Managing Disease-Modifying Therapies and Breakthrough Activity in Multiple Sclerosis Patients During the COVID-19 Pandemic: Toward an Optimized Approach

Figures & data

Table 1 Stratification of COVID-19 Risk in Multiple Sclerosis Patients

Risk Factor	Low Risk (Social Distancing)	Intermediate Risk (Social Stringency)	High Risk (Shielding)
Age^Citation93^–^Citation95	<40 years	40–49 years	≥50 years
Comorbidities^Citation96 (eg, diabetes mellitus, hypertension, cardiovascular disease)	Absent	One	Two or more
Smoking^Citation97	Non-smokers	–	Smokers
Type of MS^Citation10,Citation98	RRMS on one of the low-risk medications	RRMS on one of the intermediate-risk medications	SPMS/PPMS (EDSS >4)
Ambulation index score^Citation11,Citation98,Citation99	0–3 (walks independently)	4–5 (unilateral support or bilateral support, walks 25 feet in ≤20 seconds)	6–9 (bilateral support, walks 25 feet in >20 seconds or unable to walk 25 feet, uses wheelchair on occasions/most of the time or restricted to it)
Bulbar or respiratory symptoms related to MS^Citation99,Citation100	No bulbar symptoms	Bulbar symptoms	Bulbar and respiratory symptoms
Pregnancy^Citation101	–	Yes	–
Obesity^Citation102 (body mass index)	Normal or overweight (18.5−29.9 kg/m^2)	Obese (30–39.9 kg/m^2)	Morbidly obese (≥40 kg/m^2)
Disease-modifying therapies^Citation99	Interferons, glatiramer acetate, natalizumab, dimethyl fumarate, teriflunomide	Alemtuzumab or cladribine in the past 6 months, fingolimod, ocrelizumab or rituximab in the past 12 months	Alemtuzumab or cladribine in the past 12 weeks, AHSCT in the past 12 months, any other immunosuppressant
Lymphopenia^Citation2,Citation29,Citation93	Grade 0–1	Grade 2	Grade 3–4
Visited or living in a high-risk area for COVID-19^Citation103	No	Yes (≥14 days)	Yes (˂14 days)
Working in a health-care facility^Citation104	No	–	Yes

Abbreviations: AHSCT, autologous hematopoietic stem cell transplantation; COVID-19, coronavirus disease 2019; EDSS, Expanded Disability Status Scale; MS, multiple sclerosis; PPMS, primary progressive multiple sclerosis; RRMS, relapsing–remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis.

Table 2 Summary of Disease-Modifying Therapies Approved for Use in Multiple Sclerosis^16,51,105

	Route of Administration	Dose	Principal Proposed Mechanism of Action
Interferon ẞ-1a Interferon ẞ-1b	IM SC SC	30 µg once per week 22–44 µg 3 times per week 0.25 mg every other day	Down-regulation of MHC expression on APCs, decrease pro-inflammatory cytokines, inhibit T-cell proliferation, inhibition of leukocyte migration across the BBB
Glatiramer acetate	SC	20 mg once daily or 40 mg 3 times per week	Shifts pro-inflammatory T-helper-1 lymphocyte to regulatory T-helper2 lymphocyte
Teriflunomide	PO	7–14 mg once daily	Selective reversible inhibition of dihydroorotate dehydrogenase, T-cell activation and cytokine production inhibitor
Dimethyl fumarate	PO	120 mg bid for 1 week then 240 mg bid daily	Decreases pro-inflammatory cytokines and decreases entry of lymphocytes into the CNS (inhibits expression of adhesion molecules)
Fingolimod	PO	0.5 mg once daily	Lymphocyte sequestration in secondary lymphoid tissues
Natalizumab	IV	300 mg every 4 weeks	Interaction with α-integrins preventing lymphocytes from crossing BBB
Cladribine	PO	3.5 mg/kg body weight divided into 2 yearly treatment courses (1–2 tablets/day over 4–5 consecutive days)	Cytotoxic effects on B and T lymphocytes through impairment of DNA synthesis, resulting in long-lasting depletion of lymphocytes
Ocrelizumab (anti-CD20)	IV	Initially 300 mg once repeated after 2 weeks, then 600 mg every 6 months	Anti-CD20 and depletion of B lymphocytes
Mitoxantrone	IV	12 mg/m^2 q3m (maximum cumulative dose 140 mg/m^2)	Inhibits B cells and T cell and macrophage proliferation
Alemtuzumab	IV	12 mg daily for 5 days, then 1 year later 12 mg daily for 3 days	Anti-CD25 and depletion of lymphocytes

Abbreviations: APC, antigen-presenting cell; BBB, blood–brain barrier; bid, twice a day; CNS, central nervous system; DNA, deoxyribonucleic acid; IM, intramuscular; IV, intravenous; µg, microgram; mg, milligram; MHC, major histocompatibility complex; PO, per oral; SC, subcutaneous.

Figure 1 Algorithm of initiation and maintenance of DMTs in RRMS patients during COVID-19 pandemic.¹⁰⁶

Abbreviations: COVID-19, coronavirus disease 2019; DMF, dimethyl fumarate; DMT, disease-modifying therapy; INF, interferon; JCV, John Cunningham virus; RRMS, relapsing–remitting multiple sclerosis.

Figure 2 Algorithm of relapse management in RRMS patients during COVID-19 pandemic.

Abbreviations: COVID-19, coronavirus disease 2019; IVIG, intravenous immunoglobulins; IVMP, intravenous methylprednisolone; RRMS, relapsing–remitting multiple sclerosis.

Zhao X, Zhang B, Li P, et al. Incidence, clinical characteristics and prognostic factor of patients with COVID-19: a systematic review and meta-analysis. medRxiv. 2020.

 Google Scholar

Verity R, Okell LC, Dorigatti I, et al. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis. 2020;20(6):669–677. doi:10.1016/S1473-3099(20)30243-7

 PubMed Web of Science ®Google Scholar

Guan W-J, Liang W-H, Zhao Y, et al. Comorbidity and its impact on 1590 patients with Covid-19 in China: a nationwide analysis. Eur Respir J. 2020;55(5):2000547. doi:10.1183/13993003.00547-2020

 PubMed Web of Science ®Google Scholar

Vardavas CI, Nikitara K. COVID-19 and smoking: a systematic review of the evidence. Tob Induc Dis. 2020;18. doi:10.18332/tid/119324

 Web of Science ®Google Scholar

Montgomery S, Hillert J, Bahmanyar S. Hospital admission due to infections in multiple sclerosis patients. Eur J Neurol. 2013;20(8):1153–1160. doi:10.1111/ene.12130

 PubMed Web of Science ®Google Scholar

Nelson RE, Xie Y, DuVall SL, et al. Multiple sclerosis and risk of infection-related hospitalization and death in US veterans. Int J MS Care. 2015;17(5):221–230. doi:10.7224/1537-2073.2014-035

 PubMedGoogle Scholar

Tzelepis GE, McCool FD. Respiratory dysfunction in multiple sclerosis. Respir Med. 2015;109(6):671–679. doi:10.1016/j.rmed.2015.01.018

 PubMed Web of Science ®Google Scholar

MS and corona care and support. Available from: https://www.mssociety.org.uk/care-and-support/ms-and-coronavirus-care-and-support. Accessed April 3, 2020.

 Google Scholar

Green JR, Yunusova Y, Kuruvilla MS, et al. Bulbar and speech motor assessment in ALS: challenges and future directions. Amyotroph Lateral Scler Frontotemporal Degener. 2013;14(7–8):494–500. doi:10.3109/21678421.2013.817585

 PubMed Web of Science ®Google Scholar

Luo Y, Yin K. Management of pregnant women infected with COVID-19. Lancet Infect Dis. 2020;20(5):513–514. doi:10.1016/S1473-3099(20)30191-2

 PubMed Web of Science ®Google Scholar

Dietz W, Santos‐Burgoa C. Obesity and its Implications for COVID‐19 mortality. Obesity. 2020;28(6):1005. doi:10.1002/oby.22818

 PubMed Web of Science ®Google Scholar

Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054–1062. doi:10.1016/S0140-6736(20)30566-3

 PubMed Web of Science ®Google Scholar

Tan L, Wang Q, Zhang D, et al. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study. Signal Transduct Target Ther. 2020;5(1):1–3. doi:10.1038/s41392-019-0089-y

 PubMed Web of Science ®Google Scholar

Case definition of COVID-19 infection. Available from: https://www.health.govt.nz/our-work/diseases-and-conditions/covid-19-novel-coronavirus/covid-19-novel-coronavirus-information-specific-audiences/covid-19-novel-coronavirus-resources-health-professionals/case-definition-covid-19-infection. Accessed April 3, 2020.

 Google Scholar

Adams JG, Walls RM. Supporting the health care workforce during the COVID-19 global epidemic. JAMA. 2020;323(15):1439. doi:10.1001/jama.2020.3972

 PubMed Web of Science ®Google Scholar

Torkildsen Ø, Myhr KM, Bø L. Disease-modifying treatments for multiple sclerosis - a review of approved medications. Eur J Neurol. 2016;23(Suppl 1):18–27. doi:10.1111/ene.12883

 PubMed Web of Science ®Google Scholar

Cook S, Leist T, Comi G, et al. Safety of cladribine tablets in the treatment of patients with multiple sclerosis: an integrated analysis. Mult Scler Relat Disord. 2019;29:157–167. doi:10.1016/j.msard.2018.11.021

 PubMed Web of Science ®Google Scholar

Syed YY. Ocrelizumab: a review in multiple sclerosis. CNS Drugs. 2018;32(9):883–890. doi:10.1007/s40263-018-0568-7

 PubMed Web of Science ®Google Scholar

Yamout B, Sahraian M, Bohlega S, et al. Consensus recommendations for the diagnosis and treatment of multiple sclerosis: 2019 revisions to the MENACTRIMS guidelines. Mult Scler Relat Disord. 2020;37:101459. doi:10.1016/j.msard.2019.101459

 PubMed Web of Science ®Google Scholar