Antibody response elicited by the SARS-CoV-2 vaccine booster in patients with multiple sclerosis: Who gains from it?

BACKGROUND AND PURPOSE: Although two doses of COVID-19 vaccine elicited a protective humoral response in most persons with multiple sclerosis (pwMS), a significant group of them treated with immunosuppressive disease-modifying therapies (DMTs) showed less efficient responses. METHODS: This prospective multicenter observational study evaluates differences in immune response after a third vaccine dose in pwMS. RESULTS: Four hundred seventy-three pwMS were analyzed. Compared to untreated patients, there was a 50-fold decrease (95% confidence interval [CI] = 14.3-100.0, p < 0.001) in serum SARS-CoV-2 antibody levels in those on rituximab, a 20-fold decrease (95% CI = 8.3-50.0, p < 0.001) in those on ocrelizumab, and a 2.3-fold decrease (95% CI = 1.2-4.6, p = 0.015) in those on fingolimod. As compared to the antibody levels after the second vaccine dose, patients on the anti-CD20 drugs rituximab and ocrelizumab showed a 2.3-fold lower gain (95% CI = 1.4-3.8, p = 0.001), whereas those on fingolimod showed a 1.7-fold higher gain (95% CI = 1.1-2.7, p = 0.012), compared to patients treated with other DMTs. CONCLUSIONS: All pwMS increased their serum SARS-CoV-2 antibody levels after the third vaccine dose. The mean antibody values of patients treated with ocrelizumab/rituximab remained well below the empirical "protective threshold" for risk of infection identified in the CovaXiMS study (>659 binding antibody units/mL), whereas for patients treated with fingolimod this value was significantly closer to the cutoff.

External validation of unsupervised COVID-19 clinical phenotypes and their prognostic impact.

BACKGROUND: Hospitalized patients with coronavirus disease 2019 (COVID-19) can be classified into different clinical phenotypes based on their demographic, clinical, radiology, and laboratory features. We aimed to validate in an external cohort of hospitalized COVID-19 patients the prognostic value of a previously described phenotyping system (FEN-COVID-19) and to assess the reproducibility of phenotypes development as a secondary analysis. METHODS: Patients were classified in phenotypes A, B or C according to the severity of oxygenation impairment, inflammatory response, hemodynamic and laboratory tests according to the FEN-COVID-19 method. RESULTS: Overall, 992 patients were included in the study, and 181 (18%), 757 (76%) and 54 (6%) of them were assigned to the FEN-COVID-19 phenotypes A, B, and C, respectively. An association with mortality was observed for phenotype C vs. A (hazard ratio [HR] 3.10, 95% confidence interval [CI] 1.81-5.30, p < 0.001) and for phenotype C vs. B (HR 2.20, 95% CI 1.50-3.23, p < 0.001). A non-statistically significant trend towards higher mortality was also observed for phenotype B vs. A (HR 1.41; 95% CI 0.92-2.15, p = 0.115). By means of cluster analysis, three different phenotypes were also identified in our cohort, with an overall similar gradient in terms of prognostic impact to that observed when patients were assigned to FEN-COVID-19 phenotypes. CONCLUSIONS: The prognostic impact of FEN-COVID-19 phenotypes was confirmed in our external cohort, although with less difference in mortality between phenotypes A and B than in the original study.

Hospitalized patients with COVID-19 can be classified into different clinical phenotypes based on their demographic, clinical, radiology, and laboratory featuresIn this study, we externally confirmed the prognostic impact of clinical phenotypes previously identified by Gutierrez-Gutierrez and colleagues in a Spanish cohort of hospitalized patients with COVID-19, and the usefulness of their simplified probabilistic model for phenotypes assignmentThis could indirectly support the validity of both phenotype's development and their extrapolation to other hospitals and countries for management decisions during other possible future viral pandemics.

The effect of air pollution on COVID-19 severity in a sample of patients with multiple sclerosis.

BACKGROUND AND PURPOSE: Some studies have shown that air pollution, often assessed by thin particulate matter with diameter below 2.5 µg/m3 (PM2.5), may contribute to severe COVID-19 courses, as well as play a role in the onset and evolution of multiple sclerosis (MS). However, the impact of air pollution on COVID-19 has never been explored specifically amongst patients with MS (PwMS). This retrospective observational study aims to explore associations between PM2.5 and COVID-19 severity amongst PwMS. METHODS: Data were retrieved from an Italian web-based platform (MuSC-19) which includes PwMS with COVID-19. PM2.5 2016-2018 average concentrations were provided by the Copernicus Atmospheric Monitoring Service. Italian patients inserted in the platform from 15 January 2020 to 9 April 2021 with a COVID-19 positive test were included. Ordered logistic regression models were used to study associations between PM2.5 and COVID-19 severity. RESULTS: In all, 1087 patients, of whom 13% required hospitalization and 2% were admitted to an intensive care unit or died, were included. Based on the multivariate analysis, higher concentrations of PM2.5 increased the risk of worse COVID-19 course (odds ratio 1.90; p = 0.009). CONCLUSIONS: Even if several other factors explain the unfavourable course of COVID-19 in PwMS, the role of air pollutants must be considered and further investigated.

CD19+ B cell values predict the increase of anti-SARS CoV2 antibodies in fingolimod-treated and COVID-19-vaccinated patients with multiple sclerosis.

BACKGROUND: Treatment with fingolimod for multiple sclerosis (MS) reduces the efficacy of COVID-19 vaccination. The aim of this exploratory study was to evaluate whether main lymphocyte subsets and demographic features correlated to the subsequent increase in anti-SARS-CoV2 antibodies following the third dose of COVID-19 vaccination in fingolimod-treated MS patients. METHODS: This was a prospective single-center observational exploratory study including a subgroup of adult patients with MS (pwMS) in treatment with fingolimod who underwent COVID-19 vaccination. The association of anti-SARS-CoV2 antibody levels (reported as the Log10 of the difference between the post and pre third dose levels) with the total number and percentage of CD3+ T and CD19+ B was assessed by a linear regression model adjusted for age and sex. RESULTS: We found that peripheral blood CD19+ B lymphocytes before the third dose of vaccination in pwMS treated with fingolimod predict the subsequent increase of anti-SARS-CoV2 antibodies. CONCLUSION: This work suggests that evaluating the percentage of CD19+ B cells may be important to identify patients at risk of not producing SARS-CoV-2 antibodies, with possible reduced protection from COVID-19.

Breakthrough SARS-CoV-2 infections in MS patients on disease-modifying therapies.

BACKGROUND: Patients with multiple sclerosis (pwMS) treated with anti-CD20 or fingolimod showed a reduced humoral response to SARS-CoV-2 vaccines. OBJECTIVE: In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in pwMS on different disease-modifying therapies (DMTs). METHODS: Data on the number of vaccinated patients and the number of patients with a breakthrough infection were retrospectively collected in 27 Italian MS centers. We estimated the rate of breakthrough infections and of infection requiring hospitalization per DMT. RESULTS: 19,641 vaccinated pwMS were included in the database. After a median follow-up of 8 months, we observed 137 breakthrough infections. Compared with other DMTs, the rate of breakthrough infections was significantly higher on ocrelizumab (0.57% vs 2.00%, risk ratio (RR) = 3.55, 95% CI = 2.74-4.58, p < 0.001) and fingolimod (0.58% vs 1.62%, RR = 2.65, 95% CI = 1.75-4.00, p < 0.001), while there were no significant differences in any other DMT group. In the ocrelizumab group the hospitalization rate was 16.7% versus 19.4% in the pre-vaccination era (RR = 0.86, p = 0.74) and it was 3.9% in all the other DMT groups versus 11.9% in the pre-vaccination period (RR = 0.33, p = 0.02). CONCLUSIONS: The risk of breakthrough SARS-CoV-2 infections is higher in patients treated with ocrelizumab and fingolimod, and the rate of severe infections was significantly reduced in all the DMTs excluding ocrelizumab.

The impact of PM2.5, PM10 and NO2 on Covid-19 severity in a sample of patients with multiple sclerosis: A case-control study.

BACKGROUND: Many studies investigated the association between air pollution and Covid-19 severity but the only study focusing on patients with Multiple Sclerosis (MS) exclusively evaluated exposure to PM2.5. We aim to study, in a sample of MS patients, the impact of long-term exposure to PM2.5, PM10 and NO2 on Covid-19 severity, described as occurrence of pneumonia. METHODS: A 1:2 ratio case-control study was designed, differentiating cases and controls based on Covid-19 pneumonia. Associations between pollutants and outcome were studied using logistic regression. Weighted quantile sum (WQS) logistic regression was used to identify the individual contribution of each pollutant within the mixture; Least Absolute Shrinkage and Selection Operator (LASSO) penalized regression was performed to confirm the variable selection from WQS. All the analyses were adjusted for confounders selected a priori. RESULTS: Of the 615 eligible patients, 491 patients provided detailed place of exposure and were included in the principal analysis. Higher concentrations of air pollutants were associated with increased odds of developing Covid-19 pneumonia (PM2.5: 3rd vs 1st tercile OR(95% CI)=2.26(1.29;3.96); PM10: 3rd vs 1st tercile OR(95% CI)=2.12(1.22;3.68); NO2: 3rd vs 1st tercile OR(95% CI)=2.12(1.21;3.69)). Pollutants were highly correlated with each other; WQS index was associated to an increased risk of pneumonia (ß=0.44; p-value=0.004) and the main contributors to this association were NO2 (41%) and PM2.5 (34%). Consistently, Lasso method selected PM2.5 and NO2. CONCLUSIONS: Higher long-term exposure to PM2.5, PM10 and NO2 increased the odds of Covid-19 pneumonia among MS patients and the most dangerous pollutants were NO2 and PM2.5.

Signs and symptoms of COVID-19 in patients with multiple sclerosis.

BACKGROUND AND PURPOSE: Clinical outcomes of multiple sclerosis (MS) patients affected by coronavirus disease 2019 (COVID-19) have been thoroughly investigated, but a further analysis on main signs and symptoms and their risk factors still needs attention. The objective of this study was to group together and describe based on similarity the most common signs and symptoms of COVID-19 in MS patients and identify all factors associated with their manifestation. METHOD: Logistic and linear regression models were run to recognize factors associated with each pooled group of symptoms and their total number. RESULTS: From March 2020 to November 2021, data were collected from 1354 MS patients with confirmed infection of COVID-19. Ageusia and anosmia was less frequent in older people (odds ratio [OR] 0.98; p = 0.005) and more in smoker patients (OR 1.39; p = 0.049). Smoke was also associated with an incremental number of symptoms (OR 1.24; p = 0.031), substance abuse (drugs or alcohol), conjunctivitis and rash (OR 5.20; p = 0.042) and the presence of at least one comorbidity with shortness of breath, tachycardia or chest pain (OR 1.24; p = 0.008). Some disease-modifying therapies were associated with greater frequencies of certain COVID-19 symptoms (association between anti-CD20 therapies and increment in the number of concomitant symptoms: OR 1.29; p = 0.05). Differences in frequencies between the three waves were found for flu-like symptoms (G1, p = 0.024), joint or muscle pain (G2, p = 0.013) and ageusia and anosmia (G5, p < 0.001). All cases should be referred to variants up to Delta. CONCLUSION: Several factors along with the choice of specific therapeutic approaches might have a different impact on the occurrence of some COVID-19 symptoms.

COVID-19 severity among patients with multiple sclerosis treated with cladribine: A systematic review and meta-analysis.

BACKGROUND: The Coronavirus 19 pandemic has raised new relevant questions regarding the management of patients with multiple sclerosis (pwMS) treated with different immunosuppressive and immunomodulant drugs. In most COVID-19 outcomes analyses, due to the small available sample size, patients treated with cladribine were grouped with patients treated with other treatments. METHODS: Three major databases (PubMed, Scopus and Web of Science) and the most recent MS congress libraries were searched for extracting original articles on COVID-19 and multiple sclerosis. The key inclusion criteria were the presence of data on pwMS treated with cladribine and with documented positivity for COVID-19. The quality of the included studies was evaluated using a modified version of the Dutch Cochrane center critical review checklist proposed by MOOSE. A common-effect meta-analysis was used for estimating the pooled proportion of patients with severe events (hospitalizations, pneumonia, ICU admissions and deaths) and heterogeneity was assessed by the I2 statistic. RESULTS: 13 articles were included in the analysis and the median quality of the articles reached a level of 4. The selected studies included 5138 patients with COVID-19, of whom 107 (2.1%) were treated with cladribine. Pooled estimates of hospitalization and death were 9.36% and 0% for patients treated with cladribine, 14.98% and 2.66% for pwMS under other treatments. CONCLUSION: These results indicate that pwMS treated with cladribine are not at a greater risk of developing a severe form of COVID-19. REGISTRATION: The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO: CRD42022329464).

Lung involvement correlates with disability in MS patients with COVID-19 pneumonia.

INTRODUCTION: The visual-well aerated lung (V-WAL) is a score for the visual quantification of the well aerated lung on CT scan in COVID-19 patients and its value at admission seems to predict future COVID-19 severity. The aim of the present study was to analyze the association between V-WAL and risk factors for severe COVID-19 evolution in people with multiple sclerosis. MATERIALS AND METHODS: This is an observational retrospective study, including people with multiple sclerosis and concomitant COVID-19, who were investigated with a lung CT scan at Hospital admission. The association of V-WAL with age, sex, EDSS, comorbidities, recent steroid use, and treatment (anti-CD20 vs other) was assessed by a multivariate linear regression model. RESULTS: In this observational retrospective study, the only factor that was significantly associated to a lower V-WAL at multivariable analysis was an increasing level of the EDSS (R2 = 0.41, p = 0.001), with an average decrease of 8% of V-WAL for each additional EDSS point. DISCUSSION AND CONCLUSION: This analysis shows that a high EDSS level is the main factor associated to the severity of lung involvement in a group of people with multiple sclerosis who were hospitalized for Covid-19.

COVID-19 Severity in Multiple Sclerosis: Putting Data Into Context.

BACKGROUND AND OBJECTIVES: It is unclear how multiple sclerosis (MS) affects the severity of COVID-19. The aim of this study is to compare COVID-19-related outcomes collected in an Italian cohort of patients with MS with the outcomes expected in the age- and sex-matched Italian population. METHODS: Hospitalization, intensive care unit (ICU) admission, and death after COVID-19 diagnosis of 1,362 patients with MS were compared with the age- and sex-matched Italian population in a retrospective observational case-cohort study with population-based control. The observed vs the expected events were compared in the whole MS cohort and in different subgroups (higher risk: Expanded Disability Status Scale [EDSS] score > 3 or at least 1 comorbidity, lower risk: EDSS score ≤ 3 and no comorbidities) by the χ2 test, and the risk excess was quantified by risk ratios (RRs). RESULTS: The risk of severe events was about twice the risk in the age- and sex-matched Italian population: RR = 2.12 for hospitalization (p < 0.001), RR = 2.19 for ICU admission (p < 0.001), and RR = 2.43 for death (p < 0.001). The excess of risk was confined to the higher-risk group (n = 553). In lower-risk patients (n = 809), the rate of events was close to that of the Italian age- and sex-matched population (RR = 1.12 for hospitalization, RR = 1.52 for ICU admission, and RR = 1.19 for death). In the lower-risk group, an increased hospitalization risk was detected in patients on anti-CD20 (RR = 3.03, p = 0.005), whereas a decrease was detected in patients on interferon (0 observed vs 4 expected events, p = 0.04). DISCUSSION: Overall, the MS cohort had a risk of severe events that is twice the risk than the age- and sex-matched Italian population. This excess of risk is mainly explained by the EDSS score and comorbidities, whereas a residual increase of hospitalization risk was observed in patients on anti-CD20 therapies and a decrease in people on interferon.

The risk of infections for multiple sclerosis and neuromyelitis optica spectrum disorder disease-modifying treatments: Eighth European Committee for Treatment and Research in Multiple Sclerosis Focused Workshop Review. April 2021.

Over the recent years, the treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) has evolved very rapidly and a large number of disease-modifying treatments (DMTs) are now available. However, most DMTs are associated with adverse events, the most frequent of which being infections. Consideration of all DMT-associated risks facilitates development of risk mitigation strategies. An international focused workshop with expert-led discussions was sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and was held in April 2021 to review our current knowledge about the risk of infections associated with the use of DMTs for people with MS and NMOSD and corresponding risk mitigation strategies. The workshop addressed DMT-associated infections in specific populations, such as children and pregnant women with MS, or people with MS who have other comorbidities or live in regions with an exceptionally high infection burden. Finally, we reviewed the topic of DMT-associated infectious risks in the context of the current SARS-CoV-2 pandemic. Herein, we summarize available evidence and identify gaps in knowledge which justify further research.

A multiparametric score for assessing the individual risk of severe Covid-19 among patients with Multiple Sclerosis.

BACKGROUND: Many risk factors for the development of severe forms of Covid-19 have been identified, some applying to the general population and others specific to Multiple Sclerosis (MS) patients. However, a score for quantifying the individual risk of severe Covid-19 in patients with MS is not available. The aim of this study was to construct such score and to evaluate its performance. METHODS: Data on patients with MS infected with Covid-19 in Italy, Turkey and South America were extracted from the Musc-19 platform. After imputation of missing values, data were separated into training data set (70%) and validation data set (30%). Univariable logistic regression models were performed in the training dataset to identify the main risk factors to be included in the multivariable logistic regression analyses. To select the most relevant variables we applied three different approaches: (1) multivariable stepwise, (2) Lasso regression, (3) Bayesian model averaging. Three scores were defined as the linear combination of the coefficients estimated in the models multiplied by the corresponding value of the variables and higher scores were associated to higher risk of severe Covid-19 course. The performances of the three scores were compared in the validation dataset based on the area under the ROC curve (AUC) and an optimal cut-off was calculated in the training dataset for the score with the best performance. The probability of showing a severe Covid-19 course was calculated based on the score with the best performance. RESULTS: 3852 patients were included in the study (2696 in the training dataset and 1156 in the validation data set). 17% of the patients required hospitalization and risk factors for severe Covid-19 course were older age, male sex, living in Turkey or South America instead of living in Italy, presence of comorbidities, progressive MS, longer disease duration, higher Expanded Disability Status Scale, Methylprednisolone use and anti-CD20 treatment. The score with the best performance was the one derived using the Lasso selection approach (AUC= 0.72) and it was built with the following variables: age, sex, country, BMI, presence of comorbidities, EDSS, methylprednisolone use, treatment. An excel spreadsheet to calculate the score and the probability of severe Covid-19 is available at the following link: https://osf.io/ac47u/?view_only=691814d57b564a34b3596e4fcdcf8580. CONCLUSIONS: The originality of this study consists in building a useful tool to quantify the individual risk for Covid-19 severity based on patient's characteristics. Due to the modest predictive ability and to the need of external validation, this tool is not ready for being fully used in clinical practice to make important decisions or interventions. However, it can be used as an additional instrument to identify high-risk patients and persuade them to take important measures to prevent Covid-19 infection (i.e. getting vaccinated against Covid-19, adhering to social distancing, and using of personal protection equipment).

Breakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies during the Delta and the Omicron waves in Italy.

BACKGROUND: In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in patients with MS (pwMS) under different DMTs and to identify correlates of reduced protection. METHODS: This is a prospective Italian multicenter cohort study, long-term clinical follow-up of the CovaXiMS (Covid-19 vaccine in Multiple Sclerosis) study. 1855 pwMS scheduled for SARS-CoV-2 mRNA vaccination were enrolled and followed up to a mean time of 10 months. The cumulative incidence of breakthrough Covid-19 cases in pwMS was calculated before and after December 2021, to separate the Delta from the Omicron waves and to account for the advent of the third vaccine dose. FINDINGS: 1705 pwMS received 2 m-RNA vaccine doses, 21/28 days apart. Of them, 1508 (88.5%) had blood assessment 4 weeks after the second vaccine dose and 1154/1266 (92%) received the third dose after a mean interval of 210 days (range 90-342 days) after the second dose. During follow-up, 131 breakthrough Covid-19 infections (33 during the Delta and 98 during the Omicron wave) were observed. The probability to be infected during the Delta wave was associated with SARS-CoV-2 antibody levels measured after 4 weeks from the second vaccine dose (HR=0.57, p < 0.001); the protective role of antibodies was preserved over the whole follow up (HR=0.57, 95%CI=0.43-0.75, p < 0.001), with a significant reduction (HR=1.40, 95%CI=1.01-1.94, p=0.04) for the Omicron cases. The third dose significantly reduced the risk of infection (HR=0.44, 95%CI=0.21-0.90,p=0.025) during the Omicron wave. INTERPRETATION: The risk of breakthrough SARS-CoV-2 infections is mainly associated with reduced levels of the virus-specific humoral immune response. FUNDING: Supported by FISM - Fondazione Italiana Sclerosi Multipla - cod. 2021/Special-Multi/001 and financed or co-financed with the '5 per mille' public funding.

Severe outcomes of COVID-19 among patients with multiple sclerosis under anti-CD-20 therapies: A systematic review and meta-analysis.

BACKGROUND: COVID-19 may spread through various ways ranging from asymptomatic to severe forms, until respiratory failure, critical conditions and death occurs. There is a particular concern for patients affected by multiple sclerosis, especially for those under disease-modifying treatments. Some studies have found an association between anti-CD20 therapies (especially rituximab) and severe COVID-19. However, results were not always clear and thus a systematic review was helpful. METHODS: A systematic literature search was performed independently by two authors on the main search tools considering as key inclusion criterion the presence of data on patients under ocrelizumab or rituximab positive to COVID-19. The quality of the included studies was evaluated based on a modified version of the Dutch Cochrane center critical review checklist proposed by MOOSE and in case of missing data an email was sent to the corresponding authors asking for missing information. After excluding case-reports, a random effects meta-analysis of proportions was conducted using the continuity correction and the I2statistic was calculated to measure heterogeneity. RESULTS: 29 articles were included in the analysis and the median quality of the articles reached 4/5 after having integrated the additional details provided by the authors. The articles included 5173 patients, of whom 770 (14.8%) and 455 (8.8%) were, respectively, under ocrelizumab and rituximab. Pooled estimates of hospitalization, pneumonia and intensive care unit admission were 18.1%, 14.8% and 3.3%, respectively, while pooled estimate for death was 1.8% overall and 1.6% and 4.5%, respectively, for patients under ocrelizumab and rituximab. CONCLUSION: Patients treated with rituximab seem to be at higher risk of severe COVID-19 outcomes compared to patients under other treatments.

The MuSC-19 study: The Egyptian cohort.

OBJECTIVE: This study aimed to report the severity of COVID-19 in a cohort of Egyptian patients with multiple sclerosis (MS) with particular attention on the impact of disease modifying drugs (DMDs). METHODS AND STUDY POPULATION: We included 119 MS patients recruited from two centers, Ain-Shams university and Cairo university with confirmed or suspected COVID-19 during the period from May to September 2020 as a part of the MuSC-19 project. Univariate logistic regression was fitted to assess risk factors for severe COVID-19 (at least one outcome among hospitalization, ICU admission and death). RESULTS: Females were 77%, mean age was 34 years, mean duration of MS was 5.28 years, median EDSS was 3, most of the patients (83%) had RRMS, while 15% and 2% had respectively SPMS and PPMS. Only eleven patients (9% of study population) had a severe outcome and 3 patients (3%) died. Headache was the only symptom significantly associated with the severity of COVID-19 (OR=10.85, P = 0.001). There was no association between any of the DMDs and severe COVID-19 outcome. CONCLUSION: This study showed an acceptable safety profile of DMDs in Egyptian MS patients who developed COVID-19, as 91% of the cohort had a favorable outcome. Headache as a symptom associated with severe outcome in Egyptian patients' needs further validation.

Effect of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies.

BACKGROUND: In patients with Multiple Sclerosis (pwMS) disease-modifying therapies (DMTs) affects immune response to antigens. Therefore, post-vaccination serological assessments are needed to evaluate the effect of the vaccine on SARS-CoV-2 antibody response. METHODS: We designed a prospective multicenter cohort study enrolling pwMS who were scheduled for SARS-Cov-2 vaccination with mRNA vaccines (BNT162b2, Pfizer/BioNTech,Inc or mRNA-1273, Moderna Tx,Inc). A blood collection before the first vaccine dose and 4 weeks after the second dose was planned, with a centralized serological assessment (electrochemiluminescence immunoassay, ECLIA, Roche-Diagnostics). The log-transform of the antibody levels was analyzed by multivariable linear regression. FINDINGS: 780 pwMS (76% BNT162b2 and 24% mRNA-1273) had pre- and 4-week post-vaccination blood assessments. 87 (11·2%) were untreated, 154 (19·7%) on ocrelizumab, 25 (3·2%) on rituximab, 85 (10·9%) on fingolimod, 25 (3·2%) on cladribine and 404 (51·7%) on other DMTs. 677 patients (86·8%) had detectable post-vaccination SARS-CoV-2 antibodies. At multivariable analysis, the antibody levels of patients on ocrelizumab (201-fold decrease (95%CI=128-317), p < 0·001), fingolimod (26-fold decrease (95%CI=16-42), p < 0·001) and rituximab (20-fold decrease (95%CI=10-43), p < 0·001) were significantly reduced as compared to untreated patients. Vaccination with mRNA-1273 resulted in a systematically 3·25-fold higher antibody level (95%CI=2·46-4·27) than with the BNT162b2 vaccine (p < 0·001). The antibody levels on anti-CD20 therapies correlated to the time since last infusion, and rituximab had longer intervals (mean=386 days) than ocrelizumab patients (mean=129 days). INTERPRETATION: In pwMS, anti-CD20 treatment and fingolimod led to a reduced humoral response to mRNA-based SARS-CoV-2 vaccines. As mRNA-1273 elicits 3·25-higher antibody levels than BNT162b2, this vaccine may be preferentially considered for patients under anti-CD20 treatment or fingolimod. Combining our data with those on the cellular immune response to vaccines, and including clinical follow-up, will contribute to better define the most appropriate SARS-CoV-2 vaccine strategies in the context of DMTs and MS. FUNDING: FISM[2021/Special-Multi/001]; Italian Ministry of Health'Progetto Z844A 5 × 1000'.

Coronavirus disease 2019 in Latin American patients with multiple sclerosis.

Patients with multiple sclerosis (MS) who present coronavirus disease 2019 (COVID-19) are of particular interest to neurologists. These patients have a neuroimmune disease and receive immunomodulatory or immunosuppressive therapies in the long-term. We present here data from 73 patients with MS and a confirmed diagnosis of COVID-19 from five Latin American countries. Fifteen patients (20.5%) were hospitalized and two patients died. The use of anti-CD20 therapies was the only risk factor associated to hospitalization and death. Despite the small sample size, this study highlights the awareness regarding therapeutic options for MS during the pandemic.

SARS-CoV-2 serology after COVID-19 in multiple sclerosis: An international cohort study.

BACKGROUND: The MuSC-19 project is an Italian cohort study open to international partners that collects data on multiple sclerosis (MS) patients with COVID-19. During the second wave of the pandemic, serological tests became routinely available. OBJECTIVE: To evaluate the seroprevalence of anti-SARS-CoV-2 antibodies according to the use of disease-modifying therapy (DMT) in a subset of patients included in the MuSC-19 data set who had undergone a serological test. METHODS: We evaluated the association between positive serological test results and time elapsed since infection onset, age, sex, Expanded Disability Status Scale score, comorbidities and DMT exposure using a multivariable logistic model. RESULTS: Data were collected from 423 patients (345 from Italy, 61 from Turkey and 17 from Brazil) with a serological test performed during follow-up. Overall, 325 out of 423 tested patients (76.8%) had a positive serological test. At multivariate analysis, therapy with anti-CD20 was significantly associated with a reduced probability of developing antibodies after COVID-19 (odds ratio (OR) = 0.20, p = 0.002). CONCLUSION: Patients with MS maintain the capacity to develop humoral immune response against SARS-COV-2, although to a lesser extent when treated with anti-CD20 drugs. Overall, our results are reassuring with respect to the possibility to achieve sufficient immunization with vaccination.

Patient's point of view on the use of telemedicine in multiple sclerosis: a web-based survey.

Restrictions in the access to healthcare facilities during COVID-19 pandemic have raised the need for remote monitoring of chronic medical conditions, including multiple sclerosis (MS). In order to enable the continuity of care in these circumstances, many telemedicine applications are currently tested. While physicians' preferences are commonly investigated, data regarding the patients' point of view are still lacking. We built a 37 items web-based survey exploring patients' propensity, awareness, and opinions on telemedicine with the aim to evaluate the sustainability of this approach in MS. Analysing 613 questionnaires out of 1093 that were sent to persons with MS followed at the Multiple Sclerosis Center of Tor Vergata University, Rome, we found that more than half of respondents (54%) were open to having a televisit. Propensity toward telemedicine significantly depended on having a higher income (p = 0.037), living farther from the center (p = 0.038), using computer and tablet (p = 0.010) and using the Internet for other remote activities (p < 0.001), conversely it was not influenced by any specific disease characteristics (i.e. degree of disability). The main advantages and disadvantages of televisit reported by participants were respectively saving time (70%) and impossibility to measure physical parameters (71%). Although the majority of respondents are in favour of televisit, so far this approach is restricted to those displaying better socioeconomic conditions and higher familiarity with technology. Implications of the study are that telemedicine platforms should be better tailored to patients' demands in order to spread the use of telemedicine, to enhance usability and to increase patients' adherence.

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.