key: cord-0885090-5inyjnlo
authors: Amor, Sandra; Baker, David; Khoury, Samia J.; Schmierer, Klaus; Giovanonni, Gavin
title: SARS‐CoV‐2 and Multiple Sclerosis: Not All Immune Depleting DMTs are Equal or Bad
date: 2020-05-21
journal: Ann Neurol
DOI: 10.1002/ana.25770
sha: 461888b96606b2190635b553354102c79fc91953
doc_id: 885090
cord_uid: 5inyjnlo

A major concern during the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic1 is the use of immunosuppressive therapies for the treatment of multiple sclerosis (MS) due to an increased risk of contracting SARS-CoV-2 and more severe disease. The Society of Italian Neurologists (SIN) and the Association of British Neurologists (ABN) MS and Neuroimmunology Advisory Group published guidance for the use of current disease modifying treatments (DMTs) in MS (Table 1)2 . However, taking into account, less conservative viewpoints3 , the emerging knowledge of the biology of SARS-CoV-2, and in particular the role of the immune mechanisms contributing to the disease, we propose modification of these guidelines since it is not clear that immunosuppression is indeed detrimental in people with MS infected with SARS-CoV-2. We are thus proposing a more nuanced approach and that the categories of DMTs should be modified based on scientific principles and the biology of severe COVID-19 (Table 2). This article is protected by copyright. All rights reserved.

A major concern during the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic 1 is the use of immunosuppressive therapies for the treatment of multiple sclerosis (MS) due to an increased risk of contracting SARS-CoV-2 and more severe disease. The Society of Italian Neurologists (SIN) and the Association of British Neurologists (ABN) MS and Neuroimmunology Advisory Group published guidance for the use of disease modifying treatments (DMTs) in MS (Table 1 ). 2 However, taking into account less conservative viewpoints, 3 the emerging knowledge of the biology of SARS-CoV-2, and, in particular, the role of the immune mechanisms contributing to the disease, we propose modification of these guidelines because it is not clear that immunosuppression is indeed detrimental in people with MS infected with SARS-CoV-2. Thus, we are proposing a more nuanced approach and that the categories of DMTs should be modified based on scientific principles and the biology of severe coronavirus disease 2019 (COVID-19; Table 2 ).

The immune mechanisms contributing to severe COVID-19 include viral subversion of innate immunity and infection of macrophages, 4 and, if similar to SARS-CoV-2, may trigger apoptosis of leucocytes leading to lymphopenia. 5 The exact mechanisms are as yet unclear but suppression of innate responses due to modulation of IFN production or receptor signaling, and the apoptotic effects of virally encoded proteins have been proposed. 6 Together, these allow widespread viral infection, excessive monocyte/macrophage activation, and, in severe cases, a cytokine storm triggering severe acute respiratory distress syndrome (ARDS). The viral-specific CD8 T cell responses seem to eliminate SARS-CoV-2, whereas viral specific antibodies are probably more important to prevent reinfection and create long-lasting immunity. A direct role of B cells in the destructive COVID-19 pathology is unlikely because people with X-linked agammaglobulinemia recover from the COVID-19 pneumonia and lymphopenia without need of intensive care or oxygen ventilation. 7 In MS, although a single case, ocrelizumab treatment did not augment or prolong COVID-19 symptoms. 8 Because many of the MS DMTs have been designed to target the adaptive immune response; and for therapeutic effect most likely need to target the memory B cells, 9 it is unlikely that MS DMTs treatment impact on the innate immune responses, although there is some evidence that fingolmod 10 and alemtuzumab 11 impact on the innate immune system. In addition, DMTs do not substantially limit the antibody responses to SARS-CoV-2 and, thus, do not pose a risk in the development of protective neutralizing antibody responses, however, some DMTs will blunt this.

To avoid "throwing the baby out with the bathwater" we recommend revision of the published guidelines 2 in light of the role of the immune response in controlling SARS-CoV-2 infection (see Table 2 ), the emerging biology of COVID-19, and accumulating case reports. We propose that although administration of some DMTs should be modified, others may well control the pathogenic immune responses during severe COVID-19. For example, although the original guidelines that suggest anti-CD20 therapies may increase the risk of infection, 12,13 this does not necessarily imply a greater risk of poor outcomes following infection. In addition, most MS-related DMTs do not particularly target the innate immune system and few have any major longterm impact on CD8 T cells to limit protection against COVID-19, perhaps with the exception of alemtuzumab. 14 Importantly, MS DMTs do not generally block immature B cell development, thus allowing antibody production preventing (re)infection, as well as response to vaccines when available. However, we recommend adjustments to dosing schedules to reduce the chance of infection.

Apart from the reactivation of herpes infections, the moderate immunosuppression obtained with most MS DMTs rarely leads to problems dealing with viral infections, even in the case of novel viral infections such as dengue fever. 15 With the notable exception of progressive multifocal leukoencephalopathy (PML) and other rare central nervous system (CNS) viral infections in natalizumab treated patients, which can be de-risked by adopting extended interval dosing, 16 would indicate that the initiation and continuation of DMTs in MS does not pose an additional risk of developing more severe COVID-19 to people with MS. However, immunosuppression to treat COVID-19 has been proposed as a rational therapeutic approach. 17, 18 This hypothesis is currently being tested in several trials to evaluate several immunosuppressive therapies for COVID-19, which include fingolimod, an S1P modulator (NCT04280588) and IFNβ (NCT04343768, NCT04350671) that are widely used to treat MS. Although the information is only emerging, we anticipate that knowledge arising from registers collating data on people with MS, DMTs, and their responses to SARS-CoV2 infection (e.g., NCT04354519) will support the hypothesis that moderate immunosuppression induced by the DMT used in MS may protect against the development of severe COVID-19 infection, which is contrary to current opinion. The accumulating real-world data on the susceptibility of people with MS to develop severe COVID-19 being treated with immunosuppressive therapies will allow us to accept or reject this hypothesis. 

This study received no funding. 

COVID-19) situation report -52

ABN guidance on the use of disease-modifying therapies in multiple sclerosis in response to the threat of a coronavirus epidemic

Advice for patients with multiple sclerosis and related disorders regarding COVID-19 outbreak

Clinical characteristics of 3,062 COVID-19 patients: a meta-analysis

Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients

Bcl-xL inhibits T-cell apoptosis induced by expression of SARS coronavirus E protein in the absence of growth factors

Two X-linked agammaglobulinemia patients develop pneumonia as COVID-19 manifestation but recover

COVID-19 in a MS patient treated with ocrelizumab: does immunosuppression have a protective role? Mult Scler Relat Disord

Memory B cells are major targets for effective immunotherapy in relapsing multiple sclerosis

Fingolimod additionally acts as immunomodulator focused on the innate immune system beyond its prominent effects on lymphocyte recirculation

Schmierer marked neurtropenia: significant but rare in people with multiple sclerosis after alemtuzumab treatment

Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis

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Dengue fever in patients with multiple sclerosis taking fingolimod or natalizumab

Extended interval dosing of natalizumab in multiple sclerosis

COVID-19: consider cytokine storm syndromes and immunosuppression

Coronaviruses and immunosuppressed patients. The facts during the third epidemic