A comprehensive analysis of the epidemiology and clinical characteristics of anti-LRP4 in myasthenia gravis

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Late Onset Myasthenia Gravis Is Associated with HLA DRB1*15:01 in the Norwegian Population

BACKGROUND: Acquired myasthenia gravis (MG) is a rare antibody-mediated autoimmune disease caused by impaired neuromuscular transmission, leading to abnormal muscle fatigability. The aetiology is complex, including genetic risk factors of the human leukocyte antigen (HLA) complex and unknown environmental factors. Although associations between the HLA complex and MG are well established, not all involved components of the HLA predisposition to this heterogeneous disease have been revealed. Well-powered and comprehensive HLA analyses of subgroups in MG are warranted, especially in late onset MG. METHODOLOGY/PRINCIPAL FINDINGS: This case-control association study is of a large population-based Norwegian cohort of 369 MG patients and 651 healthy controls. We performed comprehensive genotyping of four classical HLA loci (HLA-A, -B, -C and -DRB1) and showed that the DRB1*15:01 allele conferred the strongest risk in late onset MG (LOMG; onset ≥ 60 years) (OR 2.38, p(c)7.4 × 10(-5)). DRB1*13:01 was found to be a protective allele for both early onset MG (EOMG) and LOMG (OR 0.31, p(c) 4.71 × 10(-4)), a finding not previously described. No significant association was found to the DRB1*07:01 allele (p(nc) = 0.18) in a subset of nonthymomatous anti-titin antibody positive LOMG as reported by others. HLA-B*08 was mapped to give the strongest contribution to EOMG, supporting previous studies. CONCLUSION: The results from this study provide important new information concerning the susceptibility of HLA alleles in Caucasian MG, with highlights on DRB1*15:01 as being a major risk allele in LOMG

Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations

To investigate the genetics of late-onset myasthenia gravis (LOMG), we conducted a genome-wide association study imputation of >6 million single nucleotide polymorphisms (SNPs) in 532 LOMG cases (anti-acetylcholine receptor [AChR] antibody positive; onset age ≥50 years) and 2,128 controls matched for sex and population substructure. The data confirm reported TNFRSF11A associations (rs4574025, P = 3.9 × 10−7, odds ratio [OR] 1.42) and identify a novel candidate gene, ZBTB10, achieving genome-wide significance (rs6998967, P = 8.9 × 10−10, OR 0.53). Several other SNPs showed suggestive significance including rs2476601 (P = 6.5 × 10−6, OR 1.62) encoding the PTPN22 R620W variant noted in early-onset myasthenia gravis (EOMG) and other autoimmune diseases. In contrast, EOMG-associated SNPs in TNIP1 showed no association in LOMG, nor did other loci suggested for EOMG. Many SNPs within the major histocompatibility complex (MHC) region showed strong associations in LOMG, but with smaller effect sizes than in EOMG (highest OR ∼2 versus ∼6 in EOMG). Moreover, the strongest associations were in opposite directions from EOMG, including an OR of 0.54 for DQA1*05:01 in LOMG (P = 5.9 × 10−12) versus 2.82 in EOMG (P = 3.86 × 10−45). Association and conditioning studies for the MHC region showed three distinct and largely independent association peaks for LOMG corresponding to (a) MHC class II (highest attenuation when conditioning on DQA1), (b) HLA-A and (c) MHC class III SNPs. Conditioning studies of human leukocyte antigen (HLA) amino acid residues also suggest potential functional correlates. Together, these findings emphasize the value of subgrouping myasthenia gravis patients for clinical and basic investigations and imply distinct predisposing mechanisms in LOMG

An up-date on health-related quality of life in myasthenia gravis -results from population based cohorts

Abstract Current available therapies control Myasthenia gravis (MG) reasonably well, but Health Related Quality of life (HRQOL) remains lower than expected. The aim was provide insights in how HRQOL in MG stands across borders and time, compare the scores to general population controls and other chronic disorders and assess the impact of potential predictors for quality of life such as a) clinical characteristics b) antibodies c) thymoma and d) treatment in a population-based cohort. Methods We designed a population-based cross-sectional study including 858 patients, 373 from Norway and 485 from the Netherlands. The Short Form Health Survey 36 (SF-36) and a cross-cultural validated questionnaire were used. Data were in addition compared to the general population, other chronic diseases and previous studies. Results Mean physical composite score was 59.4 and mental composite score 69.0 with no differences between the countries. The mean HRQOL score was lower in patients with bulbar and generalized symptoms (p < 0.001) compared to sex and age adjusted healthy controls, but not in patients with ocular symptoms or patients in remission. Multivariate analysis revealed that female gender, generalized symptoms and use of secondary immunosuppressive drugs at the time of testing were risk factors for reduced HRQOL. Conclusions Remission and absence of generalized symptoms were favorable factors for HRQOL in MG patients. Historically, the HRQOL levels have not changed since 2001 and no new clinical predictors could be detected in this exhaustive population-based study. Further studies should explore the impact of non clinical factors like ethnic variations, socio-economic and hormonal factors on HRQOL

Serological and experimental studies in different forms of myasthenia gravis

Antibodies to the acetylcholine receptor (AChR) have been recognized for over 40 years and have been important in the diagnosis of myasthenia gravis (MG), and its recognition in patients of different ages and thymic pathologies. The 10–20% of patients who do not have AChR antibodies are now known to comprise different subgroups, the most commonly reported of which is patients with antibodies to muscle‐specific kinase (MuSK). The use of cell‐based assays has extended the repertoire of antibody tests to clustered AChRs, low‐density lipoprotein receptor–related protein 4, and agrin. Autoantibodies against intracellular targets, namely cortactin, titin, and ryanodine receptor (the latter two being associated with the presence of thymoma), may also be helpful as biomarkers in some patients. IgG4 MuSK antibodies are clearly pathogenic, but the coexisting IgG1, IgG2, and IgG3 antibodies, collectively, have effects that question the dominance of IgG4 as the sole pathologic factor in MuSK MG. After a brief historical review, we define the different subgroups and summarize the antibody characteristics. Experiments to demonstrate the in vitro and in vivo pathogenic roles of MuSK antibodies are discussed

Genome-wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A, and Identification of ZBTB10 and Three Distinct HLA Associations.

To investigate the genetics of late-onset myasthenia gravis (LOMG), we conducted a genome-wide association study imputation of >6 million single nucleotide polymorphisms (SNPs) in 532 LOMG cases (anti-acetylcholine receptor [AChR] antibody positive; onset age ≥50 years) and 2,128 controls matched for sex and population substructure. The data confirm reported TNFRSF11A associations (rs4574025, P = 3.9 × 10−7, odds ratio [OR] 1.42) and identify a novel candidate gene, ZBTB10, achieving genome-wide significance (rs6998967, P = 8.9 × 10−10, OR 0.53). Several other SNPs showed suggestive significance including rs2476601 (P = 6.5 × 10−6, OR 1.62) encoding the PTPN22 R620W variant noted in early-onset myasthenia gravis (EOMG) and other autoimmune diseases. In contrast, EOMG-associated SNPs in TNIP1 showed no association in LOMG, nor did other loci suggested for EOMG. Many SNPs within the major histocompatibility complex (MHC) region showed strong associations in LOMG, but with smaller effect sizes than in EOMG (highest OR ∼2 versus ∼6 in EOMG). Moreover, the strongest associations were in opposite directions from EOMG, including an OR of 0.54 for DQA1*05:01 in LOMG (P = 5.9 × 10−12) versus 2.82 in EOMG (P = 3.86 × 10−45). Association and conditioning studies for the MHC region showed three distinct and largely independent association peaks for LOMG corresponding to (a) MHC class II (highest attenuation when conditioning on DQA1), (b) HLA-A and (c) MHC class III SNPs. Conditioning studies of human leukocyte antigen (HLA) amino acid residues also suggest potential functional correlates. Together, these findings emphasize the value of subgrouping myasthenia gravis patients for clinical and basic investigations and imply distinct predisposing mechanisms in LOMG

MuSK autoantibodies in myasthenia gravis detected by cell based assay-A multinational study

Seronegative myasthenia gravis (MG) presents a serious gap in MG diagnosis and understanding. We applied a cell based assay (CBA) for the detection of muscle specific kinase (MuSK) antibodies undetectable by radioimmunoassay. We tested 633 triple-seronegative MG patients' sera from 13 countries, detecting 13% as positive. MuSK antibodies were found, at significantly lower frequencies, in 1.9% of healthy controls and 5.1% of other neuroimmune disease patients, including multiple sclerosis and neuromyelitis optica. The clinical data of the newly diagnosed MuSK-MG patients are presented. 27% of ocular seronegative patients were MuSK antibody positive. Moreover, 23% had thymic hyperplasia suggesting that thymic abnormalities are more common than believed

The most strongly associated HLA alleles in early onset myasthenia gravis (EOMG).

<p>Odds Ratio (OR) and 95% confidence interval (CI) are shown for nominal p-values.</p