Associations of DMT therapies with COVID-19 severity in multiple sclerosis

  1. Steve Simpson-Yap
  2. Edward De Brouwer
  3. Tomas Kalincik
  4. Nick Rijke
  5. Jan Hillert
  6. Clare Walton
  7. Gilles Edan
  8. Yves Moreau
  9. Tim Spelman
  10. Lotte Geys
  11. Tina Parciak
  12. Clément Gautrais
  13. Nikola Lazovski
  14. Ashkan Pirmani
  15. Amin Ardeshirdavani
  16. Lars Forsberg
  17. Anna Glaser
  18. Robert McBurney
  19. Hollie Schmidt
  20. Arnfin Bergmann
  21. Stefan Braune
  22. Alexander Stahmann
  23. Rodden Middleton
  24. Amber Salter
  25. Robert J. Fox
  26. Anneke van der Walt
  27. Helmut Butzkueven
  28. Raed Al-Roughani
  29. Serkan Ozakbas
  30. Juan I Rojas
  31. Ingrid van der Mei
  32. Nupur Nag
  33. Rumen Ivanov
  34. Guilherme Sciascia do Olival
  35. Alice Estavo Dias
  36. Melinda Magyari
  37. Doralina Guimarães Brum
  38. Maria Fernanda Mendes
  39. Ricardo Alonso
  40. Richard Nicholas
  41. Johana Bauer
  42. Anibal Chertcoff
  43. Ana Zabalza
  44. Georgina Arrambide
  45. Alexander Fidao
  46. Giancarlo Comi
  47. Liesbet M. Peeters

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Abstract

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.

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  1. ScreenIT

    SciScore for 10.1101/2021.02.08.21251316: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIACUC: Data-sources: This study was approved by the ethical committee of Hasselt University [
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Disability was assessed by the Expanded Disability Status Scale (EDSS)12 or Neurostatus13.
    Neurostatus13
    suggested: None
    Data analyses were carried out using STATA/SE 16.0 (StataCorp, College Station, USA).
    StataCorp
    suggested: (Stata, RRID:SCR_012763)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    This amalgamation of DMTs is a limitation since, while comparable in terms of their infection risk, these DMTs have markedly different modes of action, especially in relation to the immunological response to SARS-CoV-215. More recently, the Italian MuSC-19 national registry study of 593 suspected and 191 confirmed COVID-19 cases, found anti-CD20 DMT use was associated with 2.6-times greater risk of severe COVID-19 compared to dimethyl fumarate, adjusted for region, age, sex, MS-phenotype, and recent methylprednisolone use9. 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 adjustment7. 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 rituxima...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  2. Version published to 10.1101/2021.02.08.21251316v1 on medRxiv