Vol 55, No 4 (2021)
Review Article
Published online: 2021-08-03

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Multiple sclerosis immunomodulatory therapies tested for effectiveness in COVID-19

Bożena Adamczyk1, Natalia Morawiec1, Monika Arendarczyk1, Monika Baran1, Krzysztof Wierzbicki1, Paweł Sowa2, Monika Adamczyk-Sowa1
Pubmed: 34346052
Neurol Neurochir Pol 2021;55(4):357-368.


Introduction: The global pandemic of COVID-19 began in Wuhan, China in December 2019. Research into effective therapies has been conducted worldwide. Currently, there is no antiviral treatment and many patients develop a severe course of the disease, including severe respiratory failure. Due to similar pathomechanisms of inflammation in multiple sclerosis (MS) and COVID-19, immunomodulatory drugs that are registered for the treatment of MS are under study in the SARS-CoV-2 infection in clinical trials.
Materials and methods: Using clinicaltrials.gov, we found information related to ongoing clinical studies on potential drugs
for COVID-19 which are also used in MS therapy. The outcomes of several trials were published on pubmed.ncbi.nlm.nih.gov.
Results: There were 18 clinical trials evaluating the effectiveness and safety of interferon-β, fingolimod, or leflunomide in
COVID-19. Some trial outcomes available at pubmed.ncbi.nlm.nih.gov suggested an association of these drug treatments with improvements in signs and symptoms, and the disease course.
Conclusion: The administration of immunomodulatory drugs in COVID-19 may result in potential beneficial effects probably
associated with their anti-inflammatory and antiviral properties. Further research is warranted to confirm the long-term effects of immunomodulatory therapies in patients with COVID-19.

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  1. Tu YF, Chien CS, Yarmishyn AA, et al. A Review of SARS-CoV-2 and the Ongoing Clinical Trials. Int J Mol Sci. 2020; 21(7).
  2. Wong ACP, Li X, Lau SKP, et al. Global Epidemiology of bat coronaviruses. Viruses. 2019; 11(2).
  3. Cucinotta D, Vanelli M. WHO Declares COVID-19 a Pandemic. Acta Biomed. 2020; 91(1): 157–160.
  4. World Health Organization. Weekly Operational Update on COVID-19 November 6, 2020. World Health Organization (WHO), Health Emergencies Programme 2020:1–12. https://www.who.int/publications/m/item/weekly-update-on-covid-19---16-october-2020.
  5. Esakandari H, Nabi-Afjadi M, Fakkari-Afjadi J, et al. A comprehensive review of COVID-19 characteristics. Biol Proced Online. 2020; 22: 19.
  6. Pascarella G, Strumia A, Piliego C, et al. COVID-19 diagnosis and management: a comprehensive review. J Intern Med. 2020; 288(2): 192–206.
  7. Wiersinga WJ, Rhodes A, Cheng AC, et al. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): A review. JAMA. 2020; 324(8): 782–793.
  8. Wu C, Liu Y, Yang Y, et al. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm Sin B. 2020; 10(5): 766–788.
  9. Huang J, Song W, Huang H, et al. Pharmacological therapeutics targeting RNA-dependent RNA polymerase, proteinase and spike protein: from mechanistic studies to clinical trials for COVID-19. J Clin Med. 2020; 9(4).
  10. Abd El-Aziz TM, Stockand JD. Recent progress and challenges in drug development against COVID-19 coronavirus (SARS-CoV-2) - an update on the status. Infect Genet Evol. 2020; 83: 104327.
  11. Hemmer B, Kerschensteiner M, Korn T. Role of the innate and adaptive immune responses in the course of multiple sclerosis. The Lancet Neurology. 2015; 14(4): 406–419.
  12. Muehler A, Peelen E, Kohlhof H, et al. Vidofludimus calcium, a next generation DHODH inhibitor for the Treatment of relapsing-remitting multiple sclerosis. Mult Scler Relat Disord. 2020; 43: 102129.
  13. Yadav SK, Mindur JE, Ito K, et al. Advances in the immunopathogenesis of multiple sclerosis. Curr Opin Neurol. 2015; 28(3): 206–219.
  14. Baker D, Amor S, Kang AS, et al. The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic. Mult Scler Relat Disord. 2020; 43: 102174.
  15. Hamming I, Timens W, Bulthuis MLC, et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004; 203(2): 631–637.
  16. Sariol A, Perlman S. Lessons for COVID-19 immunity from other coronavirus infections. Immunity. 2020; 53(2): 248–263.
  17. Serafini B, Rosicarelli B, Veroni C, et al. Epstein-Barr virus-specific CD8 T cells selectively infiltrate the brain in multiple sclerosis and interact locally with virus-infected cells: clue for a virus-driven immunopathological mechanism. J Virol. 2019; 93(24).
  18. Zhang H, Podojil JR, Luo X, et al. Intrinsic and induced regulation of the age-associated onset of spontaneous experimental autoimmune encephalomyelitis. J Immunol. 2008; 181(7): 4638–4647.
  19. Wu GF, Alvarez E. The immunopathophysiology of multiple sclerosis. Neurol Clin. 2011; 29(2): 257–278.
  20. Pawliczak R. The immune response to SARS-CoV-2. Focus on severe COVID-19 pathogenesis. Alergologia Polska - Polish Journal of Allergology. 2020; 7(3): 146–152.
  21. Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiology: A review. Clin Immunol. 2020; 215: 108427.
  22. Frohman EM, Racke MK, Raine CS. Multiple sclerosis--the plaque and its pathogenesis. N Engl J Med. 2006; 354(9): 942–955.
  23. Sredni-Kenigsbuch D. TH1/TH2 cytokines in the central nervous system. Int J Neurosci. 2002; 112(6): 665–703.
  24. Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol. 2010; 28: 445–489.
  25. Li YF, Zhang SX, Ma XW, et al. Levels of peripheral Th17 cells and serum Th17-related cytokines in patients with multiple sclerosis: A meta-analysis. Mult Scler Relat Disord. 2017; 18: 20–25.
  26. Costela-Ruiz VJ, Illescas-Montes R, Puerta-Puerta JM, et al. SARS-CoV-2 infection: The role of cytokines in COVID-19 disease. Cytokine Growth Factor Rev. 2020; 54: 62–75.
  27. Wong CK, Lam CWK, Wu AKL, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol. 2004; 136(1): 95–103.
  28. Okabayashi T, Kariwa H, Yokota Si, et al. Cytokine regulation in SARS coronavirus infection compared to other respiratory virus infections. J Med Virol. 2006; 78(4): 417–424.
  29. Compston A, Coles A. Multiple sclerosis. The Lancet. 2008; 372(9648): 1502–1517.
  30. Lemus HN, Warrington AE, Rodriguez M. Multiple sclerosis: mechanisms of disease and strategies for myelin and axonal repair. Neurol Clin. 2018; 36(1): 1–11.
  31. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet. 2020; 395(10223): 497–506.
  32. Diao Bo, Wang C, Tan Y, et al. Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19). MedRxiv. 2020.
  33. Kieseier BC. The mechanism of action of interferon-β in relapsing multiple sclerosis. CNS Drugs. 2011; 25(6): 491–502.
  34. Park A, Iwasaki A. Type I and Type III Interferons - Induction, Signaling, Evasion, and Application to Combat COVID-19. Cell Host Microbe. 2020; 27(6): 870–878.
  35. Manivannan P, Siddiqui M, Malathi K. RNase L amplifies Interferon signaling by inducing PKR-mediated antiviral stress granules. BioRxiv. 2020.
  36. Schoggins JW, Rice CM. Interferon-stimulated genes and their antiviral effector functions. Curr Opin Virol. 2011; 1(6): 519–525.
  37. Seif F, Khoshmirsafa M, Aazami H, et al. The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. Cell Commun Signal. 2017; 15(1): 23.
  38. Samuel CE. Antiviral actions of interferons. Clin Microbiol Rev. 2001; 14(4): 778–809, table of contents.
  39. Rahmani H, Davoudi-Monfared E, Nourian A, et al. Interferon β-1b in treatment of severe COVID-19: A randomized clinical trial. Int Immunopharmacol. 2020; 88: 106903.
  40. Blanco-Melo D, Nilsson-Payant BE, Liu WC, et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell. 2020; 181(5): 1036–1045.e9.
  41. Hung IN, Lung KC, Tso EK, et al. Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. The Lancet. 2020; 395(10238): 1695–1704.
  42. Zheng C, Kar I, Chen CK, et al. Multiple sclerosis disease-modifying therapy and the COVID-19 pandemic: implications on the risk of infection and future vaccination. CNS Drugs. 2020; 34(9): 879–896.
  43. Monk P, Marsden R, Tear V, et al. Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet Respiratory Medicine. 2021; 9(2): 196–206.
  44. Hong SIn, Ryu BH, Chong YP, et al. Five severe COVID-19 pneumonia patients treated with triple combination therapy with lopinavir/ritonavir, hydroxychloroquine, and interferon β-1b. Int J Antimicrob Agents. 2020; 56(2): 106052.
  45. Pan H, Peto R, Karim Q, et al. Repurposed antiviral drugs for COVID-19 –interim WHO SOLIDARITY trial results. Med Rxiv. 2020.
  46. Dastan F, Nadji SA, Saffaei A, et al. Subcutaneous administration of interferon beta-1a for COVID-19: A non-controlled prospective trial. Int Immunopharmacol. 2020; 85: 106688.
  47. Davoudi-Monfared E, Rahmani H, Khalili H, et al. A Randomized clinical trial of the efficacy and safety of interferon β-1a in treatment of severe COVID-19. Antimicrob Agents Chemother. 2020; 64(9).
  48. Groves A, Kihara Y, Chun J. Fingolimod: direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy. J Neurol Sci. 2013; 328(1-2): 9–18.
  49. Cross AH, Naismith RT. Established and novel disease-modifying treatments in multiple sclerosis. J Intern Med. 2014; 275(4): 350–363.
  50. Kloc M, Ghobrial RM. The multiple sclerosis (MS) drugs as a potential treatment of ARDS in COVID-19 patients. Mult Scler Relat Disord. 2020; 45: 102437.
  51. Pinschewer DD, Brinkmann V, Merkler D. Impact of sphingosine 1-phosphate modulation on immune outcomes. Neurology. 2011; 76(8 Suppl 3): S15–S19.
  52. Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. The Lancet Respiratory Medicine. 2020; 8(4): 420–422.
  53. Foerch C, Friedauer L, Bauer B, et al. Severe COVID-19 infection in a patient with multiple sclerosis treated with fingolimod. Mult Scler Relat Disord. 2020; 42: 102180.
  54. Maghzi AH, Houtchens MK, Preziosa P, et al. COVID-19 in teriflunomide-treated patients with multiple sclerosis. J Neurol. 2020; 267(10): 2790–2796.
  55. Aly L, Hemmer B, Korn T. From Leflunomide to Teriflunomide: Drug Development and Immunosuppressive Oral Drugs in the Treatment of Multiple Sclerosis. Curr Neuropharmacol. 2017; 15(6): 874–891.
  56. Ruiz F, Vigne S, Pot C. Resolution of inflammation during multiple sclerosis. Semin Immunopathol. 2019; 41(6): 711–726.
  57. Xiong R, Zhang L, Li S, et al. Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2. Protein Cell. 2020; 11(10): 723–739.
  58. Faissner S, Gold R. Oral therapies for multiple sclerosis. Cold Spring Harb Perspect Med. 2019; 9(1).
  59. Bar-Or A, Pachner A, Menguy-Vacheron F, et al. Teriflunomide and its mechanism of action in multiple sclerosis. Drugs. 2014; 74(6): 659–674.
  60. Wang M, Zhao Y, Hu W, et al. Treatment of COVID-19 patients with prolonged post-symptomatic viral shedding with leflunomide - a single-center, randomized, controlled clinical trial. Clin Infect Dis. 2020 [Epub ahead of print].
  61. Hu Ke, Wang M, Zhao Y, et al. A small-scale medication of leflunomide as a treatment of COVID-19 in an open-label blank-controlled clinical trial. Virol Sin. 2020; 35(6): 725–733.
  62. Abboud H, Zheng C, Kar I, et al. Current and emerging therapeutics for neuromyelitis optica spectrum disorder: Relevance to the COVID-19 pandemic. Mult Scler Relat Disord. 2020; 44: 102249.
  63. Castelnovo L, Tamburello A, Lurati A, et al. Anti-IL6 treatment of serious COVID-19 disease: A monocentric retrospective experience. Medicine (Baltimore). 2021; 100(1): e23582.
  64. NIH. Immunomodulators Under Evaluation for the Treatment of COVID-19 2020. https://www.covid19treatmentguidelines.nih.gov/immune-based-therapy/immunomodulators/.
  65. Heo YA. Satralizumab: first approval. Drugs. 2020; 80(14): 1477–1482.
  66. ClinicalTrials.gov. National Library of Medicine (U.S.). (2020, February - ). Soliris to Stop Immune Mediated Death in Covid 19 Infected Patients. A Trial of Distal Complement Inhibition. https://clinicaltrials.gov/ct2/show/NCT04288713 (February 21, 2021).

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