IgM anti-MAG± peripheral neuropathy (IMAGiNe) study protocol: An international, observational, prospective registry of patients with IgM M-protein peripheral neuropathies.

BACKGROUND: International consensus on IgM ± anti-MAG ± PNP (IgM PNP) is lacking. Despite increasing interest in clinical trials, validated disease-specific measures are needed to adequately capture limitations and changes over time. The IMAGiNe (IgM ± anti-myelin associated glycoprotein [MAG] peripheral neuropathy) study surges as an international collaboration to create a standardized registry of patients with IgM ± anti-MAG PNP. The consortium, which currently consists of 11 institutions from 7 countries, presents here the IMAGiNe study design and protocol. AIMS: Functional outcome measures will be constructed at the level of impairment, as well as activity and participation. We aim to describe the natural history of the cohort, the role of anti-MAG antibodies, the presence of clinical subtypes, and potential biomarkers. METHODS: The IMAGiNe study is a prospective, observational cohort study with a 3-year follow-up. At each assessment, researchers collect clinical data and subjects complete a list of preselected outcome measures. Among these, the "Pre-Rasch-built Overall Disability Scale (Pre-RODS)" questionnaire will be submitted to Rasch analysis to assess classic and modern clinimetric requirements. RESULTS: The final measures will include the IgM-PNP-specific RODS and Ataxia Rating Scale (IgM-PNP-ARS). Descriptions of the disease course, clinical heterogeneity, treatment regimes, variations in laboratory values, and antibody titers will help reach consensus on diagnosis and follow-up strategies. CONCLUSION: The constructed interval scales will be cross-culturally valid and suitable for use in future clinical trials and daily practice. The ultimate goals are to improve functional individualized assessment, reach international consensus, and lay the foundations for successful designs in future studies.

Limitations in daily activities and general perception of quality of life: Long term follow-up in patients with anti-myelin-glycoprotein antibody polyneuropathy.

In this study, we assessed the modifications over time of daily activities and quality of life (QoL) in 32 subjects with anti-myelin-glycoprotein (MAG) antibody neuropathy. A widespread panel including clinical scores and patient-reported questionnaires, in compliance of the terms by the International Classification of Functioning, Disability, and Health (ICF) of the World Health Organization (WHO), was employed at enrollment (T0) and at follow-up evaluation (T1) after a mean interval of 15.4 ± 5.7 months. The Sensory Modality Sum score (SMS) at four limbs showed a significant worsening over time (mean score 27.2 ± 3.9 at T0 vs 25.7 ± 3 at T1 at upper limbs, P = .03; 20.5 ± 4.8 at T0 vs 18.6 ± 5.9 at T1 at lower limbs, P = .04). The Visual Analogue Scale (VAS) for pain significantly worsened at upper limbs at T1 (mean values 0.84 ± 1.95 at T0 vs 1.78 ± 2.6 at T1, P = .03). All the other tests did not show significant differences between T0 and T1. In the subgroup who underwent rituximab (15/32 treated before T0, 3/32 patients treated between T0 and T1 with median interval of 1 year), no significant differences were observed between T0 and T1. Despite the quite long follow-up, statistical significance was not achieved either for the limited number of patients or for the lack of sensitive outcome measures. In our cohort, the significant worsening of the SMS and VAS after a median of 14 months can be considered as a reliable expression of the natural history of the disease, and suggest that these scales might represent possible outcome measures in anti-MAG antibody neuropathy.

Relevance of anti-HNK1 antibodies in the management of anti-MAG neuropathies.

INTRODUCTION: In peripheral neuropathies with antibodies against Myelin Associated Glycoprotein (MAG), an IgM monoclonal gammopathy recognizes a specific epitope called Human Natural Killer 1 (HNK1) shared by NK lymphocytes and several components of the peripheral nerve myelin. Recently an ELISA test has been developed to detect antibodies against HNK1 epitope. Objectives were to determine the usefulness of this assay in the management of anti-MAG neuropathy. METHODS: Anti-HNK1 antibodies were assessed with the GanglioCombi™ MAG ELISA test (Buhlmann) in 41 anti-MAG neuropathies and in 118 controls: 34 chronic inflammatory demyelinating polyradiculoneuropathies, 3 Miller Fisher syndromes, 12 sensory neuronopathies, 63 length-dependent axonal sensory polyneuropathies, 6 healthy controls. Anti-HNK1 antibody was tested before and 1 year after rituximab therapy in seven patients with anti-MAG neuropathy. RESULTS: Anti-HNK1 antibodies were positive in 40/41 anti-MAG neuropathies, and in 1/118 controls (sensitivity 98%, specificity 99%). Only considering controls with IgM paraprotein, specificity was 96% (23/24). In anti-MAG neuropathies, anti-HNK1 titre was correlated with sensory deficiency evaluated with the INCAT sensory sum score (r = 0.4, p = 0.01) and with disability evaluated with the Rasch-built Overall Disability Scale (r = [Formula: see text] 0.4, p = 0.01) and Overall Neuropathy Limitation Scale (r = 0.4, p = 0.02). Anti-HNK1 titres were not related to age, disease duration, atypical clinical features and anti-MAG antibodies titres. Anti-MAG titres were not associated with disease severity. Anti-HNK1 titres were decreased by 18% 1 year after rituximab treatment. CONCLUSIONS: Anti-HNK1 antibodies have good sensitivity and specificity for the diagnosis of anti-MAG neuropathy. Interestingly, anti-HNK1 titres are related to the disease severity and decrease after rituximab infusions.

Advances in the diagnosis, immunopathogenesis and therapies of IgM-anti-MAG antibody-mediated neuropathies.

Polyneuropathy with immunoglobulin M (IgM) monoclonal gammopathy is the most common paraproteinemic neuropathy, comprising a clinicopathologically and immunologically distinct entity. The clinical spectrum spans from distal paresthesias and mild gait imbalance to more severe sensory ataxia, with falls and a varying degree of distal sensorimotor deficits. In approximately 75% of patients, the monoclonal IgM immunoreacts with myelin-associated glycoprotein (MAG) and sulfoglucuronyl glycosphingolipid (SGPG), or other peripheral nerve glycolipids that serve as antigens. These antibodies are considered pathogenic because IgM and complement are deposited on the myelin sheath, splitting the myelin lamellae, while adoptive transfer of patients' IgM into susceptible host animals causes sensory ataxia and reproduces the human pathology. In spite of the apparently convincing pathogenicity of these antibodies, the response to immunotherapies remains suboptimal. Clorambuscil, cladibrine, cyclophospamide and intravenous immunoglobulin may help some patients but the benefits are minimal and transient. Open-label studies in >200 patients indicate that rituximab is helpful in 30-50% of these patients, even with long-term benefits, probably by suppressing IgM anti-MAG antibodies or inducing immunoregulatory T cells. Two controlled studies with rituximab did not however meet the primary endpoint, mostly because of the poor sensitivity of the scales used; they did however show statistical improvement in secondary endpoints and improved clinical functions in several patients. This review provides an overview of the clinical phenotypes and immunoreactivity of IgM to glycolipids or glycoproteins of peripheral nerve myelin, summarizes the progress on treatment with rituximab as a promising therapy, discusses the pitfalls of scales used, identifies possible biomarkers of response to therapy and highlights the promising new anti-B cell or target-specific immunotherapies.

Anti-MAG autoantibodies are increased in Parkinson's disease but not in atypical parkinsonism.

There is emerging evidence that glial cells are involved in the neuropathological process in Parkinson's disease (PD) in addition to degeneration of neuronal structures. Recently, we confirmed the presence of an adaptive immune response against different glial-derived antigens in PD, with a possible role of anti-MAG, anti-MBP and anti-PLP antibodies in the disease progression. The aim of the present study was to assess humoral response against myelin-associated glycoprotein (MAG) in patients with parkinsonism (both idiopathic and atypical) to check whether these antibodies could serve as biomarkers of PD, its severity and progression. Anti-MAG autoantibodies were measured by an ELISA system in 99 PD patients, 33 atypical parkinsonism patients, and 36 control subjects. In PD patients, anti-MAG IgM autoantibodies were significantly higher in comparison to healthy control subjects (p = 0.038). IgM anti-MAG autoantibodies titers were also significantly higher in the whole group of patients with parkinsonism (either idiopathic or atypical) in comparison to healthy control subjects (1.88 ± 0.84 vs 1.70 ± 1.19, p = 0.017). This difference was mainly driven by the PD group, as the atypical parkinsonism group did not differ significantly from the control group in anti-MAG antibody levels (p = 0.51). A negative correlation between anti-MAG levels and disease duration was found in PD patients. Our study provides evidence for an increased production of autoantibodies against a protein of glial origin in PD. The negative correlation between anti-MAG antibodies and disease duration may suggest possible involvement of the immune system in disease progression. Increasing evidence that glia are involved in the neurodegenerative process to a greater extent than previously thought may turn out be useful in the search for biomarkers of the neurodegenerative process in PD.

Diagnostic Utility of Auto Antibodies in Inflammatory Nerve Disorders.

A wide range of autoantibodies have been described in immune-mediated nerve disorders that target glycans borne by glycolipids and glycoproteins enriched in the peripheral nerves. Their use as diagnostic biomarkers is very widespread, despite some limitations on sensitivity and specificity, and the lack of standardized assays and access to quality assurance schemes. Although many methods have been applied to measurement, ELISA, in the form of commercial kits or in-house assays, still remains the most widely available and convenient assay methodology.Some antibodies have a particularly robust and widely appreciated clinical significance. Thus, the anti-MAG IgM antibodies that are found in IgM paraprotein related neuropathies define a relatively uniform clinical and prognostic phenotype. IgG antibodies against gangliosides GM1 and GD1a are strongly associated with motor axonal variants of Guillain-Barré syndrome, and anti-GQ1b with Miller Fisher syndrome. In other chronic neuropathies, antibodies against disialylated gangliosides including GD1b and GD3 are detected in ataxic neuropathies, usually associated with an IgM paraprotein, and antibodies against GM1 and the complex GM1:GalC are frequently found in multifocal motor neuropathy. Unfortunately, autoantibodies strongly associated with the diagnosis of chronic inflammatory demyelinating polyneuropathies and with demyelinating forms of GBS are still lacking.Identification of autoantibodies that map onto a specific clinical phenotype not only allows for improved classification, but also provides better understanding of the pathophysiology of inflammatory neuropathies and the potential for therapeutic interventions.

NK cells and their receptors in naive and rituximab-treated patients with anti-MAG polyneuropathy.

BACKGROUND: Natural killer (NK) cells can bridge innate and acquired immunity, and play a role in autoimmunity. A few studies evaluated the distribution of NK cells and the expression of their receptors in chronic immune-mediated demyelinating polyneuropathies. We investigated NK cell distribution and NK cell receptor expression in 20 naïve patients with anti-MAG polyneuropathy (MAG-PN). METHODS: Using flow cytometry, we analysed NK cells and a series of NK cell receptors in the peripheral blood of patients with MAG-PN, and, as controls, in patients with chronic inflammatory demyelinating peripheral polyradiculoneuropathy (CIDP) and in healthy subjects. Six MAG-PN patients were also tested after rituximab treatment. RESULTS: At baseline the percentage of NK cells did not differ among the groups. KIR2DL2 receptor expression in MAG-PN patients was higher, andCD94/NKG2A receptor expression in both MAG-PN and CIDP patients was lower than in healthy controls. These abnormalities did not correlate with any clinical or demographic variable. No modification was found after rituximab therapy. CONCLUSIONS: The data suggest that MAG-PN shows abnormalities in NK cell receptors that characterise other autoimmune diseases, and cannot help in differential diagnosis with CIDP. The impairment of the relevant CD94/NKG2A inhibitory pathway, which might play a central role in the development and perpetuation of MAG-PN, warrants further functional investigations.