A list of summarized articles is
at the end of this posting.
Bottom Line:
There are at least four critical questions that persons with MS may wish to have answered during the corona virus (SARS-CoV-2) pandemic. First, does having MS increase susceptibility to infection with SARS-CoV-2? Second, does being on a disease-modifying therapy for MS increase the risk of having a severe case of the virus induced disease, COVID-19? Third, what are the best choices for starting a disease-modifying therapy during the SARS-CoV-2 pandemic? Fourth, are changes necessary to the dosing of current disease-modifying therapies during this pandemic?
My response to the above questions is based upon my review of the 16 articles I found after searching the US National Library of Medicine for studies dealing with how to utilize MS therapies during the coronavirus pandemic. Please be aware that most of recommendations are based on results with small numbers of individuals with no data from controlled trials and conjectures based on the pathology of COVID-19 and the mechanisms of action of the disease-modifying therapies.
Question #1: Having MS alone does not increase the risk of infection with coronavirus. Question #2: Most MS-related disease-modifying therapies have little effect on the risk of more severe disease with COVID-19, but this varies with the disease-modifying therapy. Question #3: Persons with active MS should be treated with a disease-modifying therapy during the coronavirus pandemic. The choice of drug will vary, based upon that individual’s course of disease, the presence of other illnesses, and that individual’s risk tolerance. Question #4: If a persons with MS becomes infected with coronavirus and develops COVID-19, modifications of dosing of particular disease-modifying therapies may be needed to minimize the risk of worsening COVID-19.
Take Home Points:
1. There was consensus among the above articles that having MS per se does not increase the risk of becoming infected by the coronavirus, or necessarily having more severe disease.
2. Risks of more severe COVID-19 is increased if there are other diseases (“co-morbidities”) or behaviors. These include obesity, high blood pressure, lung disease, diabetes, smoking, older age, or more severe MS-related physical disability.
3. There are two phases to infection with the coronavirus. The first is a direct attack of the virus on cells of the body, especially cells in the lungs, but other organs too, including the brain. The second phase is the response of the person’s immune system to the viral infection.
4. In many viral infections the immune system plays a major role in eliminating a virus. This is usually the result of the action of particular immune cells, such as CD8+ T cells, monocytes, macrophages and natural killer cells or NK cells. B cells play a more modest initial role in controlling a viral infection. Their main benefit comes later in the infection from the production of anti-viral antibodies.
5. While the immune system plays a major role in combating infection with coronavirus, in some persons the immune system “overreacts,” releasing large amounts of toxic chemicals called cytokines. This phenomenon is called a “cytokine storm” and results in greatly increased tissue injury. In some cases this is sufficient to cause death.
6. Several of the papers noted that disease-modifying therapies that decrease immune responsiveness may be of benefit in coronavirus infection by reducing the risks of a “cytokine storm.” A clinical trial of the sphingosine-1-phosphate receptor modulator fingolimod is being studied in China to see if this drug can reduce lung injury in very ill COVID-19 patients. Data with other disease-modifying therapies are not available at this time.
7. Caution was advised regarding the immediate use of steroids to treat worsening symptoms of MS. Infection with the SARS-CoV-2 virus that causes COVID-19 often causes a fever, worsening MS symptoms and looking like an MS attack. Before considering treatment of a presumed MS relapse with steroids, any worsening of MS symptoms should first be evaluated for signs of infection. In the case of SARS-CoV-2 this would involve nasal swab analysis looking for the presence of coronavirus RNA.
8. There was consensus in all articles that one should initiate treatment with a disease-modifying therapy in all persons newly diagnosed with active MS. There were differences regarding which drugs to consider, mainly related to the perceived severity of a person’s MS, the need for monitoring for drug toxicity, and the effects of the drug on the immune system.
9. Several papers also suggested that in older persons with MS, stable for long periods on a disease-modifying therapy, one could consider stopping the disease-modifying therapy since the presence of acute central nervous system inflammation with MS decreases with age.
10. There was general agreement that initiating and continuing treatment with so-called “platform therapies,” was safe, with no increased risk for either contracting coronavirus infection or having worsened disease. The drugs most mentioned were high dose interferon-beta, glatiramer acetate, and teriflunomide.
11. Some papers also that suggested starting treatment with dimethyl fumarate, though this drug does require coming to a health facility for blood testing and the drug can lower numbers of immune cells, mainly lymphocytes. If low lymphocyte counts occur (called “lymphopenia”) this may potentially increase the risk for more severe disease should coronavirus infection occur. If there is severe lymphopenia, some authors advised stopping dimethyl fumarate.
12. Several of the papers noted that infection with coronavirus reduces the production of type 1 interferons. These authors suggested, with no firm supporting evidence, that administration of high dose interferon-beta, a type 1 interferon, could provide additional anti-viral benefit. Clinical trials in Hong Kong and Iran are studying this possibility.
13. There were differences in opinion regarding starting treatment with other disease-modifying therapies. The differences were related to the severity of an individual’s MS and the presence of co-morbidities.
14. There was agreement that starting a high efficacy disease-modifying therapy was important, even if that medication increased susceptibility to coronavirus infection. The importance of saving brain function superseded concerns about the increased risk.
15. The high efficacy drug most often mentioned was natalizumab. Being on natalizumab increases the risk of developing the viral brain infection progressive multifocal leukoencephalopathy (PML), However, the risk is initially low, gradually increasing over time. Natalizumab blocks entry of immune cells into the brain, and so could, theoretically, increase the risk of SARS-CoV-2 infection of the brain.
16. The frequent recommendation was to start treatment with natalizumab in newly diagnosed persons with aggressive MS, using it as bridging therapy for 6-12 months with the intent of controlling disease, then consider switching to a possibly safer disease-modifying therapy.
17. Natalizumab should even be initiated in individuals at higher risk for developing PML, such as those with elevated JC virus indices, indicating prior exposure to the JC virus, the cause of PML.
18. An alternative to stopping natalizumab in individuals with an increased risk of developing PML would be to extend the time between infusions of the drug (“extended dosing intervals”). Such an approach appears to reduce the risk of PML.
19. Abruptly stopping natalizumab without initiating treatment with another disease-modifying therapy was not recommended due to the risk of major disease rebound worsening.
20. Opinions were mixed on the relative safety of the sphingosine-1-phosphate receptor modulator drugs (fingolimod, siponimod, ponesimod and ozanimod). They function by trapping lymphocytes in lymph nodes, resulting in lower numbers of circulating lymphocytes in the blood (lymphopenia). This could trap virus-killing CD8+ T cells and increase the risk for more severe COVID-19. In addition, the risk of viral and fungal infections is increased with all sphingosine-1-phosphate receptor modulators, possibly more so with the less specific and longer acting drug, fingolimod.
21. Some papers advocated not starting a sphingosine-1-phosphate receptor modulator during the coronavirus pandemic. In individuals already on such a drug, monitoring cell counts was advised and if major lymphopenia is noted to consider stopping the drug. However, great care should be taken in this regard, especially with fingolimod, since there is a greatly increased risk of major disease rebound with stopping.
22. There was general agreement among the authors of the publications to not start treatment with disease-modifying therapies that deplete cells of the immune system, though opinions varied. Cell depleting drugs mentioned were alemtuzumab, mitoxantrone, cladribine, ocrelizumab, and rituximab.
23. Treatment of severe relapsing forms of multiple sclerosis with autologous stem cell bone marrow transplant was not advised during the coronavirus pandemic due to the high risk of severe infection. However, if the transplant had been done earlier, with recovery of immune function, risk would be reduced.
24. While starting a cell-depleting disease-modifying therapy was overall discouraged, distinctions were made regarding treatment protocols in persons already on one of these drugs.
25. Both alemtuzumab and cladribine deplete T cells, increasing the risk of having more severe COVID-19. Cladribine is less T-cell depleting than alemtuzumab. Over time the immune system gradually recovers, so in persons that received alemtuzumab or cladribine months or years earlier, the risks of more severe COVID-19 may be reduced. If that is the case, and the individual’s MS is controlled, the safest approach would be to extend the time between doses of these drugs to allow maximum recovery yet still prevent disease recurrence.
26. Mitoxantrone causes severe immune suppression as well as cardiotoxicity and should be stopped during the coronavirus pandemic.
27. In the case of anti-CD20 depleting drugs, such as ocrelizumab, ofatumumab, and rituximab the issue is slightly more complex. These drugs affect mainly B cells and only a small population of T cells. Thus, even though these agents greatly deplete B cells, this population of immune cells does not play a major role initially in fighting the coronavirus.
28. One of the above papers (#7) noted worsening of disease with anti-CD20 drugs whereas two other papers (#8 and #11) noted no worsening of disease. These were relatively small studies with no control groups, thus the need to interpret cautiously.
29. There is an increased risk of bacterial infections with the anti-CD20 drugs, and responses to anti-coronavirus vaccines may be reduced. If a person is doing well on one of these drugs, the overall recommendation was to increase intervals between doses as a safer alternative to stopping the drugs.
30. There was general consensus that newly diagnosed persons with MS should not be started on therapy with the cell-depleting drugs alemtuzumab and cladribine. Both are highly effective disease-modifying therapies, but both eliminate large populations of T cells ad thus, theoretically, could lead to worse outcomes with coronavirus infection.
31. Risks of these drugs would be reduced if they were administered previously, with sufficient time to allow rebuilding of the immune system. In such instances, if the drugs are effective in controlling a person’s MS, they should be continued rather than stopped, but continued with increased dosing intervals if feasible.
32. In all instances, careful consultation with a health care provider experienced in the care of persons with MS and disease-modifying therapies is strongly advised.
Discussion:
Review of the above noted papers revealed a relative consistency of findings, as described above. Starting, changing or stopping a disease-modifying therapy during the coronavirus pandemic involves a careful review of an individual’s neurologic and general health status, previous exposures to other disease-modifying therapies, evaluation of the benefits and side effects of the currently administered disease-modifying therapy, as well as the relative risks of worsening the course of COVID-19 due to the drug. While some drugs appear safe, and possibly even beneficial should coronavirus infection occur, others greatly increase risk and should be avoided or dosing restricted or stopped. In such a scenario it is essential to also consider the effect of stopping a disease-modifying therapy on the course of MS, such as the greatly increased risk of a major disease rebound that can occur with stopping natalizumab and fingolimod. A degree of risk acceptance may be necessary to achieve the primary goal of therapy, preventing central nervous system damage, a risk that may be greater than the risk of contracting COVID-19. In all cases persons with MS should make every effort to reduce coronavirus infection risk by following CDC guidelines. This means avoiding crowds, maintaining social distancing, wearing facial masks when outside the home, and frequent and careful handwashing. Surviving this difficult period, yet maintaining control of one’s MS, is an achievable goal.
#1-Treating multiple sclerosis and neuromyelitis optica spectrum disorder during the COVID-19 pandemic.
Brownlee W, Bourdette D, Broadley S, Killestein J, Ciccarelli O.
Neurology. 2020;94:949-52.
#2-COVID-19 and management of neuroimmunological disorders.
Hartung HP, Aktas O.
Nat Rev Neurol.
2020.
#3-SARS-CoV-2 and Multiple Sclerosis: Not All Immune Depleting
DMTs are Equal or Bad.
Amor S, Baker D, Khoury SJ, Schmierer K, Giovanonni G.
Ann Neurol. 2020;87:794-7.
#4- Consensus Statement On Immune Modulation in Multiple Sclerosis and Related Disorders During the COVID-19 Pandemic: Expert Group on Behalf of the Indian Academy of Neurology.
Bhatia R, Srivastava MVP, Khurana D, Pandit L, Mathew T, Gupta S, Netravathi M, Nair SS, Singh G, Singhal BS.
Ann Indian Acad Neurol. 2020;23:S5-S14.
#5- An Italian programme for COVID-19 infection
in multiple sclerosis.
Sormani, M. P. for the Italian Study Group on Covid-infection in multiple sclerosis.
Lancet Neurol. 2020;19:481-2.
#6- The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic.
Baker D, Amor S, Kang AS, Schmierer K, Giovannoni G.
Mult Scler Relat Disord. 2020;43:102174.
#7- B-cell depleting therapies may affect susceptibility to acute respiratory illness among patients with multiple sclerosis during the early COVID-19 epidemic in Iran.
Safavi F, Nourbakhsh B, Azimi AR.
Mult Scler Relat Disord. 2020;43:102195.
#8- Anti-CD20 and COVID-19 in multiple sclerosis
and related disorders:
A case series of 60 patients from Madrid, Spain.
Montero-Escribano P, Matias-Guiu J, Gomez-Iglesias P, Porta-Etessam J, Pytel V, Matias-Guiu JA.
Mult Scler Relat Disord. 2020;42:102185.
#9- Interferon beta-1b for COVID-19.
Shalhoub S.
Lancet. 2020;395:1670-1.
#10- Implications of COVID-19 Outbreak on Immune Therapies in Multiple Sclerosis Patients-
Lessons Learned From SARS and MERS.
Mohn N, Pul R, Kleinschnitz C, Pruss H, Witte T, Stangel M, Skripuletz T.
Front Immunol. 2020;11:1059.
#11- COVID-19 in persons with multiple sclerosis treated with ocrelizumab – A pharmacovigilance case series.
Hughes R, Pedotti R, Koendgen H.
Mult Scler Relat Disord. 2020;42:102192.
#12- COVID-19 in teriflunomide-treated patients
with multiple sclerosis.
Maghzi AH, Houtchens MK, Preziosa P, Ionete C, Beretich BD, Stankiewicz JM, Tauhid S, Cabot A, Berriosmorales I, Schwartz THW, Sloane JA, Freedman MS, Filippi M, Weiner HL, Bakshi R.
J Neurol. 2020.
#13- Treating patients with multiple sclerosis during the COVID-19 pandemic: Assessing the expert recommendations.
Guevara C, Villa E, Rosas CS, Diaz V, Naves R.
Mult Scler Relat Disord. 2020;43:102224.
#14- COVID-19 in MS: Initial observations from
the Pacific Northwest.
Bowen JD, Brink J, Brown TR, Lucassen EB, Smoot K, Wundes A, Repovic P.
Neurol Neuroimmunol Neuroinflamm. 2020;7.
#15- COVID-19 and MS disease-modifying therapies.
Berger JR, Brandstadter R, Bar-Or A.
Neurol Neuroimmunol Neuroinflamm. 2020;7.
#16- The COVID-19 pandemic and
the use of MS disease-modifying therapies.
Giovannoni G, Hawkes C, Lechner-Scott J, Levy M, Waubant E, Gold J.
Mult Scler Relat Disord. 2020;39:102073.