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  • Review Article
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Mechanism-based criteria to improve therapeutic outcomes in progressive multiple sclerosis

Nature Reviews Neurology volume 18, pages 40–55 (2022)Cite this article

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Abstract

In contrast to the multiple disease-modifying therapies that are available for relapsing–remitting multiple sclerosis (MS), the therapeutic options for progressive MS (PMS) are limited. Recent advances in our understanding of the neuroimmunology of PMS, including the mechanisms that drive slowly expanding lesions, have fuelled optimism for improved treatment of this condition. In this Review, we highlight the commonly observed neuropathology of PMS and discuss the associated mechanisms of CNS injury. We then apply this knowledge to formulate criteria for therapeutic efficacy in PMS, beginning with the need for early treatment owing to the substantial neuropathology that is already present at the initial clinical presentation. Other requirements include: antagonism of neuroaxonal injury mediators such as pro-inflammatory microglia and lymphocytes; remediation of oxidative stress resulting from iron deposition and mitochondrial dysfunction; and promotion of neuroprotection through remyelination. We consider whether current disease-modifying therapies for relapsing–remitting MS meet the criteria for successful therapeutics in PMS and suggest that the evidence favours the early introduction of sphingosine 1-phosphate receptor modulators. Finally, we weigh up emerging medications, including repurposed generic medications and Bruton’s tyrosine kinase inhibitors, against these fundamental criteria. In this new therapeutic era in PMS, success depends collectively on understanding disease mechanisms, drug characteristics (including brain penetration) and rational use.

Key points

  • Prominent pathological features of progressive multiple sclerosis (PMS) include global brain atrophy, slowly expanding lesions and a predominantly microglia/macrophage-mediated inflammatory response.

  • Neurodegeneration in MS seems to be driven by a complex interplay between compartmentalized neuroinflammation, oxidative stress, iron toxicity and mitochondrial dysfunction, and occurs as early as the radiologically and clinically isolated syndrome stages.

  • Proposed criteria for efficacious therapeutics in PMS include penetration across the blood–brain barrier, antagonism of compartmentalized lymphocytes and microglia/macrophages, and amelioration of oxidative stress.

  • Conferral of direct neuroprotection and remyelination, with the new myelin itself also exerting protective effects, are also desired features of effective treatments for PMS.

  • Emerging therapeutics for PMS that are discussed in this Review include α-lipoic acid, Bruton’s tyrosine kinase inhibitors, ibudilast and statins.

  • Repurposing of oral drugs for use in PMS is a promising area of research, and potential add-on therapeutics include hydroxychloroquine, metformin and niacin.

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Fig. 1: Brain lesions in progressive multiple sclerosis.
Fig. 2: Mechanisms of injury in progressive multiple sclerosis.
Fig. 3: Success criteria for progressive multiple sclerosis medications.
Fig. 4: Early initiation of medication in multiple sclerosis.

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Acknowledgements

V.W.Y. is funded by operating research grants from the MS Society of Canada and the Canadian Institutes of Health Research. We thank F. Yong for schematizing Fig. 1.

Review criteria

A full search of the PubMed database was conducted, combining ‘progressive multiple sclerosis’ with the following terms: ‘pathology and mechanisms’, ‘inflammation OR microglia OR oxidative injury OR mitochondria dysfunction OR iron’, ‘neurodegeneration’, ‘remyelination’ and ‘disease-modifying therapy(ies) OR immunomodulator OR clinical trial OR drug OR therapy’. For therapeutics, we used the search term ‘randomized controlled clinical drugs trials in progressive MS’. Other papers were discovered by hand-searching the references of reviews of disease-modifying therapies in progressive multiple sclerosis. We further analysed the reference lists of several key papers to identify additional papers and cross-references.

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  1. Hotchkiss Brain Institute and the Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Heather Y. F. Yong & V. Wee Yong

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H.Y.F.Y. prepared the first draft including Figs 2–4 and the tables, and revised the manuscript. V.W.Y. supervised the initial draft, revised the manuscript and approved the final version.

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Correspondence to V. Wee Yong.

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Competing interests

V.W.Y. has received honoraria from Biogen, Novartis, Roche, Sanofi-Genzyme and Teva for industry-sponsored talks, and consulting fees from EMD Serono, Novartis, Roche, Sanofi-Genzyme and Teva. He is the recipient of unrestricted educational grants from Biogen, EMD Serono, Novartis, Roche, Sanofi-Genzyme and Teva to support educational activities of the Alberta MS Network, which he directs. H.Y.F.Y. declares no competing interests.

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Nature Reviews Neurology thanks H. Lassmann, A. Thompson and R. Reynolds for their contribution to the peer review of this work.

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Yong, H.Y.F., Yong, V.W. Mechanism-based criteria to improve therapeutic outcomes in progressive multiple sclerosis. Nat Rev Neurol 18, 40–55 (2022). https://doi.org/10.1038/s41582-021-00581-x

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