Abstract: Journal of Neurology https://doi.org/10.1007/s00415-023-11618-0 ORIGINAL COMMUNICATION Modifiable risk factors of COVID‑19 in patients with multiple sclerosis: a single‑centre case–control study Federico Montini1 · Agostino Nozzolillo1 · Paola M. V. Rancoita2 · Chiara Zanetta1 · Lucia Moiola1 · Federica Cugnata2 · Federica Esposito1 · Maria A. Rocca1,3,4 · Vittorio Martinelli1 · Massimo Filippi1,3,4,5,6 Received: 21 December 2022 / Revised: 8 February 2023 / Accepted: 8 February 2023 © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany 2023 Abstract Background Disease and treatment-associated immune system abnormalities may confer higher risk of Coronavirus disease 2019 (COVID-19) to people with multiple sclerosis (PwMS). We assessed modifiable risk factors associated with COVID19 in PwMS. Methods Among patients referring to our MS Center, we retrospectively collected epidemiological, clinical and laboratory data of PwMS with confirmed COVID-19 between March 2020 and March 2021 (MS-COVID, n = 149). We pursued a 1:2 matching of a control group by collecting data of PwMS without history of previous COVID-19 (MS-NCOVID, n = 292). MS-COVID and MS-NCOVID were matched for age, expanded disability status scale (EDSS) and line of treatment. We compared neurological examination, premorbid vitamin D levels, anthropometric variables, life-style habits, working activity, and living environment between the two groups. Logistic regression and Bayesian network analyses were used to evaluate the association with COVID-19. Results MS-COVID and MS-NCOVID were similar in terms of age, sex, disease duration, EDSS, clinical phenotype and treatment. At multiple logistic regression, higher levels of vitamin D (OR 0.93, p < 0.0001) and active smoking status (OR 0.27, p < 0.0001) emerged as protective factors against COVID-19. In contrast, higher number of cohabitants (OR 1.26, p = 0.02) and works requiring direct external contact (OR 2.61, p = 0.0002) or in the healthcare sector (OR 3.73, p = 0.0019) resulted risk factors for COVID-19. Bayesian network analysis showed that patients working in the healthcare sector, and therefore exposed to increased risk of COVID-19, were usually non-smokers, possibly explaining the protective association between active smoking and COVID-19. Conclusions Higher Vitamin D levels and teleworking may prevent unnecessary risk of infection in PwMS. Keywords Multiple sclerosis · Case–control studies · Viral infections · Medical care Vittorio Martinelli and Massimo Filippi have equally contributed to this work. Background * Massimo Filippi filippi.massimo@hsr.it Demographic, ecological, and politico-economic factors together with comorbidities have influenced the severity of Coronavirus disease 2019 (COVID-19) worldwide [1]. Among others, this pandemic has also raised health concerns related to people with multiple sclerosis (PwMS) in the acute phase of the outbreak. These people have been considered at higher risk to contract SARS-CoV-2 infection and have a more severe COVID-19 course due to their clinical disability, comorbidities, disease-associated immune alterations and the use of disease modifying therapies (DMTs) [2, 3]. In the general population more than 6,500,000 deaths have been reported in the world [4]. Data collected during the pandemic suggest that COVID-19 may determine 1 Neurology Unit, IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132 Milan, Italy 2 University Centre for..