Can I see your #MSCOVID19 paper?

I few days ago I mentioned not wanting to review someones COVID-19 and MS review, because it was missing published information and so I did not want to write their review. I submitted my constructive review of the paper for the authors benefit and then bowed out of the referering process.

You said that I should put my review online. However, that review was a critique of their paper, not a review of the literature. However, you spurred me into action.

You asked for it and now you’ve got it. We have written a review. Make a big mug of tea, sit back and have a read.

It is meant to be scientific and it is not a sound bite.

It may not be completely correct and will be revised as you spot any howlers or as new information arises. There are currently 200-500 papers a day to scan on COVID-19, in addition to the MS stuff. So forgive me if I missed some. Again the confusion lies in the pathology. I expected the lungs to full of CD8 cells , but of the pathology studies surfacing this does not appear to be the case. I think it also needs a couple of sentences on the thrombi (clots) and haemorrages, which if they are the major issue may not have much to do with most MS treatments. This version has now been submitted to a Journal, as not everyone reads the blog and it is aimed to be scientific. Whilst BioRXiv and MedRXiv is a place were preprints can be put before publication they don’t do reviews. However, it will never see the light of day as it is today , because it is already out of date and will need to be revised. The reviewers may have different opinions that need to be incorporated. Within a Week there will be 1,000-2,000 more papers to accomodate and within a month perhaps 5,000 papers to accomodate, so I hope the reviewers are quick. Maybe they will think it is too boring to publish.

Not all the source information has been peer-reviewed, but as we know that process is not infallible. However most statements are supported by more than one published paper

You can be the reviewers. This has not been peer-reviewed

The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic.

David Baker¹, Sandra Amor^1,2, Angray S. Kang^1,3, Klaus Schmierer^1,4, Gavin Giovannoni^1,4

¹Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom,

²Pathology Department, VUmc, Amsterdam UMC, Amsterdam, The Netherlands

³Centre for Oral Immunobiology and Regenerative Medicine, Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom.

⁴Clinical Board:Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom.

ABBREVIATIONS: ACE2 angiotensin converting enzyme two, ARDS acute respiratory distress syndrome, ASC antibody secreting cells, CNS central nervous system, DMT, disease modifying therapies, haematopoietic stem cell therapy (HSCT), IRT immune reconstitution therapies, MS multiple sclerosis, RBD receptor binding domain, RNA ribonucleic acid, SARS Severe acute respiratory syndrome,

ABSTRACT

Background: SARS-CoV-2 viral infection causes COVID-19 that can result in severe acute respiratory distress syndrome (ARDS), which can cause significant mortality, leading to concern that immunosuppressive treatments for multiple sclerosis and other disorders have significant risks for both infection and ARDS.

Objective: To examine the biology that potentially underpins immunity to the SARS-Cov-2 virus and the immunity-induced pathology related to COVID-19 and determine how this impinges on the use of current disease modifying treatments in multiple sclerosis.

Observations:  Although information about the mechanisms of immunity are scant, it appears that monocyte/macrophages and then CD8 T cells are important in eliminating the SARS-CoV-2 virus. This may be facilitated via anti-viral antibody responses that may prevent re-infection. However, viral escape and infection of leucocytes to promote lymphopenia coupled with apparent CD8 T cell exhaustion coupled with a cytokine storm appears to contribute to the damage in ARDS.

Implications: In contrast to ablative haematopoietic stem cell therapy, most multiple-sclerosis-related disease modifying therapies do not particularly target the innate immune system and few have any major long-term impact on CD8 T cells to limit protection against COVID-19. In addition, few block the formation of immature B cells within lymphoid tissue that will provide antibody-mediated protection from (re)infection. However, adjustments to dosing schedules may help de-risk the chance of infection further and reduce the concerns of people with MS being treated during the COVID-19 pandemic.
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SARS-Cov-2 and COVID-19 a new pandemic. COVID-19 is the disease caused by infection with the severe acute respiratory syndrome (SARS) coronavirus two (SARS-CoV-2) that is causing a pandemic resulting in the death of thousands of humans (Zhu et al. 2020a; Zhou et al. 2020; Gabutti et al. 2020). It seems that a majority, perhaps up to 80% of people (Day. 2020) infected with SARS-CoV-2 results in a mild a self-limiting illness. However, about 20% of individuals required hospitalisation due to cardiovascular issues and respiratory tract distress (Kimball et al. 2020; Day. 2020), and about a quarter of these hospitalised patients require critical care and potential ventilatory support. The mortality in those who require ventilatory support is about 40-50% (Weiss & Murdoch 2020; Zhu et al. 2020b). Death from COVID-19 is associated with older age and the presence of comorbidities such as cardiovascular disease, smoking, lung disease, obesity and diabetes (Zhu et al. 2020a; Li et al. 2020, Lippi et al. 2020; Gabutti et al. 2020). Mortality in young people and those without comorbidities may well be related to excessive viral load (Lui et al 2020a; Chen et al. 2020a; To et al. 2020), possibility explaining the deaths in the critical care medical personnel. Whilst the typical clinical features requiring self-isolation, and potentially hospitalization, are fever, dry cough and shortness of breath related to upper and lower respiratory tract infection (Zhu et al. 2020a; Zhu et al. 2020b), many other symptoms such as headache and gastrointestinal symptoms may go unnoticed or under-appreciated leading to spreading of the virus (Zhu et al. 2020b; Kimball et al. 2020; Huang et al. 2020). People shed infective virus days before symptoms occur and continue to shed virus via the lungs and faeces whilst symptoms develop and resolve, often for more than 7 days (Pung et al. 2020, Lauer et al. 2020; Xu et al. 2020a; He et al.2020a), indicating the need to self-isolate for more than 7 days after symptom onset to avoid infecting others.

The SARS-CoV-2 is a betacoronavirus (lineage B) that originated in wild animals prior to transmission to humans, in which the viral ribonucleic acid (RNA) is bound by the nucleocapsid protein and encapsulated in a lipid envelope formed by the host cell membrane that contains the viral structural spike, envelope and membrane proteins (Chen et al. 2020b, Lu et al. 2020). The spike protein contains the receptor binding domain (RBD) that is important for binding to the angiotensin converting enzyme two (ACE2) cell receptor and thus key to the cellular target, host range and viral infection (Zhou et al. 2020; Shi et al. 2020. Figure 1). The nucleocapsid protein is highly immunogenic, as is the spike protein that can be neutralised by antibodies, that are distinct from SARS-CoV neutralisation, the closely related virus that caused the SARS outbreak in 2002-2004 (Haveri et al. 2020; Ou et al. 2020; Okba et al. 2020; de Assis et al. 2020). The cell entry of SARS-Cov2 depends on binding of the viral spike proteins to the ACE2 receptor as well as host cell serine proteases such as TMPRSS2 necessary to prime the spike protein (Zhou et al. 2020; Hoffman et al. 2020; Tai et al. 2020; Gabutti et al. 2020). The ACE2 receptor is expressed on the vasculature and is present in many tissues, such as the kidney, gut, renal tubules, seminal vesicles, cardiomyocytes as well as lung epithelia (Hamming et al. 2004; Lukassen et al. 2020). There is very low expression of ACE2 on immune cells, but other receptors may be important in SARS-Cov-2 uptake and appears to involve other co-receptors and proteases (Letko et al 2020) and include CD147 on monocytes/macrophages and T cells (Chen et al 2005, Wang et al 2020a) as well as lectins as evidenced by similarities with the SARS-CoV virus (Yang et al. 2004; Marzi et al. 2004; Granberg et al. 2005).

Immune response against SARS-CoV-2 virus. As the immune system is vital defence against viral infection, it has led to concern for people taking immunosuppressive agents or treatments such as haematopoietic stem cell therapy (HSCT), as immune compromised people are particularly vulnerable to infection (Coles et al. 2020; Willis & Robertson 2020). Such vulnerable people have been advised to self-shield and socially distance themselves to avoid infection until herd immunity, anti-viral agents or effective vaccines have been developed (Kwok et al. 2020; Stein 2020). Multiple sclerosis (MS) is a major neurological disease that causes disability and can require hospitalisation for uncontrolled disease activity (Compston & Coles 2008). MS is currently managed with a variety of different immunomodulatory drugs (Pardo & Jone 2017). This has led neurologists to recommend maintaining the status quo or curtailing the use of certain disease modifying treatments (DMT) in a pragmatic or in a non-pragmatic way (Coles et al 2020, Giovannoni et al. 2020; Brownlee et al. 2020. Table 1). It is therefore important that such recommendations are made on a rational basis using knowledge on the mode of actions of the various agents and their ability to impact on the functioning of the various components of the immune system.  This is important as there is no evidence that immunosuppressed people are at increased risk to other coronavirus infections (D’Antiga 2020). To understand the risks posed to people with MS using DMT, it is important to understand the mechanisms of action and the impact of the treatments on the risk of infections, vaccination responses to fight infections and the mechanisms of pathology and immunity to SARS-CoV-2. Although there are many gaps in our knowledge of the pathogenesis of COVID-19, understanding can be gained from the study of SARS-CoV infection that was epidemic in 2002/2003 as well as other coronaviruses and lower respiratory tract infections (Channappanavar et al. 2014; Prompetchara et al. 2020; Rokni et al. 2020, Sarzi-Puttini et al. 2020). 

Protective immunity against coronaviruses involves both the innate and the adaptive immune response as is typical for most viral infections (Yen et al. 2006; Prompetchara et al. 2020). However, consistent with SARS, some influenza infections and COVID-19, it appears to be the immune response and destruction of virally-infected cells and lung epithelial tissue that cause the acute respiratory distress syndromes (ARDS) and the resultant pneumonia that leads to fluid accumulation in the lungs and respiratory failure, which lead to death in a significant number of people (Chen et al. 2020b; Zhang et al. 2020a; Li et al. 2020). It appears that the immune response to SARS-CoV-2 occurs in two phases involving an immune and a lung tissue damaging phase. 

Figure 1. The protective and destructive immune response against the SARS-CoV-2 virus. 

Immune cells target the SARS-CoV-2 virus that initially involves the innate immune response, which is then supplemented with anti-viral cytotoxic T cell responses and neutralizing and binding antibodies. 

Immune Phase. Following infection there is an asymptomatic period reported to be a median of 4-5 days, although some reports indicate this can be up to 3 weeks (Pung et al. 2020, Lauer et al. 2020; Lai et al. 2020), during which time the virus attempts to escape immune surveillance through the inhibition of interferon production and blockade of interferon receptor signalling activity, similar to SARS-CoV (Prompetchara et al. 2020; Chu et al. 2020; O’Brien et al. 2020). There is an early phase of the immune response where the innate and then the adaptive immune response eliminates the virus as seen in non-human primates and by inference in humans (Bao et al. 2020; Thevarajan et al. 2020). Given that the majority of infections appear to be asymptomatic (Kimball et al. 2020; Day 2020) indicates that this is a dominant mechanism in most people with COVID-19. In vitro data suggest that there could be an early innate response, notably from the alveolar macrophages and/or monocytes that may be recruited from the circulation (Yen et al. 2006; Thevarajan et al. 2020). Histological studies of cancerous lungs of people subsequently found to have COVID19, exhibited significant macrophage activity (Cai et al. 2020; Tian et al. 2020a). Macrophages as opposed to neutrophils appear important as an early defence mechanism, which are limited in SARS and COVID-19 lesions (Prompetchara et al. 2020; Tian et al. 2020a; Cai et al. 2020). This is probably followed by a CD8 cytotoxic T cell response that is generated within days of infection (Channappanavar et al. 2014; Prompetchara et al. 2020; Thevarajan et al. 2020).

The SARS-CoV-2 may be eliminated before significant peripheral blood antibody titres are generated as seen in non-human primate infections and case reports (Figure 2. Thevarajan et al. 2020, Bao et al. 2020). These antibody responses are generated by about 12 days (IgM) and 14 days (IgG), although this is earlier in some individuals (Zhoa et al. 2020, Guo et al. 2020; Okba et al. 2020; Xiang et al. 2020). Antibodies are predominantly generated against the nucleocapsid and spike proteins (Leung et al. 2020; Okba et al. 2020, de Assis et al. 2020). Antibodies against the RBD of the spike protein are clearly neutralizing, are able to prevent infection (Okba et al. 2020, Tai et al. 2020; Tian et al. 2020b) and appear to be protective, as evidenced by the use of convalescent sera to protect against severe COVID-19 (Duan et al. 2020; Pei et al. 2020; Shen et al. 2020; Bloch et al. 2020). Although CD8 T cells are important in viral immunity, antibodies will be an essential part of the vaccination response to prevent primary infection and reinfection as most infected subjects will develop an immunoglobulin anti-viral response within 1 month (Zhoa et al. 2020, Okba et al. 2020; de Assis et al. 2020). This appears to prevent re-infection as shown in non-human primates (Bao et al. 2020. Figure 2). However, immunity may not be completely protective since people with COVID-19 can rarely present with SARS-CoV-2 re-activation (Ye et al. 2020a; Chen et al. 2020c). However, as the virus may persist in many sites and may not be eliminated at the same rates can explain why viral RNA can be detected in faeces when nasopharyngeal swabs become negative (Chen et al. 2020d). There are clearly viral variants (Foster et al. 2020; Yao et al. 2020) and may be important as vaccines will need to target disease-causing pathogenic variants. This data suggests that immunosuppression of macrophage function and probably CD8 activity may limit anti-viral protection while blunting or inhibition of antibody formation may limit immunity to reinfection.

Figure 2. Removal of the SARS-CoV-2 virus occurs before a significant anti-viral antibody response is generated.

Rhesus macaques were infected with coronavirus and the viral titre was assessed using nasal swabs. Animals were re-infected one month later. The results show the responses of two individual monkeys relating to viral titre and anti-viral antibody response. Adapted from Bao et al. 2020. DoI.org/10.1101/2020.03.13.990226

Destructive Phase. Although most people appear to tolerate COVID-19 a significant number of people experience respiratory distress (Chen et al. 2020e; Zhu et al. 2020b). Severe disease is associated with peripheral blood neutrophilia and notably lymphopenia (Chen et al. 2020e, Lui et al. 2020b, Wang et al. 2020b), where it seems that viral load relates to the severity of lymphopenia (Lui et al. 2020c). The lymphopenia could relate to extravasation or sequestration of cells into the infected tissues as part of the anti-viral response. Post-mortem histology demonstrates significant mononuclear infiltration into the lung and often, but not always, a paucity of natural killer cells and neutrophils, unless associated with secondary infection (Xu et al. 2020b; Fox et al. 2020; Yoa et al.2020; Magro et al. 2020). There is a paucity of B cells and perhaps of relevance is that the lymphocytes are predominantly CD4 T cells (Xu et al. 2020b; Yoa et al. 2020b). Low peripheral blood CD8 T cell numbers are a poor prognostic feature (Du et al. 2020) and this is consistent with a common feature of the COVID-19 lung pathology, where there is a paucity of CD8 T cells (Xu et al. 2020; Yoa et al. 2020; Zhang et al. 2020b). This may reflect senescence and exhaustion of the anti-viral CD8 response contributing to pathology (Zheng et al. 2020; Cossarizza et al. 2020). Whether this contributes to severe disease and fatality remains to be established. However, this would be consistent with age being a major poor prognostic feature (Huang et al. 2020). It appears that T cells can be infected via CD147 (Wang et al. 2020c). In addition, infection and expression of envelope protein and Open Reading Frame protein sequestration that has been shown to have an apoptotic effect at least after SARS-CoV infection (Yang et al. 2005). This may play a role in the lymphopenia and immune suppression of the anti-viral response. There is marked atrophy of lymphoid tissues that may contribute to the lymphopenic state (Zhang et al. 2020b, Yoa et al.2020, Chen et al. 2020f). Macrophages may also become infected and can take-up the virus due to expression of CD147 (Wang et al 2020a), lectins (Yang et al 2004; Marzi et al 2004; Granberg et al 2005) as well as expression of Toll-like receptors known to recognize SARS-CoV pathogen associated molecular pattern recognition elements such as single stranded viral RNA (Li et al 2013). Macrophage derived cytokines are produced, which lead to cytokines storms associated with worse prognosis (Chen et al. 2020c; Ye et al. 2020b; Herold et al. 2020; Wen et al. 2020). Therefore, agents such as interleukin-6 receptor and IL-1 blockers used in rheumatoid arthritis, and the case of IL-6R off-label in neuromyelitis optica, are being used to limit severe COVID-19 (Luo et al. 2020). Plasma cell-supporting cytokines such as TNFSF13 may be associated with recovery (Wen et al. 2020), however, the antibody response may contribute to macrophage hyper-activation. As such, severe disease is associated with the highest titres of antibodies (Liu et al. 2019; Zhoa et al. 2020) and antibody-dependent enhancement of disease may occur (Iwaski & Yang Y 2020). There is complement activation and microthrombi that develop indicative of damage consistent with IgG3 anti-viral responses and IgG antibody-dependent cellular cytotoxicity by macrophages and in some instance neutrophils (Magro et al. 2020; Zhang et al. 2020b). Interestingly it has been shown that spike-specific antibody may promote interleukin-8 and macrophage chemotactic protein one (CCL2) production that skews macrophage accumulation towards a destructive phenotype (Liu et al 2019).  As such in other lower respiratory tract infections antibodies can sometimes have destructive potential (Kim et al. 1969), therefore immunomodulation during periods of lung damage may offer some benefit. 

Multiple sclerosis agents. Shortly after the outbreak of COVID-19 in Europe, where multiple sclerosis (MS) is more prevalent than Far East Asia (Compston & Coles 2008), concern about loss of viral immunity in immunosuppressed people, lead to a number of guidelines recommending limitation of use of DMT in autoimmune central nervous system disease (Coles et al. 2020) (Figure 2). People with MS may have a modest increased risk of infection. This is clearly the case when you examine people taking DMT, notably the more effective DMT (Willis & Robertson 2020). However, it is important to recognize the risks of poorly controlled MS may outweigh the perceived risks from COVID-19 (Giovannoni et al. 2020; Brownlee et al. 2020) and an essential goal of MS care must be to limit exposure to SARS-COV-2 infection. Therefore, care must be to prevent disease activation and limit the need for hospitalization that could potentially increase the risk of exposure to people with COVID-19. This must be balanced by the requirement of hospitalization for infusion treatments and the level of monitoring that each agent requires, that is particularly arduous with alemtuzumab, but minimal with ocrelizumab and glatiramer acetate (Pardo & Jones 2017).

Table 1. Initial recommendations use of MS-related DMT by some European neurological associations 

Composite guidelines generated from recommendations to treat MS from the Society of Italian Neurologists (SIN) and the Association of British Neurologists (Coles et al. 2020).

Mechanisms driving multiple sclerosis may be distinct from COVID-19 protection and pathogenesis. Although it is widely considered that CD4, TH17 T cells are the central mediators of MS (Kunkl et al. 2020), control of MS is highly consistent with observation that therapeutic agents that block memory B cell function with high efficacy are those most effective in MS (Baker et al. 2017a; Baker et al. 2018), possibly secondary to inhibition of T cell function (Sabatino et al. 2019a, 2019b). Although there are many different mechanisms of action ascribed to the different disease modifying treatments used in MS (Pardo & Jones 2017), all active DMT inhibit memory B cell function (Baker et al. 2017a) and notably there is a treatment hierarchy, unrelated to CD4 or CD8 activity, which correlates well with memory B cell inhibition and relapsing disease (Baker et al. 2017a; Baker et al. 2018). Targeting the memory B cell subsets, and possibly CD4, Th17 T cells, is not likely to prevent SARS-Cov-2 elimination by CD8 T cells and the innate immune responses. Targeting memory B cells may only be relevant if treatment is continuous or long lasting such as with CD20-depleting antibody therapies that maintains peripheral B cells in a nadir state (Sabatino et al. 2019a; Baker et al. 2020a) and may prevent the formation of antibody secreting cells (ASC). However, ASC can be generated by germinal centre cells independent of the CD27+, memory B cell pathway (Baker et al. 2018; Hammarlund et al. 2017; Khodadadi et al. 2019). An example of this is observation that 60-85% of people receiving alemtuzumab produce anti-drug antibody responses within the first month of treatment, despite the essential absence of peripheral blood T and B cells (Baker et al. 2017b, Baker et al. 2020b). This would indicate that peripheral B-cell depletion is unlikely to prevent the generation of SARS-CoV-2 anti-viral responses. Novel vaccine responses will be generated from the immature/naïve B cell compartments that regenerate following B cell depleting therapies such as alemtuzumab, ocrelizumab and cladribine (Baker et al. 2017b, Baker et al. 2019, Baker et al. 2020a). Once formed, anti-viral responses will reside within the long-lived plasma cell pool with lymphoid tissue and bone marrow (Khodadadi et al. 2019; Baker et al. 2018). As such, plasma cells are relatively quiescent (Khodadadi et al. 2019) and thus avoid the action of agents that target proliferating cells and express low levels of the targets for current DMT, including CD52, deoxycytidine kinase and CD20 (Baker et al. 2020b; Sabatino et al. 2019a, Baker et al. 2019). Furthermore, they reside predominantly in the bone marrow, a site that may not be effectively targeted by depleting antibodies as cell elimination would require entry of antibodies, complement components and effector accessory cells required for depletion (Baker et al. 2018). Once plasma cells have formed they are not particularly well targeted by any of the current DMT, except HSCT that purges the lymphoid tissues and bone marrow. Therefore, it will be important to consider how best to deliver a SARS-CoV-2 vaccine in the future, once developed and shown to be active (Amanat & Krammer 2020; Chen et al. 2020g). Strategies could be developed for the highly active agents that accommodate the long-depletion of memory B cells and the more rapid population of naïve cells to create a potential for vaccination against SARS-Cov-2 whilst maintaining protection against MS. 

Low efficacy MS immunomodulators are unlikely to limit anti-viral immunity. The components of the immune response that drive autoimmunity and control infections use overlapping cellular mechanisms and therefore removal of significant immune subsets may have the capacity to reduce anti-viral responses, in a manner that reflects their immunosuppressive potential. Low treatment-efficacy agents such as glatiramer acetate, beta interferons and teriflunomide (Table 1) are not associated with significant immunosuppression, notable increased risk of viral infections, nor lack of responsiveness to vaccines (Pardo & Jones 2017; Comi et al. 2019a; Wijnands et al. 2018; Olberg et al. 2018; Hauser et al. 2019). Indeed, interferon beta and teriflunomide may have anti-viral activity that could be beneficial (Hensley et al. 2004; Bilger et al), as such beta interferon has been shown to inhibit SARS-CoV replication and is currently being trialled in COVID-19 (Dahl et al. 2004; Hensley et al. 2004; NCT04350671; NCT04343768). However, these agents have a downside in that they are not that effective in controlling MS disease activity.

Moderate efficacy MS immunomodulators carry higher, but modest infection risks. Dimethyl fumarate is modestly immunosuppressive and targets lymphocytes rather than monocytes (Pardo & Jones 2017; Diebold et al. 2018). Immature/transitional B cells are less affected compared to memory B cell targeting (Mehta et al. 2019). Although plasmablasts and plasma cells can be affected by dimethyl fumarate therapy (Mehta et al. 2019), immunoglobulin levels are not unduly affected (Diebold et al. 2018). Importantly, vaccine responses on dimethyl fumarate were no different to that occurring in people treated with beta interferons (von Hehm et al. 2017). However, in some individuals persistent lymphopenia has been reported (Mehta et al. 2019; Diebold et al. 2018), notably about 20% of people will exhibit CD8 T cell levels below the lower limit of normal (Mehta et al. 2019). Although this is not generally associated with increased infection rates (Boffa et al. 2020), viral infections, including upper respiratory and lung infections occur with the monomethyl fumarate producing compounds (Pardo & Jones 2017; Diebold et al. 2018; Perini et al. 2018; Fernández et al. 2017; Naismith et al. 2019). 

Functional lymphopenia occurs with sphingosine-1-phosphate receptor modulators such as fingolimod (Pardo & Jones 2017; Diebold et al. 2018) and appears to modestly elevate efficacy and infection risks (Pardo & Jones 2017; Kalincik et al. 2019). Agents such as fingolimod and siponimod are reported to sequester lymphocytes within lymphoid tissues and exhibit limited activity on the innate immune response (Kowarik et al. 2012; Pardo & Jones 2017; Thomas et al. 2017; Angerer et al. 2018). This targets CD4 more than CD8 T cells and notably the naïve and central memory T cell subsets to retain them in lymphoid tissues where anti-viral responses would be generated (Kowarik et al. 2012; Angerer et al. 2018; Hjoorth et al. 2020) and exhibits a more modest decrease in effector memory CD4 and CD8 T cells that will enter inflamed tissues (Angerer et al. 2018). Infections rates are modest (Diebold et al. 2018), but some bacterial and viral, infections such as herpes and varicella, are marginally more common after fingolimod treatment (Calibresi et al. 2014; Pardo & Jones 2017; Diebold et al 2019). There may be subtle differences between fingolimod and the other sphingosine-1-phosphate receptor modulators in terms of infections and adverse effects, however it has a relatively long-half-life compared to other agents, which may be relevant if one wants to stop treatment (Subei et al. 2015; Swallow et al. 2020). A small scale trial of fingolimod has been reported for severe COVID-19 (NCT04280588). Sphingosine-1-phosphate is involved with maintaining the germinal centre and B cell niche (Cinamon et al. 2008) and there may be reduced serum immunoglobulin level following fingolimod treatment (Zoehner et al. 2019) as such vaccine responses, whilst present are slightly reduced compared to the interferons (Olberg et al. 2018; Signoriello et al. 2020) as occurs with natalizumab (Olberg et al. 2018).

Natalizumab as the preferred high-efficacy agent. Currently natalizumab is perceived to be the high-efficacy treatment of choice (Coles et al. 2020. Table 1). Natalizumab, unlike depleting highly-active DMT, is potentially more rapidly reversible using plasma exchange and is not likely to inhibit migration of immune cells into lymphoid tissues and prevent novel immune responses, and as such has no or limited influence on vaccine antibody responses (Vågberg et al. 2012; Kaufman et al. 2014; Olber et al. 2018). The value of the use of natalizumab may also be enhanced because it is perceived to simply inhibit T cell migration into the central nervous system (Yednock et al.199; Schwab et al. 2015). However, both B cells and importantly monocytes express alpha 4 integrin (CD49d) and thus the antibody directed to CD49d inhibits monocyte binding to vascular cell adhesion molecule one (VCAM-1) (Yednock et al. 1992; Hyduk et al. 2009). Importantly, although natalizumab is used to block migration into the inflamed central nervous system and gut (Schwab et al. 2015), VCAM-1 is expressed in virally-inflamed lungs (Brodie et al. 1999). Therefore, alpha 4 integrin is likely to be involved in mononuclear cell diapedesis into the inflamed lung during SARS-CoV-2 infection (Brodie et al. 1999; Yen et al. 2006). This potential activity is perhaps consistent with increased lung infections in MS following treatment with natalizumab (Polman et al. 2006). Furthermore, that SARS-CoV-2 is neutrotrophic, (Baig et al. 2020; Moriguchi et al. 2020, Helms et al 2020) suggests that a potential risk of natalizumab treatment is that it blocks viral immunosurveillance of the central nervous system (Hoepner et al. 2014), however this issue is perhaps limited by the extended interval dosing that has been suggested to limit MS activation, reduce the risk of progressive multifocal leukoencephalopathy infection (Ryerson et al. 2019; Clerico et al. 2020). Thus, perhaps whilst natalizumab use could potentially be a risk factor for severe COVID-19, it is likely to limit monocyte and T cell damage to the lung, hopefully allowing recovery by other immune mechanisms and avoiding severe complications.

High-efficacy depleting agents are not the same and have distinct COVID-19 risks. Based on initial suggestions, immune reconstitution therapies (IRT) were not recommended to be started and ongoing treatment, i.e. additional courses, should be delayed (Table 1. Coles et al. 2020). Autologous HSCT is seen as a high risk strategy to initiate during the mass-infection stage of COVID-19 pandemic (Table 1) and will probably remain so until herd immunity (Kwok et al. 2020) develops to protect vulnerable individuals. Myeloablative HSCT removes both the adaptive and notably the innate immune systems and it is already well recognised that loss of the neutrophils, monocytes and other elements of the innate immune system puts people at risk of mortality from infection and until the innate and adaptive immune response reconstitutes people will be at risk for some time (Storek et al. 2008; Ge et al. 2019; Rush et al. 2019). However, once reconstituted the capacity to generate new immune responses occurs as seen following vaccination against childhood infections, to replace the lost immunity due to the HSCT procedure (Brinkmann et al. 2007, Rush et al. 2019). Therefore, there are clear risks from viral infections until the immune system reconstitutes. It is suggested that current licenced IRT, which both deplete T and B cells (Baker et al. 2017b; Baker et al. 2017c) carry similar risk (Coles et al. 2020). However, this does not seem to accommodate the actual biologies and as such, oral cladribine is dissimilar to alemtuzumab, in terms of its risk for SARS-CoV-2 infection and appears more similar to ocrelizumab in its immunodepletion profile (Table 2).

Table 2: High efficacy agents are not the same and oral cladribine is more similar to ocrelizumab than alemtuzumab 

Different characteristics of alemtuzumab, cladribine and ocrelizumab, relevant to efficacy and side-effect potential and their capacity to control MS and exhibit an effective anti-viral immune response. CRS cytokine release syndrome. NK natural killer. 1.Lemtrada® 2019. 2. Thomas et al. 2016, 3. Baker et al. 2017d, 4. Gross et al. 2016, 5. Baker et al. 2017b, 6. Baker et al. 2020b, 7. McCarthy et al. 2013, 8. Mavenclad® 2018, 9. Baker et al. 2017c, 10 Ceroni et al. 2018, 11. Baker et al. 2019, 12. Ocrevus® 2018; 13. Baker et al. 2020a, 14. Fernandez-Verlasco et al. 2019, 15. Stokmaier et al. 2018.

Alemtuzumab. This is a CD52-depleting antibody that induces rapid, long-lasting and 80-90% depletion of CD4, CD8 T cells and memory B cells (Table 2. Baker et al. 2017; Akgün et al. 2020). Alemtuzumab induces long-term disease remission if treated sufficiently early after symptom onset (Cohen et al. 2012. Havrdova et al. 2017, He et al. 2020b). Two short cycles of treatment give long term disease remission. Alemtuzumab treatment cycles are generally given at least 12 months apart, but this interval may be extended, even up to 18 months, which supports the important activity of memory B cells as they, and CD4 T cells, can be depleted for at least this time (Tuohy et al. 2015, Havrdova et al. 2017, Akgün et al. 2020). However, alemtuzumab induces transient monocyte depletion and can induce very long-term CD4 and CD8 T cell depletion (Kousin-Ezewu et al. 2014; Thomas et al. 2016, Baker et al. 2017b; Akgün et al. 2020). This could and does influence response to viral and other infections (Cohen et al. 2012; Wray et al. 2019) and could thus impact on SARS-CoV-2 outcome. Severe lymphopenia increases the risk of infections and pneumonia (Warny et al. 2018). Neutropenia can be marked and significant, but is unusual (Baker et al. 2017d). Infection risk is notable following infusion and then decreases with time as cellular repopulation occurs (Buonomo et al 2018; Wray et al. 2019). Alemtuzumab has a relatively short half-life and is cleared from the circulation within about a month (Li et al. 2018). Therefore, surviving cells can repopulate in response to infection and given the relatively low dose and delivery over a single week, allows cells escaping elimination to recover. Transitional/immature B cells rapidly repopulate in the relative absence of T cell regulation, possibly related to limited purging of the bone marrow, and can generate anti-drug responses within a month of treatment in 60-83% of people (Baker et al. 2017b). Therefore, perhaps it may be possible to generate anti-viral responses. As such childhood vaccine responses persist and novel vaccine responses are not notably inhibited with alemtuzumab within 6 months of treatment (McCarthy et al 2013). Thus with time people with MS are likely to be able to generate a SARS-CoV-2 response and respond to vaccination. Although the treatment protocol means that few infusion visits are required (Cohen et al. 2012; Havrdora et al. 2017), the adverse events, notably the secondary autoimmunities that develop in many people with MS (Tuohy et al. 2015; Havrdora et al. 2017) means that intensive monitoring is required, compared to ocrelizumab that required essentially no inter-infusion monitoring (Pardo & Jones 2017).

Ocrelizumab is a CD20-depleting antibody used to treat relapsing and active primary progressive MS (Hauser et al. 2017; Montalban et al. 2017). This depletes peripheral B cells including memory B cells (Fernandez Velasco et al. 2019). Based on a common mechanism of action (Baker et al. 2017a), there is an unanswered question of whether ocrelizumab will behave like alemtuzumab and cladribine and provide long-term disease inhibition from a short term treatment cycle (Table 2). Even if it does not behave as an IRT, based on memory B cell depletion and slow repopulation characteristics (Palanichamy et al. 2014; Baker et al. 2018), it may provide some comfort to suggest that delays of 6-12 months may be feasible without MS disease activity reoccurring. The latter is based on information from off-label and phase I/II studies with rituximab in MS (Bar-Or et al. 2008; Juto et al. 2020) and phase II extension trial data of ocrelizumab (Kappos et al. 2012; Baker et al. 2020a). As such looking at retreatment to maintain remission based on repopulation of CD27+ memory B cell population, after 3-4 cycles it seems that doses, at least with rituximab, can be extended to less than once a year (Novi et al. 2019; Novi et al. 2020). Given that ocrelizumab exhibits depletion for a longer duration than rituximab suggests similar or better results can be obtained with rituximab (Baker et al. 2020a). Although ocrelizumab can deplete CD8 T cells, this is only a relatively mild steady state depletion of only 6-8% depletion of CD8 cells and 1-2% of CD4 T cells and has a minor impact on monocytes (Gingele et al. 2018; Baker et al. 2020a). Although infections are generally mild following ocrelizumab treatment (Hauser et al. 2017), some viral infections do occur and can be serious and very rarely life threatening (Hauser et al. 2017; Nicolni et al. 2019). Importantly, this may become a problem with persistent B cell depletion as that which occurs with ocrelizumab (Hauser et al. 2017). In time this can lead to IgM, IgA and IgG hypogammaglobulinemia that will increase infection risk (Tallantrye et al. 2018; Vollmer et al. 2020). However, a delay in repeated cycles may allow immature cells that provide immunity to new infections to partially regenerate, although this process is slow with ocrelizumab (Kappos et al. 2012; Baker et al. 2020a), and improve the vaccination response. Consistent with marked B cell depletion, it is apparent that vaccination responses are blunted when initiated 3 months after infusion however, they are not absent (Stokmaier et al. 2018). As plasma cells do not express CD20, once formed they will not be directly targeted by ocrelizumab (Sabitino et al. 2019a). Ofatumumab is a novel subcutaneous CD20-depleting antibody awaiting licencing following a successful phase III programme (Hauser el al 2019). Ofatumumab dosing shows relatively rapid repopulation of immature B cells compared with slower repopulation with ocrelizumab (Savelieva et al. 2017; Baker et al. 2020a) and thus it remains to be established if the advantage of home injection and reversibility changes the use of anti-CD20 therapies compared to infusions with rituximab and ocrelizumab (Hauser el al. 2017, Hauser et al. 2019). Likewise, the real-life extended dosing experiment with ocrelizumab is probably now ongoing (Table 1). If data being captured by registries shows efficacy it is likely that the dosing schedule of ocrelizumab will eventually change on grounds of conveniences, safety and cost-effectiveness although this will need formal testing (Novi et a. 2019; Baker et al. 2020a).

Cladribine. This is an oral small molecule that behaves as an IRT that gives long term-term benefit from short treatment cycles (Giovannoni et al. 2010; Giovannoni et al. 2018). This is a 

B and T cell depletion agent that is eliminated within one day of treatment (Table 2) (Baker et al. 2017c; Baker et al. 2019; Hermann et al. 2019). Treatment induces depletion via apoptosis rather than cell lysis and thus avoids the need for steroids to manage infusion reactions associated with alemtuzumab and ocrelizumab (Cohen et al. 2012; Hauser et al. 2017). Cladribine can induce comparable long-term memory B cell depletion similar to that which is observed with alemtuzumab, but without the innate cell and the severe lymphopenia associated with alemtuzumab (Ceronie et al. 2018; Ruggieri et al. 2019). Indeed, the T cell depletion is more modest and CD4 cells are depleted by about 40-50% and CD8 T cells are depleted by 30-40% compared to baseline. In comparison, alemtuzumab results in B and T cell depletion of 80-90% (Baker et al 2017c). As such the T cells generally remain within the lower limit of the normal range as do natural killer cells that show modest depletion (Baker et al. 2017c; Comi et al. 2019b). The CD19 B cells recover perhaps slower than post-alemtuzumab, as cladribine probably penetrates and acts more in lymphoid tissues, and the dosing schedule of doses being given a month apart targets any rapidly emerging cells (Baker et al. 2017c, Baker et al. 2019). However, B cells probably emerge faster after cladribine compared to ocrelizumab as depleting titres of ocrelizumab remain high for months after infusion (Genovese et al. 2008; Baker et al. 2017c, Baker et al. 2020a). Unfortunately, there is no information available concerning the influence of vaccination responses of oral cladribine. Although there is an increased risk of viral infections (Giovannoni et al. 2010), these are notably less severe than with alemtuzumab (Pardo & Jones 2017) associated with the milder immunosuppression induced by cladribine. Thus, oral cladribine, behaves like a chemical CD19/CD20 depleter with some additional T cell activity and is perhaps functionally closer to CD20-depleting antibodies than CD52 depleting antibody and has the advantage that treatment is not continuous. During the time of self-isolation and shielding agents such as cladribine may have some merit as it is a high efficacy IRT that can be administered at home, with minimal post-dosing monitoring requirements (Table 2). 

Preliminary Experience and Personal View of Treatment. As analysis of the mechanisms of action of the different DMT coupled with emerging knowledge of the anti-viral and pathogenic mechanisms in COVID-19, suggest that initial fears relating to immunosuppression in MS, have yet to be realised, supporting that found in the SARS epidemics (D’Antiga 2020; Giovannoni 2020). The pragmatic approach of examining an individual patient’s circumstances, their prognostic profile and level of MS disease activity may help guide treatment approaches (Giovannoni et al. 2020; Giovannoni 2020). Although these are early days in the initial infection wave of COVID-19, already a number of PwMS have been infected with SAR-CoV-2 with the majority surviving based on early social media and registry data. Although a few people with MS have died they have tended to be older, with more advanced disease and multiple comorbidities. There are now over 360 people with MS and COVID-19 within Italian COVID MS registry with only 5 reported deaths, with only 2 people being treated with DMT and all having comorbidities associated with poor COVID-19 prognosis in the general population. Thus, there does not yet appear evidence that people with MS are at particular risk of severe COVID-19. As such we suggest that risks should be reviewed (Table 3) and advice regarding the risks associated with individual MS-DMT adjusted. Delays in treatment cycles may provide information on the biology of relapsing MS and, if successful may change prescribing habits in the future as there are risk/cost/benefit advantages of reduced dosing frequency. Thus, it will be interesting to determine whether one returns to the current status quo after the COVID-19 pandemic wanes or whether extended interval-dosing remains. Likewise, it will be intriguing to determine if real-life data shows that ocrelizumab exhibits IRT-like characteristics whereby long-term benefit can be seen with only short-term treatment cycle as seen with alemtuzumab and oral cladribine. The positive aspect of this unfortunate human experiment created by the SARS-CoV-2 epidemic, is that it will teach us more about the biology of MS and help inform how best to treat this disease and as safely as possible.

Table 3. Our opinion of altered risks of different MS DMT for COVID-19.

  This opinion was formed 18 April 2020 

Funding: This study received no funding

Disclosures: No company was involved in the decision to write or was involved in the content of this paper. Therefore, disclosures are not considered relevant, however within the past 5 years: DB received consultancy/speaker fees from: Canbex therapeutics, Inmunebio, Lundbeck, Merck, Novartis, Sanofi Genzyme. SA has received consultancy from Novartis. SA is section editor of multiple sclerosis and related disorders and associative editor at Clinical and Experimental Immunology. ASK has nothing relevant to declare. KS has received consultancy, speaker fees from: Biogen, Lipomed, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. GG has received received consultancy, speaker fees or research support from: Abbvie, Actelion, Atara, Biogen, Canbex therapeutics, Celgene, MedDay, Merck, Novartis, Roche, Sanofi-Genzyme, Takeda, Teva. GG has received consultancy, speaker fees or research support from: Abbvie, Actelion, Atara, Biogen, Canbex therapeutics, Celgene, MedDay, Merck, Novartis, Roche, Sanofi-Genzyme, Takeda, Teva. Editor of multiple sclerosis and related disorders.

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