key: cord-0708409-xxsaxgwl authors: Garjani, A.; Middleton, R. M.; Hunter, R.; Tuite-Dalton, K. A.; Coles, A.; Dobson, R.; Duddy, M.; Hughes, S.; Pearson, O. R.; Rog, D.; Tallantyre, E. C.; das Nair, R.; Nicholas, R.; Evangelou, N. title: COVID-19 is associated with multiple sclerosis exacerbations that are prevented by disease modifying therapies date: 2021-03-10 journal: nan DOI: 10.1101/2021.03.08.21253141 sha: d8cee12a6f515e317ab4de614b729ec4c21a7527 doc_id: 708409 cord_uid: xxsaxgwl Background: Infections can trigger exacerbations of multiple sclerosis (MS). The effects of the coronavirus disease 2019 (COVID-19) on MS are not known. The aim of this study was to understand the impact of COVID-19 on new and pre-existing symptoms of MS. Methods: The COVID-19 and MS study is an ongoing community-based, prospective cohort study conducted as part of the United Kingdom MS Register. People with MS and COVID-19 were invited by email to complete a questionnaire about their MS symptoms during the infection. An MS exacerbation was defined as developing new MS symptoms and/or worsening of pre-existing MS symptoms. Results: Fifty-seven percent (230/404) of participants had an MS exacerbation during their infection; 82 developed new MS symptoms, 207 experienced worsened pre-existing MS symptoms, and 59 reported both. Disease modifying therapies (DMTs) reduced the likelihood of developing new MS symptoms during the infection (OR 0.556, 95%CI 0.316-0.978). Participants with a higher pre-COVID-19 webEDSS (web-based Expanded Disability Status Scale) score (OR 1.251, 95%CI 1.060-1.478) and longer MS duration (OR 1.042, 95%CI 1.009-1.076) were more likely to experience worsening of their pre-existing MS symptoms during the infection. Conclusion: COVID-19 infection was associated with exacerbation of MS. DMTs reduced the chance of developing new MS symptoms during the infection. The role of systemic infections in provoking exacerbations of multiple sclerosis (MS) is well described. 1 Potential safety concerns about using immunosuppressive MS disease modifying therapies (DMTs) during the COVID-19 pandemic, 2 along with disruptions to MS services, 3 have resulted in changes to the treatment plans of many people with MS. However, a decrease in the use of DMTs during the pandemic could lead to excessive MS relapses. Further understanding of the relationship between COVID-19, MS relapses and DMTs will inform decision-making about altering or delaying treatment with DMTs. In this paper, we study the impact of COVID-19 on pre-existing and new symptoms of MS in a large cohort of people with MS and COVID-19. We also assess potential factors associated with COVID-19 related MS exacerbations. The COVID-19 and MS study is an ongoing national community-based, prospective cohort study conducted as part of the United Kingdom (UK) MS Register (UKMSR) 4 . People with MS report whether they have had symptoms consistent with COVID-19, whether the diagnosis was confirmed by a healthcare provider based on their clinical or laboratory findings, and whether they have been admitted to a hospital because of their infection 4 . People with MS and symptoms consistent with COVID-19 were invited to complete a questionnaire about their MS symptoms during or soon after the infection between 20th of July 2020 and 25th of January 2021. We asked participants about any new or worsened pre-. CC-BY-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted March 10, 2021. ; https://doi.org/10.1101/2021.03.08.21253141 doi: medRxiv preprint existing MS symptoms. Here, we report our cross-sectional findings according to the STROBE guidelines 5 . We defined an MS exacerbation as developing new MS symptoms, worsening of pre-existing MS symptoms, or experiencing both during a COVID-19 infection. We asked participants about limitation in daily activities caused by the new symptoms and classified them as mild (no limitation), moderate (less than 50% limitation), or severe (more than 50% limitation). We correlated the COVID-19 and MS symptoms data with information held by the UKMSR on participants' demographics (age, sex, and ethnicity), clinical characteristics (MS type, disease duration from diagnosis, and DMTs), most recent recorded web-based Expanded Disability Status Scale (webEDSS) scores (scored 0 -10, with higher scores indicating more neurological impairment) from before their infection 6 , and most recent Hospital Anxiety and Depression Scale scores (scored 0 -21, with scores ≥11 considered as probable cases of anxiety or depression) 7 . is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted March 10, 2021. ; https://doi.org/10.1101/2021.03.08.21253141 doi: medRxiv preprint multivariable binomial logistic regression analysis. To avoid introducing bias by controlling for colliders and mediators in the regression analyses models, directed acyclic graphs (DAGs) were built to determine confounding factors for individual regression analyses 8 9 . Confounding factors controlled for in each analysis have been stated. Listwise deletion was implemented for missing data. The results of the regression analyses are presented as odds ratio (OR) and 95% confidence intervals (95% CI). Ethical approval for UKMSR studies was obtained from South West-Central Bristol Research Ethics Committee (16/SW/0194). Participants provided informed consent online. The study is registered on clinicaltrials.gov: NCT04354519. Data are stored on the UKMSR Secure e-Research Platform at Swansea University Medical School. Line level data cannot be released, but qualified researchers, subject to governance, can request access to data. We invited 978 people with MS and COVID-19 to complete the MS symptoms questionnaire and 404 (41%) responded within a median (IQR) duration of 14 (9 -17) weeks from reporting a diagnosis of COVID-19 (Table 1) . is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Thirty-nine percent (77/196) of the participants with an MS exacerbation required additional support for their daily activities during COVID-19 infection, as opposed to only 6% (7/114) of the participants without an exacerbation (p <0.001). Among the 82 participants with new MS symptoms during the infection, the most reported new symptoms were sensory, motor, or both (n =58; 71%) ( Table 2 ). Some COVID-19 symptoms such as fatigue, memory problems, or mobility problems can mimic MS symptoms. Most participant who reported fatigue (n =18), memory problems (n =17), or mobility problems (n =24) as part of their new MS symptoms during the infection had additional non-COVID-19 related neurological symptoms including sensory, motor, visual, or balance problems (89%, 88%, and 71%, respectively). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint . CC-BY-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Among the 207 participants with worsened pre-existing MS symptoms during the infection (Table 5) , 190 (92%) reported this worsening to be the same as (n=91) or worse than (n=99) their previous non-COVID-19 systemic infection. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint . CC-BY-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted March 10, 2021. ; https://doi.org/10.1101/2021.03.08.21253141 doi: medRxiv preprint The pre-existing MS symptoms of participants with a higher pre-COVID-19 webEDSS score (adjusted OR 1.251, 95% CI 1.060 -1.478) and longer MS disease duration (adjusted OR 1.042, 95% CI 1.009 -1.076) were more likely to worsen during the infection (Table 3) . Sixty-three (30%) participants who experienced worsening of their pre-existing MS symptoms during the infection reported returning to baseline; 42 (20%) recovered within three weeks. Among the 144 participants who had not returned to baseline, the median (IQR) duration from reporting COVID-19 to responding to the questionnaire was 14 (9 -16) weeks. This large community-based study found that 57% of people with MS and COVID-19 experience an MS exacerbation during their infection, including 20% who develop new MS . CC-BY-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint symptoms. Previous studies have demonstrated an increased risk of MS exacerbations associated with other infections, 1 but the rates (9% to 41%) [10] [11] [12] [13] [14] are lower than COVID-19 related exacerbations reported in this study. We could not objectively assess the reported new MS symptoms by neurological examination to confirm that they were relapses due to the restrictions caused by the pandemic. Previously, it has been shown that relapses reported by people with MS are often also diagnosed as relapses by clinicians 15 . An association between DMT use and reduction of infection-related exacerbations of MS has not been conclusively established 11 13 . We found that taking a DMT reduces the probability of developing new MS symptoms during COVID-19 infection by 44%, which is consistent with the overall relapse rate reduction observed in clinical trials of current DMTs 16 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted March 10, 2021. ; https://doi.org/10.1101/2021.03.08.21253141 doi: medRxiv preprint answer this question with confidence without paraclinical tests, but we found that most individuals with fatigue, memory, or mobility problems also reported other neurological symptoms suggestive of MS. Although more individuals with anxiety or depression reported an MS exacerbation during their COVID-19 infection than individuals without anxiety or depression, the rate of MS exacerbations was above 50% in both groups, suggesting that over-reporting of symptoms linked to anxiety or depression has not driven these results 17 . In this study, we demonstrate that COVID-19 is associated with MS exacerbations. This finding highlights the importance of protecting people with MS against the infection which is now feasible with the increasing number of COVID-19 vaccines. Fewer people taking DMTs experience new neurological symptoms following COVID-19, and, therefore, it is important to consider carefully before altering or delaying treatment with DMTs because of concerns about their safety during the pandemic. The research was supported by the UK MS Society (funding reference 131). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint ET has received consulting or speaker honoraria from Roche, Novartis, and Takeda and travel expenses to attend educational meetings from Biogen, Merck, and Roche. Committee. He has received funding to prepare and deliver lectures on cognitive rehabilitation in multiple sclerosis from Novartis and Biogen. RN has received support for advisory boards and travel from Novartis, Roche, and Biogen. He has received grant support from the UK MS Society. He is a member of a NICE HTA committee. . 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