Multiple sclerosis (MS) is an immune-mediated chronic disease of the central nervous system (CNS). In most patients, MS starts with a relapsing-remitting (RR) disease course followed by a secondary progressive (SP) phase with slowly accumulating disability, often in the absence of acute exacerbations. Few patients develop a primary progressive (PP) disease course with no circumscribable relapses from the very beginning. A recently proposed new classification of the clinical course of MS puts active and progressive disease as the 2 main phenotypes in the focus. While the pathophysiological correlate of relapses is assumed to be a concerted infiltration by systemic leukocytes resulting in a magnetic resonance imaging–detectable focal inflammatory CNS white matter lesion, the mechanisms behind the slowly progressing aspect of MS are not well understood. Emerging evidence suggests that, besides focal white matter lesions, widespread diffuse inflammation throughout otherwise “normal-appearing” white matter and involvement of the gray matter could be the major cause of tissue loss in MS brains and by that be the main correlate of gradually declining cognitive and motor function. Most importantly, this CNS-intrinsic inflammation is believed to be sustained by positive feedback loops between CNS resident cells, such as astrocytes and microglia and CNS-established leukocytes, and accordingly, disease progression may therefore no longer depend on de novo CNS infiltration by peripheral leukocytes; this likely scenario could explain why all current MS agents primarily targeting function or migration of peripheral immune cells essentially failed to halt progression in progressive MS.1
Fereidan-Esfahani M, Brück W, Weber MS. Targeting Central Nervous System B Cells in Progression of Multiple Sclerosis: Is Intrathecal Anti-CD20 a Therapeutic Option? JAMA Neurol. 2015;72(12):1407–1408. doi:10.1001/jamaneurol.2015.2869
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