key: cord-305793-xmkiqgbn
authors: Giovannoni, Gavin
title: Anti-CD20 immunosuppressive disease-modifying therapies and COVID-19
date: 2020-04-18
journal: Mult Scler Relat Disord
DOI: 10.1016/j.msard.2020.102135
sha: 
doc_id: 305793
cord_uid: xmkiqgbn

nan

It is clear that a small proportion of COVID-19 patients will develop severe disease. Risk factors are old age and the presence of comorbidities such as hypertension, diabetes, obesity, smoking and cardiovascular and lung disease. It is also assumed that people who are immunocompromised, for example, patients with multiple sclerosis (MS) on immunosuppressive disease-modifying therapies (DMTs) are also at increased risk of severe COVID-19.

It is therefore very reassuring to read in this issue a case report of a patient with primary progressive MS previously treated with ocrelizumab, an anti-CD20 B-cell depleting monoclonal antibody, who developed uncomplicated COVID-19 (Novi G, Mikulska M, Briano F, Toscanini F, Tazza F, Uccelli A, Inglese M, 2020) . Although one swallow doesn't make a summer this case report is in keeping with online accounts, mainly on social media, of other patients receiving immunosuppressive MS therapies who have experienced uncomplicated COVID-19. The few instances of patients with MS and severe COVID-19, not surprisingly tend to be older, with comorbidities and more advanced disease.

This case and online reports support the hypothesis that immunosuppression, or at the least moderate immunosuppression associated with MS DMTs, may protect against the development of severe COVID-19 infection. This is not unexpected as the severe pulmonary complications of COVID-19 infection are consistent with acute respiratory distress syndrome (ARDS), which appears to be immune-mediated (Ramanathan et al., 2020) . At present numerous exploratory trials of several immunosuppressive therapies are underway in COVID-19. These include fingolimod (NCT04280588) an S1P modulator, tocilizumab (NCT04331795) an anti-IL6-receptor antagonist, anakinra (NCT04341584) an IL1 receptor antagonist and emapalumab (NCT04324021) an anti-interferon-gamma monoclonal antibody. All these are currently being tested as treatments for COVID-19 associated ARDS.

In a recent study, the UK's Intensive Care National Audit & Research Centre compared 2249 patients with severe COVID-19 to 4759 patients with viral pneumonia who had been admitted to ITU in the UK between 2017 and 2019 (Icnarc Website,2020). The proportion of immunocompromised patients in the COVID-19 cohort was 3.7x lower than that in the viral pneumonia cohort (2.3% vs. 8.5%, p<0.00001; Figure 1 ) (Icnarc Website, 2020). This information is likely to be biased, in that those patients deemed too frail and/or disabled with COVID-19 may never reach ITU and it may include a disproportionate number of immunosuppressed patients.

At least in a non-MS population it implies that immunosuppressive therapies may be associated with better disease outcome in those with COVID-19.

The initial antiviral responses are driven mainly by T-cells, in particular CD8+ cytotoxic Tlymphocytes, and natural killer cells and less so by B-cells. This may explain why patients on anti-CD20 therapies cope relatively well with viral infections. Ocrelizumab and other anti-CD20 therapies have a relatively minor impact on T-cell counts and have not been associated with severe viral infections (Mayer et al., 2019) . In the MS registration trials of ocrelizumab, infections were slightly more frequent on ocrelizumab compared to comparator arms (interferon-beta-1a or placebo) (Hauser et al., 2017; Montalban et al., 2017) . The identifiable viral infection in these trials was mild and moderate. Severe infections were most likely bacterial, i.e pneumonia, urinary tract infections and cellulitis. However, there are always rare exceptions to the rule; for example, a single case report of fulminant hepatitis associated with an unusual echovirus-25 infection in a patient on ocrelizumab therapy (Nicolini et al., 2019; Novi G, Mikulska M, Briano F, Toscanini F, Tazza F, Uccelli A, Inglese M, 2020) .

In light of this case report and the other supportive data, the MS community may now reconsider its advice about not giving MS DMTs during the COVID-19 pandemic (Alasdair Coles and the MS Advisory Group, 2020). For patients with highly active MS, the consequences of delaying treatment or delaying access to high efficacy therapies need to be considered carefully, particularly as the risks of COVID-19 to individual immunosuppressed patients can be managed with selfisolation and shielding. Witholding immunosuppressive therapies in active MS may unintentionally increase the chances of severe COVID-19. The real-world data that is being collected currently will hopefully provide us with a definitive answer to these questions. The existing and emerging data indicate that anti-CD20 therapies are likely to be safe to initiate and redose during the COVID-19 pandemic.

In the last five years, I have received research grant support from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Takeda. I have also received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from Abbvie, Actelion, Atara Bio, Biogen, Canbex Celgene, Genentech, MedDay, Merck, Novartis, Roche, Sanofi-Genzyme and Teva.

ABN GUIDANCE ON THE USE OF DISEASE-MODIFYING THERAPIES IN MULTIPLE SCLEROSIS IN RESPONSE TO THE THREAT OF A CORONAVIRUS EPIDEMIC [WWW Document]. Association of British Neurologists

Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis

Ocrelizumab infusion experience in patients with relapsing and primary progressive multiple sclerosis: Results from the phase 3 randomized OPERA I, OPERA II, and ORATORIO studies

ORATORIO Clinical Investigators, 2017. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis

Fulminant Hepatitis Associated With Echovirus 25 During Treatment With Ocrelizumab for Multiple Sclerosis

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

Planning and provision of ECMO services for severe ARDS during the COVID-19 pandemic and other outbreaks of emerging infectious diseases. The Lancet Respiratory Medicine

Report on 2249 Patients Critically Ill with COVID-19