Anti-NF155 chronic inflammatory demyelinating polyradiculoneuropathy strongly associates to HLA-DRB15.

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Anti-NF155 chronic inflammatory demyelinating polyradiculoneuropathy strongly associates to HLA-DRB15.

J Neuroinflammation. 2017 Nov 16;14(1):224

Authors: Martinez-Martinez L, Lleixà MC, Boera-Carnicero G, Cortese A, Devaux J, Siles A, Rajabally Y, Martinez-Piñeiro A, Carvajal A, Pardo J, Delmont E, Attarian S, Diaz-Manera J, Callegari I, Marchioni E, Franciotta D, Benedetti L, Lauria G, de la Calle Martin O, Juárez C, Illa I, Querol L

Abstract
BACKGROUND: The aim of the research is to study the human leukocyte antigen (HLA) class II allele frequencies in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) associated with anti-neurofascin 155 (NF155) antibodies.
METHODS: Thirteen anti-NF155+ and 35 anti-NF155 negative (anti-NF155neg) CIDP patients were included in a case-control study. The frequencies of the DRB1 HLA allele were analyzed in all patients while DQ frequencies were only studied in patients sharing the DRB1*15 allele. In silico HLA-peptide binding and NF155 antigenicity, predictions were performed to analyze overlap between presented peptides and antigenic regions.
RESULTS: DRB1*15 alleles (DRB1*15:01 and DRB1*15:02) were present in 10 out of 13 anti-NF155+ CIDP patients and in only 5 out of 35 anti-NF155neg CIDP patients (77 vs 14%; OR = 20, CI = 4.035 to 99.13). DRB1*15 alleles appeared also in significantly higher proportions in anti-NF155+ CIDP than in normal population (77 vs 17%; OR = 16.9, CI = 4.434 to 57.30). Seven anti-NF155+ CIDP patients (53%) and 5 anti-NF155neg CIDP patients had the DRB1*15:01 allele (OR = 7, p = 0.009), while 3 anti-NF155+ CIDP patients and none of the anti-NF155neg CIDP patients had the DRB1*15:02 allele (OR = 23.6, p = 0.016). In silico analysis of the NF155 peptides binding to DRB1*15 alleles showed significant overlap in the peptides presented by the 15:01 and 15:02 alleles, suggesting functional homology.
CONCLUSIONS: DRB1*15 alleles are the first strong risk factor associated to a CIDP subset, providing additional evidence that anti-NF155+ CIDP patients constitute a differentiated disease within the CIDP syndrome.

PMID: 29145880 [PubMed - in process]

Antibodies against peripheral nerve antigens in chronic inflammatory demyelinating polyradiculoneuropathy.

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Antibodies against peripheral nerve antigens in chronic inflammatory demyelinating polyradiculoneuropathy.

Sci Rep. 2017 Oct 31;7(1):14411

Authors: Querol L, Siles AM, Alba-Rovira R, Jáuregui A, Devaux J, Faivre-Sarrailh C, Araque J, Rojas-Garcia R, Diaz-Manera J, Cortés-Vicente E, Nogales-Gadea G, Navas-Madroñal M, Gallardo E, Illa I

Abstract
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a heterogeneous disease in which diverse autoantibodies have been described but systematic screening has never been performed. Detection of CIDP-specific antibodies may be clinically useful. We developed a screening protocol to uncover novel reactivities in CIDP. Sixty-five CIDP patients and 28 controls were included in our study. Three patients (4.6%) had antibodies against neurofascin 155, four (6.2%) against contactin-1 and one (1.5%) against the contactin-1/contactin-associated protein-1 complex. Eleven (18.6%) patients showed anti-ganglioside antibodies, and one (1.6%) antibodies against peripheral myelin protein 2. No antibodies against myelin protein zero, contactin-2/contactin-associated protein-2 complex, neuronal cell adhesion molecule, gliomedin or the voltage-gated sodium channel were detected. In IgG experiments, three patients (5.3%) showed a weak reactivity against motor neurons; 14 (24.6%) reacted against DRG neurons, four of them strongly (7.0%), and seven (12.3%) reacted against Schwann cells, three of them strongly (5.3%). In IgM experiments, six patients (10.7%) reacted against DRG neurons, while three (5.4%) reacted against Schwann cells. However, results were not statistically significant when compared to controls. Immunoprecipitation experiments identified CD9 and L1CAM as potential antigens, but reactivity could not be confirmed with cell-based assays. In summary, we describe a diverse autoantibody repertoire in CIDP patients, reinforcing the hypothesis of CIDP's pathophysiological heterogeneity.

PMID: 29089585 [PubMed - in process]

Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study.

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Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study.

Lancet Neurol. 2017 Oct 20;:

Authors: Howard JF, Utsugisawa K, Benatar M, Murai H, Barohn RJ, Illa I, Jacob S, Vissing J, Burns TM, Kissel JT, Muppidi S, Nowak RJ, O'Brien F, Wang JJ, Mantegazza R, REGAIN Study Group

Abstract
BACKGROUND: Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial.
METHODS: We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II-IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229.
FINDINGS: Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference -11·7, 95% CI -24·3 to 0·96; p=0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy.
INTERPRETATION: The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed.
FUNDING: Alexion Pharmaceuticals.

PMID: 29066163 [PubMed - as supplied by publisher]

230th ENMC International Workshop:: Improving future assessment and research in IgM anti-MAG peripheral neuropathy: A consensus collaborative effort, Naarden, The Netherlands, 24-26 February 2017.

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230th ENMC International Workshop:: Improving future assessment and research in IgM anti-MAG peripheral neuropathy: A consensus collaborative effort, Naarden, The Netherlands, 24-26 February 2017.

Neuromuscul Disord. 2017 Aug 02;:

Authors: Pruppers MHJ, Merkies ISJ, Lunn MPT, Notermans NC, IMAGiNe Study Group

PMID: 28927829 [PubMed - as supplied by publisher]

Autoantibodies in chronic inflammatory neuropathies: diagnostic and therapeutic implications.

Autoantibodies in chronic inflammatory neuropathies: diagnostic and therapeutic implications.

Nat Rev Neurol. 2017 Jul 14;:

Authors: Querol L, Devaux J, Rojas-Garcia R, Illa I

Abstract
The chronic inflammatory neuropathies (CINs) are rare, very disabling autoimmune disorders that generally respond well to immune therapies such as intravenous immunoglobulin (IVIg). The most common forms of CIN are chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy, and polyneuropathy associated with monoclonal gammopathy of unknown significance. The field of CIN has undergone a major advance with the identification of IgG4 autoantibodies directed against paranodal proteins in patients with CIDP. Although these autoantibodies are only found in a small subset of patients with CIDP, they can be used to guide therapeutic decision-making, as these patients have a poor response to IVIg. These observations provide proof of concept that identifying the target antigens in tissue-specific antibody-mediated autoimmune diseases is important, not only to understand their underlying pathogenic mechanisms, but also to correctly diagnose and treat affected patients. This state-of-the-art Review focuses on the role of autoantibodies against nodes of Ranvier in CIDP, a clinically relevant emerging field of research. The role of autoantibodies in other immune-mediated neuropathies, including other forms of CIN, primary autoimmune neuropathies, neoplasms, and systemic diseases that resemble CIN, are also discussed.

PMID: 28708133 [PubMed - as supplied by publisher]

Autoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy.

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Autoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy.

Brain. 2017 May 28;:

Authors: Delmont E, Manso C, Querol L, Cortese A, Berardinelli A, Lozza A, Belghazi M, Malissart P, Labauge P, Taieb G, Yuki N, Illa I, Attarian S, Devaux JJ

Abstract
Chronic inflammatory demyelination polyneuropathy is a heterogeneous and treatable immune-mediated disorder that lacks biomarkers to support diagnosis. Recent evidence indicates that paranodal proteins (contactin 1, contactin-associated protein 1, and neurofascin-155) are the targets of autoantibodies in subsets of patients showing distinct clinical presentations. Here, we identified neurofascin-186 and neurofascin-140 as the main targets of autoantibodies in five patients presenting IgG reactivity against the nodes of Ranvier. Four patients displayed predominantly IgG4 antibodies, and one patient presented IgG3 antibodies that activated the complement pathway in vitro. These patients present distinct clinical features compared to those with anti-neurofascin-155 IgG4. Most patients had a severe phenotype associated with conduction block or decreased distal motor amplitude. Four patients had a subacute-onset and sensory ataxia. Two patients presented with nephrotic syndromes and one patient with an IgG4-related retroperitoneal fibrosis. Intravenous immunoglobulin and corticosteroids were effective in three patients, and one patient remitted following rituximab treatment. Clinical remission was associated with autoantibody depletion and with recovery of conduction block and distal motor amplitude suggesting a nodo-paranodopathy. Our data demonstrate that the pathogenic mechanisms responsible for chronic inflammatory demyelination polyneuropathy are broad and may include dysfunctions at the nodes of Ranvier in a subgroup of patients.

PMID: 28575198 [PubMed - as supplied by publisher]

Absence of antibodies against KIR4.1 in multiple sclerosis: A three-technique approach and systematic review.

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Absence of antibodies against KIR4.1 in multiple sclerosis: A three-technique approach and systematic review.

PLoS One. 2017;12(4):e0175538

Authors: Navas-Madroñal M, Valero-Mut A, Martínez-Zapata MJ, Simón-Talero MJ, Figueroa S, Vidal-Fernández N, López-Góngora M, Escartín A, Querol L

Abstract
INTRODUCTION: Antibodies targeting the inward-rectifying potassium channel KIR4.1 have been associated with multiple sclerosis (MS) but studies using diverse techniques have failed to replicate this association. The detection of these antibodies is challenging; KIR4.1 glycosylation patterns and the use of diverse technical approaches may account for the disparity of results. We aimed to replicate the association using three different approaches to overcome the technical limitations of a single technique. We also performed a systematic review to examine the association of anti-KIR4.1 antibodies with MS.
METHODS: Serum samples from patients with MS (n = 108) and controls (n = 77) were tested for the presence of anti-KIR4.1 antibodies using three methods: 1) by ELISA with the low-glycosylated fraction of recombinant KIR4.1 purified from transfected HEK293 cells according to original protocols; 2) by immunocytochemistry using KIR4.1-transfected HEK293 cells; and 3) by immunocytochemistry using the KIR4.1.-transfected MO3.13 oligodendrocyte cell line. We developed a systematic review and meta-analysis of the association of anti-KIR4.1 antibodies with MS according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
RESULTS: We did not detect anti-KIR4.1 antibodies in the MS patients or in controls using ELISA. Neither did we detect any significant reactivity against the antigen on the cell surface using the KIR4.1-transfected HEK293 cells or the KIR4.1-transfected MO3.13 cells. We included 13 prospective controlled studies in the systematic review. Only three studies showed a positive association between anti-KIR4.1 and MS. Clinical and statistical heterogeneity between studies precluded meta-analysis of their results.
CONCLUSION: We found no association between anti-KIR4.1 antibody positivity and MS. Although this lack of replication may be due to technical limitations, evidence from our study and others is mounting against the role of KIR4.1 as a relevant MS autoantigen.

PMID: 28414733 [PubMed - in process]

Compromised fidelity of B-cell tolerance checkpoints in AChR and MuSK myasthenia gravis.

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Compromised fidelity of B-cell tolerance checkpoints in AChR and MuSK myasthenia gravis.

Ann Clin Transl Neurol. 2016 Jun;3(6):443-54

Authors: Lee JY, Stathopoulos P, Gupta S, Bannock JM, Barohn RJ, Cotzomi E, Dimachkie MM, Jacobson L, Lee CS, Morbach H, Querol L, Shan JL, Vander Heiden JA, Waters P, Vincent A, Nowak RJ, O'Connor KC

Abstract
OBJECTIVE: Myasthenia gravis (MG) is an autoimmune condition in which neurotransmission is impaired by binding of autoantibodies to acetylcholine receptors (AChR) or, in a minority of patients, to muscle specific kinase (MuSK). There are differences in the dominant IgG subclass, pathogenic mechanisms, and treatment responses between the two MG subtypes (AChR or MuSK). The antibodies are thought to be T-cell dependent, but the mechanisms underlying their production are not well understood. One aspect not previously described is whether defects in central and peripheral tolerance checkpoints, which allow autoreactive B cells to accumulate in the naive repertoire, are found in both or either form of MG.
METHODS: An established set of assays that measure the frequency of both polyreactive and autoreactive B cell receptors (BCR) in naive populations was applied to specimens collected from patients with either AChR or MuSK MG and healthy controls. Radioimmuno- and cell-based assays were used to measure BCR binding to AChR and MuSK.
RESULTS: The frequency of polyreactive and autoreactive BCRs (n = 262) was higher in both AChR and MuSK MG patients than in healthy controls. None of the MG-derived BCRs bound AChR or MuSK.
INTERPRETATION: The results indicate that both these MG subtypes harbor defects in central and peripheral B cell tolerance checkpoints. Defective B cell tolerance may represent a fundamental contributor to autoimmunity in MG and is of particular importance when considering the durability of myasthenia gravis treatment strategies, particularly biologics that eliminate B cells.

PMID: 27547772 [PubMed]

Clinical Characteristics of Patients With Double-Seronegative Myasthenia Gravis and Antibodies to Cortactin.

Clinical Characteristics of Patients With Double-Seronegative Myasthenia Gravis and Antibodies to Cortactin.

JAMA Neurol. 2016 Jul 5;

Authors: Cortés-Vicente E, Gallardo E, Martínez MÁ, Díaz-Manera J, Querol L, Rojas-García R, Illa I

Abstract
Importance: Double-seronegative myasthenia gravis (dSNMG) includes patients with myasthenia gravis (MG) without detectable antibodies to the nicotinic acetylcholine receptor (AChR) or to muscle-specific tyrosine kinase (MuSK). The lack of a biomarker hinders the diagnosis and clinical management in these patients. Cortactin, a protein acting downstream from agrin/low-density lipoprotein receptor-related protein 4 (LRP4)/MuSK, has been described as an antigen in dSNMG.
Objective: To describe the frequency and clinical features of patients with dSNMG who have cortactin antibodies.
Design, Setting, and Participants: A retrospective cross-sectional study was conducted at Hospital de la Santa Creu i Sant Pau, an institutional practice referral center in Barcelona, Spain, between May 1, 2015, and November 30, 2015. We included 250 patients with a definitive diagnosis of MG with available serum samples at the time of diagnosis. Descriptive and comparative data analyses were performed.
Exposures: Cortactin antibodies were measured by enzyme-linked immunosorbent assay and Western blot; AChR, MuSK, and anti-striated muscle antibodies were detected using a standard method; and LRP4 antibodies were tested using a cell-based assay.
Main Outcomes and Measures: The primary outcome was the frequency of patients with dSNMG who have cortactin antibodies. Secondary outcomes were demographic, clinical, neurophysiological, and laboratory data.
Results: Of 250 patients (mean [SD] age at onset, 49.7 [21.2] years; 56% female), 38 (15.2%) had dSNMG, 201 (80.4%) had MG with AChR antibodies, and 11 (4.4%) had MG with MuSK antibodies. Cortactin antibodies were identified in 28 patients with MG: 9 of 38 (23.7%) who had dSNMG, 19 of 201 (9.5%) who had MG with AChR antibodies (significantly lower than those with dSNMG: 9.5% vs 23.7%; P = .02), and 0 of 11 who had MG with MuSK antibodies; 0 of 29 controls had cortactin antibodies. At onset, among the 9 patients with dSNMG and cortactin antibodies, 6 had ocular MG and 3 had Myasthenia Gravis Foundation of America clinical classification IIA. Two patients with ocular MG developed generalized MG. The group with dSNMG and cortactin antibodies, compared with those who had MG with AChR antibodies, more frequently had mild forms at onset (100.0% vs 62.7%; P = .03), had fewer bulbar signs at maximal worsening (0% vs 41.3%; P = .01), and were younger at onset (median [interquartile range], 34.9 [9.5] vs 53.9 [38.5] years; P = .03); the group with dSNMG and cortactin antibodies also more frequently had ocular MG at onset than those with MG and AChR antibodies, although the difference was not statistically significant (66.7% vs 40.8%; P = .17). Of 17 patients with ocular dSNMG, 4 (23.5%) had antibodies to cortactin.
Conclusions and Relevance: In this study, patients with cortactin antibodies and dSNMG had an ocular or mild generalized phenotype of MG. Including the detection of cortactin antibodies in the routine diagnosis of dSNMG may be helpful in ocular MG.

PMID: 27379450 [PubMed - as supplied by publisher]

Correlation of the patient’s reported outcome Inflammatory-RODS with an objective metric in immune-mediated neuropathies.

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Correlation of the patient's reported outcome Inflammatory-RODS with an objective metric in immune-mediated neuropathies.

Eur J Neurol. 2016 Apr 29;

Authors: Draak TH, Gorson KC, Vanhoutte EK, van Nes SI, van Doorn PA, Cornblath DR, van den Berg LH, Faber CG, Merkies IS, PeriNomS Study Group

Abstract
BACKGROUND AND PURPOSE: There is increasing interest in using patient-reported outcome measures (PROMs) in clinical studies to capture individual changes over time. However, PROMs have also been criticized because they are entirely subjective. Our objective was to examine the relationship between a subjective PROM and an objective outcome tool in patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and gammopathy-related polyneuropathy (MGUSP).
METHODS: The Inflammatory Rasch-built Overall Disability Scale (I-RODS©, a multi-item scale that examines functionality) was completed by 137 patients with newly diagnosed (or relapsing) GBS (55), CIDP (59) and MGUSP (23) who were serially examined (GBS/CIDP, T0/T1/T3/T6/T12 months; MGUSP, T0/T3/T12). Possible association between the I-RODS findings and the vigorimeter scores, an objective linear instrument to assess grip strength, was examined.
RESULTS: A significant correlating trend was found between the I-RODS and grip strength scores for the overall group and in each illness, independently.
CONCLUSION: The objectivity of patients' subjective report on their functional state based on a strong correlation between the I-RODS and grip strength in patients with GBS, CIDP and MGUSP has been demonstrated. These findings provide further support to use the I-RODS and grip strength in future clinical studies in these conditions.

PMID: 27129110 [PubMed - as supplied by publisher]