Treatment modifiers across different regimens of natalizumab treatment in MS: An Italian real-world experience

despite its widespread use in clinical practice, the effectiveness of natalizumab extended interval dosing (EID) adopted from treatment start across different treatment intervals and individual modifiers (body mass index BMI) is still under-investigated. here, seven-hundred and forty-five multiple sclerosis (MS) patients, exposed to natalizumab for 3.30 +/- 1.34 years, were retrospectively enrolled in an observational multicenter study. after stratifying patients in EID or standard interval dosing (SID), we assessed differences in time to relapse, MRI activity and expanded disability status scale (EDSS) progression. the primary analysis was conducted on patients exposed to EID interval from 5 weeks and 1 day to 7 weeks, while a secondary analysis included also EID periods up to 8 weeks. an additional analysis explored the impact of BMI. no differences in time to first relapse, time to radiological activity, time to EDSS progression or time to EDA (evidence of disease activity) were detected between SID and EID group (EID interval from 5 weeks to 1 day to 7 weeks). when including EID periods from 7 weeks and 1 day to 8 weeks, the EID group showed a trend towards higher risk of experience clinical relapses than the SID group. a higher EDA risk was also identified in EID patients with BMI above median. In conclusion, a higher risk of relapses seems to occur for EID above 7 weeks. Independently from the EID scheme adopted, higher BMI increases the risk of EDA in these patients

Transient Receptor Potential Vanilloid 1 Modulates Central Inflammation in Multiple Sclerosis

Introduction: Disease course of multiple sclerosis (MS) is negatively influenced by proinflammatory molecules released by activated T and B lymphocytes and local immune cells. The endovanilloid system plays different physiological functions, and preclinical data suggest that transient receptor potential vanilloid type 1 (TRPV1) could modulate neuroinflammation in this disorder.Methods: The effect of TRPV1 activation on the release of two main proinflammatory cytokines, tumor necrosis factor (TNF) and interleukin (IL)-6, was explored in activated microglial cells. Furthermore, in a group of 132 MS patients, the association between the cerebrospinal fluid (CSF) levels of TNF and IL-6 and a single nucleotide polymorphisms (SNP) influencing TRPV1 protein expression and function (rs222747) was assessed.Results: In in vitro experiments, TRPV1 stimulation by capsaicin significantly reduced TNF and IL-6 release by activated microglial cells. Moreover, the anti-inflammatory effect of TRPV1 activation was confirmed by another TRPV1 agonist, the resiniferatoxin (RTX), whose effects were significantly inhibited by the TRPV1 antagonist, 5-iodoresiniferatoxin (5-IRTX). Vice versa, BV2 pre-treatment with 5-IRTX increased the inflammatory response induced by LPS. Moreover, in MS patients, a significant association emerged between TRPV1 SNP rs222747 and CSF TNF levels. In particular, the presence of a G allele, known to result in increased TRPV1 protein expression and function, was associated to lower CSF levels of TNF.Conclusions: Our results indicate that TRPV1 influences central inflammation in MS by regulating cytokine release by activated microglial cells. The modulation of the endovanilloid system may represent a useful approach to contrast neuroinflammation in MS

Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis

Objective: This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS). Methods: We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results. Results: Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses. Interpretation: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists

DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon

Recency effect in anterograde amnesia: evidence for distinct memory stores underlying enhanced retrieval of terminal items in immediate and delayed recall paradigms

This study was devised to investigate immediate and delayed recency effects in anterograde amnesic patients. For this purpose, a word-list immediate recall paradigm and a modified version of the procedure devised by Baddeley and Hitch [Attention and Performance, Erlbaum, NJ, 1977] for eliciting the recency effect in delayed recall conditions was administered to a sample of amnesic patients and to a group of age-matched healthy subjects. Amnesics disclosed a fully normal recency effect in the immediate recall paradigm and a deficient recency effect in the delayed recall condition. These data, taken together with experimental evidence from a patient affected by a pure form of phonological short-term memory impairment [35], draw a double neuropsychological dissociation suggesting a differential origin for the two kinds of recency effects: a short-term memory output underlying enhanced recall of terminal items in immediate recall paradigms, and an ordinal retrieval strategy applied to long-term memory stored units at the root of the delayed recency effect

Perceptual and conceptual components in implicit and explicit stem completion

This study was aimed at investigating functional and neuropsychological dissociations between repetition priming and explicit memory tasks. The explicit and implicit versions of the stem completion task were administered to a group of amnesics and a group of control subjects. In Experiment 1 both the explicit and implicit stem completions were significantly higher when the same presentation modality was used for studying and testing than when a change in modality from studying to testing occurred. Amnesics had normal implicit and deficient explicit completion performance. Experiment 2 revealed an advantage of the semantic over the phonological condition only in the explicit task and only in control subjects. Amnesic patients completed the same percentage of words as normal subjects in the phonological and semantic conditions of the implicit task and in the phonological condition of the explicit task but were deficient in intentionally completing semantically processed words. Possible interpretations of these results are discussed according to theoretical models that distinguish memory tasks along an explicit-implicit dichotomy (multiple memory system theory) or along a perceptual-conceptual dichotomy (transfer-appropriate procedures approach), and alternative theoretical positions are evaluated regarding repetition priming and memory deficits in amnesic patients