Search strategy used to obtain the clinical trials included in this review was combining the MeSH terms (“Multiple sclerosis”, “Inflammation”, “Remyelination”, and “Therapy”) with Boolean operators (AND, OR, and NOT).
CM and AV: Conceptualization, Investigation, Formal analysis, Writing—original draft, Writing—review & editing. AV: Visualization, Supervision, Validation, Funding acquisition. Both authors read and approved the submitted version.
Conflicts of interest
The authors declare no conflicts of interest.
Ethical approval
Not applicable.
Consent to participate
Not applicable.
Consent to publication
Not applicable.
Availability of data and materials
The datasets supporting the findings of this study are available from the corresponding author upon reasonable request.
Funding
This work was supported by the Portuguese Foundation for Science and Technology (FCT) through funding to the Research Centre for Natural Resources, Environment and Society—CERNAS [UIDB/00681]. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.
References
Fazia T, Baldrighi GN, Nova A, Bernardinelli L. A systematic review of Mendelian randomization studies on multiple sclerosis.Eur J Neurosci. 2023;58:3172–94. [DOI] [PubMed]
Dunalska A, Saramak K, Szejko N. The Role of Gut Microbiome in the Pathogenesis of Multiple Sclerosis and Related Disorders.Cells. 2023;12:1760. [DOI] [PubMed] [PMC]
The Multiple Sclerosis International Federation (MSIF). Atlas of MS, 3rd Edition. The Multiple Sclerosis International Federation (MSIF); 2020.
Morse BL. Global Perspectives.Nurse Educ. 2022;47:218. [DOI] [PubMed]
Correia I, Cunha C, Bernardes C, Nunes C, Macário C, Sousa L, et al. Prevalence, Incidence, and Mortality of Multiple Sclerosis in Coimbra, Portugal.Neuroepidemiology. 2024;58:57–63. [DOI] [PubMed] [PMC]
de Sá J, Alcalde-Cabero E, Almazán-Isla J, Sempere A, de Pedro-Cuesta J. Capture-recapture as a potentially useful procedure for assessing prevalence of multiple sclerosis: methodologic exercise using Portuguese data.Neuroepidemiology. 2012;38:209–16. [DOI] [PubMed]
Branco M, Alves I, Martins da Silva A, Pinheiro J, Sá MJ, Correia I, et al. The epidemiology of multiple sclerosis in the entre Douro e Vouga region of northern Portugal: a multisource population-based study.BMC Neurol. 2020;20:195. [DOI] [PubMed] [PMC]
Haki M, Al-Biati HA, Al-Tameemi ZS, Ali IS, Al-Hussaniy HA. Review of multiple sclerosis: Epidemiology, etiology, pathophysiology, and treatment.Medicine (Baltimore). 2024;103:e37297. [DOI] [PubMed] [PMC]
Olsson T. Epstein Barr virus infection and immune defense related to HLA-DR15: consequences for multiple sclerosis.Eur J Immunol. 2021;51:56–9. [DOI] [PubMed] [PMC]
Wekerle H. B cells in multiple sclerosis.Autoimmunity. 2017;50:57–60. [DOI] [PubMed]
Fettke F, Schumacher A, Costa SD, Zenclussen AC. B cells: the old new players in reproductive immunology.Front Immunol. 2014;5:285. [DOI] [PubMed] [PMC]
Maroto-García J, Martínez-Escribano A, Delgado-Gil V, Mañez M, Mugueta C, Varo N, et al. Biochemical biomarkers for multiple sclerosis.Clin Chim Acta. 2023;548:117471. [DOI] [PubMed]
El-Sayed MM, Mohak S, Gala D, Fabian R, Peterfi Z, Fabian Z. The Role of the Intestinal Microbiome in Multiple Sclerosis-Lessons to Be Learned from Hippocrates.Biology (Basel). 2023;12:1463. [DOI] [PubMed] [PMC]
López-Muguruza E, Matute C. Alterations of Oligodendrocyte and Myelin Energy Metabolism in Multiple Sclerosis.Int J Mol Sci. 2023;24:12912. [DOI] [PubMed] [PMC]
Michaličková D, Öztürk HKK, Das D, Bukhari SO, Slanař O. Molecular biomarkers in multiple sclerosis.Arh Farm (Belgr). 2022;72:127–48. [DOI]
van Munster CE, Uitdehaag BM. Outcome Measures in Clinical Trials for Multiple Sclerosis.CNS Drugs. 2017;31:217–36. [DOI] [PubMed] [PMC]
Gul M, Jafari AA, Shah M, Mirmoeeni S, Haider SU, Moinuddin S, et al. Molecular biomarkers in multiple sclerosis and its related disorders: A critical review.Int J Mol Sci. 2020;21:6020. [DOI]
Yang J, Hamade M, Wu Q, Wang Q, Axtell R, Giri S, et al. Current and Future Biomarkers in Multiple Sclerosis.Int J Mol Sci. 2022;23:5877. [DOI] [PubMed] [PMC]
Gaspar A, Eusébio I, Duarte R, Morgado M, Fonseca O. Terapêuticas orais modificadoras da doença na esclerose múltipla disponíveis em Portugal.Cartas Al Director. 2018;28:350–2. Portuguese.
Hauser SL, Cree BAC. Treatment of Multiple Sclerosis: A Review.Am J Med. 2020;133:1380–90.e2. [DOI]
Amin M, Hersh CM. Updates and advances in multiple sclerosis neurotherapeutics.Neurodegener Dis Manag. 2023;13:47–70. [DOI] [PubMed] [PMC]
Zhang X, Chen F, Sun M, Wu N, Liu B, Yi X, et al. Microglia in the context of multiple sclerosis.Front Neurol. 2023;14:1157287. [DOI] [PubMed] [PMC]
Ramirez AI, de Hoz R, Salobrar-Garcia E, Salazar JJ, Rojas B, Ajoy D, et al. The Role of Microglia in Retinal Neurodegeneration: Alzheimer’s Disease, Parkinson, and Glaucoma.Front Aging Neurosci. 2017;9:214. [DOI] [PubMed] [PMC]
Wang J, Wang J, Wang J, Yang B, Weng Q, He Q. Targeting Microglia and Macrophages: A Potential Treatment Strategy for Multiple Sclerosis.Front Pharmacol. 2019;10:286. [DOI] [PubMed] [PMC]
Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination.Nat Neurosci. 2013;16:1211–8. [DOI] [PubMed] [PMC]
Prinz M, Priller J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease.Nat Rev Neurosci. 2014;15:300–12. [DOI] [PubMed]
Gomez PT, Carver CM, Rodriguez SL, Wang L, Zhang X, Schafer MJ. Aging and senescent fates of oligodendrocyte precursor cells in the mouse brain.NPJ Aging. 2024;10:47. [DOI] [PubMed] [PMC]
Miron VE. Microglia-driven regulation of oligodendrocyte lineage cells, myelination, and remyelination.J Leukoc Biol. 2017;101:1103–8. [DOI] [PubMed]
Guo S, Wang H, Yin Y. Microglia Polarization From M1 to M2 in Neurodegenerative Diseases.Front Aging Neurosci. 2022;14:815347. [DOI] [PubMed] [PMC]
Gacem N, Nait-Oumesmar B. Oligodendrocyte Development and Regenerative Therapeutics in Multiple Sclerosis.Life (Basel). 2021;11:327. [DOI] [PubMed] [PMC]
Franklin RJM, Simons M. CNS remyelination and inflammation: From basic mechanisms to therapeutic opportunities.Neuron. 2022;110:3549–65. [DOI] [PubMed]
Kuhlmann T, Moccia M, Coetzee T, Cohen JA, Correale J, Graves J, et al.; International Advisory Committee on Clinical Trials in Multiple Sclerosis. Multiple sclerosis progression: time for a new mechanism-driven framework.Lancet Neurol. 2023;22:78–88. [DOI] [PubMed] [PMC]
Hammer C, Stepniak B, Schneider A, Papiol S, Tantra M, Begemann M, et al. Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity.Mol Psychiatry. 2014;19:1143–9. [DOI] [PubMed]
Zhao X, Jacob C. Mechanisms of Demyelination and Remyelination Strategies for Multiple Sclerosis.Int J Mol Sci. 2023;24:6373. [DOI] [PubMed] [PMC]
Kutzelnigg A, Lassmann H. Pathology of multiple sclerosis and related inflammatory demyelinating diseases.Handb Clin Neurol. 2014;122:15–58. [DOI] [PubMed]
Ingelfinger F, Gerdes LA, Kavaka V, Krishnarajah S, Friebel E, Galli E, et al. Twin study reveals non-heritable immune perturbations in multiple sclerosis.Nature. 2022;603:152–8. [DOI] [PubMed] [PMC]
Mishra MK, Yong VW. Myeloid cells - targets of medication in multiple sclerosis.Nat Rev Neurol. 2016;12:539–51. [DOI] [PubMed]
Franklin RJM, Ffrench-Constant C. Regenerating CNS myelin - from mechanisms to experimental medicines.Nat Rev Neurosci. 2017;18:753–69. [DOI] [PubMed]
Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, et al. The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases.Immunity. 2017;47:566–81.e9. [DOI] [PubMed] [PMC]
Bosch-Queralt M, Cantuti-Castelvetri L, Damkou A, Schifferer M, Schlepckow K, Alexopoulos I, et al. Diet-dependent regulation of TGFβ impairs reparative innate immune responses after demyelination.Nat Metab. 2021;3:211–27. [DOI] [PubMed] [PMC]
Lloyd AF, Davies CL, Holloway RK, Labrak Y, Ireland G, Carradori D, et al. Central nervous system regeneration is driven by microglia necroptosis and repopulation.Nat Neurosci. 2019;22:1046–52. [DOI] [PubMed] [PMC]
Shen K, Reichelt M, Kyauk RV, Ngu H, Shen YA, Foreman O, et al. Multiple sclerosis risk gene Mertk is required for microglial activation and subsequent remyelination.Cell Rep. 2021;34:108835. [DOI] [PubMed]
Ren J, Dai C, Zhou X, Barnes JA, Chen X, Wang Y, et al. Qki is an essential regulator of microglial phagocytosis in demyelination.J Exp Med. 2021;218:e20190348. [DOI] [PubMed] [PMC]
Berghoff SA, Spieth L, Sun T, Hosang L, Schlaphoff L, Depp C, et al. Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis.Nat Neurosci. 2021;24:47–60. [DOI] [PubMed] [PMC]
Neumann B, Baror R, Zhao C, Segel M, Dietmann S, Rawji KS, et al. Metformin Restores CNS Remyelination Capacity by Rejuvenating Aged Stem Cells.Cell Stem Cell. 2019;25:473–85.e8. [DOI] [PubMed] [PMC]
Rawji KS, Young AMH, Ghosh T, Michaels NJ, Mirzaei R, Kappen J, et al. Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system.Acta Neuropathol. 2020;139:893–909. [DOI] [PubMed] [PMC]
Dombrowski Y, O’Hagan T, Dittmer M, Penalva R, Mayoral SR, Bankhead P, et al. Regulatory T cells promote myelin regeneration in the central nervous system.Nat Neurosci. 2017;20:674–80. [DOI] [PubMed] [PMC]
Hanf KJM, Arndt JW, Liu Y, Gong BJ, Rushe M, Sopko R, et al. Functional activity of anti-LINGO-1 antibody opicinumab requires target engagement at a secondary binding site.MAbs. 2020;12:1713648. [DOI] [PubMed] [PMC]
Owens TD, Smith PF, Redfern A, Xing Y, Shu J, Karr DE, et al. Phase 1 clinical trial evaluating safety, exposure and pharmacodynamics of BTK inhibitor tolebrutinib (PRN2246, SAR442168).Clin Transl Sci. 2022;15:442–50. [DOI] [PubMed] [PMC]
Fox RJ, Coffey CS, Conwit R, Cudkowicz ME, Gleason T, Goodman A, et al. Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis.N Engl J Med. 2018;379:846–55. [DOI]
Zurmati BM, Khan J. Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: A phase 2b, randomized, double-blind, placebo-controlled trial by Daniel S Reich et Al.Mult Scler Relat Disord. 2023;77:104850. [DOI] [PubMed]
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.BMJ. 2021;372:n71. [DOI] [PubMed] [PMC]
Kandi V, Vadakedath S. Clinical Trials and Clinical Research: A Comprehensive Review.Cureus. 2023;15:e35077. [DOI] [PubMed] [PMC]
Gold J, Marta M, Meier UC, Christensen T, Miller D, Altmann D, et al. A phase II baseline versus treatment study to determine the efficacy of raltegravir (Isentress) in preventing progression of relapsing remitting multiple sclerosis as determined by gadolinium-enhanced MRI: The INSPIRE study.Mult Scler Relat Disord. 2018;24:123–8. [DOI] [PubMed]
Soiza RL, Donaldson AIC, Myint PK. Vaccine against arteriosclerosis: an update.Ther Adv Vaccines. 2018;9:259–61. [DOI]
Hartung HP, Derfuss T, Cree BA, Sormani MP, Selmaj K, Stutters J, et al. Efficacy and safety of temelimab in multiple sclerosis: Results of a randomized phase 2b and extension study.Mult Scler. 2022;28:429–40. [DOI] [PubMed]
Kolind S, Abel S, Taylor C, Tam R, Laule C, Li DKB, et al. Myelin water imaging in relapsing multiple sclerosis treated with ocrelizumab and interferon beta-1a.Neuroimage Clin. 2022;35:103109. [DOI] [PubMed] [PMC]
Abdelhak A, Cordano C, Boscardin WJ, Caverzasi E, Kuhle J, Chan B, et al. Plasma neurofilament light chain levels suggest neuroaxonal stability following therapeutic remyelination in people with multiple sclerosis.J Neurol Neurosurg Psychiatry. 2022;93:972–7. [DOI] [PubMed] [PMC]
Talbot J, Højsgaard Chow H, Mahler M, Buhelt S, Holm Hansen R, Lundell H, et al. Relationship between cerebrospinal fluid biomarkers of inflammation and tissue damage in primary progressive multiple sclerosis.Mult Scler Relat Disord. 2022;68:104209. [DOI] [PubMed]
Sy M, Newton BL, Pawling J, Hayama KL, Cordon A, Yu Z, et al. N-acetylglucosamine inhibits inflammation and neurodegeneration markers in multiple sclerosis: a mechanistic trial.J Neuroinflammation. 2023;20:209. [DOI] [PubMed] [PMC]
Newsome SD, Tian F, Shoemaker T, Fitzgerald KC, Cassard SD, Fiol J, et al. A Phase 1b, Open-Label Study to Evaluate the Safety and Tolerability of the Putative Remyelinating Agent, Liothyronine, in Individuals with MS.Neurotherapeutics. 2023;20:1263–74. [DOI] [PubMed] [PMC]
Genchi A, Brambilla E, Sangalli F, Radaelli M, Bacigaluppi M, Furlan R, et al. Neural stem cell transplantation in patients with progressive multiple sclerosis: an open-label, phase 1 study.Nat Med. 2023;29:75–85. [DOI] [PubMed] [PMC]
Louapre C, Rosenzwajg M, Golse M, Roux A, Pitoiset F, Adda L, et al. A randomized double-blind placebo-controlled trial of low-dose interleukin-2 in relapsing-remitting multiple sclerosis.J Neurol. 2023;270:4403–14. [DOI] [PubMed]
Nezhad NN, Parnow A, Khamoushian K, Eslami R, Baker JS. Resistance training modifies of serum levels of matrix metalloproteinase 2 and tissue inhibitor of matrix metalloproteinases in multiple sclerosis women - a randomized controlled trail.BMC Neurosci. 2024;25:13. [DOI] [PubMed] [PMC]
Nakamura K, Thoomukuntla B, Bena J, Cohen JA, Fox RJ, Ontaneda D. Ibudilast reduces slowly enlarging lesions in progressive multiple sclerosis.Mult Scler. 2024;30:369–80. [DOI] [PubMed] [PMC]
Cayre M, Falque M, Mercier O, Magalon K, Durbec P. Myelin Repair: From Animal Models to Humans.Front Cell Neurosci. 2021;15:604865. [DOI] [PubMed] [PMC]
Leenders F, Koole L, Slaets H, Tiane A, Hove DVD, Vanmierlo T. Navigating oligodendrocyte precursor cell aging in brain health.Mech Ageing Dev. 2024;220:111959. [DOI] [PubMed]
Keough MB, Rogers JA, Zhang P, Jensen SK, Stephenson EL, Chen T, et al. An inhibitor of chondroitin sulfate proteoglycan synthesis promotes central nervous system remyelination.Nat Commun. 2016;7:11312. [DOI] [PubMed] [PMC]
Zveik O, Rechtman A, Ganz T, Vaknin-Dembinsky A. The interplay of inflammation and remyelination: rethinking MS treatment with a focus on oligodendrocyte progenitor cells.Mol Neurodegener. 2024;19:53. [DOI] [PubMed] [PMC]
Turner TJ, Brun P, Gruber RC, Ofengeim D. Comparative CNS Pharmacology of the Bruton’s Tyrosine Kinase (BTK) Inhibitor Tolebrutinib Versus Other BTK Inhibitor Candidates for Treating Multiple Sclerosis.Drugs R D. 2024;24:263–74. [DOI] [PubMed] [PMC]
Montague T, Drummond J, Ng K, Parratt J. Advancements in multiple sclerosis.Intern Med J. 2025;55:895–904. [DOI] [PubMed] [PMC]
