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. 2022 Oct;9(10):1626-1642.
doi: 10.1002/acn3.51662. Epub 2022 Sep 17.

Remyelination varies between and within lesions in multiple sclerosis following bexarotene

J William L Brown  1   2   3 , Ferran Prados  2   4   5 , Daniel R Altmann  6 , Baris Kanber  2   5   7 , Jonathan Stutters  2 , Nick G Cunniffe  1 , Joanne L Jones  1 , Zoya G Georgieva  1 , Edward J Needham  1 , Cyrus Daruwalla  1 , Claudia Gandini Wheeler-Kingshott  2   8   9 , Peter Connick  10 , Siddharthan Chandran  10   11 , Robin Franklin  1   12 , David MacManus  2 , Rebecca Samson  2 , Alasdair Coles  1 , Declan Chard  2   7
Affiliations

Remyelination varies between and within lesions in multiple sclerosis following bexarotene

J William L Brown et al. Ann Clin Transl Neurol. 2022 Oct.

Abstract

Objective: In multiple sclerosis chronic demyelination is associated with axonal loss, and ultimately contributes to irreversible progressive disability. Enhancing remyelination may slow, or even reverse, disability. We recently trialled bexarotene versus placebo in 49 people with multiple sclerosis. While the primary MRI outcome was negative, there was converging neurophysiological and MRI evidence of efficacy. Multiple factors influence lesion remyelination. In this study we undertook a systematic exploratory analysis to determine whether treatment response - measured by change in magnetisation transfer ratio - is influenced by location (tissue type and proximity to CSF) or the degree of abnormality (using baseline magnetisation transfer ratio and T1 values).

Methods: We examined treatment effects at the whole lesion level, the lesion component level (core, rim and perilesional tissues) and at the individual lesion voxel level.

Results: At the whole lesion level, significant treatment effects were seen in GM but not WM lesions. Voxel-level analyses detected significant treatment effects in WM lesion voxels with the lowest baseline MTR, and uncovered gradients of treatment effect in both WM and CGM lesional voxels, suggesting that treatment effects were lower near CSF spaces. Finally, larger treatment effects were seen in the outer and surrounding components of GM lesions compared to inner cores.

Interpretation: Remyelination varies markedly within and between lesions. The greater remyelinating effect in GM lesions is congruent with neuropathological observations. For future remyelination trials, whole GM lesion measures require less complex post-processing compared to WM lesions (which require voxel level analyses) and markedly reduce sample sizes.

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Conflict of interest statement

William Brown reports consultancy fees, advisory board work and speaking fees from Novartis, Biogen and Intesso. Robin Franklin reports personal fees from Frequency Therapeutics and Rewind Therapeutics, outside the submitted work. Siddharthan Chandran reports funding from Phenotherapeutics, outside the submitted work. Declan Chard is a consultant for Hoffmann‐La Roche. In the last 3 years he has been a consultant for Biogen, has received research funding from Hoffmann‐La Roche, the International Progressive MS Alliance, the MS Society, the Medical Research Council, and the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, and a speaker's honorarium from Novartis. He co‐supervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, which is supported by Merck.

All other authors declare no competing interests of relevance to the current work.

Figures

Figure 1
Figure 1
Adjusted treatment difference of whole lesion MTR (pu) in pure WM lesions, pure CGM lesions and pure DGM lesions. Each row has stratified the lesions according to a different baseline feature. Increasing treatment difference favours bexarotene. Error bars represent 95% confidence intervals. Interaction term examines differences in treatment effects between subgroups of lesions.
Figure 2
Figure 2
Adjusted treatment difference of voxel‐level lesional MTR (pu) within pure WM lesions, pure CGM lesions and pure DGM lesions. Each row has stratified the voxels according to a different baseline features. Increasing treatment difference favours bexarotene. Error bars represent 95% confidence intervals. Interaction term examines differences in treatment effects between subgroups of voxels.
See this image and copyright information in PMC

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