COVID-19 and disease-modifying therapies in patients with demyelinating diseases of the central nervous system: A systematic review

Abstract

Introduction: The Coronavirus disease-19 (COVID-19) pandemic continues to expand across the world. This pandemic has had a significant impact on patients with chronic diseases. Among patients with demyelinating diseases of the central nervous system (CNS), such as Multiple Sclerosis (MS) or Neuromyelitis Optica Spectrum Disorder (NMOSD), concerns remain about the potential impact of COVID-19 on these patients given their treatment with immunosuppressive or immunomodulatory therapies. In this study, we review the existing literature investigating the impact of disease-modifying therapies(DMT) on COVID-19 risks in this group of patients.

Method: For this systematic review, we searched PubMed from January 1, 2020, to December 3, 2020. The following keywords were used: "COVID-19" AND "Multiple Sclerosis" OR "Neuromyelitis Optica." Articles evaluating COVID-19 in patients with demyelinating diseases of CNS were included. This study evaluates the different aspects of the DMTs in these patients during the COVID-19 era.

Results and conclusion: A total of 262 articles were found. After eliminating duplicates and unrelated research papers, a total of 84 articles met the final inclusion criteria in our study. Overall, the experiences of 2493 MS patients and 37 NMOSD patients with COVID-19 were included in this review. Among them, 46(1.8%) MS patients died(the global death-to-case ratio of Covid-19 was reported about 2.1%). Among DMTs, Rituximab had the highest mortality rate (4%). Despite controversies, especially concerning anti-CD20 monoclonal antibody therapies, a relation between DMT-use and COVID-19 disease- course was not found in many studies. This observation reinforces the recommendation of not stopping current DMTs. Other variables such as age, higher expanded disability status scale (EDSS) scores, cardiac comorbidities, and obesity were independent risk factors for severe COVID-19. Despite the risks of infection, most patients were willing to continue their DMT during the pandemic because of more significant concern about the risk of relapse or worsening MS symptoms. After the infection, an immune response's attenuation was seen in the patients on Fingolimod and anti-CD20 monoclonal antibodies. This may be a critical finding in future vaccinations.

Keywords: COVID-19; Disease-modifying therapies; Multiple sclerosis; Neuromyelitis optica spectrum disorder.

Fig. 1.

PRISMA chart of this study. *Among the selected articles, those with relation to the rate of infection in patients on DMTs, articles related to psychiatric problems and anxiety in MS and NMOSD patients during pandemic (with focus on the articles which evaluated the risk of different DMT and attitude of the patients about continuing or discontinuing of the DMT) and articles related to vaccination were included. Other articles were excluded (to have a more focused review).

Fig. 2.

SARS-CoV-2 inhibits the antiviral type 1 IFN molecules' production by the infected cells and the intracellular antioxidant NRF2 pathway. GA causes a shift from a pro-inflammatory to an anti-inflammatory response. DMF blocks pro-inflammatory cytokine production and can inhibit macrophage function. Teriflunomide may affect the replication of SARS-CoV-2 inside the infected cell. Fingolimod enhancing lung endothelial cell integrity. Natalizumab as an antibody against α4- integrin might be protective toward the infection. Anti-CD20 monoclonal antibodies moderately reduced immune response by peripheral B cell reduction, which might play a favorable role in COVID-19. Designed with https://biorender.com/ . ARDS: Acute respiratory distress syndrome , GA: Glatiramer acetate, DMF: Dimethyl fumarate, IFN: Interferon beta. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3.

Prevalence of reported MS patients with COVID-19 on different DMTs, categorized according to the risk of infection. DMF: Dimethyl fumarate, GA: Glatiramer acetate, Ter: Teriflunomide, Nat: Natalizumab, Al: Alemtuzumab,Ocr: Ocrelizumab, Cladri: Cladribine, Rituxi:Rituximab,Fingo:Fingolimod, INF: Interferon beta.

Fig. 4

Prevalence of reported mortality in MS patients with COVID-19 on different DMTs (On Med), without medication (No Med), or undetermined (Undet) groups. (In this chart, we divided the mortality case in each group by the total number of patients who died(46 patients)). DMF: Dimethyl fumarate, GA: Glatiramer acetate, Ter: Teriflunomide, Nat: Natalizumab, Ocr: Ocrelizumab, Rituxi:Rituximab,Fingo:Fingolimod.