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Associations of Disease-Modifying Therapies With COVID-19 Severity in Multiple Sclerosis
Steve Simpson-Yap1, Edward De Brouwer2, Tomas Kalincik2
1From the CORe (S.S.-Y., T.K.), Department of Medicine, and Neuroepidemiology Unit (S.S.-Y., N.N., A.F.), Melbourne School of Population & Global Health, University of Melbourne, Parkville, Australia; Menzies Institute for Medical Research (S.S.-Y.), University of Tasmania, Hobart, Australia; ESAT-STADIUS (E.D.B., Y.M., A.P.), KU Leuven, Belgium; Department of Neurology (T.K.), Melbourne MS Centre, Royal Melbourne Hospital, Parkville, Australia; MS International Federation (N.R., C.W.), London, UK; Department of Clinical Neuroscience (J.A.H., T.S., L.F., A.G.), Swedish MS Registry, Stockholm, Sweden; Department of Neurology (G.E.), CHU Pontchaillou, Rennes, France; Karolinska Institutet (T.S.), Solna, Sweden; Biomedical Research Institute-Data Science Institute (L.G., A.P., L.P.), Hasselt University, Belgium; Department of Medical Informatics (T.P.), University Medical Center Göttingen, Germany; Department of Computer Science and AI (C.G.), KU Leuven, Belgium; QMENTA (N.L.), Barcelona, Spain; Medpace Reference Laboratories (A.A.), Molecular Unit, Leuven, Belgium; iConquerMS People-Powered Research Network (R. McBurney, H.S.), Accelerated Cure Project for MS, Waltham, MA; NeuroTransData Study Group (A.B.B., S.B.), NeuroTransData, Neuburg, Germany; German MS-Register by the National MS Society (A. Stahmann), MS Forschungs- und Projektentwicklungs-gGmbH, Hannover, Germany; UK MS Register (R. Middleton, R.S.N.), Swansea University, UK; COViMS (A. Salter, R.J.F.), US; Division of Biostatistics (A. Salter), Washington University in St. Louis, St Louis, MO; Mellen Center for Multiple Sclerosis (R.J.F.), Cleveland Clinic, Cleveland, OH; Department of Neuroscience (A.v.d.W., H.B.), Central Clinical School, Monash University, Melbourne, Australia; Al-Amiri Hospital (R.A.), Kuwait City, Kuwait; Dokuz Eylul University (S.O.), Izmir, Turkey; Neurology Department (J.I.R.), Hospital Universitario de CEMIC; RELACOEM (J.I.R., R.N.A.), Buenos Aires, Argentina; Australian MS Longitudinal Study (I.v.d.M.), Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia; Bulgarian SmartMS COVID-19 Dataset (R.I.), Sofia, Bulgaria; ABEM-Brazilian MS Patients Association (G.S.d.O., A.E.D.), São Paulo, Brazil; Danish Multiple Sclerosis Registry (M.M.), Department of Neurology, University Hospital Rigshospitalet, Glostrup, Denmark; Universidade Estadual Paulista (D.B.), Unesp, Faculdade de Medicina, Botucatu, Brazil; REDONE.br-Brazilian Registry of Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders (D.B., M.F.M.); Irmandade da Santa Casa de Misericórdia de São Paulo (M.F.M.), Brazil; Multiple Sclerosis University Center (R.N.A.), Ramos Mejia Hospital-EMA, Buenos Aires, Argentina; Imperial College London (R.S.N.); Swansea University (R.S.N.), Swansea, UK; Mental Health Area (J.B.); MS and Demyelinating Diseases (A.S.C.)., Hospital Británico de Buenos Aires, EMA, Argentina; Servei de Neurologia-Neuroimmunologia (A.Z., G.A.), Centre d'Esclerosi Múltiple de Catalunya, (Cemcat); Vall d'Hebron Institut de Recerca (A.Z., G.A.), Vall d'Hebron Hospital Universitari; Universitat Autònoma de Barcelona (A.Z., G.A.), Spain; and Institute of Experimental Neurology (G.C.), Ospedale San Raffaele, Milan, Italy. liesbet.peeters@uhasselt.be.
Insights
People with multiple sclerosis (MS) taking rituximab or ocrelizumab disease-modifying therapies (DMTs) faced higher risks of severe COVID-19 outcomes, including hospitalization and ICU admission. These findings highlight potential risks associated with specific MS treatments during the pandemic.
Area of Science:
- Neurology
- Immunology
- Infectious Diseases
Background:
- Multiple sclerosis (MS) patients on immunosuppressive therapies are at higher risk for severe COVID-19.
- Understanding COVID-19 severity in this vulnerable population is crucial.
Purpose of the Study:
- To examine the characteristics and risk factors for COVID-19 severity in an international cohort of MS patients.
- To investigate the association between specific disease-modifying therapies (DMTs) and COVID-19 outcomes.
Main Methods:
- Aggregated data from 12 international sources (28 countries) on MS patients with suspected/confirmed COVID-19.
- Analyzed demographic, clinical, and DMT data against COVID-19 severity outcomes (hospitalization, ICU, ventilation, death).
- Utilized multilevel mixed-effects logistic regression adjusted for key patient characteristics.
Main Results:
- Older age, progressive MS, and higher disability correlated with worse COVID-19 outcomes.
- Rituximab and ocrelizumab were associated with increased hospitalization and ICU admission compared to dimethyl fumarate and other DMTs.
- Rituximab also showed a higher risk for artificial ventilation.
Conclusions:
- Rituximab and ocrelizumab use may be associated with increased risk of severe COVID-19 outcomes in MS patients.
- Findings suggest these DMTs could be risk factors for more severe COVID-19, warranting further investigation.
- No DMTs were associated with an increased risk of death from COVID-19.
Background And Objectives:
People with multiple sclerosis (MS) are a vulnerable group for severe coronavirus disease 2019 (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 (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, along with COVID-19 severity outcomes, hospitalization, intensive care unit (ICU) admission, need for 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 Expanded Disability Status Scale (EDSS) score.
Results:
Six hundred fifty-seven (28.1%) with suspected and 1,683 (61.9%) with confirmed COVID-19 were analyzed. Among suspected plus confirmed and confirmed-only COVID-19, 20.9% and 26.9% were hospitalized, 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 hospitalization (adjusted odds ratio [aOR] 1.56, 95% confidence interval [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), although 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 hospitalization (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 was associated with artificial ventilation (aOR 6.15, 95% CI 3.09-12.27). Compared to natalizumab, ocrelizumab and rituximab were associated with hospitalization (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 was associated with ventilation (aOR 5.52, 95% CI 1.71-17.84). Associations persisted on restriction to confirmed COVID-19 cases. No associations were observed between DMTs and death. Stratification by age, MS phenotype, and EDSS score found no indications that DMT associations with COVID-19 severity reflected differential DMT allocation by underlying COVID-19 severity.
Discussion:
Using the largest cohort of people with MS and COVID-19 available, we demonstrated consistent associations of rituximab with increased risk of hospitalization, ICU admission, and need for artificial ventilation and of ocrelizumab with hospitalization and ICU admission. Despite the cross-sectional design of the study, the internal and external consistency of these results with prior studies suggests that rituximab/ocrelizumab use may be a risk factor for more severe COVID-19.
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