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Therapeutic strategies for relapsing–remitting multiple sclerosis: a special focus on reduction of grey matter damage as measured by brain atrophy

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Abstract

In the past two decades, several pathological and radiological findings convincingly demonstrated that damage of the cortical and deep grey matter is a key issue in multiple sclerosis with a significant impact on physical and cognitive disability. Moreover, it has become increasingly evident that the effect of available therapies on the inflammatory white matter damage is not a guarantee of a meaningful effect on the neurodegenerative process mainly affecting the grey matter. Despite the efficacy of all approved disease-modifying drugs should be measured considering such a relevant aspect of the disease, data from clinical trials are few, scattered and heterogeneous. The aim of this review is to summarize the evidence so far acquired on the effect of reducing grey matter damage produced by current and emerging disease-modifying therapies for multiple sclerosis.

Financial & competing interests disclosure

M Calabrese serves as consultant of Biogen Idec, Genzyme-Sanofi, Bayer, Teva Pharmaceutics, Novartis Pharma, Mercks Serono. A Gajofatto has been a consultant for Biogen, Merck Serono and Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

  • Here, we reviewed the most relevant multiple sclerosis clinical trials that included measures of neurodegeneration to evaluate the effect of current disease-modifying drugs on reducing grey matter (GM) damage.

  • Although occurrence of GM injury might be assumed on clinical grounds (disability progression, cognitive impairment, etc.), only morphological measures (e.g., non-conventional MRI) and molecular assays (e.g., cerebrospinal fluid analysis) may provide direct proof of GM damage.

  • The few data available are limited by wide differences in measuring GM damage, by the short duration of trials and by the design usually focused on clinical or conventional MRI primary endpoints.

  • No evidence of neuroprotective effects exists for azathioprine, cyclophosphamide, mitoxantrone, whereas significant, even though inconsistent results are available for IFN-β and glatiramer acetate.

  • Evidence is more robust for newly approved or emerging agents, such as natalizumab, fingolimod, dimethylfumarate and laquinimod.

  • Despite the evidence of a statistically significant benefit of several therapeutic agents on brain atrophy their clinical relevance in the long-term course remains to be confirmed.

  • Additional studies aimed at evaluating the effect of disease-modifying drugs on more specific morphological and molecular measures of GM integrity are required to confirm the impact of such therapies on neurodegeneration.

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