key: cord-0733403-2voryxwp authors: Simpson-Yap, S.; De Brouwer, E.; Kalincik, T.; Rijke, N.; Hillert, J.; Walton, C.; Edan, G.; MOREAU, Y. Y.; Spelman, T.; Geys, L.; Parciak, T.; Gautrais, C.; Lazovski, N.; Pirmani, A.; Ardeshirdavani, A.; Forsberg, L.; Glaser, A.; McBurney, R.; Schmidt, H.; Bergmann, A.; Braune, S.; Stahmann, A.; Middleton, R.; Salter, A.; Fox, R. J.; van der Walt, A.; Butzkueven, H.; Al-Roughani, R.; Ozakbas, S.; Rojas, J. I.; van der Mei, I.; Nag, N.; Ivanov, R.; Sciascia do Olival, G.; Estavo Dias, A.; Magyari, M.; Brum, D. G.; Mendes, M. F.; Alonso, R.; Nicholas, R.; Bauer, J.; Chertcoff, A.; Zabalza, A. title: Associations of DMT therapies with COVID-19 severity in multiple sclerosis date: 2021-02-10 journal: nan DOI: 10.1101/2021.02.08.21251316 sha: 6e42b9b8c5881da961a08d4d26ec601978b6f442 doc_id: 733403 cord_uid: 2voryxwp Background: People with multiple sclerosis (MS) are a vulnerable group for severe 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. Demographic and clinical covariates were queried, alongside COVID-19 clinical severity outcomes, hospitalisation, admission to ICU, requiring artificial ventilation, and death. Characteristics of outcomes were assessed in patients with suspected/confirmed COVID-19 using multilevel mixed-effects logistic regression. Results: 657 (28.1%) with suspected and 1,683 (61.9%) with confirmed COVID-19 were analysed. 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 hospitalisation (aOR=1.56,95%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), though 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 hospitalisation (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 with artificial ventilation (aOR=6.15,95%CI=3.09-12.27). Compared to natalizumab, ocrelizumab and rituximab were associated with hospitalisation (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 with ventilation (aOR=5.52,95%CI=1.71-17.84). Importantly, associations persisted on restriction to confirmed COVID-19 cases. No associations were observed between DMTs and death. Conclusions: Using the largest cohort of people with MS and COVID-19 available, we demonstrated consistent associations of rituximab with increased risk of hospitalisation, ICU admission, and requiring artificial ventilation, and ocrelizumab with hospitalisation and ICU admission, suggesting their use may be a risk factor for more severe COVID-19. Disease-modifying therapies (DMTs) that act by immunomodulatory/immunosuppressive mechanisms are a mainstay of treatment of multiple sclerosis (MS) but can increase infection All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 10, 2021. ; https://doi.org/10.1101/2021.02.08.21251316 doi: medRxiv preprint susceptibility 1 . Of current concern is the novel coronavirus, SARS-CoV-2, the cause of Coronavirus Disease of 2019 (COVID- 19) 2 . It remains unclear whether people with MS, especially those treated with immunosuppressive DMTs, are more susceptible to more severe COVID-19. Case-series 3-6 and cohort [7] [8] [9] studies suggest that MS in general does not increase risk for developing severe COVID-19, but comorbidities, age, sex, progressive MSphenotype, and higher disability do 7, 9 . Some studies have also identified associations of certain DMT classes, particularly B-celldepleting DMTs, with COVID-19 severity. However, this varied among studies, potentially due to limited sample size and regional differences in DMT usage 7, 9 . Large and geographically inclusive cohorts are required to assess the risk of severe COVID-19 for specific MS DMTs. Accordingly, we established a global data-sharing initiative 10 to investigate characteristics of COVID-19 severity in people with MS. This study was approved by the ethical committee of Hasselt University [CME2020/025]. Individual data-sources obtained additional ethics approval as required. Data from a core questionnaire regarding COVID-19, and relevant patient demographic and neurological information, were reported by treating clinicians, as described previously 10 . Data were entered in three fashions: 1) "Direct entry to central platform"; 2) "Patient-level data sharing via participating registries/cohorts", where MS registries and cohorts are regularly invited to share and upload their COVID-19 core dataset into the central data platform; and 3) All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 10, 2021. ; https://doi.org/10.1101/2021.02.08.21251316 doi: medRxiv preprint "Aggregated data sharing via participating registries/cohorts", where some registries do not share patient-level data, but share aggregated results from specific queries. Multidimensional contingency tables from 12 different data-sources were merged and then a combined anonymised dataset was reconstructed. Data was entered for a given participant once, but information for that participant could be reentered and this then replacing the original record. This thus made for serial iterations of the analysis dataset, which were analysed over time as the dataset expanded, thus allowing for assessment of temporal consistency of observed associations. Previous iterations of the dataset have been presented 11 but this article describes only the present iteration of the dataset. The study sponsors had no role in the study design, data collection, analysis, interpretation data, in the writing of the report, or the decision to submit for publication. COVID-19 status was defined as confirmed, based on a positive diagnostic test, or suspected, based on clinician judgement. Patient age at the time of reporting was categorised into four groups: 0-17, 18-49, 50-69, and ≥ 70 years; the 0-17 group was excluded (n=5). MS-phenotype was grouped into relapsingremitting MS (RRMS) and progressive MS (SPMS, PPMS). Disability was assessed by the Expanded Disability Status Scale (EDSS) 12 or Neurostatus 13 . Disability was dichotomised into 0-6.0 and >6.0. Comorbidities were queried, including cardiovascular disease, hypertension, diabetes, chronic liver disease, kidney disease, other All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Associations with hospitalisation, ICU admission, ventilation, and death were assessed using multilevel mixed-effects logistic regression, random effects grouped by data source, as univariable and adjusted for age, sex, MS-phenotype, and disability. In addition, sensitivityanalyses were completed serially excluding each data-source to assess whether influential data sources underlay associations. Subgroup analyses were also undertaken where data on comorbidities, BMI, and smoking were available, allowing additional adjustment for these covariates. All analyses were complete-case. For DMTs, individual DMTs were first compared with dimethyl fumarate. Despite leading to lymphopenia in some patients, dimethyl fumarate has not been associated with increased risk of infection 14 , and its biological mechanism of action is unlikely to interfere with the immunological response to SARS-CoV-2 15 , while being common in the sample. Next ocrelizumab and rituximab and the untreated were compared with pooled other DMTs. Finally, ocrelizumab and rituximab were evaluated vs natalizumab to assess ascertainment bias, since natalizumab-treated patients present for infusions every 28-42 days, compared to biannual infusions for anti-CD20 DMTs. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 10, 2021. ; https://doi.org/10.1101/2021.02.08.21251316 doi: medRxiv preprint Data analyses were carried out using STATA/SE 16.0 (StataCorp, College Station, USA). The cohort comprised 2,340 patients, of whom 657 (28.1%) had suspected COVID-19 and 1,683 (71.9%) had confirmed COVID-19. Among suspected/confirmed COVID-19 cases, which was the primary analysis dataset, 20.9% were hospitalised, 5.4% admitted to ICU, 4.1% required artificial ventilation, and 3.2% died. Proportions were slightly higher among confirmed COVID-19 cases (Table 1) . Data sources were located in: 1) Sweden (n=290); 2) Australia, Belgium, Brasil, Kuwait, Romania, Saudi Arabia, Turkey (n=97); 3) Argentina, Chile, Colombia, Ecuador, Honduras, Mexico (n=159); 4) Bulgaria (n=3); 5) Germany, Italy (n=45); 6) Denmark (n=56); 7) Brasil (n=96); 8) Australia, Bahamas, Belgium, Czech Republic, Finland, France, Netherlands, New Zealand, Serbia, Spain, UK, USA (n=114); 9) Germany (n=41); 10) USA (n=1,161); 11) UK (n=131); 12) Spain (n=147). Sources-2 and 10 had higher proportions with confirmed COVID-19 and Sources-4 and 5 higher with non-suspected COVID-19. Among suspected/confirmed COVID-19 cases, hospitalisation was higher in Source-11 and lower in Sources-2, 4, 5, and 7; ICU admission was higher in Sources-3, 9, and 10, and lower in Sources-2, 4, 7, 9, 11, and 12; ventilation was higher in Sources-3 and 8, and lower in Sources-2, 4, 5, 6, 7, 9, and 11; death was higher in Source-11 and lower in Sources-2, 4, 5, 6, 7, 8, and 9. Results were comparable on restriction to confirmed-only COVID-19 (data not shown). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 10, 2021. ; https://doi.org/10.1101/2021.02.08.21251316 doi: medRxiv preprint Compared to dimethyl fumarate, a lower proportion of females were untreated or treated with interferon or ocrelizumab (Table S1 ). Larger proportions of those aged 50-69 and ≥ 70 were untreated or treated with ocrelizumab, teriflunomide, or Other DMT. Greater proportions of progressive MS patients were untreated or treated with ocrelizumab, rituximab, or Other DMTs. Of more disabled patients (EDSS>6), higher proportions were either untreated or treated with ocrelizumab or Other DMTs. Similar results were seen among confirmed-only COVID-19 (data not shown). Demographic and clinical characteristics of hospitalisation and ICU admission ( Table 2 ) and requiring artificial ventilation and death (Table 3 ) among suspected/confirmed COVID-19 cases were assessed. In multivariable models, female sex showed an inverse trend with risks of hospitalisation and death, while older age was positively associated with hospitalisation and death. Progressive MS-phenotype was associated with higher risk of hospitalisation. Higher EDSS was associated with higher risks of all outcomes. Among confirmed-only COVID-19, most of these associations persisted (Tables S2-S3 ). In the subset of data sources with data available, having comorbidities was associated with increased risk of death and obese BMI with increased risks of hospitalisation, ICU admission, and ventilation, while smoking was not associated with any outcomes. Compared to dimethyl fumarate, rituximab use was associated with greater risks of hospitalisation (aOR=2.43), ICU admission (aOR=3.93), and artificial ventilation (aOR=4.00, Table 4 ). Ocrelizumab showed similar trends for hospitalisation (aOR=1.56) and ICU All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 10, 2021. ; https://doi.org/10.1101/2021.02.08.21251316 doi: medRxiv preprint admission (aOR=2.30), but not artificial ventilation (aOR=1.04). No DMTs were associated with death. Untreated patients had increased risk of hospitalisation (aOR=1.79) but no independent associations with other outcomes were seen. These associations persisted among confirmed-only COVID-19 (Figures 1-3 , Table S4 ). Compared to all other DMTs (Table 4 ), those using rituximab had higher risks of hospitalisation (aOR=2.76), ICU admission (aOR=4.32), and artificial ventilation (aOR=6.15). Ocrelizumab showed similar trends for hospitalisation (aOR=1.75) and ICU admission (aOR=2.55) but not ventilation (aOR=1.60). Neither rituximab or ocrelizumab were associated with risk of death. Untreated patients had increased risks of hospitalisation (aOR=2.05), ventilation (aOR=2.07), and death (aOR=2.53). These results persisted among confirmed-only COVID-19 cases (Table S5) . Compared to natalizumab, rituximab was associated with higher risks of hospitalisation (aOR=2.88), ICU admission (aOR=3.23), and ventilation (aOR=5.52, Table 4 ). Ocrelizumab showed similar trends for hospitalisation (aOR=1.86), but did not reach significance for ICU admission and was not associated with ventilation. Neither rituximab or ocrelizumab was associated with increased risk of death. Results were similar among confirmed-only COVID-19 (Table S5) . To mitigate the impact of potential heterogeneity among the individual data sources influencing the results, particularly that for source C10 which comprised nearly half the All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 10, 2021. sample, we utilised random-effects logistic regression. However, in addition, serial exclusion analyses were undertaken wherein analyses were run excluding each dataset in turn. These analyses showed no material differences in associations compared to the main analysis (data not shown). To assess whether the associations seen for ocrelizumab and rituximab with outcomes was genuinely a function of the DMTs, rather than the characteristics of patients commonly treated with these medications (older, progressive MS, higher disability), we undertook stratified analyses evaluating associations among persons aged>70 years vs ≤ 70, among RRMS vs progressive, and among EDSS≤6 vs EDSS>6. These analyses showed that associations were actually present in persons of younger age, of RRMS phenotype, and lower EDSS, indicating that the observed associations were a function of the DMT, not underlying risk profile (Tables S6-S8 ). In the largest sample of people with MS with suspected and confirmed COVID-19 to date, we demonstrated that the anti-CD20 DMTs rituximab, and to a lesser extent ocrelizumab, were associated with more severe COVID-19. Compared to dimethyl fumarate, pooled other DMTs, and natalizumab, anti-CD20 DMTs were associated with higher risks of hospitalisation and ICU admission, while only rituximab was associated with greater risk of requiring artificial ventilation for each analysis. Comparison to natalizumab is particularly important, suggesting that anti-CD20 associations do not reflect ascertainment bias. Regardless of comparator, rituximab consistently showed stronger associations with All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 10, 2021. ; https://doi.org/10.1101/2021.02.08.21251316 doi: medRxiv preprint outcomes than ocrelizumab for hospitalisation and ICU admission, and was solely associated with requiring artificial ventilation. Moreover, DMT associations were not merely driven by older patients, progressive MS-phenotype, or higher disability. We also found that older age, progressive MS-phenotype, and higher disability were over-represented among MS patients with more severe COVID-19. In sub-analyses where data was available, DMT associations were robust to further adjustment for comorbidities, BMI, and smoking status. Anti-CD20 DMTs, which selectively deplete circulating B-lymphocytes, alemtuzumab and cladribine which act through broader immunosuppressive mechanisms, and fingolimod, which sequesters lymphocytes from circulation, are highly effective MS treatments, but can increase infection risk 1, 16 . This has raised concern during the COVID- 19 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 10, 2021. ; https://doi.org/10.1101/2021.02.08.21251316 doi: medRxiv preprint Untreated patients showed consistent positive trends towards associations with hospitalisation, ICU admission, and requiring ventilation, albeit attenuating on adjustment. This is in keeping with prior results. Louapre and colleagues found higher frequencies of severe COVID-19 among the untreated vs treated (46.0% vs 15.5%), though this difference did not persist on adjustment 7 . Sormani and colleagues compared untreated to dimethyl fumarate-treated, finding they were 2.83-times more likely to have severe COVID-19, though this disappeared on adjustment (aOR=1.04) 9 . The lack of independence of the untreated associations here and previously likely reflects the untreated comprising to variable degree people with more benign MS course or other reasons to not use DMTs, so adjustment for MS-phenotype and disability largely captures differences in COVID-19 severity. Of interest are the differences in the magnitudes of associations seen for ocrelizumab and rituximab, since both bind the same CD20 epitope on the outer loop of the protein, albeit in slightly different fashions 17, 18 . In comparison to dimethyl fumarate, to pooled other DMTs, and to natalizumab, rituximab consistently showed stronger associations with outcomes than ocrelizumab. Importantly, in analyses stratifying associations of DMT exposure with COVID19 severity by age, MS-phenotype, and EDSS, there was no evidence that the anti-CD20 DMT associations merely reflects patients with underlying risk factors being disposed to use these treatments. The differences seen, both in magnitudes of associations with hospitalisation and ICU admission and the lack of association with ventilation, are puzzling. This weaker magnitude for ocrelizumab has been seen in prior iterations of the analysis but also in those prior iterations ocrelizumab was significantly associated with ventilation as well as hospitalisation and ICU admission, albeit of weaker magnitude 11 . That ocrelizumab was no longer associated in this iteration of the data may reflect changes in medical practice for COVID-19 treatment, including the introduction of more effective treatments that reduce the All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 10, 2021. ; https://doi.org/10.1101/2021.02.08.21251316 doi: medRxiv preprint need for patients to require artificial ventilation. The weaker magnitudes of associations may reflect ocrelizumab's slightly lower affinity to CD20 or possibly their different provenance, rituximab being a chimeric IgG while ocrelizumab is humanised 17, 18 . Also, the mode of Bcell elimination differs, with ocrelizumab using more antibody and less complementmediated cytotoxicity compared to rituximab 19 . Alternatively, this difference may represent unmeasured confounding as the dataset, while large, was limited in the number of characteristics assessed, so potentially relevant factors like socioeconomic status and access to care or factors impacting on respiratory health could not be assessed. That said, our results are broadly in line with those seen in other studies 7, 9 , providing external consistency. This preliminary observation is worth exploring in laboratory studies. That anti-CD20 DMTs were not associated with death conflicts with the results seen for the other outcomes, as well as with the MuSC-19 study which found a positive trend between anti-CD20 DMTs and death. The issue may lie in ascertainment bias, with fewer of the older patients included in our sample: we had only 9.1% of confirmed COVID-19 cases over 60 years old, vs 17.7% in the MuSC-19 cohort 9 . The potential impacts of these DMTs on death due to COVID-19 should be further explored. In contrast to prior clinic-based studies, our cohort focused on a pre-defined limited set of demographic and clinical characteristics 10 . Thus, we could not assess other clinical features, particularly prior MS clinical course and DMT use, paraclinical information such as radiological burden of MS, or the nuanced details of COVID-19 onset and evolution. Another limitation of our data is that they likely comprise greater proportions of severe cases requiring medical attention. One particular element lacking in our data is treatment duration or duration All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 10, 2021. ; https://doi.org/10.1101/2021.02.08.21251316 doi: medRxiv preprint since treatment, since these both may have bearing on the degree of B-cell depletion and thence on COVID-19 severity. This data was included in the core questionnaire but the level of missingness was too high to be a component of analyses. Heterogeneity in the definitions of exposure and outcomes and in patient inclusion among the data-sources is a known problem in combining multiple data-sources. Related to this are the differences in protocols for hospital and ICU admission and initiation of artificial ventilation between hospitals. To ensure that our results were not being driven by single influential datasources, we undertook all analyses using random-effects logistic regression, as well as serialexclusion sensitivity analyses. These analyses showed that, while there was some variation in the magnitudes and significance of associations, trends tracked as seen for the whole cohort, indicating that the results were not driven by a specific data-source. Another issue lies in the anonymous nature of the data entry, such that patients may be entered more than once in different data-sources. We are unable to account for whether participants already participated or had their data entered in another study as there is no identifying information to assess this, nor any query of prior participation in the survey. Another issue is the comparator used for individual DMTs. We initially planned to compare to glatiramer acetate given its absence of impact on infection risk; however, infrequency of outcomes among these patients precluded its being the comparator. Interferon-beta and teriflunomide were potential comparators but their potential impacts on infection immune response argued against this. Dimethyl fumarate was identified as a suitable comparator, being common in the sample and was also that used for the MuSC-19 study 9 . The untreated All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 10, 2021. ; https://doi.org/10.1101/2021.02.08.21251316 doi: medRxiv preprint were not regarded as an appropriate primary comparator because these patients differed markedly from the rest of the cohort in age, disability, and MS-phenotype. Another issue is the nature of the data aggregation, with some data sources providing individual patient-level data but others only tabulations of discrete categorical terms. Thus, we were obliged to use three-level categories of age and two-level EDSS, rather than more exact values of each. That said, these levels are generally aligned with the levels of each associated with increased COVID-19 severity. Another issue is the definition of outcome values. Where these values were missing, we have left them as such, rather than inferring for instance that patients who were not hospitalised were also not admitted to ICU or required artificial ventilation. This was a conservative allocation that increased the proportions missing for such parameters, rather than coding them to null values, but analyses coding such to null values made little impact on results (data not shown). In the largest population yet studied, we have shown that MS patients treated with anti-CD20 DMTs, rituximab and ocrelizumab, are at higher risk of more severe COVID-19 compared to those treated with dimethyl fumarate, to pooled other DMTs, and to natalizumab. This risk is additional to the risk associated with demographic and clinical characteristics. These results agree with smaller cohort studies and suggest that the risk-vs-benefit of continued or new exposure to CD20-depleting treatment strategies compared to other DMTs needs to be considered in the context of the ongoing COVID-19 pandemic. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 10, 2021. ; https://doi.org/10.1101/2021.02.08.21251316 doi: medRxiv preprint Note: null set denotes analyses which could not be undertaken due to no events occurring in the exposed group. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 10, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 10, 2021. Sanofi. RM has received no personal funding from any sources, but works for the UK MS Register which is funded by the UK MS Society and has received funding for specific projects from Novartis, Sanofi-Genzyme and Merck KGaA. RJF has received personal consulting fees from Actelion, Biogen, Celgene, EMD Serono, Genentech, Immunic, Novartis, Sanofi, Teva, and TG Therapeutics, and has served on advisory committees for All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 10, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 10, 2021. Infection Risks Among Patients With Multiple Sclerosis Treated With Fingolimod, Natalizumab, Rituximab, and Injectable Therapies The emergence of a novel coronavirus their biology and therapeutic options Anti-CD20 and COVID-19 in multiple sclerosis and related disorders: A case series of 60 patients from Madrid, Spain. Multiple sclerosis and related disorders 2020 COVID-19 in multiple sclerosis: The Dutch experience. Multiple sclerosis (Houndmills Risk of COVID-19 infection in MS and neuromyelitis optica spectrum disorders B-cell depleting therapies may affect susceptibility to acute respiratory illness among patients with multiple sclerosis during the early COVID-19 epidemic in Iran. Multiple sclerosis and related disorders 2020 Clinical Characteristics and Outcomes in Patients With Coronavirus Disease 2019 and Multiple Sclerosis Self-diagnosed COVID-19 in people with multiple sclerosis: a community-based cohort of the UK MS Register Disease modifying therapies and Covid-19 severity in Multiple Sclerosis COVID-19 in people with multiple sclerosis: A global data sharing initiative. Multiple sclerosis (Houndmills 04 -First results of the COVID-19 in MS Global Data Sharing Initiative suggest anti-CD20 DMTs are associated with worse COVID-19 outcomes Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS) Neurostatus e-Scoring improves consistency of Expanded Disability Status Scale assessments: A proof of concept study. Multiple sclerosis (Houndmills Effect of dimethyl fumarate on lymphocytes in RRMS: Implications for clinical practice The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic. Multiple sclerosis and related disorders 2020 Disease-modifying drugs for multiple sclerosis and infection risk: a cohort study B cell depletion in the treatment of multiple sclerosis Epitope interactions of monoclonal antibodies targeting CD20 and their relationship to functional properties Ocrelizumab and Other CD20(+) B-Cell-Depleting Therapies in Multiple Sclerosis Analysis by multilevel mixed-effects logistic regression, estimating OR (95% CI). a Multivariable models adjusted for age, sex, MS phenotype, and EDSS. Abbreviations: DMT = disease-modifying therapy MS = multiple sclerosis; OR = odds ratio All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.