Sars-CoV2 infection in pregnant women with multiple sclerosis.

BACKGROUND: In the general population, maternal SARS-CoV-2 infection during pregnancy is associated with worse maternal outcomes; however, only one study so far has evaluated COVID-19 clinical outcomes in pregnant and postpartum women with multiple sclerosis, showing no higher risk for poor COVID-19 outcomes in these patients. OBJECTIVE: In this multicenter study, we aimed to evaluate COVID-19 clinical outcomes in pregnant patients with multiple sclerosis. METHODS: We recruited 85 pregnant patients with multiple sclerosis who contracted COVID-19 after conception and were prospectively followed-up in Italian and Turkish Centers, in the period 2020-2022. A control group of 1354 women was extracted from the database of the Multiple Sclerosis and COVID-19 (MuSC-19). Univariate and subsequent logistic regression models were fitted to search for risk factors associated with severe COVID-19 course (at least one outcome among hospitalization, intensive care unit [ICU] admission and death). RESULTS: In the multivariable analysis, independent predictors of severe COVID-19 were age, body mass index ⩾ 30, treatment with anti-CD20 and recent use of methylprednisolone. Vaccination before infection was a protective factor. Vaccination before infection was a protective factor. Pregnancy was not a risk nor a protective factor for severe COVID-19 course. CONCLUSION: Our data show no significant increase of severe COVID-19 outcomes in patients with multiple sclerosis who contracted the infection during pregnancy.

Une étude multicentrique, ouverte, à un bras, de phase IIIb (CONSONANCE) visant à évaluer l'efficacité et la tolérance d'ocrélizumab chez des patients atteints de SEP-PP et SEP-SP : résultats de l'analyse intermédiaire à 2 ans

Introduction Ocrélizumab (OCR) a démontré son efficacité sur l'évolution de la sclérose en plaques primaire-progressive (SEP-PP). Cependant, des données sont manquantes sur l'ensemble des formes progressives, dont la SEP-secondairement progressive (-SP). Objectifs CONSONANCE (NCT03523858) est une étude de phase 3b à un bras, d'une durée de 4 ans, évaluant pour la première fois l'efficacité et la tolérance d'OCR dans la SEP-PP et la SEP-SP. Les résultats à 2 ans sont rapportés. Méthodes Des patients atteints de SEP progressive active ou non active avec une progression du handicap dans les 2 ans étaient inclus. Les critères d'évaluation étaient : (1) proportion de patients sans signe de progression (NEP, pas d'augmentation de l'EDSS sur ≥ 24 semaines, ≥ 20 % du temps aux tests T25FWT et 9HPT, pas de décès lié à la SEP ou d'arrêt de traitement pour manque d'efficacité) ;(2) proportion de patients sans signe de progression ni activité de la maladie (NEPAD, NEP+pas de poussées ni lésions T1 au gadolinium et T2 nouvelles/élargies). Résultats Les patients (n=629, SEP-SP n=324, SEP-PP n=305) avaient un âge moyen (DS) de 48,5 (9,2) ans et 52 % étaient des femmes. À l'inclusion, les scores EDSS médians (IQR)/moyens (DS) étaient de 6,0 (4,5–6,0)/5,3 (1,3) pour les patients SEP-SP et 5,0 (4,0–6,0)/4,8 (1,3) pour les patients SEP-PP. Les temps médians des tests 9HPT et T25FWT étaient de 27,9 et 9,4sec. Sur 2 ans, 311/586 (53,1 %) patients ont atteint le NEP (SEP-SP : 55,8 % ;SEP-PP : 50,2 %) et 283/588 (48,1 %) le NEPAD (SEP-SP : 49,5 % ;SEP-PP : 46,7 %). Discussion L'EDSS est resté stable de l'inclusion à 2 ans (évolution moyenne [DS] de +0,07 [0,79] points). Au total, 29,8 % des patient avec un EDSS à l'inclusion ≥ 2,0 (n=528) ont eu une amélioration confirmée du handicap à 24 semaines (EDSS, T25FWT, 9HPT). Les taux d'événements indésirables graves et d'infections étaient de 7,6/100 patients-années (PA) et de 3,2/100 PA. Huit décès ont été rapportés (COVID-19=6, embolie pulmonaire=1, cancer du poumon=1). Conclusion Sur 2 ans, le traitement par OCR a été associé à des taux comparables de NEP et NEPAD chez les patients SEP-SP et SEP-PP avec des améliorations fonctionnelles pour 1/3 des patients. Le profil de tolérance était conforme à celui connu pour OCR.

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. ANN NEUROL 2021;89:780-789.

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.

Biopsychosocial Response to the COVID-19 Lockdown in People with Major Depressive Disorder and Multiple Sclerosis.

BACKGROUND: Changes in lifestyle, finances and work status during COVID-19 lockdowns may have led to biopsychosocial changes in people with pre-existing vulnerabilities such as Major Depressive Disorders (MDDs) and Multiple Sclerosis (MS). METHODS: Data were collected as a part of the RADAR-CNS (Remote Assessment of Disease and Relapse-Central Nervous System) program. We analyzed the following data from long-term participants in a decentralized multinational study: symptoms of depression, heart rate (HR) during the day and night; social activity; sedentary state, steps and physical activity of varying intensity. Linear mixed-effects regression analyses with repeated measures were fitted to assess the changes among three time periods (pre, during and post-lockdown) across the groups, adjusting for depression severity before the pandemic and gender. RESULTS: Participants with MDDs (N = 255) and MS (N = 214) were included in the analyses. Overall, depressive symptoms remained stable across the three periods in both groups. A lower mean HR and HR variation were observed between pre and during lockdown during the day for MDDs and during the night for MS. HR variation during rest periods also decreased between pre- and post-lockdown in both clinical conditions. We observed a reduction in physical activity for MDDs and MS upon the introduction of lockdowns. The group with MDDs exhibited a net increase in social interaction via social network apps over the three periods. CONCLUSIONS: Behavioral responses to the lockdown measured by social activity, physical activity and HR may reflect changes in stress in people with MDDs and MS. Remote technology monitoring might promptly activate an early warning of physical and social alterations in these stressful situations. Future studies must explore how stress does or does not impact depression severity.

Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis: Up to 5 years of follow-up in the DAYBREAK open-label extension trial.

BACKGROUND: Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in multiple countries for treatment of relapsing forms of MS. OBJECTIVE: To characterize long-term safety and efficacy of ozanimod. METHODS: Patients with relapsing MS who completed a phase 1‒3 ozanimod trial were eligible for an open-label extension study (DAYBREAK) of ozanimod 0.92 mg/d. DAYBREAK began 16 October 2015; cutoff for this interim analysis was 2 February 2021. RESULTS: This analysis included 2494 participants with mean 46.8 (SD 11.9; range 0.033‒62.7) months of ozanimod exposure in DAYBREAK. During DAYBREAK, 2143 patients (85.9%) had treatment-emergent adverse events (TEAEs; similar in nature to those in the parent trials), 298 (11.9%) had a serious TEAE, and 75 (3.0%) discontinued treatment due to TEAEs. Serious infections (2.8%), herpes zoster infections (1.7%), confirmed macular edema cases (0.2%), and cardiac TEAEs (2.8%) were infrequent. Adjusted annualized relapse rate was 0.103 (95% confidence interval, 0.086‒0.123). Over 48 months, 71% of patients remained relapse free. Adjusted mean numbers of new/enlarging T2 lesions/scan and gadolinium-enhancing lesions were low and similar across parent trial treatment subgroups. CONCLUSIONS: This long-term extension of ozanimod trials confirmed a favorable safety/tolerability profile and sustained benefit on clinical and magnetic resonance imaging measures of disease activity.

Updated Results of the COVID-19 in MS Global Data Sharing Initiative: Anti-CD20 and Other Risk Factors Associated With COVID-19 Severity.

BACKGROUND AND OBJECTIVES: Certain demographic and clinical characteristics, including the use of some disease-modifying therapies (DMTs), are associated with severe acute respiratory syndrome coronavirus 2 infection severity in people with multiple sclerosis (MS). Comprehensive exploration of these relationships in large international samples is needed. METHODS: Clinician-reported demographic/clinical data from 27 countries were aggregated into a data set of 5,648 patients with suspected/confirmed coronavirus disease 2019 (COVID-19). COVID-19 severity outcomes (hospitalization, admission to intensive care unit [ICU], requiring artificial ventilation, and death) were assessed using multilevel mixed-effects ordered probit and logistic regression, adjusted for age, sex, disability, and MS phenotype. DMTs were individually compared with glatiramer acetate, and anti-CD20 DMTs with pooled other DMTs and with natalizumab. RESULTS: Of 5,648 patients, 922 (16.6%) with suspected and 4,646 (83.4%) with confirmed COVID-19 were included. Male sex, older age, progressive MS, and higher disability were associated with more severe COVID-19. Compared with glatiramer acetate, ocrelizumab and rituximab were associated with higher probabilities of hospitalization (4% [95% CI 1-7] and 7% [95% CI 4-11]), ICU/artificial ventilation (2% [95% CI 0-4] and 4% [95% CI 2-6]), and death (1% [95% CI 0-2] and 2% [95% CI 1-4]) (predicted marginal effects). Untreated patients had 5% (95% CI 2-8), 3% (95% CI 1-5), and 1% (95% CI 0-3) higher probabilities of the 3 respective levels of COVID-19 severity than glatiramer acetate. Compared with pooled other DMTs and with natalizumab, the associations of ocrelizumab and rituximab with COVID-19 severity were also more pronounced. All associations persisted/enhanced on restriction to confirmed COVID-19. DISCUSSION: Analyzing the largest international real-world data set of people with MS with suspected/confirmed COVID-19 confirms that the use of anti-CD20 medication (both ocrelizumab and rituximab), as well as male sex, older age, progressive MS, and higher disability are associated with more severe course of COVID-19.

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.

Severity of COVID19 infection among patients with multiple sclerosis treated with interferon-ß.

BACKGROUND: Interferon-ß, a disease-modifying therapy (DMT) for MS, may be associated with less severe COVID-19 in people with MS. RESULTS: Among 5,568 patients (83.4% confirmed COVID-19), interferon-treated patients had lower risk of severe COVID-19 compared to untreated, but not to glatiramer-acetate, dimethyl-fumarate, or pooled other DMTs. CONCLUSIONS: In comparison to other DMTs, we did not find evidence of protective effects of interferon-ß on the severity of COVID-19, though compared to the untreated, the course of COVID19 was milder among those on interferon-ß. This study does not support the use of interferon-ß as a treatment to reduce COVID-19 severity in MS.

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.

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).

Researching COVID-19 in progressive MS requires a globally coordinated, multi-disciplinary and multi-stakeholder approach-perspectives from the International Progressive MS Alliance.

Background: The COVID-19 pandemic has reinforced the importance of research for the health of our society and highlighted the need for stakeholders of the health research and care continuum to form a collaborative and interdependent ecosystem. Objective: With the world still reeling from waves of the COVID-19 pandemic and adapting to the vaccine rollout at widely different rates, the International Progressive MS Alliance (hereafter Alliance) organized a meeting (April 2021) to consider how the Covid-19 pandemic impacts the health and well-being of people with progressive Multiple Sclerosis (MS). Methods: We invited the Alliance stakeholders and experts to present what they have learned about SARS-CoV-2 infection and progressive MS and to define future scientific priorities. Results: The meeting highlighted three priorities for additional focus: (1) the impact of Disease Modifying Therapies (DMTs) on the risk of COVID-19 and on the efficacy of COVID-19 vaccines in people with progressive MS; (2) the long-term impact of COVID-19 and COVID-19 vaccines on the biology of progressive MS; and (3) the impact on well-being of people with progressive MS. Conclusion: This paper's calls to action could represent a path toward a shared research agenda. Multi-stakeholder and long-term investigations will be required to drive and evolve such an agenda.

Risk of Getting COVID-19 in People With Multiple Sclerosis: A Case-Control Study.

BACKGROUND AND OBJECTIVES: Several studies have assessed risk factors associated with the severity of COVID-19 outcomes in people with multiple sclerosis (PwMS). The potential role of disease-modifying therapies (DMTs) and demographic and clinical factors on the risk of acquiring SARS-CoV-2 infection has not been evaluated so far. The objective of this study was to assess risk factors of contracting SARS-CoV-2 infection in PwMS by using data collected in the Italian MS Register (IMSR). METHODS: A case-control (1:2) study was set up. Cases included PwMS with a confirmed diagnosis of COVID-19, and controls included PwMS without a confirmed diagnosis of COVID-19. Both groups were propensity score-matched by the date of COVID-19 diagnosis, the date of last visit, and the region of residence. No healthy controls were included in this study. COVID-19 risk was estimated by multivariable logistic regression models including demographic and clinical covariates. The impact of DMTs was assessed in 3 independent logistic regression models including one of the following covariates: last administered DMT, previous DMT sequences, or the place where the last treatment was administered. RESULTS: A total of 779 PwMS with confirmed COVID-19 (cases) were matched to 1,558 PwMS without COVID-19 (controls). In all 3 models, comorbidities, female sex, and a younger age were significantly associated (p < 0.02) with a higher risk of contracting COVID-19. Patients receiving natalizumab as last DMT (OR [95% CI]: 2.38 [1.66-3.42], p < 0.0001) and those who underwent an escalation treatment strategy (1.57 [1.16-2.13], p = 0.003) were at significantly higher COVID-19 risk. Moreover, PwMS receiving their last DMT requiring hospital access (1.65 [1.34-2.04], p < 0.0001) showed a significant higher risk than those taking self-administered DMTs at home. DISCUSSION: This case-control study embedded in the IMSR showed that PwMS at higher COVID-19 risk are younger, more frequently female individuals, and with comorbidities. Long-lasting escalation approach and last therapies that expose patients to the hospital environment seem to significantly increase the risk of SARS-CoV2 infection in PwMS. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that among patients with MS, younger age, being female individuals, having more comorbidities, receiving natalizumab, undergoing an escalating treatment strategy, or receiving treatment at a hospital were associated with being infected with COVID-19. Among patients with MS who were infected with COVID-19, a severe course was associated with increasing age and having a progressive form of MS, whereas not being on treatment or receiving an interferon beta agent was protective.

Associations of Disease-Modifying Therapies With COVID-19 Severity in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: People with multiple sclerosis (MS) are a vulnerable group for severe coronavirus disease 2019 (COVID-19), particularly those taking immunosuppressive disease-modifying therapies (DMTs). We examined the characteristics of COVID-19 severity in an international sample of people with MS. METHODS: Data from 12 data sources in 28 countries were aggregated (sources could include patients from 1-12 countries). Demographic (age, sex), clinical (MS phenotype, disability), and DMT (untreated, alemtuzumab, cladribine, dimethyl fumarate, glatiramer acetate, interferon, natalizumab, ocrelizumab, rituximab, siponimod, other DMTs) covariates were queried, along with COVID-19 severity outcomes, hospitalization, intensive care unit (ICU) admission, need for artificial ventilation, and death. Characteristics of outcomes were assessed in patients with suspected/confirmed COVID-19 using multilevel mixed-effects logistic regression adjusted for age, sex, MS phenotype, and Expanded Disability Status Scale (EDSS) score. RESULTS: Six hundred fifty-seven (28.1%) with suspected and 1,683 (61.9%) with confirmed COVID-19 were analyzed. Among suspected plus confirmed and confirmed-only COVID-19, 20.9% and 26.9% were hospitalized, 5.4% and 7.2% were admitted to ICU, 4.1% and 5.4% required artificial ventilation, and 3.2% and 3.9% died. Older age, progressive MS phenotype, and higher disability were associated with worse COVID-19 outcomes. Compared to dimethyl fumarate, ocrelizumab and rituximab were associated with hospitalization (adjusted odds ratio [aOR] 1.56, 95% confidence interval [CI] 1.01-2.41; aOR 2.43, 95% CI 1.48-4.02) and ICU admission (aOR 2.30, 95% CI 0.98-5.39; aOR 3.93, 95% CI 1.56-9.89), although only rituximab was associated with higher risk of artificial ventilation (aOR 4.00, 95% CI 1.54-10.39). Compared to pooled other DMTs, ocrelizumab and rituximab were associated with hospitalization (aOR 1.75, 95% CI 1.29-2.38; aOR 2.76, 95% CI 1.87-4.07) and ICU admission (aOR 2.55, 95% CI 1.49-4.36; aOR 4.32, 95% CI 2.27-8.23), but only rituximab was associated with artificial ventilation (aOR 6.15, 95% CI 3.09-12.27). Compared to natalizumab, ocrelizumab and rituximab were associated with hospitalization (aOR 1.86, 95% CI 1.13-3.07; aOR 2.88, 95% CI 1.68-4.92) and ICU admission (aOR 2.13, 95% CI 0.85-5.35; aOR 3.23, 95% CI 1.17-8.91), but only rituximab was associated with ventilation (aOR 5.52, 95% CI 1.71-17.84). Associations persisted on restriction to confirmed COVID-19 cases. No associations were observed between DMTs and death. Stratification by age, MS phenotype, and EDSS score found no indications that DMT associations with COVID-19 severity reflected differential DMT allocation by underlying COVID-19 severity. DISCUSSION: Using the largest cohort of people with MS and COVID-19 available, we demonstrated consistent associations of rituximab with increased risk of hospitalization, ICU admission, and need for artificial ventilation and of ocrelizumab with hospitalization and ICU admission. Despite the cross-sectional design of the study, the internal and external consistency of these results with prior studies suggests that rituximab/ocrelizumab use may be a risk factor for more severe COVID-19.

Fitbeat: COVID-19 estimation based on wristband heart rate using a contrastive convolutional auto-encoder.

This study proposes a contrastive convolutional auto-encoder (contrastive CAE), a combined architecture of an auto-encoder and contrastive loss, to identify individuals with suspected COVID-19 infection using heart-rate data from participants with multiple sclerosis (MS) in the ongoing RADAR-CNS mHealth research project. Heart-rate data was remotely collected using a Fitbit wristband. COVID-19 infection was either confirmed through a positive swab test, or inferred through a self-reported set of recognised symptoms of the virus. The contrastive CAE outperforms a conventional convolutional neural network (CNN), a long short-term memory (LSTM) model, and a convolutional auto-encoder without contrastive loss (CAE). On a test set of 19 participants with MS with reported symptoms of COVID-19, each one paired with a participant with MS with no COVID-19 symptoms, the contrastive CAE achieves an unweighted average recall of 95.3 % , a sensitivity of 100 % and a specificity of 90.6 % , an area under the receiver operating characteristic curve (AUC-ROC) of 0.944, indicating a maximum successful detection of symptoms in the given heart rate measurement period, whilst at the same time keeping a low false alarm rate.

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.

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.

Blood neurofilament light chain and total tau levels at admission predict death in COVID-19 patients.

BACKGROUND AND AIMS: Patients infected with SARS-CoV-2 range from asymptomatic, to mild, moderate or severe disease evolution including fatal outcome. Thus, early predictors of clinical outcome are highly needed. We investigated markers of neural tissue damage as a possible early sign of multisystem involvement to assess their clinical prognostic value on survival or transfer to intensive care unit (ICU). METHODS: We collected blood from 104 patients infected with SARS-CoV-2 the day of admission to the emergency room and measured blood neurofilament light chair (NfL), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and total tau protein levels. RESULTS: We found that NfL, GFAP, and tau were significantly increased in patients with fatal outcome, while NfL and UCH-L1 in those needing ICU transfer. ROC and Kaplan-Meier curves indicated that total tau levels at admission accurately predict mortality. CONCLUSIONS: Blood neural markers may provide additional prognostic value to conventional biomarkers used to predict COVID-19 outcome.

Using Smartphones and Wearable Devices to Monitor Behavioral Changes During COVID-19.

BACKGROUND: In the absence of a vaccine or effective treatment for COVID-19, countries have adopted nonpharmaceutical interventions (NPIs) such as social distancing and full lockdown. An objective and quantitative means of passively monitoring the impact and response of these interventions at a local level is needed. OBJECTIVE: We aim to explore the utility of the recently developed open-source mobile health platform Remote Assessment of Disease and Relapse (RADAR)-base as a toolbox to rapidly test the effect and response to NPIs intended to limit the spread of COVID-19. METHODS: We analyzed data extracted from smartphone and wearable devices, and managed by the RADAR-base from 1062 participants recruited in Italy, Spain, Denmark, the United Kingdom, and the Netherlands. We derived nine features on a daily basis including time spent at home, maximum distance travelled from home, the maximum number of Bluetooth-enabled nearby devices (as a proxy for physical distancing), step count, average heart rate, sleep duration, bedtime, phone unlock duration, and social app use duration. We performed Kruskal-Wallis tests followed by post hoc Dunn tests to assess differences in these features among baseline, prelockdown, and during lockdown periods. We also studied behavioral differences by age, gender, BMI, and educational background. RESULTS: We were able to quantify expected changes in time spent at home, distance travelled, and the number of nearby Bluetooth-enabled devices between prelockdown and during lockdown periods (P<.001 for all five countries). We saw reduced sociality as measured through mobility features and increased virtual sociality through phone use. People were more active on their phones (P<.001 for Italy, Spain, and the United Kingdom), spending more time using social media apps (P<.001 for Italy, Spain, the United Kingdom, and the Netherlands), particularly around major news events. Furthermore, participants had a lower heart rate (P<.001 for Italy and Spain; P=.02 for Denmark), went to bed later (P<.001 for Italy, Spain, the United Kingdom, and the Netherlands), and slept more (P<.001 for Italy, Spain, and the United Kingdom). We also found that young people had longer homestay than older people during the lockdown and fewer daily steps. Although there was no significant difference between the high and low BMI groups in time spent at home, the low BMI group walked more. CONCLUSIONS: RADAR-base, a freely deployable data collection platform leveraging data from wearables and mobile technologies, can be used to rapidly quantify and provide a holistic view of behavioral changes in response to public health interventions as a result of infectious outbreaks such as COVID-19. RADAR-base may be a viable approach to implementing an early warning system for passively assessing the local compliance to interventions in epidemics and pandemics, and could help countries ease out of lockdown.

COVID-19 in people with multiple sclerosis: A global data sharing initiative.

BACKGROUND: We need high-quality data to assess the determinants for COVID-19 severity in people with MS (PwMS). Several studies have recently emerged but there is great benefit in aligning data collection efforts at a global scale. OBJECTIVES: Our mission is to scale-up COVID-19 data collection efforts and provide the MS community with data-driven insights as soon as possible. METHODS: Numerous stakeholders were brought together. Small dedicated interdisciplinary task forces were created to speed-up the formulation of the study design and work plan. First step was to agree upon a COVID-19 MS core data set. Second, we worked on providing a user-friendly and rapid pipeline to share COVID-19 data at a global scale. RESULTS: The COVID-19 MS core data set was agreed within 48 hours. To date, 23 data collection partners are involved and the first data imports have been performed successfully. Data processing and analysis is an on-going process. CONCLUSIONS: We reached a consensus on a core data set and established data sharing processes with multiple partners to address an urgent need for information to guide clinical practice. First results show that partners are motivated to share data to attain the ultimate joint goal: better understand the effect of COVID-19 in PwMS.