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

Steve Simpson-Yap, Edward De Brouwer, Tomas Kalincik, Nick Rijke, Jan A. Hillert, Clare Walton, Gilles Edan, Yves Moreau, Tim Spelman, Lotte Geys, Tina Parciak, Clement Gautrais, Nikola Lazovski, Ashkan Pirmani, Amin Ardeshirdavanai, Lars Forsberg, Anna Glaser, Robert McBurney, Hollie Schmidt, Arnfin B. Bergmann, Stefan Braune, Alexander Stahmann, Rod Middleton Orcid Logo, Amber Salter, Robert J. Fox, Anneke van der Walt, Helmut Butzkueven, Raed Alroughani, Serkan Ozakbas, Juan I. Rojas, Ingrid van der Mei, Nupur Nag, Rumen Ivanov, Guilherme Sciascia do Olival, Alice Estavo Dias, Melinda Magyari, Doralina Brum, Maria Fernanda Mendes, Ricardo N. Alonso, Richard S. Nicholas, Johana Bauer, Aníbal Sebastián Chertcoff, Anna Zabalza, Georgina Arrambide, Alexander Fidao, Giancarlo Comi, Liesbet Peeters

Neurology, Volume: 97, Issue: 19, Pages: e1870 - e1885

Swansea University Author: Rod Middleton Orcid Logo

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DOI (Published version): 10.1212/wnl.0000000000012753

Abstract

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. Data from 12 data-sources in 28 countrie...

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Published in: Neurology
ISSN: 0028-3878 1526-632X
Published: Ovid Technologies (Wolters Kluwer Health) 2021
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URI: https://cronfa.swan.ac.uk/Record/cronfa58429
first_indexed 2021-10-20T11:16:57Z
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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, alongside COVID-19 severity outcomes, hospitalisation, ICU admission, requiring 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 EDSS. 657(28.1%) with suspected and 1,683(61.9%) with confirmed COVID-19 were analysed. Among suspected+confirmed and confirmed-only COVID-19, 20.9% and 26.9% were hospitalised, 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 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 wereassociated 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. Stratification by age, MS-phenotype, and EDSS found no indications that DMT associations with COVID-19 severity reflected differential DMT allocation by underlying COVID-19 severity. 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. Despite the study's cross-sectional design, the internal and external consistency of these results with prior studies suggests rituximab/ocrelizumab use may be a risk factor for more severe COVID-19.</abstract><type>Journal Article</type><journal>Neurology</journal><volume>97</volume><journalNumber>19</journalNumber><paginationStart>e1870</paginationStart><paginationEnd>e1885</paginationEnd><publisher>Ovid Technologies (Wolters Kluwer Health)</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>0028-3878</issnPrint><issnElectronic>1526-632X</issnElectronic><keywords/><publishedDay>9</publishedDay><publishedMonth>11</publishedMonth><publishedYear>2021</publishedYear><publishedDate>2021-11-09</publishedDate><doi>10.1212/wnl.0000000000012753</doi><url/><notes/><college>COLLEGE NANME</college><department>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</DepartmentCode><institution>Swansea University</institution><apcterm/><lastEdited>2021-11-17T14:58:30.7520233</lastEdited><Created>2021-10-20T12:14:19.4778911</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Steve</firstname><surname>Simpson-Yap</surname><order>1</order></author><author><firstname>Edward De</firstname><surname>Brouwer</surname><order>2</order></author><author><firstname>Tomas</firstname><surname>Kalincik</surname><order>3</order></author><author><firstname>Nick</firstname><surname>Rijke</surname><order>4</order></author><author><firstname>Jan A.</firstname><surname>Hillert</surname><order>5</order></author><author><firstname>Clare</firstname><surname>Walton</surname><order>6</order></author><author><firstname>Gilles</firstname><surname>Edan</surname><order>7</order></author><author><firstname>Yves</firstname><surname>Moreau</surname><order>8</order></author><author><firstname>Tim</firstname><surname>Spelman</surname><order>9</order></author><author><firstname>Lotte</firstname><surname>Geys</surname><order>10</order></author><author><firstname>Tina</firstname><surname>Parciak</surname><order>11</order></author><author><firstname>Clement</firstname><surname>Gautrais</surname><order>12</order></author><author><firstname>Nikola</firstname><surname>Lazovski</surname><order>13</order></author><author><firstname>Ashkan</firstname><surname>Pirmani</surname><order>14</order></author><author><firstname>Amin</firstname><surname>Ardeshirdavanai</surname><order>15</order></author><author><firstname>Lars</firstname><surname>Forsberg</surname><order>16</order></author><author><firstname>Anna</firstname><surname>Glaser</surname><order>17</order></author><author><firstname>Robert</firstname><surname>McBurney</surname><order>18</order></author><author><firstname>Hollie</firstname><surname>Schmidt</surname><order>19</order></author><author><firstname>Arnfin B.</firstname><surname>Bergmann</surname><order>20</order></author><author><firstname>Stefan</firstname><surname>Braune</surname><order>21</order></author><author><firstname>Alexander</firstname><surname>Stahmann</surname><order>22</order></author><author><firstname>Rod</firstname><surname>Middleton</surname><orcid>0000-0002-2130-4420</orcid><order>23</order></author><author><firstname>Amber</firstname><surname>Salter</surname><order>24</order></author><author><firstname>Robert J.</firstname><surname>Fox</surname><order>25</order></author><author><firstname>Anneke van der</firstname><surname>Walt</surname><order>26</order></author><author><firstname>Helmut</firstname><surname>Butzkueven</surname><order>27</order></author><author><firstname>Raed</firstname><surname>Alroughani</surname><order>28</order></author><author><firstname>Serkan</firstname><surname>Ozakbas</surname><order>29</order></author><author><firstname>Juan I.</firstname><surname>Rojas</surname><order>30</order></author><author><firstname>Ingrid van der</firstname><surname>Mei</surname><order>31</order></author><author><firstname>Nupur</firstname><surname>Nag</surname><order>32</order></author><author><firstname>Rumen</firstname><surname>Ivanov</surname><order>33</order></author><author><firstname>Guilherme Sciascia do</firstname><surname>Olival</surname><order>34</order></author><author><firstname>Alice Estavo</firstname><surname>Dias</surname><order>35</order></author><author><firstname>Melinda</firstname><surname>Magyari</surname><order>36</order></author><author><firstname>Doralina</firstname><surname>Brum</surname><order>37</order></author><author><firstname>Maria Fernanda</firstname><surname>Mendes</surname><order>38</order></author><author><firstname>Ricardo N.</firstname><surname>Alonso</surname><order>39</order></author><author><firstname>Richard S.</firstname><surname>Nicholas</surname><order>40</order></author><author><firstname>Johana</firstname><surname>Bauer</surname><order>41</order></author><author><firstname>An&#xED;bal Sebasti&#xE1;n</firstname><surname>Chertcoff</surname><order>42</order></author><author><firstname>Anna</firstname><surname>Zabalza</surname><order>43</order></author><author><firstname>Georgina</firstname><surname>Arrambide</surname><order>44</order></author><author><firstname>Alexander</firstname><surname>Fidao</surname><order>45</order></author><author><firstname>Giancarlo</firstname><surname>Comi</surname><order>46</order></author><author><firstname>Liesbet</firstname><surname>Peeters</surname><order>47</order></author></authors><documents><document><filename>58429__21553__799f23814ab145ada754e25225ec978a.pdf</filename><originalFilename>58429.pdf</originalFilename><uploaded>2021-11-17T14:39:54.9388143</uploaded><type>Output</type><contentLength>765691</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>&#xA9; 2021 The Author(s). 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spelling 2021-11-17T14:58:30.7520233 v2 58429 2021-10-20 Associations of Disease-Modifying Therapies With COVID-19 Severity in Multiple Sclerosis 005518f819ef1a2a13fdf438529bdfcd 0000-0002-2130-4420 Rod Middleton Rod Middleton true false 2021-10-20 MEDS 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. 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, alongside COVID-19 severity outcomes, hospitalisation, ICU admission, requiring 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 EDSS. 657(28.1%) with suspected and 1,683(61.9%) with confirmed COVID-19 were analysed. Among suspected+confirmed and confirmed-only COVID-19, 20.9% and 26.9% were hospitalised, 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 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 wereassociated 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. Stratification by age, MS-phenotype, and EDSS found no indications that DMT associations with COVID-19 severity reflected differential DMT allocation by underlying COVID-19 severity. 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. Despite the study's cross-sectional design, the internal and external consistency of these results with prior studies suggests rituximab/ocrelizumab use may be a risk factor for more severe COVID-19. Journal Article Neurology 97 19 e1870 e1885 Ovid Technologies (Wolters Kluwer Health) 0028-3878 1526-632X 9 11 2021 2021-11-09 10.1212/wnl.0000000000012753 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University 2021-11-17T14:58:30.7520233 2021-10-20T12:14:19.4778911 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Steve Simpson-Yap 1 Edward De Brouwer 2 Tomas Kalincik 3 Nick Rijke 4 Jan A. Hillert 5 Clare Walton 6 Gilles Edan 7 Yves Moreau 8 Tim Spelman 9 Lotte Geys 10 Tina Parciak 11 Clement Gautrais 12 Nikola Lazovski 13 Ashkan Pirmani 14 Amin Ardeshirdavanai 15 Lars Forsberg 16 Anna Glaser 17 Robert McBurney 18 Hollie Schmidt 19 Arnfin B. Bergmann 20 Stefan Braune 21 Alexander Stahmann 22 Rod Middleton 0000-0002-2130-4420 23 Amber Salter 24 Robert J. Fox 25 Anneke van der Walt 26 Helmut Butzkueven 27 Raed Alroughani 28 Serkan Ozakbas 29 Juan I. Rojas 30 Ingrid van der Mei 31 Nupur Nag 32 Rumen Ivanov 33 Guilherme Sciascia do Olival 34 Alice Estavo Dias 35 Melinda Magyari 36 Doralina Brum 37 Maria Fernanda Mendes 38 Ricardo N. Alonso 39 Richard S. Nicholas 40 Johana Bauer 41 Aníbal Sebastián Chertcoff 42 Anna Zabalza 43 Georgina Arrambide 44 Alexander Fidao 45 Giancarlo Comi 46 Liesbet Peeters 47 58429__21553__799f23814ab145ada754e25225ec978a.pdf 58429.pdf 2021-11-17T14:39:54.9388143 Output 765691 application/pdf Version of Record true © 2021 The Author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY) true eng http://creativecommons.org/licenses/by/4.0/
title Associations of Disease-Modifying Therapies With COVID-19 Severity in Multiple Sclerosis
spellingShingle Associations of Disease-Modifying Therapies With COVID-19 Severity in Multiple Sclerosis
Rod Middleton
title_short Associations of Disease-Modifying Therapies With COVID-19 Severity in Multiple Sclerosis
title_full Associations of Disease-Modifying Therapies With COVID-19 Severity in Multiple Sclerosis
title_fullStr Associations of Disease-Modifying Therapies With COVID-19 Severity in Multiple Sclerosis
title_full_unstemmed Associations of Disease-Modifying Therapies With COVID-19 Severity in Multiple Sclerosis
title_sort Associations of Disease-Modifying Therapies With COVID-19 Severity in Multiple Sclerosis
author_id_str_mv 005518f819ef1a2a13fdf438529bdfcd
author_id_fullname_str_mv 005518f819ef1a2a13fdf438529bdfcd_***_Rod Middleton
author Rod Middleton
author2 Steve Simpson-Yap
Edward De Brouwer
Tomas Kalincik
Nick Rijke
Jan A. Hillert
Clare Walton
Gilles Edan
Yves Moreau
Tim Spelman
Lotte Geys
Tina Parciak
Clement Gautrais
Nikola Lazovski
Ashkan Pirmani
Amin Ardeshirdavanai
Lars Forsberg
Anna Glaser
Robert McBurney
Hollie Schmidt
Arnfin B. Bergmann
Stefan Braune
Alexander Stahmann
Rod Middleton
Amber Salter
Robert J. Fox
Anneke van der Walt
Helmut Butzkueven
Raed Alroughani
Serkan Ozakbas
Juan I. Rojas
Ingrid van der Mei
Nupur Nag
Rumen Ivanov
Guilherme Sciascia do Olival
Alice Estavo Dias
Melinda Magyari
Doralina Brum
Maria Fernanda Mendes
Ricardo N. Alonso
Richard S. Nicholas
Johana Bauer
Aníbal Sebastián Chertcoff
Anna Zabalza
Georgina Arrambide
Alexander Fidao
Giancarlo Comi
Liesbet Peeters
format Journal article
container_title Neurology
container_volume 97
container_issue 19
container_start_page e1870
publishDate 2021
institution Swansea University
issn 0028-3878
1526-632X
doi_str_mv 10.1212/wnl.0000000000012753
publisher Ovid Technologies (Wolters Kluwer Health)
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description 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. 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, alongside COVID-19 severity outcomes, hospitalisation, ICU admission, requiring 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 EDSS. 657(28.1%) with suspected and 1,683(61.9%) with confirmed COVID-19 were analysed. Among suspected+confirmed and confirmed-only COVID-19, 20.9% and 26.9% were hospitalised, 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 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 wereassociated 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. Stratification by age, MS-phenotype, and EDSS found no indications that DMT associations with COVID-19 severity reflected differential DMT allocation by underlying COVID-19 severity. 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. Despite the study's cross-sectional design, the internal and external consistency of these results with prior studies suggests rituximab/ocrelizumab use may be a risk factor for more severe COVID-19.
published_date 2021-11-09T14:08:28Z
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