Multiple Sclerosis | NEJM Resident 360

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Q: Do currently available disease-modifying medications delay the clinical progression of multiple sclerosis?

A: More than a dozen disease-modifying medications are available to reduce the frequency of transient episodes of neurologic disability and limit the accumulation of focal white-matter lesions on magnetic resonance imaging (MRI). No medication fully prevents or reverses the progressive neurologic deterioration, characterized most commonly by impaired ambulation, loss of bladder control, and slowed cognitive processing, but the question of whether disease-modifying medications can delay clinical progression is controversial.

Morning Report Questions

Q: How effective are T-cell–targeted and B-cell–targeted therapies for multiple sclerosis?

A: On the T-cell side, both helper (CD4+) and cytotoxic (CD8+) T cells have been described in multiple sclerosis lesions: CD4+ T cells are more concentrated in the perivascular cuff, whereas CD8+ T cells are widely distributed within the parenchyma. Drugs that limit T-cell access to the CNS can reduce or eliminate new multiple sclerosis lesions. However, T cells that are reactive to myelin antigens have been observed in similar proportions in people with and people without multiple sclerosis, which suggests either that these cells are dysfunctional in multiple sclerosis or that other immune factors also play critical roles. Because of the dramatic success of B-cell–depleting antibodies in limiting multiple sclerosis lesion formation and clinical disease activity, there is renewed attention on the role of B cells. It has long been known that the CSF of most patients with multiple sclerosis harbors unique antibodies (oligoclonal bands) that are produced within the CNS. There is evidence that the antibody-producing function of B-lineage cells is important in some multiple sclerosis lesions. However, because of the rapidity of the clinical response to B-cell depletion (as early as 8 to 12 weeks), even before the reduction of circulating immunoglobulin, it seems more likely that other functions of B cells, including antigen presentation to helper T cells and cytokine production, are more relevant.

Q: What are some of non-immune therapies for multiple sclerosis currently under investigation?

A: Beyond the immune system, a great deal of work has revolved around tissue repair and protection. On the repair side, small studies have preliminarily reported mixed results for therapies that promote endogenous remyelination through various pathways. On the basis of preclinical data, several approved drugs (targeting, e.g., nuclear hormone receptor, histaminic, cholinergic [muscarinic], and adrenergic pathways) are being tested for remyelination or myelin protection. Transplantation of neural or oligodendrocyte precursor cells into the brain is effective in animal models, but well-designed clinical trials involving patients with multiple sclerosis have not been undertaken. Axonal protection is actively being examined. Results from initial clinical trials of a wide variety of drugs have been published or reported, with several medium-to-large studies currently under way.

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