Objective:To evaluate the immune-specific response after the full SARS-CoV-2 vaccination of multiple sclerosis (MS) patients treated with different Disease Modifying drugs by the detection of both serological- and T-cell responses.Methods:Health care workers (HCWs) and MS patients, having completed the two-dose schedule of an mRNA-based vaccine against SARS-CoV-2 in the last 2-4 weeks, were enrolled from two parallel prospective studies conducted in Rome, Italy, at the National Institute for Infectious diseases Spallanzani–IRCSS and San Camillo Forlanini Hospital. Serological response was evaluated by quantifying the Region-Binding-Domain (RBD) and neutralizing-antibodies. Cell-mediated response was analyzed by a whole-blood test quantifying interferon (IFN)-γ response to spike peptides. Cells responding to spike stimulation were identified by FACS analysis.Results:We prospectively enrolled 186 vaccinated individuals: 78 HCWs and 108 MS patients. Twenty-eight MS patients were treated with IFN-β, 35 with fingolimod, 20 with cladribine, and 25 with ocrelizumab. A lower anti-RBD-antibody response rate was found in patients treated with ocrelizumab (40%, p<0.0001) and fingolimod (85.7%, p=0.0023) compared to HCWs and patients treated with cladribine or IFN-β. Anti-RBD-antibody median titer was lower in patients treated with ocrelizumab (p<0.0001), fingolimod (p<0.0001) and cladribine (p=0.010) compared to HCWs and IFN-β-treated patients. Importantly, serum neutralizing activity was present in all the HCWs tested and only in a minority of the fingolimod-treated patients (16.6%). T-cell-specific response was detected in the majority of MS patients (62%), albeit with significantly lower IFN-γ levels compared to HCWs. The lowest frequency of T-cell response was found in fingolimod-treated patients (14.3%). T-cell-specific response correlated with lymphocyte count and anti-RBD antibody titer (rho=0.554, p<0.0001 and rho=0.255, p=0.0078 respectively). Finally, IFN-γ T-cell response was mediated by both CD4+ and CD8+ T cells.Conclusion:mRNA vaccines induce both humoral and cell-mediated specific immune responses against spike peptides in all HCWs and in the majority of MS patients. These results carry relevant implications for managing vaccinations suggesting to promote vaccination in all treated MS patients.Classification of Evidence:This study provides Class III data that COVID mRNA vaccination induces both humoral and cell-mediated specific immune responses against viral spike proteins in a majority of MS patients.

Background. The early detection of wearing-off in Parkinson disease (DEEP) observational study demonstrated that women with Parkinson's disease (PD) carry an increased risk (80.1%) for wearing-off (WO). This post hoc analysis of DEEP study evaluates gender differences on WO and associated phenomena. Methods. Patients on dopaminergic treatment for ≥1 year were included in this multicenter observational cross-sectional study. In a single visit, WO was diagnosed based on neurologist assessment as well as the use of the 19-item wearing-off questionnaire (WOQ-19); WO was defined for scores ≥2. Post hoc analyses were conducted to investigate gender difference for demographic and clinical features with respect to WO. Results. Of 617 patients enrolled, 236 were women and 381 were men. Prevalence of WO was higher among women, according to both neurologists' judgment (61.9% versus 53.8%, P = 0.045) and the WOQ-19 analysis (72.5% versus 64.0%, P = 0.034). In patients with WO (WOQ-19), women experienced ≥1 motor symptom in 72.5% versus 64.0% in men and ≥1 nonmotor symptom in 44.5% versus 36.7%, in men. Conclusions. Our results suggest WO as more common among women, for both motor and nonmotor symptoms. Prospective studies are warranted to investigate this potential gender-effect.

In this independent, multicentre post-marketing study we directly compared the effectiveness of natalizumab (NTZ), fingolimod (FNG) and self-injectable drugs (INJ), in non-responders to first immunomodulating treatment and in highly active treatment-naïve patients with multiple sclerosis. As main outcome measure we considered the proportions of patients with no evidence of disease activity (NEDA-3), defined as absence of relapses, disability worsening and radiological activity. A total of 567 non-responders to interferon beta (IFNB) or glatiramer acetate (GA) [dataset A] and 216 highly active treatment-naïves [dataset B] were followed up to 24 months from the beginning of NTZ, FNG or INJ, i.e. switching from IFNB to GA or viceversa (in the case of non-responders) or starting high-dose IFNB (in the case of highly active treatment-naïves). Propensity score matching in a 1:1:1 ratio was used to select only patients with similar baseline characteristics, retaining 330 and 120 patients in dataset A and B, respectively. In dataset A, the 24-month proportion with NEDA-3 was greater in both NTZ group (67%) and FNG group (42%) than in INJ group (35%) (p ≤ 0.016); however, NTZ was superior to FNG in promoting the attainment of NEDA-3 status (p = 0.034). In dataset B, the 24-month proportion with NEDA-3 was greater in NTZ group (75%) and FNG group (67%) than in INJ group (40%), but the small cohort sizes most likely prevented the detection of any statistically significant difference. Our study provides real-world evidence that NTZ was more effective than both FNG and INJ in non-responders, while it could seem that, in highly active treatment-naïves, NTZ was as effective as FNG and both were superior to INJ.

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In this independent, multicenter, post-marketing study, we directly compare induction immunosuppression versus escalation strategies on the risk of reaching the disability milestone of Expanded Disability Status Scale (EDSS) ≥ 6.0 over 10 years in previously untreated patients with relapsing-remitting multiple sclerosis. We collected data of patients who started interferon beta (escalation) versus mitoxantrone or cyclophosphamide (induction) as initial treatment. Main eligibility criteria included an EDSS score ≤ 4.0 at treatment start and either ≥ 2 relapses or 1 disabling relapse with evidence of ≥ 1 gadolinium-enhancing lesion at magnetic resonance imaging scan in the pre-treatment year. Since patients were not randomized to treatment group, we performed a propensity score (PS)-based matching procedure to select individuals with homogeneous baseline characteristics. Comparisons were then conducted using Cox models stratified by matched pairs. Overall, 75 and 738 patients started with induction and escalation, respectively. Patients in the induction group were older and more disabled than those in the escalation group (p < 0.05). The PS-matching procedure retained 75 patients per group. In the re-sampled population, a lower proportion of patients reached the outcome after induction (21/75, 28.0%) than escalation (29/75, 38.7%) (hazard ratio = 0.48; p = 0.024). Considering the whole sample, serious adverse events occurred more frequently after induction (8/75, 10.7%) than escalation (18/ 738, 2.4%) (odds ratio = 3.36, p = 0.015). These findings suggest that, in patients with poor prognostic factors, induction was more effective than escalation in reducing the risk of reaching the disability milestone, albeit with a worse safety profile. Future studies are warranted to explore if newer induction agents may provide a more advantageous long-lasting risk:benefit profile.