COVID-19 and multiple sclerosis

In response to the uncertainties concerning the management of multiple sclerosis during the pandemic, we asked Senior Associate Editor Dr. Anthony Reder to answer some key questions regarding COVID-19 and multiple sclerosis.

Anthony T Reder MD (Dr. Reder, Professor of Neurology at the University of Chicago Medicine, received honorariums from Bayer, Biogen Idec, Caremark Rx, Genentech, Genzyme, Novartis, Mallinckrodt, Mylan, Serono, and Teva-Marion for service on advisory boards and as a consultant as well as stock options from NKMax America for advisory work.)
Veronica P Cipriani MD MS (Dr. Cipriani, Assistant Professor of Neurology at the University of Chicago Medicine, received consulting fees from Genetech as an advisory board participant.)
Originally released: April 5, 2020

 

Patients with multiple sclerosis get fewer noticeable “colds” than expected. They are likely to have been exposed to the same number of rhinoviruses (approximately 50%) and coronaviruses (approximately 20%) that cause upper respiratory infections.  They will have immunity to both types of virus, with more immunity to more strains as they get older (Panitch et al 1994).

The multiple sclerosis immune system is overactive in some ways (the disease itself, higher antibody titers against measles and perhaps Epstein-Barr virus), in parallel with many defects in immune regulation and immune suppression (Feng et al 2019).  This overactivity occurs despite fewer new immune cells emigrating from the thymus and bone marrow causing a prematurely aged, dysregulated immune system.  Plus, patients have low levels of interferons and a defect in interferon signaling (Feng et al 2019), the very system that attacks viruses. The resistance to viruses may be possible because only part of the interferon system is disrupted (Feng et al 2002), causing immune abnormalities but allowing excellent antiviral function in multiple sclerosis.

Response of the immune system to coronavirus infection. COVID-19 virus sometimes has no symptoms (25% to 50% in Iceland) (Gudbjartsson et al 2020); perhaps this is because the virus blocks the body’s interferon response in at least 7 different sites in the interferon signaling pathway.  These asymptomatic carriers can spread the virus as it buds out of the endoplasmic reticulum of lung cells into the pulmonary alveoli.  COVID-19 is then present in oral and nasal secretions and in cough droplets.

When symptoms appear, there is an initial effort by the body to clear the virus.  Interferons are eventually induced at high levels along with other cytokines.   In a second very destructive phase, the immune system is over-activated and causes destruction of lung tissues. This is similar to the events of the 1918 flu, but this coronavirus is much more lethal in older people instead of the young.  In the case of COVID-19, age and other medical conditions allow a hyperactive immune response.  The mechanism is not clear, but is possibly a consequence of pre-existing immunity to coronavirus plus poor immune regulation in the aged.

How is this relevant to multiple sclerosis therapy during virus infection?

The asymptomatic phase and early phase of COVID-19. Could the multiple sclerosis immune system ameliorate infection by this virus?  Patients with multiple sclerosis do not seem to be at increased risk, based and on data discussed in a world-wide phone conference on April 1, 2020 (E Waubant, M Sormani, International Federation of Women in MS).  Approximately 200 patients with multiple sclerosis have had symptomatic coronavirus infections, and few have died.  They were largely older and had high EDSS scores.  Note this is very preliminary data, collected during a crisis in many of the hospitals.

Which drugs could enhance antiviral responses? Interferons are one of the most potent arms of the antiviral response.  Interferon-beta is produced first, and it then activates many types of interferon-alpha.  All of these type I interferons induce enzymes that degrade virus RNA and DNA and activate antiviral NK cells and enhance production of antibodies to the virus.   The interferon-beta used to treat multiple sclerosis may, thus, be protective early.

Teriflunomide and leflunomide have antiviral properties.  For instance, leflunomide inhibits the BK virus, related to the JC virus that causes progressive multifocal leukoencephalopathy.  These drugs also have in vitro antiviral activity against coronaviruses (Xiong et al 2020).

The other multiple sclerosis therapies should have minimal or no effect on viral infections (glatiramer) or in those that cause mild immune suppression, may allow more virus spread.  With most of the other multiple sclerosis therapies, viral infections are minimally increased.  Older patients on these multiple sclerosis therapies have higher risk of viral and opportunistic infections.  Alemtuzumab has more risk of virus infections, although this may not translate to the coronavirus.  Additional concerns include the degree of lymphocyte depletion, but in general there is weak or no correlation between lymphocyte levels and infections with fingolimod and teriflunomide.  The main risk factors for complications from COVID-19 may be medical comorbidities and age, as with non-multiple sclerosis patients.

Reduced CNS traffic of immune cells is also a concern.  SARS coronavirus spreads through olfactory pathways to the entorhinal cortex (Netland et al 2008).  A common complaint with COVID-19 is anosmia, suggesting COVID-19 may also spread to CNS through nasal nerves.  Natalizumab and fingolimod reduce T cell penetration into the CNS.  The relevance to COVID-19 is unknown.

The hyperimmune pulmonary necrosis phase of COVID-19. Here, interferons may have no benefit.  Interferons may be slightly damaging, based on SARS data.

Multiple sclerosis drugs that suppress the immune system, however, may alleviate this phase.  As proof of principle, the drug in trials in the United States and elsewhere utilize an anti-IL-6 receptor antibody.  Preliminary data show that it has some benefit in suppressing the excess inflammation.

New and ongoing multiple sclerosis therapies. Despite the risks discussed above, it must be remembered that multiple sclerosis patients – have multiple sclerosis.  This is a serious inflammatory brain disease.  In most cases, it should be treated.  We now have an easily transmissible and somewhat lethal virus to add to the treatment equation.

Discussions when starting a new multiple sclerosis treatment must include the antiviral effects of the therapy and the consequences of short-term and long-term immune suppression.  “Immune modulation” is a property of all multiple sclerosis drugs.  Some are immunosuppressive, but all multiple sclerosis therapies have complex effects on immunity, including worse or better antiviral immunity.

With ongoing therapy during the COVID-19 outbreak, there is some consensus among multiple sclerosis experts to extend infusions for natalizumab to every 5 to 6 weeks instead of 4 weeks.  This assumes that natalizumab increases COVID-19 risks, and this may not be true.  Many suggest that we should extend anti-CD20 infusions to longer than every 6 months, especially after 1 year of therapy, and consider monitoring B cell levels.  Again, this is not data-driven.  The doses should not be extended if there is disease activity. 

Fingolimod and dimethyl fumarate lose efficacy if doses are reduced, so the lymphocyte count should be monitored.  Some would reduce dosing or change therapy if the lymphocyte count falls below 200 (current guideline), 500 (in young), or 800 (in aged).  But again, this is not evidence based as there was no relation between lymphocyte count and infections in the fingolimod pivotal trials.  Cladribine confers an early immunosuppressed state, but few virus infections later on, so temporary (but up to 3-month) self-quarantine after the dose should be considered.

Interferon-beta, glatiramer acetate, and teriflunomide dosing should not be changed. 

Data. It is essential that everyone who treats patients with multiple sclerosis and COVID-19 infections will enter data into the North American, European, and other databases.  This will generate large numbers for “real-world” analysis of the effects of multiple sclerosis severity, age, multiple sclerosis therapy, concomitant therapy, and any benefits of antiviral treatments in the multiple sclerosis immune and CNS ecology.

References cited

Feng X, Bao R, Li L, Deisenhammer F, Arnason BG, Reder AT. Interferon-beta corrects massive gene dysregulation in multiple sclerosis: Short-term and long-term effects on immune regulation and neuroprotection. EBioMedicine 2019;49:269-83. PMID 31648992

Feng X, Petraglia AL, Chen M, Byskosh PV, Boos MD, Reder AT. Low expression of interferon-stimulated genes in active multiple sclerosis is linked to subnormal phosphorylation of STAT1. J Neuroimmunol 2002;129(1-2):205-15. PMID 12161037

Gudbjartsson D, Helgason A, Jonsson H, et al. Early spread of SARS-Cov-2 in the Icelandic population. medRxiv 2020.03.26.20044446; doi: https://doi.org/10.1101/2020.03.26.20044446.

Netland J, Meyerholz DK, Moore S, Cassell M, Perlman S. Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J Virol 2008;82(15):7264-75. PMID 18495771

Panitch HS. Influence of infection on exacerbations of multiple sclerosis. Ann Neurol 1994;36 Suppl:S25-8. PMID 8017885

Xiong R, Zhang L, Li S, et al. Novel and potent inhibitors targeting DHODH, a rate-limiting enzyme in de novo pyrimidine biosynthesis, are broad-spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2. bioRxiv 2020.03.11.983056; doi: https://doi.org/10.1101/2020.03.11.983056.