Invited Review: Anti–myelin-associated glycoprotein neuropathy: Where do we stand?-Article

Article

Pdf Summary

Anti-myelin-associated glycoprotein (MAG) neuropathy is a rare, acquired, immune-mediated demyelinating polyneuropathy, affecting roughly 1 in 100,000 individuals, predominantly men in their sixth or seventh decade. It progresses slowly, starting with distal sensory-predominant neuropathy; over time, it may lead to motor dysfunction in the distal limbs, and a loss of muscle stretch reflexes.<br /><br />MAG, a transmembrane glycoprotein crucial for myelin sheath formation, becomes the target for pathogenic IgM antibodies in this condition, leading to characteristic histopathological findings and electrophysiological abnormalities, especially in distal nerves. Despite its well-characterized pathology, effective therapies are still lacking, and treatments such as plasma exchange, intravenous immunoglobulin (IVIg), and rituximab yield inconsistent and often modest benefits.<br /><br />There are significant challenges in finding effective treatments due to the slowly progressive nature of the disease and the lack of sensitive and specific outcome measures. Current clinicometric tools such as the Inflammatory Neuropathy Cause and Treatment (INCAT) disability score lack sensitivity for detecting meaningful clinical changes. Emerging tools like the Inflammatory Rasch-built Overall Disability Scale (I-RODS) and ambulation assessments show promise but need further validation.<br /><br />Research is ongoing into various biomarkers and novel therapies. Anti-MAG antibodies, measured via commercial ELISA assays, have been the primary diagnostic tool, though their role in monitoring disease activity is debated. Newer markers like human natural killer-1 (HNK1) and B-cell–activating factors (BAFF) show potential but require further study. Genetic profiling (MYD88, CXCR4 mutations) could also provide prognostic information and guide therapies.<br /><br />Rituximab, an anti-CD20 monoclonal antibody, remains a frequently used treatment despite mixed trial results. The ongoing THERAMAG trial aims to clarify its efficacy in select patient populations. Emerging treatments include other B-cell depleting agents, tyrosine kinase inhibitors like ibrutinib, and lenalidomide, though substantial clinical validation is needed. Future research will focus on better clinicometric tools, biomarkers, and robustly designed clinical trials to develop effective treatments for this challenging neuropathy.

Keywords

Anti-MAG neuropathy

immune-mediated

demyelinating polyneuropathy

pathogenic IgM antibodies

plasma exchange

intravenous immunoglobulin

rituximab

biomarkers

clinicometric tools

THERAMAG trial