinants of GC sensitivity, multidrug resistance protein 1 (MDR1/ABCB1) and glucocorticoid receptor (GR/NR3C1), was investigated in proinflammatory Th subsets and compared between natalizumab-treated patients with MS and healthy individuals. Blood, CSF, and brain compartments from patients with MS were assessed for the recruitment of GC-resistant Th subsets using fluorescence-activated cell sorting (FACS), quantitative polymerase chain reaction (qPCR), immunohistochemistry, and immunofluorescence. RESULTS: An MS-associated Th subset termed Th17.1 showed a distinct GC-resistant phenotype as reflected by high MDR1 and low GR expression. This expression ratio was further elevated in Th17.1 cells that accumulated in the blood of patients with MS treated with natalizumab, a drug that prevents their entry into the CNS. Proinflammatory markers C-C chemokine receptor 6, IL-23R, IFN-γ, and GM-CSF were increased in MDR1-expressing Th17.1 cells. This subset predominated the CSF of patients with early MS, which was not seen in the paired blood or in the CSF from patients with other inflammatory and noninflammatory neurologic disorders. The potential of MDR1-expressing Th17.1 cells to infiltrate brain tissue was confirmed by their presence in MS white matter lesions. CONCLUSION: This study reveals that GC resistance coincides with preferential CNS recruitment of pathogenic Th17.1 cells, which may hamper the long-term efficacy of GCs in early MS