key: cord-0830326-2bkwjcj9 authors: Irene, Schiavetti; Marta, Ponzano; Alessio, Signori; Francesca, Bovis; Luca, Carmisciano; Pia, Sormani Maria title: Severe outcomes of Covid-19 among patients with Multiple Sclerosis under anti-CD-20 therapies: a systematic review and meta-analysis date: 2021-11-05 journal: Mult Scler Relat Disord DOI: 10.1016/j.msard.2021.103358 sha: 0aaeab0533d7518a11ce0a104f7c3c8c9c09dad6 doc_id: 830326 cord_uid: 2bkwjcj9 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 Centre 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 I(2) statistic 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. of missing data, an email was sent to the corresponding authors asking to complete the missing information. All selected articles were rigorously appraised by two authors according to a modified version of the Dutch Cochrane Centre critical review checklist proposed by MOOSE [8] . Key However, since two domains (IV and V) were considered irrelevant for the purpose of this study, only four (I, II, III, VI) were combined in an overall reporting quality score (ranging from 0 to 4 points). A study was defined of highest quality if all criteria were rated as "yes" because free from intra-study bias. To estimate the mortality rate among patients treated with ocrelizumab and rituximab and to evaluate the overall rate of mortality, hospitalization, and ICU admission, a random effects meta-analysis of proportions using the continuity correction was conducted, with the I 2 statistic to measure heterogeneity. Case reports were excluded from the meta-analysis to avoid misleading results and to not overestimate the rate of severe outcomes (case reports usually describe more serious cases rather than mild disease courses). Meta-analysis was performed using Stata version 16.0 (Stata Corporation, College Station, TX, USA). Out of 269 articles retrieved from investigated databases, 29 were included in the final analysis ( Figure 1 ). The quality of selected studies ranged from 1 to 4 points (median = 3) by considering original published data, whereas with implemented details provided by authors the total quality score of manuscripts improved to 2 to 4 points (median = 4) (Table III) . These studies involved 5173 patients (81% with confirmed Covid-19), with an age ranging from 17 to 84 years, and 71% of the participants were females. The sample size for the included studies ranged from 1 (single case report) to 1626 cases. As about MS history, 80.6% of the sample presented a relapsing remitting form of disease, 770 (14.8%) patients were in treatment with ocrelizumab and 455 (8.8%) with rituximab (Table IV) . Frequencies of Covid-19 outcomes and results from the meta-analysis are reported in Table V The pooled estimate of the hospitalization rate was 18.1%, slightly lower compared to the rate observed in a systematic review which included studies on MS and Covid-19 without restrictions based on the treatment type (20.7%) [9] . In general, hospitalization rates were found to vary widely depending on several characteristics, including age, gender, presence of comorbidities, residence area and reference period under study [10] . For a deeper analysis of these results, it is important to consider that MS population differ from the general population in distribution of several characteristics, such as age, gender, and presence of comorbidities [11] . In addition, the high heterogeneity (88%) found in this meta-analysis can be partially explained by the fact that data are collected from different Countries, referred to different periods of pandemic and based on different study designs. Similar considerations can be made to explain the high heterogeneity for the pneumonia rate, with lower and upper confidence interval ranged from 9.6% to 20.1%. Furthermore, pneumonia data were not always available, probably due to the difficulty in assessing its presence in retrospective studies. Concerning ICU admissions, the highest percentages of occurrence were observed from two studies (13% and 11%), but in half of the studies there were no patients admitted in ICU. However, it is relevant that for many patients included in this work (N=591) information on ICU admissions were not available or unclear. ICU admissions should be more investigated and reported due to their relevance in Covid-19 mortality. Indeed, a meta-analysis conducted on the general population showed an ICU Covid-19 mortality rate of 35.5% [12] . On the other hand, clear and complete information on deaths were reported in all the studies, almost always with details regarding assumed treatments. Specifically, only 115 out of 5173 (2.2%) patients presented a fatal event, resulting in a pooled estimate of 1.8% and in a heterogeneity of 77%. The frequency of deaths was lower than the one observed in a previous study on MS and Covid-19 (3.0%) [9] but regarding patients on rituximab, there were 10/455 (2.2%) fatal events compared to 15/770 (1.9%) on ocrelizumab, with estimates of 4.5% and 1.6%. This higher rate of deaths among patients under rituximab is consistent with the stronger association with hospitalization already found in a previous work [5] . Patients treated with rituximab seem to be at higher risk of severe Covid-19 outcomes compared to patients under other treatments. The reason for this difference has been suggested by a sensitivity analysis from the Italian work [4] which revealed a trend of an increased risk of anti-CD20 agents with therapy duration. In particular, as compared to patients treated with other therapies, patients on anti-CD20 therapy for less than six months had an OR = 1.65 (95% CI = 0.56-4.90, p = 0.36), patients on anti-CD20 therapy between six and twelve months had an OR = 2.24 (95% CI = 0.91-5.55, p = 0.08), and patients on anti-CD20 therapy for more than twelve months had an OR = 2.98 (95% CI = 1.37-6.46, p = 0.006). Therefore, the increased risk of patients in Rituximab can be due to their longer therapy duration compared to that of patients in Ocrelizumab. Schiavetti I, Ponzano M, Signori A, Bovis F, Carmisciano L have nothing to disclose. Sormani MP received consulting fees from Merck, Biogen, Novartis, Sanofi-Genzyme, Roche, Celgene, Geneuro, GSK, Medday, Immunic. 14. Barzegar *Data provided by the authors but not published. Montero-Escribano P. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention Disease-modifying therapies and infectious risks in multiple sclerosis DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis Outcomes and Risk Factors Associated With SARS-CoV-2 Infection in a North American Registry of Patients With Multiple Sclerosis COVID-19 severity and mortality in multiple sclerosis are not associated with immunotherapy: Insights from a nation-wide Austrian registry Clinical Characteristics and Outcomes in Patients With Coronavirus Disease 2019 and Multiple Sclerosis Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group COVID-19 Among Patients With Multiple Sclerosis: A Systematic Review Hospitalization Rates and Characteristics of Patients Hospitalized with Laboratory-Confirmed Coronavirus Disease 2019 -COVID-NET, 14 States The Multiple Sclerosis International Federation, Atlas of MS Mortality in patients admitted to intensive care with COVID-19: an updated systematic review and meta-analysis of observational studies SARS-CoV-2 Infection in Multiple Sclerosis: Results of the Spanish Neurology Society Registry NA/7 (NA) NA/262 (NA) We really thank authors which have provided some additional data of their samples or have confirmed some unclear measures.