Nowe perspektywy leczenia stwardnienia rozsianego Artykuł przeglądowy
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Opublikowane:
gru 31, 2021
Słowa kluczowe:
stwardnienie rozsiane, leczenie, badania kliniczne
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Abstrakt
Mimo postępu w zakresie terapii stwardnienia rozsianego w ciągu ostatnich 30 lat leczenie tej choroby, w szczególności postaci postępujących, pozostaje niesatysfakcjonujące. W niniejszym artykule autorzy przeanalizowali bazę ClinicalTrials.gov pod kątem trwających lub zakończonych w ciągu ostatnich 2 lat badań klinicznych III fazy w różnych postaciach stwardnienia rozsianego. Pokrótce omówiono również wybrane leki będące obecnie w II fazie badań klinicznych. W artykule skupiono się na badaniach klinicznych oceniających skuteczność i bezpieczeństwo nowych preparatów, takich jak: inhibitory kinazy tyrozynowej Brutona, masytynib czy ibudilast. Przytoczono również wyniki badań z cząsteczkami wykorzystującymi znane już mechanizmy działania w tej chorobie, a także z lekami stosowanymi dotychczas w innych wskazaniach niż stwardnienie rozsiane. Przedstawiono też wstępne wyniki badań z preparatami o właściwościach remielinizacyjnych w stwardnieniu rozsianym.
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Artykuły
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Bibliografia
1. Dobson R, Giovannoni G. Multiple sclerosis – a review. Eur J Neurol. 2019; 26: 27-40.
2. Wnuk M, Maluchnik M, Perwieniec J et al. Multiple sclerosis incidence and prevalence in Poland: Data from administrative health claims. Mult Scler Relat Disord. 2021; 55: 103162.
3. De Angelis F, John NA, Brownlee WJ. Disease-modifying therapies for multiple sclerosis. BMJ. 2018; 363: k4674.
4. Cao L, Li M, Yao L et al. Siponimod for multiple sclerosis. Cochrane Database Syst Rev. 2021; 11: CD013647.
5. Hartung H-P, Gonsette R, Konig N et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002; 360: 2018-25.
6. Wawrzyniak S, Rzepiński Ł. Is there a new place for mitoxantrone in the treatment of multiple sclerosis? Neurol Neurochir Pol. 2020; 54: 54-61.
7. Piehl F. Current and emerging disease-modulatory therapies and treatment targets for multiple sclerosis. J Intern Med. 2021; 289: 771-91.
8. García-Merino A. Bruton’s tyrosine kinase inhibitors: A new generation of promising agents for multiple sclerosis therapy. Cells. 2021; 10: 2560.
9. Mohamed AJ, Yu L, Bäckesjö C-M et al. Bruton’s tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev. 2009; 228: 58-73.
10. Reich DS, Arnold DL, Vermersch P et al. Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2021; 20: 729-38.
11. Lechner KS, Neurath MF, Weigmann B. Role of the IL-2 inducible tyrosine kinase ITK and its inhibitors in disease pathogenesis. J Mol Med. 2020; 98: 1385-95.
12. Dolgin E. BTK blockers make headway in multiple sclerosis. Nat Biotechnol. 2021; 39: 3-5.
13. Isenberg D, Furie R, Jones NS et al. Efficacy, Safety, and Pharmacodynamic Effects of the Bruton’s Tyrosine Kinase Inhibitor Fenebrutinib (GDC-0853) in Systemic Lupus Erythematosus: Results of a Phase II, Randomized, Double-Blind, Placebo-Controlled Trial. Arthritis Rheumatol. 2021; 73: 1835-46.
14. Montalban X, Arnold DL, Weber MS et al. Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis. N Engl J Med. 2019; 380: 2406-17.
15. Dhillon S. Orelabrutinib: First Approval. Drugs. 2021; 81: 503-7.
16. von Hundelshausen P, Siess W. Bleeding by bruton tyrosine kinase-inhibitors: Dependency on drug type and disease. Cancers (Basel). 2021; 13: 1-33.
17. Dubreuil P, Letard S, Ciufolini M et al. Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS One. 2009; 4: e7258.
18. Brown MA, Weinberg RB. Mast cells and innate lymphoid cells: Underappreciated players in CNS autoimmune demyelinating disease. Front Immunol. 2018; 9: 1-14.
19. Vermersch P, Brieva-Ruiz L, Fox RJ et al. Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2022; 9: e1148.
20. Vermersch P, Benrabah R, Schmidt N et al. Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study. BMC Neurol. 2012; 12: 36.
21. Piette F, Belmin J, Vincent H et al. Masitinib as an adjunct therapy for mild-to-moderate Alzheimer’s disease: a randomised, placebo-controlled phase 2 trial. Alzheimers Res Ther. 2011; 3: 16.
22. Mora JS, Genge A, Chio A et al. Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial. Amyotroph Lateral Scler Front Degener. 2020; 21: 5-14.
23. Fox R, Coffey C, Conwit R et al. Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis. N Engl J Med. 2018; 379: 846-55.
24. Cho Y, Crichlow GV, Vermeire JJ et al. Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast. Proc Natl Acad Sci. 2010; 107: 11313-8.
25. Ruiz-Pérez D, Benito J, Polo G et al. The Effects of the Toll-Like Receptor 4 Antagonist, Ibudilast, on Sevoflurane’s Minimum Alveolar Concentration and the Delayed Remifentanil-Induced Increase in the Minimum Alveolar Concentration in Rats. Anesth Analg. 2016; 122: 1370-6.
26. Barkhof F, Hulst HE, Drulovic J et al. Ibudilast in relapsing-remitting multiple sclerosis: A neuroprotectant? Neurology. 2010; 74: 1033-40.
27. Bermel RA, Fedler JK, Kaiser P et al. Optical coherence tomography outcomes from SPRINT-MS, a multicenter, randomized, double-blind trial of ibudilast in progressive multiple sclerosis. Mult Scler J. 2021; 27: 1384-90.
28. Naismith RT, Bermel RA, Coffey CS et al. Effects of Ibudilast on MRI Measures in the Phase 2 SPRINT-MS Study. Neurology. 2021; 96: e491-500.
29. Fox E, Lovett-Racke AE, Gormley M et al. A phase 2 multicenter study of ublituximab, a novel glycoengineered anti-CD20 monoclonal antibody, in patients with relapsing forms of multiple sclerosis. Mult Scler J. 2021; 27: 420-9.
30. Steinman L, Fox E, Hartung H-P et al. Efficacy and safety of ublituximab versus teriflunomide in relapsing multiple sclerosis: Results of the Phase 3 ULTIMATE I and II trials. Neurology. 2021; 96(15 suppl): 4494.
31. Wray S, Then Bergh F, Wundes A et al. Efficacy and Safety Outcomes with Diroximel Fumarate After Switching from Prior Therapies or Continuing on DRF: Results from the Phase 3 EVOLVE-MS-1 Study. Adv Ther. 2022; 39(4): 1810-31.
32. 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.
33. Kappos L, Fox RJ, Burcklen M et al. Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis in the Active-Comparator Phase 3 OPTIMUM Study. JAMA Neurol. 2021; 78: 558.
34. Mamani-Matsuda M, Cosma A, Weller S et al. The human spleen is a major reservoir for long-lived vaccinia virus-specific memory B cells. Blood. 2008; 111: 4653-9.
35. Hauser SL, Bar-Or A, Cohen JA et al. Ofatumumab versus Teriflunomide in Multiple Sclerosis. N Engl J Med. 2020; 383: 546-57.
36. Burt RK, Balabanov R, Burman J et al. Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis. JAMA. 2019; 321: 165.
37. Bose G, Thebault S, Rush CA et al. Autologous hematopoietic stem cell transplantation for multiple sclerosis: A current perspective. Mult Scler J. 2021; 27: 167-73.
38. Mohammadi R, Aryan A, Omrani MD et al. Autologous hematopoietic stem cell transplantation (Ahsct): An evolving treatment avenue in multiple sclerosis. Biol Targets Ther. 2021; 15: 53-9.
39. Sormani MP, Muraro PA, Schiavetti I et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis. Neurology. 2017; 88: 2115-22.
40. Arrambide G, Iacobaeus E, Amato M et al. Aggressive multiple sclerosis (2): Treatment. Mult Scler. 2020; 26: 1045-63.
41. Harris VK, Stark J, Vyshkina T et al. Phase I Trial of Intrathecal Mesenchymal Stem Cell-derived Neural Progenitors in Progressive Multiple Sclerosis. EBioMedicine. 2018; 29: 23-30.
42. Suuring M, Moreau A. Regulatory macrophages and tolerogenic dendritic cells in myeloid regulatory cell-based therapies. Int J Mol Sci. 2021; 22: 7970.
43. Quirant-Sánchez B, Mansilla MJ, Navarro-Barriuso J et al. Combined therapy of vitamin d3-tolerogenic dendritic cells and interferon-β in a preclinical model of multiple sclerosis. Biomedicines. 2021; 9: 1758.
44. Tourbah A, Lebrun-Frenay C, Edan G et al. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study. Mult Scler J. 2016; 22: 1719-31.
45. Motte J, Gold R. High-dose biotin in multiple sclerosis: the end of the road. Lancet Neurol. 2020; 19: 965-6.
46. Cree BAC, Cutter G, Wolinsky JS, Freedman MS et al. Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2020; 19: 988-97.
47. Gifford JL, Sadrzadeh SMH, Naugler C. Biotin interference: Underrecognized patient safety risk in laboratory testing. Can Fam Physician. 2018; 64: 370.
48. Goldschmidt CH, Cohen JA. The Rise and Fall of High-Dose Biotin to Treat Progressive Multiple Sclerosis. Neurotherapeutics. 2020; 17: 968-70.
49. Cadavid D, Mellion M, Hupperts R et al. Safety and efficacy of opicinumab in patients with relapsing multiple sclerosis (SYNERGY): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2019; 18: 845-56.
50. Ahmed Z, Fulton D, Douglas MR. Opicinumab: is it a potential treatment for multiple sclerosis? Ann Transl Med. 2020; 8: 892.
51. Hanf KJM, Arndt JW, Liu YT et al. Functional activity of anti-LINGO-1 antibody opicinumab requires target engagement at a secondary binding site. MAbs. 2020; 12: 1-14.
52. Chataway J, Schuerer N, Alsanousi A et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (M-STAT): A randomised, placebo-controlled, phase 2 trial. Lancet. 2014; 383: 2213-21.
53. van der Most PJ, Dolga AM, Nijholt IM et al. Statins: Mechanisms of neuroprotection. Prog Neurobiol. 2009; 88: 64-75.
54. Giannopoulos S, Katsanos AH, Tsivgoulis G et al. Statins and Cerebral Hemodynamics. J Cereb Blood Flow Metab. 2012; 32: 1973-6.
55. Green AJ, Gelfand JM, Cree BA et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017; 390: 2481-9.
56. Dziedzic A, Saluk-Bijak J, Miller E et al. Metformin as a potential agent in the treatment of multiple sclerosis. Int J Mol Sci. 2020; 21: 1-19.
57. Negrotto L, Farez MF, Correale J. Immunologic Effects of Metformin and Pioglitazone Treatment on Metabolic Syndrome and Multiple Sclerosis. JAMA Neurol. 2016; 73: 520.
58. Brown D, Moezzi D, Dong Y et al. Combination of Hydroxychloroquine and Indapamide Attenuates Neurodegeneration in Models Relevant to Multiple Sclerosis. Neurotherapeutics. 2021; 18: 387-400.
59. Rankin KA, Mei F, Kim K et al. Selective estrogen receptor modulators enhance CNS remyelination independent of estrogen receptors. J Neurosci. 2019; 39: 2184-94.
60. Ysrraelit MC, Correale J. Impact of sex hormones on immune function and multiple sclerosis development. Immunology. 2019; 156: 9-22.
61. Metzger-Peter K, Kremer LD, Edan G et al. The TOTEM RRMS (Testosterone Treatment on neuroprotection and Myelin Repair in Relapsing Remitting Multiple Sclerosis) trial: Study protocol for a randomized, double-blind, placebo-controlled trial. Trials. 2020; 21: 1-11.
62. Monti DA, Zabrecky G, Leist TP et al. N-acetyl Cysteine Administration Is Associated With Increased Cerebral Glucose Metabolism in Patients With Multiple Sclerosis: An Exploratory Study. Front Neurol. 2020; 11: 1-8.
63. El Sharouny SH, Shaaban MH, Elsayed RM et al. N-acetylcysteine protects against cuprizone-induced demyelination: histological and immunohistochemical study. Folia Morphol (Warsz). 2021. http://doi.org/10.5603/FM.a2021.0044.
64. Torkildsen Ø, Myhr K-M, Skogen V et al. Tenofovir as a treatment option for multiple sclerosis. Mult Scler Relat Disord. 2020; 46: 102569.
65. Berger JR, Kakara M. The elimination of circulating Epstein-Barr virus infected B cells underlies anti-CD20 monoclonal antibody activity in multiple sclerosis: A hypothesis. Mult Scler Relat Disord. 2022; 59: 103678.
66. Pender MP, Csurhes PA, Smith C et al. Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis. JCI Insight. 2020; 5: e144624.
67. Huang L, Fung E, Bose S et al. Elezanumab, a clinical stage human monoclonal antibody that selectively targets repulsive guidance molecule A to promote neuroregeneration and neuroprotection in neuronal injury and demyelination models. Neurobiol Dis. 2021; 159: 105492.
68. Demicheva E, Cui Y-F, Bardwell P et al. Targeting Repulsive Guidance Molecule A to Promote Regeneration and Neuroprotection in Multiple Sclerosis. Cell Rep [Internet]. 2015; 10: 1887-98.
69. Cree B, Ziemann A, Pfleeger K et al. ECTRIMS 2021 – Oral Presentations – Safety and efficacy of elezanumab in relapsing and progressive forms of multiple sclerosis: Results from two phase 2 studies, RADIUS-R and RADIUS-P. Mult Scler J. 2021; 27: 92.
70. Küry P, Nath A, Créange A et al. Human Endogenous Retroviruses in Neurological Diseases. Trends Mol Med. 2018; 24: 379-94.
71. Hartung HP, Derfuss T, Cree BAC et al. Efficacy and safety of temelimab in multiple sclerosis: Results of a randomized phase 2b and extension study. Mult Scler J. 2022; 28: 429-40.
72. Kremer D, Förster M, Schichel T et al. The neutralizing antibody GNbAC1 abrogates HERV-W envelope protein-mediated oligodendroglial maturation blockade. Mult Scler J. 2015; 21: 1200-3.
73. Fadul CE, Mao-Draayer Y, Ryan KA et al. Safety and Immune Effects of Blocking CD40 Ligand in Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2021; 8: e1096.
74. Becher B, Durell BG, Miga AV et al. The clinical course of experimental autoimmune encephalomyelitis and inflammation is controlled by the expression of CD40 within the central nervous system. J Exp Med. 2001; 193: 967-74.
75. Li Y, Chu N, Hu A et al. Increased IL-23p19 expression in multiple sclerosis lesions and its induction in microglia. Brain. 2007; 130: 490-501.
76. Derdelinckx J, Cras P, Berneman ZN et al. Antigen-Specific Treatment Modalities in MS: The Past, the Present, and the Future. Front Immunol. 2021; 12: 1-13.
77. Vandenbark AA, Culbertson NE, Bartholomew RM et al. Therapeutic vaccination with a trivalent T-cell receptor (TCR) peptide vaccine restores deficient FoxP3 expression and TCR recognition in subjects with multiple sclerosis. Immunology. 2008; 123: 66-78.
78. Glanzman R, Rin J, Greenberg B et al. ACTRIMS Forum 2021 – Poster Presentations: Effects of Nanocatalysis on CNS Bioenergetic Markers in Patients Treated with CNM-Au8: Interim Results from Two Phase 2 31Phosphorous Imaging Studies. Mult Scler J. 2021; 27: 35-6.
79. Hoffman M. CNM-Au8 Shows Effects on Brain Bioenergetic Metabolism, Supports Candidacy in Multiple Sclerosis (access: 11.04.2022).
80. Glanzman R, Beadnall H, Barnett M et al. ACTRIMS Forum 2021 – VISIONARY-MS: Update to a Phase 2 Clinical Trial of Catalytic Gold Nanocrystals, CNM-Au8, for the Treatment of Chronic Optic Neuropathy. Mult Scler J. 2021; 27(1 suppl): 39-40.
81. Navarrete C, García-Martin A, Garrido-Rodríguez M et al. Effects of EHP-101 on inflammation and remyelination in murine models of Multiple sclerosis. Neurobiol Dis. 2020; 143: 104994.
82. Gacem N, Nait-Oumesmar B. Oligodendrocyte development and regenerative therapeutics in multiple sclerosis. Life. 2021; 11: 327.
83. Sorboni SG, Moghaddam HS, Jafarzadeh-Esfehani R et al. A Comprehensive Review on the Role of the Gut Microbiome in Human Neurological Disorders. Clin Microbiol Rev. 2022; 35: e0033820.
84. Li K, Wei S, Hu L et al. Protection of Fecal Microbiota Transplantation in a Mouse Model of Multiple Sclerosis. Mediators Inflamm. 2020; 2020: 1-13.
85. Ghezzi L, Cantoni C, Pinget GV et al. Targeting the gut to treat multiple sclerosis. J Clin Invest. 2021; 131: e143774.
2. Wnuk M, Maluchnik M, Perwieniec J et al. Multiple sclerosis incidence and prevalence in Poland: Data from administrative health claims. Mult Scler Relat Disord. 2021; 55: 103162.
3. De Angelis F, John NA, Brownlee WJ. Disease-modifying therapies for multiple sclerosis. BMJ. 2018; 363: k4674.
4. Cao L, Li M, Yao L et al. Siponimod for multiple sclerosis. Cochrane Database Syst Rev. 2021; 11: CD013647.
5. Hartung H-P, Gonsette R, Konig N et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002; 360: 2018-25.
6. Wawrzyniak S, Rzepiński Ł. Is there a new place for mitoxantrone in the treatment of multiple sclerosis? Neurol Neurochir Pol. 2020; 54: 54-61.
7. Piehl F. Current and emerging disease-modulatory therapies and treatment targets for multiple sclerosis. J Intern Med. 2021; 289: 771-91.
8. García-Merino A. Bruton’s tyrosine kinase inhibitors: A new generation of promising agents for multiple sclerosis therapy. Cells. 2021; 10: 2560.
9. Mohamed AJ, Yu L, Bäckesjö C-M et al. Bruton’s tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev. 2009; 228: 58-73.
10. Reich DS, Arnold DL, Vermersch P et al. Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2021; 20: 729-38.
11. Lechner KS, Neurath MF, Weigmann B. Role of the IL-2 inducible tyrosine kinase ITK and its inhibitors in disease pathogenesis. J Mol Med. 2020; 98: 1385-95.
12. Dolgin E. BTK blockers make headway in multiple sclerosis. Nat Biotechnol. 2021; 39: 3-5.
13. Isenberg D, Furie R, Jones NS et al. Efficacy, Safety, and Pharmacodynamic Effects of the Bruton’s Tyrosine Kinase Inhibitor Fenebrutinib (GDC-0853) in Systemic Lupus Erythematosus: Results of a Phase II, Randomized, Double-Blind, Placebo-Controlled Trial. Arthritis Rheumatol. 2021; 73: 1835-46.
14. Montalban X, Arnold DL, Weber MS et al. Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis. N Engl J Med. 2019; 380: 2406-17.
15. Dhillon S. Orelabrutinib: First Approval. Drugs. 2021; 81: 503-7.
16. von Hundelshausen P, Siess W. Bleeding by bruton tyrosine kinase-inhibitors: Dependency on drug type and disease. Cancers (Basel). 2021; 13: 1-33.
17. Dubreuil P, Letard S, Ciufolini M et al. Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS One. 2009; 4: e7258.
18. Brown MA, Weinberg RB. Mast cells and innate lymphoid cells: Underappreciated players in CNS autoimmune demyelinating disease. Front Immunol. 2018; 9: 1-14.
19. Vermersch P, Brieva-Ruiz L, Fox RJ et al. Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2022; 9: e1148.
20. Vermersch P, Benrabah R, Schmidt N et al. Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study. BMC Neurol. 2012; 12: 36.
21. Piette F, Belmin J, Vincent H et al. Masitinib as an adjunct therapy for mild-to-moderate Alzheimer’s disease: a randomised, placebo-controlled phase 2 trial. Alzheimers Res Ther. 2011; 3: 16.
22. Mora JS, Genge A, Chio A et al. Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial. Amyotroph Lateral Scler Front Degener. 2020; 21: 5-14.
23. Fox R, Coffey C, Conwit R et al. Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis. N Engl J Med. 2018; 379: 846-55.
24. Cho Y, Crichlow GV, Vermeire JJ et al. Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast. Proc Natl Acad Sci. 2010; 107: 11313-8.
25. Ruiz-Pérez D, Benito J, Polo G et al. The Effects of the Toll-Like Receptor 4 Antagonist, Ibudilast, on Sevoflurane’s Minimum Alveolar Concentration and the Delayed Remifentanil-Induced Increase in the Minimum Alveolar Concentration in Rats. Anesth Analg. 2016; 122: 1370-6.
26. Barkhof F, Hulst HE, Drulovic J et al. Ibudilast in relapsing-remitting multiple sclerosis: A neuroprotectant? Neurology. 2010; 74: 1033-40.
27. Bermel RA, Fedler JK, Kaiser P et al. Optical coherence tomography outcomes from SPRINT-MS, a multicenter, randomized, double-blind trial of ibudilast in progressive multiple sclerosis. Mult Scler J. 2021; 27: 1384-90.
28. Naismith RT, Bermel RA, Coffey CS et al. Effects of Ibudilast on MRI Measures in the Phase 2 SPRINT-MS Study. Neurology. 2021; 96: e491-500.
29. Fox E, Lovett-Racke AE, Gormley M et al. A phase 2 multicenter study of ublituximab, a novel glycoengineered anti-CD20 monoclonal antibody, in patients with relapsing forms of multiple sclerosis. Mult Scler J. 2021; 27: 420-9.
30. Steinman L, Fox E, Hartung H-P et al. Efficacy and safety of ublituximab versus teriflunomide in relapsing multiple sclerosis: Results of the Phase 3 ULTIMATE I and II trials. Neurology. 2021; 96(15 suppl): 4494.
31. Wray S, Then Bergh F, Wundes A et al. Efficacy and Safety Outcomes with Diroximel Fumarate After Switching from Prior Therapies or Continuing on DRF: Results from the Phase 3 EVOLVE-MS-1 Study. Adv Ther. 2022; 39(4): 1810-31.
32. 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.
33. Kappos L, Fox RJ, Burcklen M et al. Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis in the Active-Comparator Phase 3 OPTIMUM Study. JAMA Neurol. 2021; 78: 558.
34. Mamani-Matsuda M, Cosma A, Weller S et al. The human spleen is a major reservoir for long-lived vaccinia virus-specific memory B cells. Blood. 2008; 111: 4653-9.
35. Hauser SL, Bar-Or A, Cohen JA et al. Ofatumumab versus Teriflunomide in Multiple Sclerosis. N Engl J Med. 2020; 383: 546-57.
36. Burt RK, Balabanov R, Burman J et al. Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis. JAMA. 2019; 321: 165.
37. Bose G, Thebault S, Rush CA et al. Autologous hematopoietic stem cell transplantation for multiple sclerosis: A current perspective. Mult Scler J. 2021; 27: 167-73.
38. Mohammadi R, Aryan A, Omrani MD et al. Autologous hematopoietic stem cell transplantation (Ahsct): An evolving treatment avenue in multiple sclerosis. Biol Targets Ther. 2021; 15: 53-9.
39. Sormani MP, Muraro PA, Schiavetti I et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis. Neurology. 2017; 88: 2115-22.
40. Arrambide G, Iacobaeus E, Amato M et al. Aggressive multiple sclerosis (2): Treatment. Mult Scler. 2020; 26: 1045-63.
41. Harris VK, Stark J, Vyshkina T et al. Phase I Trial of Intrathecal Mesenchymal Stem Cell-derived Neural Progenitors in Progressive Multiple Sclerosis. EBioMedicine. 2018; 29: 23-30.
42. Suuring M, Moreau A. Regulatory macrophages and tolerogenic dendritic cells in myeloid regulatory cell-based therapies. Int J Mol Sci. 2021; 22: 7970.
43. Quirant-Sánchez B, Mansilla MJ, Navarro-Barriuso J et al. Combined therapy of vitamin d3-tolerogenic dendritic cells and interferon-β in a preclinical model of multiple sclerosis. Biomedicines. 2021; 9: 1758.
44. Tourbah A, Lebrun-Frenay C, Edan G et al. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study. Mult Scler J. 2016; 22: 1719-31.
45. Motte J, Gold R. High-dose biotin in multiple sclerosis: the end of the road. Lancet Neurol. 2020; 19: 965-6.
46. Cree BAC, Cutter G, Wolinsky JS, Freedman MS et al. Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2020; 19: 988-97.
47. Gifford JL, Sadrzadeh SMH, Naugler C. Biotin interference: Underrecognized patient safety risk in laboratory testing. Can Fam Physician. 2018; 64: 370.
48. Goldschmidt CH, Cohen JA. The Rise and Fall of High-Dose Biotin to Treat Progressive Multiple Sclerosis. Neurotherapeutics. 2020; 17: 968-70.
49. Cadavid D, Mellion M, Hupperts R et al. Safety and efficacy of opicinumab in patients with relapsing multiple sclerosis (SYNERGY): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2019; 18: 845-56.
50. Ahmed Z, Fulton D, Douglas MR. Opicinumab: is it a potential treatment for multiple sclerosis? Ann Transl Med. 2020; 8: 892.
51. Hanf KJM, Arndt JW, Liu YT et al. Functional activity of anti-LINGO-1 antibody opicinumab requires target engagement at a secondary binding site. MAbs. 2020; 12: 1-14.
52. Chataway J, Schuerer N, Alsanousi A et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (M-STAT): A randomised, placebo-controlled, phase 2 trial. Lancet. 2014; 383: 2213-21.
53. van der Most PJ, Dolga AM, Nijholt IM et al. Statins: Mechanisms of neuroprotection. Prog Neurobiol. 2009; 88: 64-75.
54. Giannopoulos S, Katsanos AH, Tsivgoulis G et al. Statins and Cerebral Hemodynamics. J Cereb Blood Flow Metab. 2012; 32: 1973-6.
55. Green AJ, Gelfand JM, Cree BA et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017; 390: 2481-9.
56. Dziedzic A, Saluk-Bijak J, Miller E et al. Metformin as a potential agent in the treatment of multiple sclerosis. Int J Mol Sci. 2020; 21: 1-19.
57. Negrotto L, Farez MF, Correale J. Immunologic Effects of Metformin and Pioglitazone Treatment on Metabolic Syndrome and Multiple Sclerosis. JAMA Neurol. 2016; 73: 520.
58. Brown D, Moezzi D, Dong Y et al. Combination of Hydroxychloroquine and Indapamide Attenuates Neurodegeneration in Models Relevant to Multiple Sclerosis. Neurotherapeutics. 2021; 18: 387-400.
59. Rankin KA, Mei F, Kim K et al. Selective estrogen receptor modulators enhance CNS remyelination independent of estrogen receptors. J Neurosci. 2019; 39: 2184-94.
60. Ysrraelit MC, Correale J. Impact of sex hormones on immune function and multiple sclerosis development. Immunology. 2019; 156: 9-22.
61. Metzger-Peter K, Kremer LD, Edan G et al. The TOTEM RRMS (Testosterone Treatment on neuroprotection and Myelin Repair in Relapsing Remitting Multiple Sclerosis) trial: Study protocol for a randomized, double-blind, placebo-controlled trial. Trials. 2020; 21: 1-11.
62. Monti DA, Zabrecky G, Leist TP et al. N-acetyl Cysteine Administration Is Associated With Increased Cerebral Glucose Metabolism in Patients With Multiple Sclerosis: An Exploratory Study. Front Neurol. 2020; 11: 1-8.
63. El Sharouny SH, Shaaban MH, Elsayed RM et al. N-acetylcysteine protects against cuprizone-induced demyelination: histological and immunohistochemical study. Folia Morphol (Warsz). 2021. http://doi.org/10.5603/FM.a2021.0044.
64. Torkildsen Ø, Myhr K-M, Skogen V et al. Tenofovir as a treatment option for multiple sclerosis. Mult Scler Relat Disord. 2020; 46: 102569.
65. Berger JR, Kakara M. The elimination of circulating Epstein-Barr virus infected B cells underlies anti-CD20 monoclonal antibody activity in multiple sclerosis: A hypothesis. Mult Scler Relat Disord. 2022; 59: 103678.
66. Pender MP, Csurhes PA, Smith C et al. Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis. JCI Insight. 2020; 5: e144624.
67. Huang L, Fung E, Bose S et al. Elezanumab, a clinical stage human monoclonal antibody that selectively targets repulsive guidance molecule A to promote neuroregeneration and neuroprotection in neuronal injury and demyelination models. Neurobiol Dis. 2021; 159: 105492.
68. Demicheva E, Cui Y-F, Bardwell P et al. Targeting Repulsive Guidance Molecule A to Promote Regeneration and Neuroprotection in Multiple Sclerosis. Cell Rep [Internet]. 2015; 10: 1887-98.
69. Cree B, Ziemann A, Pfleeger K et al. ECTRIMS 2021 – Oral Presentations – Safety and efficacy of elezanumab in relapsing and progressive forms of multiple sclerosis: Results from two phase 2 studies, RADIUS-R and RADIUS-P. Mult Scler J. 2021; 27: 92.
70. Küry P, Nath A, Créange A et al. Human Endogenous Retroviruses in Neurological Diseases. Trends Mol Med. 2018; 24: 379-94.
71. Hartung HP, Derfuss T, Cree BAC et al. Efficacy and safety of temelimab in multiple sclerosis: Results of a randomized phase 2b and extension study. Mult Scler J. 2022; 28: 429-40.
72. Kremer D, Förster M, Schichel T et al. The neutralizing antibody GNbAC1 abrogates HERV-W envelope protein-mediated oligodendroglial maturation blockade. Mult Scler J. 2015; 21: 1200-3.
73. Fadul CE, Mao-Draayer Y, Ryan KA et al. Safety and Immune Effects of Blocking CD40 Ligand in Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2021; 8: e1096.
74. Becher B, Durell BG, Miga AV et al. The clinical course of experimental autoimmune encephalomyelitis and inflammation is controlled by the expression of CD40 within the central nervous system. J Exp Med. 2001; 193: 967-74.
75. Li Y, Chu N, Hu A et al. Increased IL-23p19 expression in multiple sclerosis lesions and its induction in microglia. Brain. 2007; 130: 490-501.
76. Derdelinckx J, Cras P, Berneman ZN et al. Antigen-Specific Treatment Modalities in MS: The Past, the Present, and the Future. Front Immunol. 2021; 12: 1-13.
77. Vandenbark AA, Culbertson NE, Bartholomew RM et al. Therapeutic vaccination with a trivalent T-cell receptor (TCR) peptide vaccine restores deficient FoxP3 expression and TCR recognition in subjects with multiple sclerosis. Immunology. 2008; 123: 66-78.
78. Glanzman R, Rin J, Greenberg B et al. ACTRIMS Forum 2021 – Poster Presentations: Effects of Nanocatalysis on CNS Bioenergetic Markers in Patients Treated with CNM-Au8: Interim Results from Two Phase 2 31Phosphorous Imaging Studies. Mult Scler J. 2021; 27: 35-6.
79. Hoffman M. CNM-Au8 Shows Effects on Brain Bioenergetic Metabolism, Supports Candidacy in Multiple Sclerosis (access: 11.04.2022).
80. Glanzman R, Beadnall H, Barnett M et al. ACTRIMS Forum 2021 – VISIONARY-MS: Update to a Phase 2 Clinical Trial of Catalytic Gold Nanocrystals, CNM-Au8, for the Treatment of Chronic Optic Neuropathy. Mult Scler J. 2021; 27(1 suppl): 39-40.
81. Navarrete C, García-Martin A, Garrido-Rodríguez M et al. Effects of EHP-101 on inflammation and remyelination in murine models of Multiple sclerosis. Neurobiol Dis. 2020; 143: 104994.
82. Gacem N, Nait-Oumesmar B. Oligodendrocyte development and regenerative therapeutics in multiple sclerosis. Life. 2021; 11: 327.
83. Sorboni SG, Moghaddam HS, Jafarzadeh-Esfehani R et al. A Comprehensive Review on the Role of the Gut Microbiome in Human Neurological Disorders. Clin Microbiol Rev. 2022; 35: e0033820.
84. Li K, Wei S, Hu L et al. Protection of Fecal Microbiota Transplantation in a Mouse Model of Multiple Sclerosis. Mediators Inflamm. 2020; 2020: 1-13.
85. Ghezzi L, Cantoni C, Pinget GV et al. Targeting the gut to treat multiple sclerosis. J Clin Invest. 2021; 131: e143774.