Advances in multiple sclerosis: from reduced relapses to remedies
https://www.sciencedirect.com/science/a ... 2217304179
Progress in multiple sclerosis research continues at an impressive pace, with contributions from basic science, translational research, and experimental therapeutics. Several publications in the past year have had a major impact on both our understanding of the disease and our ability to treat it.
The pathogenesis of multiple sclerosis is complex, with over 200 gene variants and several environmental factors associated with increased risk, including exposure to Epstein–Barr virus, low serum vitamin D concentrations, cigarette smoking, and childhood obesity. Moreover, there is now mounting evidence for a role of alterations in the intestinal microbiome. Two studies1,2 showed that bacteria from faeces of people with multiple sclerosis can activate immune cells and worsen disease when transplanted into germ-free animals with experimental autoimmune encephalomyelitis. Remarkably, faeces from an identical twin with multiple sclerosis worsened autoimmune encephalomyelitis more than the faecal transplant from an unaffected twin. These findings suggest that gut bacteria might activate pathogenic immune responses in multiple sclerosis, and regulating these organisms could be beneficial.
Multiple sclerosis therapies suppress inflammation and relapses but have variable effectiveness in slowing disease progression and brain atrophy. A limitation of monitoring CNS tissue destruction has been that brain atrophy measures on MRI are insensitive to microscopic damage. The ability to measure very low concentrations of neurofilament light chain in serum and CSF, by use of the single molecule array approach, might turn out to be a powerful and practical biomarker to monitor tissue damage and test neuroprotective drugs.3 Serum concentrations of neurofilament light chain were abnormally high in people with multiple sclerosis, baseline concentrations correlated with and predicted traditional measures of clinical disease, such as the Expanded Disability Status Scale score and presence of relapses, and these concentrations were reduced with treatment for multiple sclerosis.3
On the therapeutic front, ocrelizumab (an anti-CD20 antibody) was effective in reducing annualised relapse rate and disease progression compared with subcutaneous interferon beta-1a in relapsing-remitting multiple sclerosis.4 Additionally, B-cell depletion with ocrelizumab modestly slowed disease progression in primary progressive multiple sclerosis. A recurrent lesson of progressive multiple sclerosis studies has been that younger patients (the mean age in this study was 45 years) and those with disease activity on MRI (25% at baseline had gadolinium-enhancing lesions) seem to benefit from anti-inflammatory treatment even in the absence of relapses.
B-cell depletion suppresses effector functions of B cells, including cytokine release and antigen presentation to T cells, with minimal effect on immunoglobulins. The approval of ocrelizumab by the US Food and Drug Administration adds this drug to the other high efficacy monoclonal antibodies available for highly active multiple sclerosis (natalizumab and alemtuzumab), and raises the questions of whether these drugs should be used at disease onset to arrest inflammation and if such an approach might prevent progressive disease decades later. Although ocrelizumab appeared to be safe, with no cases of progressive multifocal leukoencephalopathy during the development programme, the safety of this drug, and that of all the high efficacy treatments, needs ongoing assessment because of the risks associated with impaired immune surveillance.
Primary neuroprotection and tissue repair have remained elusive goals. Recent studies have shown that myelination by the highly proliferative and abundant oligodendrocyte precursor cells continues into adulthood, and that this remyelination pathway might explain why some people with multiple sclerosis show signs of thinly myelinated axons, which is thought to be evidence of partial remyelination. Two studies attempting to facilitate myelin repair by enhancing developmental myelination pathways were reported in 2017. The first6 sought to block LINGO-1 (leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein-1), a surface receptor thought to suppress differentiation of oligodendrocyte precursor cells after initial myelination is mostly completed. A monoclonal antibody, opicinumab, was given intravenously to 82 people with relapsing multiple sclerosis and acute optic neuritis, and the adjusted mean treatment difference in latency delay for opicinumab versus placebo was −3·5 ms (95% CI −10·6 to 3·7, 17% difference between groups; p=0·33) in the intention-to-treat population, and −7·6 ms (−15·1 to 0·0, 34%; p=0·050) in the per-protocol population at week 24. In the second study,7 the allergy drug clemastine fumarate, which had been identified in a high throughput screen of agents promoting differentiation of oligodendrocyte precursor cells and myelination of micropillars, was administered to 50 people with a history of optic neuritis; the latency delay was reduced by 1·7 ms per eye (95% CI 0·5–2·9; p=0·0048) compared with placebo. Neither trial showed significant benefits in clinical (visual acuity) or structural (MRI or optical coherence tomography) measurements, but this is not unexpected in a short, phase 2 trial. Both studies not only offer some evidence of endogenous remyelination, but also raise questions regarding whether the strategy of targeting developmental myelination will be adequate, and whether we should also try to suppress inhibitory signals within multiple sclerosis plaques that might reduce differentiation of oligodendrocyte precursor cells and limit therapeutic effects.
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