Effector mechanisms in anti-MAG antibody-mediated and other demyelinating neuropathies

Latov, Norman; Renaud, Susanne

doi:10.1016/j.jns.2004.03.012

Cited by 24 publications

(22 citation statements)

References 43 publications

(49 reference statements)

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“…The antibodies are likely pathogenic by reacting with the HNK-1 epitope displayed by the extracellular domain of MAG which is located in the Schwann cell membrane [1][2][3][4][5][6][7][8]. MAG is involved in adhesion between myelin lamellae and Schwann cell axon signaling resulting in neurofilament phosphorylation [8,9].…”

Section: Introductionmentioning

confidence: 99%

“…The anti-MAG antibodies may also react with other Schwann cell glycoproteins which display the HNK-1 epitope, including peripheral myelin protein 22 (PMP22) [4,7,8]. Because a loss of PMP22 function caused by a deletion in the PMP22 gene gives rise to hereditary neuropathy with liability to pressure palsies (HNPP), impaired PMP22 function due to the anti-MAG antibodies may also result in an increased sensitivity to nerve en-■ Abstract Anti-myelin associated glycoprotein (MAG) neuropathy is a chronic disorder in which IgM antibodies react with Schwann cell glycoproteins, including MAG and peripheral myelin protein 22 (PMP22).…”

Section: Introductionmentioning

confidence: 99%

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Entrapment in anti myelin-associated glycoprotein neuropathy

et al. 2009

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Anti-myelin associated glycoprotein (MAG) neuropathy is a chronic disorder in which IgM antibodies react with Schwann cell glycoproteins, including MAG and peripheral myelin protein 22 (PMP22). Nerve conduction studies show features of axon loss and predominantly distal slowing consistent with demyelination. Because a genetic loss of PMP22 function yields hereditary neuropathy with liability to pressure palsies (HNPP), loss of PMP22 function due to anti- MAG antibodies may result in increased sensitivity to entrapment. We investigated this by performing standardized electrophysiological studies in 16 patients with anti-MAG neuropathy and 16 disease controls with genetically confirmed HNPP. Disproportionate slowing relative to adjacent segments occurred in similar proportions of patients with anti-MAG neuropathy and HNPP, and was of the same magnitude in each group. Affected were the elbow, carpal tunnel and the wrist-hand segments of the median and ulnar nerves. However, in anti-MAG neuropathy as compared to HNPP, absolute values of distal motor latencies and conduction velocities outside entrapment sites were slower and amplitudes were lower. In conclusion, increased sensitivity for entrapment may occur in anti-MAG neuropathy and contribute to part of the nerve damage.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Entrapment in anti myelin-associated glycoprotein neuropathy

et al. 2009

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“…[1][2][3][4][5][6][7][8] Patients present with a striking immunochemical profile, suggesting the possibility of an autoimmune mechanism: monoclonal IgM recognizes a carbohydrate MAG epitope, which is shared with a number of other glycoconjugates involved in cell adhesion, including the Po glycoprotein of myelin, peripheral myelin protein-22, sulfated sphingolipid, and other related glycolipids. 9,10 The disease may progress slowly over many years in some patients, whereas others develop significant disability mostly due to dysesthesias and ataxia; thus, there is a need to develop effective treatments.…”

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confidence: 99%

Placebo-controlled trial of rituximab in IgM anti-myelin–associated glycoprotein neuropathy

et al. 2013

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Objective: To determine whether rituximab 375 mg/m 2 was efficacious in patients with immunoglobulin M (IgM) anti-myelin-associated glycoprotein antibody demyelinating neuropathy (IgM anti-MAG demyelinating neuropathy).Methods: Fifty-four patients with IgM anti-MAG demyelinating neuropathy were enrolled in this randomized, double-blind, placebo-controlled trial. The inclusion criteria were inflammatory neuropathy cause and treatment (INCAT) sensory score (ISS) $4 and visual analog pain scale .4 or ataxia score $2. The primary outcome was mean change in ISS at 12 months.Results: Twenty-six patients were randomized to a group receiving 4 weekly infusions of 375 mg/m 2 rituximab, and 28 patients to placebo. Intention-to-treat analysis, with imputation of missing ISS values by the last observation carried forward method, showed a lack of mean change in ISS at 12 months, 1.0 6 2.7 in the rituximab group, and 1.0 6 2.8 in the placebo group. However, changes were observed, in per protocol analysis at 12 months, for the number of patients with an improvement of at least 2 points in the INCAT disability scale (p 5 0.027), the self-evaluation scale (p 5 0.016), and 2 subscores of the Short Form-36 questionnaire. Within the spectrum of chronic immune-mediated neuropathies, demyelinating neuropathy associated with immunoglobulin M (IgM) monoclonal gammopathy and antibodies against myelin-associated glycoprotein (MAG) is a distinct entity that typically presents with progressive sensory ataxia and painful paresthesias.1-8 Patients present with a striking immunochemical profile, suggesting the possibility of an autoimmune mechanism: monoclonal IgM recognizes a carbohydrate MAG epitope, which is shared with a number of other glycoconjugates involved in cell adhesion, including the Po glycoprotein of myelin, peripheral myelin protein-22, sulfated sphingolipid, and other related glycolipids.9,10 The disease may progress slowly over many years in some patients, whereas others develop significant disability mostly due to dysesthesias and ataxia; thus, there is a need to develop effective treatments.

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“…Experimental pathogenicity of anti-MAG antibodies has been established in anti-MAG polyneuropathies [6]. RTX is a monoclonal antibody designed to target the B-cells producing anti-MAG antibodies and then expected to reverse the pathogenic process.…”

Section: Dear Sirsmentioning

confidence: 99%

Treatment with rituximab in patients with polyneuropathy with anti-MAG antibodies

et al. 2011

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Efficacy of rituximab (RTX), a monoclonal anti-CD20 antibody, has been suggested in a recent controlled trial in polyneuropathies with antibodies against myelin-associated glycoprotein (PN-MAG) [1]. Aims of this study were to evaluate the efficacy and safety of RTX in PN-MAG and to search for predictive factors of response to treatment.Six patients fulfilling diagnosis criteria for PN-MAG [2] received four weekly infusions of RTX (375 mg/m 2 ). Clinical status of each patient was evaluated, before treatment (M0) then every 3 months during 9 months, by assessing Overall Neuropathy Limitation Scale (ONLS) [3], INCAT Sensory Score (ISS) [4], and MRC sum score on 28 muscle groups [5]. Anti-MAG titers (Buhlmann ELISA technique) and B cells expressing CD19 blood count were concomitantly quantified. Nerve conduction studies were performed before treatment and 9 months after (M9), on fibular, tibial, median and ulnar nerves [5]. Treatment was considered efficient only when ONLS score decreased by at least 1 point at M9. Demographic, clinical, biological and electrophysiological status before RTX, were statistically compared between patients with efficient and non-efficient response to treatment using the MannWhitney and Fisher's exact tests. The level of statistical significance was set at p = 0.05. Patients were asked to give informed consent for use of data in a journal publication.Mean age of patients (70 years old, range 57-86 years), duration before treatment from onset of the disease (5 years, range 2-10 years), main clinical manifestations of each patient and previous immunotherapies are detailed in Table 1. Before RTX treatment, ONLS score ranged from 2 to 6 (mean 3.7) and ISS score from 2 to 12 (mean 6.2). Nine months after the last RTX infusion, ONLS score improved by 1 point in two patients, by 2 points in one, remained stable in the three others. ISS score improved in five patients (mean 3.8 points), MRC score improved in three patients (mean 2.7 points). Decrease of anti-MAG titers was observed in all the six patients at M9 by a mean of 43% (Fig. 1). By the meantime, IgM monoclonal titers decreased in five patients but did not change in one. As expected, CD19 B-cells blood count dramatically decreased, after treatment and stayed low at M9 (138 9

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Effector mechanisms in anti-MAG antibody-mediated and other demyelinating neuropathies

Cited by 24 publications

References 43 publications

Entrapment in anti myelin-associated glycoprotein neuropathy

Entrapment in anti myelin-associated glycoprotein neuropathy

Placebo-controlled trial of rituximab in IgM anti-myelin–associated glycoprotein neuropathy

Treatment with rituximab in patients with polyneuropathy with anti-MAG antibodies

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