19 research outputs found

    Campylobacter jejuni Infection, Anti-Ganglioside Antibodies, and Neuropathy

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    Preceding infection with Campylobacter jejuni (Cj) occurs in approximately 30% of patients with Guillain–Barre syndrome (GBS), and the risk of GBS following Cj infection is increased by 77 to 100-fold. GBS is most often of the axonal subtype and is thought to be mediated by IgG antibodies to peripheral nerve gangliosides that are cross reactive with oligosaccharides in the Cj lipopolysaccharides (LPS). The antibodies are thought to be induced by molecular mimicry, where immune reactivity to a cross reactive epitope in the infectious organism and normal tissue can cause autoimmune disease. Clonally restricted IgM antibodies that react with the same oligosaccharides in gangliosides and Cj-LPS are associated with chronic neuropathies of otherwise similar phenotypes. The anti-ganglioside antibodies in GBS are of the IgG1 and IgG3 subclasses, indicating T-cell reactivity to the same antigens that could help disrupt the blood–nerve barrier. Cj infection can activate multiple innate and adoptive pro-inflammatory pathways that can overcome immune tolerance and induce autoimmunity. Elucidation of the specific immune mechanisms involved in the development of the autoantibodies and neuropathy would help our understanding of the relation between infection and autoimmunity and aid in the development of more effective preventive interventions and therapies

    Time course of the autoantibody response to therapy in anti-MAG neuropathy: TWO case REPORTS

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    Background: Anti-MAG neuropathy is a slowly progressive demyelinating neuropathy that can lead to disability. The neuropathy is thought to be caused by monoclonal IgM antibodies that target the Myelin Associated Glycoprotein (MAG) in peripheral nerves. Therapy is directed at lowering the autoantibody concentrations with B-cells depleting agents, most often rituximab, based on case series and uncontrolled trials reporting improvement. There are no FDA approved treatments for anti-MAG neuropathy, however, and two relatively short duration randomized controlled trials with rituximab failed to achieve their pre-specified primary endpoints. There is also little information regarding the number or duration of treatments that are required to effectively reduce the antibody concentrations. Case presentations: We report the time course of the anti-MAG antibody response in two patients with anti-MAG neuropathy that were treated with rituximab for several years. A reduction of 50% in the anti-MAG IgM was seen after 19 and 58 months respectively, and of 70% after 74 or 104 months of treatment respectively. Titres remained low, without evidence of recurrence after the treatments were discontinued. Conclusion: Therapy of anti-MAG neuropathy with rituximab may require repeat treatments over more than one year to achieve a significant reduction in autoantibody concentrations. These considerations should inform treatment decisions and the design of clinical trials

    Intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): mechanisms of action and clinical and genetic considerations

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    Introduction: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune peripheral nerve disorder that is characterized by subacute onset, progressive or relapsing weakness, and sensory deficits. Proven treatments include intravenous immunoglobulin (IVIg), corticosteroids, and plasma exchange. This review focuses on the mechanisms of action, pharmacodynamics, genetic variations, and disease characteristics that can affect the efficacy of IVIg. Areas covered: The proposed mechanisms of action of IVIg that can mediate its therapeutic effects are reviewed. These include anti-idiotypic interactions, inhibition of neonatal Fc receptors (FcRn), anti-complement activity, upregulation of inhibitory FcγRIIB receptors, and downregulation of macrophage activation or co-stimulatory and adhesion molecules. Clinical and genetic factors that can affect the therapeutic response include misdiagnosis, degree of axonal damage, pharmacokinetic variability, and genetic variations. Expert opinion: The mechanisms of action of IVIg in CIDP and their relative contribution to its efficacy are subject of ongoing investigation. Studies in other autoimmune neurological conditions, in addition, highlight the role of key immunopathological pathways and factors that are likely to be affected. Further investigation into the pathogenesis of CIDP and the mechanisms of action of IVIg may lead to the development of improved diagnostics, better utilization of IVIg, and more targeted and effective therapies

    IgM deposits at nodes of ranvier in a patient with amyotrophic lateral sclerosis, anti-GM1 antibodies, and multifocal motor conduction block

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    We studied a patient with amyotrophic lateral sclerosis, multifocal motor conduction block, and IgM anti-GM1 antibodies. A sural nerve biopsy demonstrated deposits of IgM at nodes of Ranvier by direct immunofluorescence. The deposits were granular and located in the nodal gap between adjacent myelin internodes, and in some instances, they extended along the surface of the paranodal myelin sheath. When injected into rat sciatic nerve, the serum IgM bound to the nodes of Ranvier, and the binding activity was removed by preincubation with GM1. These observations suggest that anti-GM1 antibodies may have caused motor dysfunction by binding to the nodal and paranodal regions of peripheral nerve

    Safety and Tolerability of Immune Globulin Intravenous in Chronic S Inflammatory Demyelinating Polyradiculoneuropathy

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    Background: Chronic inflammatory demyelinating poly-radiculoneuropathy (CIDP) is a common inflammatory neuropathy that can be progressive, stepwise progressive, or relapsing and remitting. Objectives: To further evaluate the long-term safety and tolerability of immune globulin intravenous, 10% caprylate chromatography purified immune globulin intravenous in CIDP. Design: Randomized multicenter trial. Setting: Hospitals and outpatient clinics. Patients: Adults with CIDP (n = 113). Interventions: Immune globulin intravenous, 10% caprylate chromatography purified (2 g/kg of body weight) or placebo was infused as a baseline loading dose, followed by a maintenance dose (1 g/kg) every 3 weeks for up to 24 weeks. Patients who responded were rerandomized into a double-blind extension phase of immune globulin intravenous, 10% caprylate chromatography purified (1 g/kg) or placebo every 3 weeks for up to 24 weeks. Patients who relapsed during the extension phase were withdrawn from the study. Main Outcome Measures: Additional analyses of safety and tolerability. Results: Overall, 113 patients and 95 patients were exposed to immune globulin intravenous, 10% caprylate chromatography purified and placebo, respectively. Exposure to immune globulin intravenous, 10% caprylate chromatography purified was approximately twice that of placebo (1096 vs 575 infusions). Most maintenance dose courses were administered over 1 day in the immune globulin intravenous, 10% caprylate chromatography purified (89.1% of 783 dose courses) and placebo (91.1% of 359 dose courses) groups. The most common drug-related adverse events (AEs) with immune globulin intravenous, 10% caprylate chromatography purified were headache (4.0 per 100 infusions) and pyrexia (2.4 per 100 infusions). Five drug-related serious AEs (pulmonary embolism, pyrexia, vomiting, and 2 headache events) were reported in 3 patients (2.7%) exposed to immune globulin intravenous, 10% caprylate chromatography purified. The incidence of drug-elated serious AEs was higher after loading dose infusions than after maintenance dose infusions (4 AEs vs 1 AE). Age, weight, CIDP severity, and previous immune globulin intravenous exposure had no substantial effect on the percentage of patients with AEs, including serious AEs. Conclusion: Data support a favorable safety and tolerability profile for administration of immune globulin intravenous, 10% caprylate chromatography purified as CIDP maintenance therapy

    Timing and Course of Clinical Response to Intravenous Immunoglobulin in Chronic Inflammatory Demyelinating Polyradiculoneuropathy

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    Objective: To investigate the timing, course, and clinical characteristics of the response to intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Design: Data were extracted from the ICE trial, a randomized, double-blind, placebo-controlled trial of immune globulin intravenous, 10% caprylate/chromatography purified (IGIV-C). Setting: Multiple international centers. Participants: One hundred seventeen individuals with CIDP. Intervention: Treatment with IGIV-C (Gamunex, n=59) or placebo (n=58), with IGIV-C administered as a 2-g/kg loading dose followed by a 1-g/kg maintenance dose every 3 weeks, for up to 24 weeks. Main Outcome Measures: The primary efficacy parameter was an improvement of 1 or more points in adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. Participants treated with IGIV-C were divided into subgroups based on meeting responder vs non-responder definitions and by time to first improvement. Results: Among 30 responders to IGIV-C, 14 (47%) patients had improved adjusted INCAT scores by week 3, and 16 (53%) patients improved at week 6 after a second infusion. Participants who improved by week 3 were more severely disabled at baseline than those who improved at 6 weeks. In patients who improved, the number of individuals reaching maximal improvement continued to increase during maintenance therapy for up to 24 weeks. For patients with first improvement by week 3, the change in dominant-hand grip strength over time tended to parallel the INCAT score. In patients with first improvement by week 6, however, the improvement in dominant-hand grip strength preceded initial improvement in INCAT score. Conclusions: Data suggest that treatment with 2 courses of IGIV-C administered 3 weeks apart may be required for initial improvement, and continued maintenance therapy may be necessary to achieve a maximal therapeutic response
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