Long-term outcome in chronic inflammatory demyelinating polyneuropathy patients treated with intravenous immunoglobulin: a retrospective study.

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Long-term outcome in chronic inflammatory demyelinating polyneuropathy patients treated with intravenous immunoglobulin: a retrospective study.

Muscle Nerve. 2013 Dec;48(6):870-6

Authors: Querol L, Rojas-Garcia R, Casasnovas C, Sedano MJ, Muñoz-Blanco JL, Alberti MA, Paradas C, Sevilla T, Pardo J, Capablo JL, Sivera R, Guerrero A, Gutierrez-Rivas E, Illa I

Abstract
INTRODUCTION: The objective of this retrospective study was to describe the short- and long-term patterns of IVIg use, safety, and response to treatment in patients with chronic inflammatory demyelinating polyneuropathy (CIDP).
METHODS: Response to therapy was defined as an improvement of ≥ 1 point on the modified Rankin score at short- and mid-term visits. Patient status at long term was classified as remission, stability, or non-responder.
RESULTS: Eighty-six patients were included; 60.5% responded at short term and 54.6% at mid-term. At long term, 25.6% of patients were in remission, 65.1% were stable, and 9.3% were non-responders. The only variable associated with remission was a better response during the first 6 months of follow-up.
CONCLUSIONS: A significant percentage of patients did not require any additional drugs in the long term. This suggests that treatment effect or disease outcome may be stable over time, and treatment regimens should therefore be individualized to avoid overtreatment.

PMID: 23512566 [PubMed - indexed for MEDLINE]

196th ENMC international workshop: Outcome measures in inflammatory peripheral neuropathies 8-10 February 2013, Naarden, The Netherlands.

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196th ENMC international workshop: Outcome measures in inflammatory peripheral neuropathies 8-10 February 2013, Naarden, The Netherlands.

Neuromuscul Disord. 2013 Nov;23(11):924-33

Authors: Vanhoutte EK, Faber CG, Merkies IS, PeriNomS study group

PMID: 23835324 [PubMed - indexed for MEDLINE]

Protein array-based profiling of CSF identifies RBPJ as an autoantigen in multiple sclerosis.

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Protein array-based profiling of CSF identifies RBPJ as an autoantigen in multiple sclerosis.

Neurology. 2013 Sep 10;81(11):956-63

Authors: Querol L, Clark PL, Bailey MA, Cotsapas C, Cross AH, Hafler DA, Kleinstein SH, Lee JY, Yaari G, Willis SN, O'Connor KC

Abstract
OBJECTIVE: To profile the reactivity of CSF-derived immunoglobulin from patients with multiple sclerosis (MS) against a large panel of antigens, to identify disease-specific reactivities.
METHODS: CSF from subjects with MS with elevated immunoglobulin G and CSF from control subjects presenting with other inflammatory neurologic disease were screened against a protein array consisting of 9,393 proteins. Reactivity to a candidate protein identified using these arrays was confirmed with ELISA and immunocytochemistry.
RESULTS: Autoantibodies against one protein on the array, recombination signal binding protein for immunoglobulin kappa J region (RBPJ), discriminated between patients with MS and controls (p = 0.0052). Using a large validation cohort, we found a higher prevalence of autoantibodies against RBPJ in the CSF of patients with MS (12.5%) compared with the CSF of patients with other neurologic diseases (1.6%; p = 0.02) by ELISA. This difference in reactivity was restricted to the CSF as serum reactivity against RBPJ did not differ between patients and controls. The presence of CSF autoantibodies against RBPJ was further confirmed by immunocytochemistry.
CONCLUSIONS: These data indicate that RBPJ, a ubiquitous protein of the Notch signaling pathway that plays an important role in Epstein-Barr virus infection, is a novel MS autoantigen candidate that is recognized by CSF-derived immunoglobulin G in a subset of patients with MS.

PMID: 23921886 [PubMed - indexed for MEDLINE]

Myasthenia gravis and the neuromuscular junction.

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Myasthenia gravis and the neuromuscular junction.

Curr Opin Neurol. 2013 Oct;26(5):459-65

Authors: Querol L, Illa I

Abstract
PURPOSE OF REVIEW: Myasthenic disorders are a well characterized group of diseases of the neuromuscular junction. Their pathogenesis is diverse, including genetic and autoimmune mechanisms. We review recent findings on risk factors, pathogenesis and treatment of autoimmune myasthenia gravis.
RECENT FINDINGS: Better knowledge of congenital myasthenia has led to the development of efficient diagnostic algorithms that have therapeutic implications. New epidemiological and genetic risk factors have been identified and are considered to play a role in the development of myasthenia gravis. The study of the role of innate immunity in myasthenia gravis has identified relevant pathways to explain myasthenia gravis causes. The description of the pathogenic role of IgG4 anti-MuSK antibodies has revealed heterogeneous immune mechanisms that should lead to more specific therapies. Rituximab seems to be particularly effective in MuSK myasthenia gravis, and eculizumab arises as an option in refractory AChR myasthenia gravis. Therapeutic algorithms need to be tailored to each myasthenia subtype.
SUMMARY: Increasing knowledge about the environmental and genetic risk factors and basic immunopathogenesis of myasthenia gravis, including the role of innate immunity, regulatory T cell impairment and autoantibody heterogeneity, is providing a rationale for treatment with new biological agents. Current immunotherapies in myasthenia gravis undoubtedly provide benefits, but also cause side-effects. Controlled trials are, therefore, needed to confirm initial results from pilot studies.

PMID: 23945282 [PubMed - indexed for MEDLINE]

Endothelial progenitor cells in acute ischemic stroke.

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Endothelial progenitor cells in acute ischemic stroke.

Brain Behav. 2013 Nov;3(6):649-55

Authors: Martí-Fàbregas J, Crespo J, Delgado-Mederos R, Martínez-Ramírez S, Peña E, Marín R, Dinia L, Jiménez-Xarrié E, Fernández-Arcos A, Pérez-Pérez J, Querol L, Suárez-Calvet M, Badimon L

Abstract
OBJECTIVES: The levels of circulating endothelial progenitor cells (EPCs) in ischemic stroke have not been studied extensively and reported results are inconsistent. We aimed to investigate the time course, the prognostic relevance, and the variables associated with EPC counts in patients with ischemic stroke at different time points.
MATERIAL AND METHODS: We studied prospectively 146 consecutive patients with ischemic stroke within the first 48 h from the onset of symptoms (baseline). We evaluated demographic data, classical vascular risk factors, treatment with thrombolysis and statins, stroke etiology, National Institute of Health and Stroke Scale score and outcome (favorable when Rankin scale score 0-2). Blood samples were collected at baseline, at day 7 after stroke (n = 121) and at 3 months (n = 92). The EPC were measured by flow cytometry.
RESULTS: We included 146 patients with a mean age of 70.8 ± 12.2 years. The circulating EPC levels were higher on day 7 than at baseline or at 3 months (P = 0.045). Pretreatment with statins (odds ratio [OR] 3.11, P = 0.008) and stroke etiology (P = 0.032) were predictive of EPC counts in the baseline sample. EPC counts were not associated with stroke severity or functional outcome in all the patients. However, using multivariate analyses, a better functional outcome was found in patients with higher EPC counts in large-artery atherosclerosis and small-vessel disease etiologic subtypes.
CONCLUSIONS: After acute ischemic stroke, circulating EPC counts peaked at day 7. Pretreatment with statins increased the levels of EPC. In patients with large-artery atherosclerosis and small-vessel disease subtypes, higher counts were related to better outcome at 3 months.

PMID: 24363968 [PubMed]

Specific contactin N-glycans are implicated in neurofascin binding and autoimmune targeting in peripheral neuropathies.

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Specific contactin N-glycans are implicated in neurofascin binding and autoimmune targeting in peripheral neuropathies.

J Biol Chem. 2014 Mar 14;289(11):7907-18

Authors: Labasque M, Hivert B, Nogales-Gadea G, Querol L, Illa I, Faivre-Sarrailh C

Abstract
Cell adhesion molecules (CAMs) play a crucial role in the formation of the nodes of Ranvier and in the rapid propagation of the nerve impulses along myelinated axons. These CAMs are the targets of autoimmunity in inflammatory neuropathies. We recently showed that a subgroup of patients with aggressive chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) shows autoantibodies to contactin (1). The complex of contactin·Caspr·neurofascin-155 (NF155) enables the formation of paranodal junctions, suggesting that antibody attack against paranodes may participate in the severity of CIDP. In the present study, we mapped the molecular determinants of contactin targeted by the autoantibodies. In three patients, immunoreactivity was directed against the Ig domains of contactin and was dependent on N-glycans. The serum of one patient was selectively directed against contactin bearing mannose-rich N-glycans. Strikingly, the oligomannose type sugars of contactin are required for association with its glial partner NF155 (2). To investigate precisely the role of contactin N-glycans, we have mutated each of the nine consensus N-glycosylation sites independently. We found that the mutation of three sites (N467Q/N473Q/N494Q) in Ig domain 5 of contactin prevented soluble NF155-Fc binding. In contrast, these mutations did not abolish cis-association with Caspr. Next, we showed that the cluster of N-glycosylation sites (Asn-467, Asn-473, and Asn-494) was required for immunoreactivity in one patient. Using cell aggregation assays, we showed that the IgGs from the four CIDP patients prevented adhesive interaction between contactin·Caspr and NF155. Importantly, we showed that the anti-contactin autoantibodies induced alteration of paranodal junctions in myelinated neuronal culture. These results strongly suggest that antibodies to CAMs may be pathogenic and induce demyelination via functional blocking activity.

PMID: 24497634 [PubMed - indexed for MEDLINE]

Neurofascin IgG4 antibodies in CIDP associate with disabling tremor and poor response to IVIg.

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Neurofascin IgG4 antibodies in CIDP associate with disabling tremor and poor response to IVIg.

Neurology. 2014 Mar 11;82(10):879-86

Authors: Querol L, Nogales-Gadea G, Rojas-Garcia R, Diaz-Manera J, Pardo J, Ortega-Moreno A, Sedano MJ, Gallardo E, Berciano J, Blesa R, Dalmau J, Illa I

Abstract
OBJECTIVE: To describe the frequency of antibodies against neurofascin in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and the associated clinical features.
METHODS: Immunocytochemistry was used to identify antibodies to neurofascin 155 (NF155) and 186. Serum reactivity with paranodes and brain tissue was tested with immunohistochemistry of teased-nerve fibers and rat brain. Antibody titers and immunoglobulin (Ig) G isotypes were determined using ELISA. Clinical information was obtained retrospectively.
RESULTS: Two of 53 patients, but none of 204 controls, had antibodies to NF155 (p = 0.041). The 2 patients with NF155 antibodies developed severe polyradiculoneuropathy with predominant distal weakness that was refractory to IVIg. Eight additional patients with IVIg-refractory CIDP were then identified from a national database; 2 of them with the same clinical features also had NF155 antibodies. Overall, 3 of the 4 patients with NF155 antibodies had a disabling and characteristic tremor (high amplitude, low frequency, postural, and intention). Patients' antibodies reacted with the paranodes in teased-nerve fibers and with the neuropil of rat cerebellum, brain, and brainstem. Anti-NF155 antibodies were predominantly of the IgG4 isotype in all patients.
CONCLUSION: Patients with CIDP positive for IgG4 NF155 antibodies constitute a specific subgroup with a severe phenotype, poor response to IVIg, and disabling tremor. Autoantibodies against paranodal structures associate with distinct clinical features in CIDP and their identification has diagnostic, prognostic, and therapeutic implications.
CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that autoantibodies to NF155 identify a CIDP subtype characterized by severe neuropathy, poor response to IVIg, and disabling tremor.

PMID: 24523485 [PubMed - indexed for MEDLINE]

Altered RIG-I/DDX58-mediated innate immunity in dermatomyositis.

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Altered RIG-I/DDX58-mediated innate immunity in dermatomyositis.

J Pathol. 2014 Jul;233(3):258-68

Authors: Suárez-Calvet X, Gallardo E, Nogales-Gadea G, Querol L, Navas M, Díaz-Manera J, Rojas-Garcia R, Illa I

Abstract
We investigated the molecular mechanisms involved in the pathogenesis of three inflammatory myopathies, dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM). We performed microarray experiments(†) using microdissected pathological muscle fibres from 15 patients with these disorders and five controls. Differentially expressed candidate genes were validated by immunohistochemistry on muscle biopsies, and the altered pathways were analysed in human myotube cultures. Up-regulation of genes involved in viral and nucleic acid recognition were found in the three myopathies but not in controls. In DM, retinoic acid-inducible gene 1 (RIG-I, DDX58) and the novel antiviral factor DDX60, which promotes RIG-I-mediated signalling, were significantly up-regulated, followed by IFIH1 (MDA5) and TLR3. Immunohistochemistry confirmed over-expression of RIG-I in pathological muscle fibres in 5/5 DM, 0/5 PM and 0/5 IBM patients, and in 0/5 controls. Stimulation of human myotubes with a ligand of RIG-I produced a significant secretion of interferon-β (IFNβ; p < 0.05) and up-regulation of class I MHC, RIG-I and TLR3 (p < 0.05) by IFNβ-dependent and TLR3-independent mechanisms. RIG-I-mediated innate immunity, triggered by a viral or damage signal, plays a significant role in the pathogenesis of DM, but not in that of PM or IBM.

PMID: 24604766 [PubMed - indexed for MEDLINE]

Analysis of serum miRNA profiles of myasthenia gravis patients.

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Analysis of serum miRNA profiles of myasthenia gravis patients.

PLoS One. 2014;9(3):e91927

Authors: Nogales-Gadea G, Ramos-Fransi A, Suárez-Calvet X, Navas M, Rojas-García R, Mosquera JL, Díaz-Manera J, Querol L, Gallardo E, Illa I

Abstract
Myasthenia gravis (MG) is an autoimmune disease characterized by the presence of autoantibodies, mainly against the acetylcholine receptor (AChR). The mechanisms triggering and maintaining this chronic disease are unknown. MiRNAs are regulatory molecules that play a key role in the immune system and are altered in many autoimmune diseases. The aim of this study was to evaluate miRNA profiles in serum of 61 AChR MG patients. We studied serum from patients with early onset MG (n = 22), late onset MG (n = 27) and thymoma (n = 12), to identify alterations in the specific subgroups. In a discovery cohort, we analysed 381 miRNA arrays from 5 patients from each subgroup, and 5 healthy controls. The 15 patients had not received any treatment. We found 32 miRNAs in different levels in MG and analysed 8 of these in a validation cohort that included 46 of the MG patients. MiR15b, miR122, miR-140-3p, miR185, miR192, miR20b and miR-885-5p were in lower levels in MG patients than in controls. Our study suggests that different clinical phenotypes in MG share common altered mechanisms in circulating miRNAs, with no additional contribution of the thymoma. MG treatment intervention does not modify the profile of these miRNAs. Novel insights into the pathogenesis of MG can be reached by the analysis of circulating miRNAs since some of these miRNAs have also been found low in MG peripheral mononuclear cells, and have targets with important roles in B cell survival and antibody production.

PMID: 24637658 [PubMed - indexed for MEDLINE]

Severe exacerbation of Andersen-Tawil syndrome secondary to thyrotoxicosis.

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Severe exacerbation of Andersen-Tawil syndrome secondary to thyrotoxicosis.

J Hum Genet. 2014 Aug;59(8):465-6

Authors: Díaz-Manera J, Querol L, Alejaldre A, Rojas-García R, Ramos-Fransi A, Gallardo E, Illa I

Abstract
Thyrotoxic periodic paralysis (TPP) is a rare complication of hyperthyroidism characterized by episodes of weakness. Although TPP has been described in patients all over the world, it is especially frequent in Asiatic patients. Recently, two genomewide association studies have found a susceptibility locus on chromosome 17q24.3 near the KCNJ2 gene, which is responsible for another cause of periodic paralysis, the Andersen-Tawil syndrome (ATS). We report the first patient diagnosed with ATS with a de novo c.G899C mutation in the KCNJ2 gene in 2010 who developed an autoimmune hyperthyroidism and TPP in 2013. At the time of the ATS diagnosis other causes of periodic paralysis, including thyroid dysfunction, were ruled out. The condition of the patient, who had mild episodes of proximal weakness at follow-up, deteriorated dramatically in 2013, presenting continuous episodes of severe generalized weakness associated with low levels of potassium requiring frequent admissions to the hospital. After a few months, he also presented signs of hyperthyroidism, and a diagnosis of Grave's disease was made. In our opinion, this case clearly demonstrates that a dysfunction of the Kir2.1 potassium channel encoded by the KCNJ2 gene is a risk factor to develop TPP, and can be a useful tool to identify patients at risk in daily clinics.

PMID: 24849934 [PubMed - indexed for MEDLINE]