SARS-CoV-2 antibodies in inflammatory neurological conditions: a multicentre retrospective comparative study.

It is well established that neurological and non-neurological autoimmune disorders can be triggered by viral infections. It remains unclear whether SARS-CoV-2 infection induces similar conditions and whether they show a distinctive phenotype. We retrospectively identified patients with acute inflammatory CNS conditions referred to our laboratory for antibody testing during the pandemic (March 1 to August 31, 2020). We screened SARS-COV-2 IgA/IgG in all sera by ELISA and confirmed the positivity with additional assays. Clinical and paraclinical data of SARS-COV-2-IgG seropositive patients were compared to those of seronegative cases matched for clinical phenotype, geographical zone, and timeframe. SARS-CoV-2-IgG positivity was detected in 16/339 (4%) sera, with paired CSF positivity in 3/16. 5 of these patients had atypical demyelinating disorders and 11 autoimmune encephalitis syndromes. 9/16 patients had a previous history of SARS-CoV-2 infection and 6 of them were symptomatic. In comparison with 32 consecutive seronegative controls, SARS-CoV-2-IgG-positive patients were older, frequently presented with encephalopathy, had lower rates of CSF pleocytosis and other neurological autoantibodies, and were less likely to receive immunotherapy. When SARS-CoV-2 seropositive versus seronegative cases with demyelinating disorders were compared no differences were seen. Whereas seropositive encephalitis patients less commonly showed increased CSF cells and protein, our data suggest that an antecedent symptomatic or asymptomatic SARS-CoV-2 infection can be detected in patients with autoimmune neurological conditions. These cases are rare, usually do not have specific neuroglial antibodies.

Severe Multiple Sclerosis Relapse After COVID-19 Vaccination: A Case Report.

We describe a case of acute relapse in a woman with Multiple Sclerosis (MS) shortly after the mRNA COVID-19 vaccination. The patient received a diagnosis of MS in November 2016 at the MS Centre of the A. Cardarelli Hospital (South of Italy). Since that moment, her clinical conditions and pharmacological therapies have been managed at this MS centre where, according to national recommendations, in April 2021, the patient received the BNT162b2 vaccine. Almost 48 h after receiving the vaccine, the patient developed paraesthesia and weakness in her left arm and limbs. The neurological examination revealed walking difficulties while the MRI showed three new voluminous enhancing lesions. After having received methylprednisolone iv for 5 days, the patient's neurological symptoms fully recovered. Along with the implementation of COVID-19 vaccination programmes among vulnerable population, further studies are needed in order to improve our knowledge on the benefit/risk ratio of COVID-19 vaccines.

The Framingham cardiovascular risk score and 5-year progression of multiple sclerosis.

BACKGROUND AND PURPOSE: Cardiovascular risk factors and comorbidities can affect the prognosis of multiple sclerosis (MS). The Framingham risk score is an algorithm that can estimate the 10-year risk of developing macrovascular disease. Our objectives were to evaluate the possible association between the Framingham risk score at baseline and MS relapses, disability, and disease-modifying therapy (DMT) choices over a 5-year follow-up. METHODS: This is a retrospective cohort study including 251 MS subjects. At baseline, we calculated the Framingham risk score considering the following variables: age, sex, diabetes, smoking, systolic blood pressure, and body mass index. MS outcomes including relapses, disability, and treatments were collected over 5 years. Cox proportional regression models were employed to estimate hazard ratios (HRs). RESULTS: A one-point increase in the Framingham risk score was associated with 31% higher risk of relapse (HR = 1.31; 95% confidence interval [CI] = 1.03, 1.68), 19% higher risk of reaching of EDSS 6.0 (HR = 1.19; 95% CI = 1.05, 3.01), and 62% higher risk of DMT escalation (HR = 1.62; 95% CI = 1.22, 3.01). CONCLUSIONS: Higher cardiovascular risk was associated with higher risk of relapses, disability, and DMT escalation in MS. Early identification, correction, and treatment of cardiovascular comorbidities should be carefully considered within MS management.

Remission of early persistent cladribine-induced neutropenia after filgrastim therapy in a patient with Relapsing - Remitting Multiple Sclerosis.

BACKGROUND: Cladribine tablets were recently approved for the treatment of Relapsing-Remitting Multiple Sclerosis (RRMS), reducing B cells and T cells, followed by reconstitution of the adaptive immune system, with transient and mild effects on the innate one. Cladribine is also the standard first-line and subsequent treatment for Hairy-Cell Leukemia (HCL), frequently complicated by neutropenic fever. Recombinant human Granulocyte Colony-Stimulating Factor (G-CSF; Filgrastim) has been proved to reduce neutropenia by increasing neutrophil count. CASE REPORT: To the best of our knowledge, we report the first case of early and persistent high grade non febrile neutropenia after oral cladribine therapy in a 49-year-old RR-MS patient, successfully treated with Filgrastim. CONCLUSIONS: This report suggests that in selected cases, cladribine requires early monitoring of blood sample as it may be responsible for early neutropenia, requiring specific treatment.

First therapy choice in newly diagnosed Multiple Sclerosis patients: A multicenter Italian study.

BACKGROUND: The approval of an increasing number of disease modifying drugs for the treatment of Multiple Sclerosis (MS) creates new challenges for patients and clinicians on the first treatment choice. The main aim of this study was to assess factors impacting first therapy choice in a large Italian MS cohort. METHODS: Newly diagnosed relapsing-remitting (RR) MS patients (2010-2018) followed in 24 Italian MS centres were included in the study. We evaluated the association of baseline demographics, clinical and MRI characteristics to the first treatment choice by logistic regression models applied to pre-defined binary alternatives: dimethyl fumarate vs injectables (interferon and glatiramer acetate), teriflunomide vs injectables, fingolimod vs dimethyl fumarate and fingolimod vs natalizumab. RESULTS: We enrolled 3025 patients in the period between January 2010 and June 2018. Relapses in the previous year (OR = 2.75; p = 0.001), presence of spinal cord lesions (OR = 1.80; p = 0.002) and higher number (>9) of T2 lesions on the baseline brain MRI scan (OR = 1.65; p = 0.022) were the factors associated to dimethyl fumarate choice as first therapy vs an injectable drug. Older age (OR = 1.06; p < 0.001), male sex (OR = 2.29; p = 0.001) and higher EDSS (OR = 1.36; p < 0.001) were the factors associated with the choice of teriflunomide vs injectables. In more recent years, dimethyl fumarate (OR = 3.23; p < 0.001) and teriflunomide (OR = 2.53; p < 0.001) were chosen more frequently than injectables therapies. The main determinant for the choice of fingolimod as compared with dimethyl fumarate was a higher EDSS (OR = 1.56; p = 0.001), while there was a weak association with a longer disease duration (p = 0.068) and a longer time from onset to diagnosis (p = 0.085). Compared to fingolimod, natalizumab was preferred in patients with a younger age (OR = 0.95; p = 0.003) and higher EDSS (OR = 1.45; p = 0.007) and a shorter disease duration (OR = 0.52; p = 0.076). CONCLUSION: Many factors guided therapeutic decision for our Italian cohort of MS patients; they are mainly related to MS disease activity, baseline EDSS, disease duration and age.

Treatment of multiple sclerosis with rituximab: A multicentric Italian-Swiss experience.

BACKGROUND: Rituximab, an anti-CD20 monoclonal antibody leading to B lymphocyte depletion, is increasingly used as an off-label treatment option for multiple sclerosis (MS). OBJECTIVE: To investigate the effectiveness and safety of rituximab in relapsing-remitting (RR) and progressive MS. METHODS: This is a multicenter, retrospective study on consecutive MS patients treated off-label with rituximab in 22 Italian and 1 Swiss MS centers. Relapse rate, time to first relapse, Expanded Disability Status Scale (EDSS) progression, incidence of adverse events, and radiological outcomes from 2009 to 2019 were analyzed. RESULTS: A total of 355/451 enrolled subjects had at least one follow-up visit and were included in the outcome analysis. Annualized relapse rate significantly decreases after rituximab initiation versus the pre-rituximab start year in RRMS (from 0.86 to 0.09, p < .0001) and in secondary-progressive (SP) MS (from 0.34 to 0.06, p < .0001) and had a slight decrease in primary-progressive (PP) MS patients (from 0.12 to 0.07, p = 0.45). After 3 years from rituximab start, the proportion of patients with a confirmed EDSS progression was 14.6% in the RRMS group, 24.7% in the SPMS group, and 41.5% in the PPMS group. No major safety concerns arose. CONCLUSION: Consistently with other observational studies, our data show effectiveness of rituximab in reducing disease activity in patients with MS.

Retrospectively acquired cohort study to evaluate the long-term impact of two different treatment strategies on disability outcomes in patients with relapsing multiple sclerosis (RE.LO.DI.MS): data from the Italian MS Register.

BACKGROUND: The increase in disease-modifying drugs (DMDs) allows individualization of treatment in relapsing multiple sclerosis (RMS); however, the long-term impact of different treatment sequences is not well established. This is particularly relevant for MS patients who may need to postpone more aggressive DMD strategies. OBJECTIVE: To evaluate different therapeutic strategies and their long-term outcomes, measured as relapses and confirmed disability progression (CDP), in MS 'real-world' settings. METHODS: Multicentre, observational, retrospectively acquired cohort study evaluating the long-term impact of different treatment strategies on disability outcomes in patients with RMS in the Italian MS Register. RESULTS: We evaluated 1152 RMS-naïve patients after propensity-score adjustment. Patients included were receiving: interferon beta-1a (IFN-ß1a) 44 µg switching to fingolimod (FTY; IFN-switchers; n = 97); FTY only (FTY-stayers; n = 157); IFN-ß1a only (IFN-stayers; n = 849). CDP and relapses did not differ between FTY-stayers and IFN-switchers [HR (95% CI) 0.99 (0.48-2.04), p = 0.98 and 0.81 (0.42-1.58), p = 0.55, respectively]. However, IFN-stayers showed increased risk of relapses compared with FTY-stayers [HR (95% CI) 1.46 (1.00-2.12), p = 0.05]. CONCLUSION: The ideal treatment option for MS is becoming increasingly complex, with the need to balance benefit and risks. Our results suggest that starting with FTY affects the long-term disease outcome similarly to escalating from IFN-ß1a to FTY.

Determinants of therapy switch in multiple sclerosis treatment-naïve patients: A real-life study.

BACKGROUND: With many options now available, first therapy choice is challenging in multiple sclerosis (MS) and depends mainly on neurologist and patient preferences. OBJECTIVES: To identify prognostic factors for early switch after first therapy choice. METHODS: Newly diagnosed relapsing-remitting MS patients from 24 Italian centers were included. We evaluated the association of baseline demographics, clinical, and magnetic resonance imaging (MRI) data to the switch probability for lack of efficacy or intolerance/safety with a multivariate Cox analysis and estimated switch rates by competing risks models. RESULTS: We enrolled 3025 patients. The overall switch frequency was 48% after 3 years. Switch risk for lack of efficacy was lower with fingolimod (hazard ratio (HR) = 0.50; p = 0.009), natalizumab (HR = 0.13; p < 0.001), dimethyl-fumarate (HR = 0.60; p = 0.037), teriflunomide (HR = 0.21; p = 0.031) as compared to interferons. Younger age (HR = 0.96; p < 0.001), diagnosis delay (HR = 1.23; p = 0.021), higher baseline Expanded Disability Status Scale (HR = 1.17; p = 0.001), and spinal cord lesions (HR = 1.46; p = 0.001) were independently associated with higher inefficacy switch rates. We found lower switch for intolerance/safety with glatiramer acetate (HR = 0.61; p = 0.001), fingolimod (HR = 0.35; p = 0.002), and dimethyl-fumarate (HR = 0.57; p = 0.022) as compared to interferons, while it increased with natalizumab (HR = 1.43; p = 0.022). Comorbidities were associated with intolerance switch (HR = 1.28; p = 0.047). CONCLUSION: Several factors are associated with higher switch risk in patients starting a first-line therapy and could be integrated in the decision-making process of first treatment choice.

Assessing association of comorbidities with treatment choice and persistence in MS: A real-life multicenter study.

OBJECTIVE: To assess whether the presence of concomitant diseases at multiple sclerosis (MS) diagnosis is associated with the choice and the treatment persistence in an Italian MS cohort. METHODS: We included newly diagnosed patients (2010-2016) followed in 20 MS centers and collected demographic and clinical data. We evaluated baseline factors related to the presence of comorbidities and the association between comorbidities and the clinical course of MS and the time to the first treatment switch. RESULTS: The study cohort included 2,076 patients. Data on comorbidities were available for 1,877/2,076 patients (90.4%). A total of 449/1,877 (23.9%) patients had at least 1 comorbidity at MS diagnosis. Age at diagnosis (odds ratio 1.05, 95% confidence interval [CI] 1.04-1.06; p < 0.001) was the only baseline factor independently related to the presence of comorbidities. Comorbidities were not significantly associated with the choice of the first disease-modifying treatment, but were significantly associated with higher risk to switch from the first treatment due to intolerance (hazard ratio 1.42, CI 1.07-1.87; p = 0.014). Association of comorbidities with risk of switching for intolerance was significantly heterogeneous among treatments (interferon ß, glatiramer acetate, natalizumab, or fingolimod; interaction test, p = 0.04). CONCLUSIONS: Comorbidities at diagnosis should be taken into account at the first treatment choice because they are associated with lower persistence on treatment.

Longitudinal assessment of immuno-metabolic parameters in multiple sclerosis patients during treatment with glatiramer acetate.

OBJECTIVE: We investigated the effect of glatiramer acetate (GA) on the modulation of immune cell subpopulations and serum levels of multiple immune/metabolic markers in patients with relapsing-remitting multiple sclerosis (RRMS) to understand whether the treatment with GA could induce a specific change in the immunometabolic asset of patients with RRMS. MATERIAL AND METHODS: We performed an extensive peripheral blood immunophenotyping and measured serum levels of several parameters involved in the pathogenesis of RRMS and also relevant in the pathogenesis of metabolic syndrome and obesity such as leptin, soluble leptin-receptor (sLep-R), myeloperoxidase (MPO), soluble CD40 ligand (sCD40-L), soluble tumor necrosis factor-receptor (sTNF-R), monocyte chemoattractant protein 1 (MCP-1), soluble Inter-Cellular Adhesion Molecule-1 (sICAM-1) and osteoprotegerin (OPG), in 20 naïve-to-treatment RRMS patients and 20 healthy controls. We repeated these analyses over time at 6 and 12 months after starting GA treatment. RESULTS: Our analysis showed that naïve-to-treatment RRMS patients had a lower number of CD16(+)CD56(+) NK cells, CD19(+) B cells, CD4(+) T cells co-expressing the MHC class II activation marker HLA-DR (CD4(+)DR(+)) and naïve CD4(+)CD45RA(+) T cells in basal conditions. GA treatment induced a specific and significant decrease of circulating CD19(+) B cells. Naïve-to-treatment RRMS patients also showed a significantly higher number of CD4(+) T cells with a memory phenotype (CD4(+)CD45RO(+)) whose peripheral frequency was not affected by GA treatment. These changes over time associated with a higher serum concentration of leptin and lower levels of MPO. GA treatment also reduced significantly the circulating levels of sCD40-L and sTNF-R overtime. CONCLUSIONS: Our data suggest that the clinical outcome of GA treatment is associated with changes in immune cell subpopulations and modulation of specific immunometabolic markers. These data add substantial evidence of the immune modulating effect of GA during RRMS and could be of relevance in understanding the pathogenesis of disease and its follow-up.