Fumiko Oda

HLA-DRB1*14 and DQB1*05 are associated with Japanese anti-MuSK antibody-positive myasthenia gravis patients

BACKGROUND Myasthenia gravis (MG) is an autoimmune disorder presumed to be associated with genetic susceptibility. This study aims to determine whether HLA is associated with MG in Japanese patients. METHODS We included 58 MG patients with anti-acetylcholine receptor antibody (AChR+MG) and 14 MG patients with muscle-specific receptor tyrosine kinase (MuSK+MG) and determined HLA-A, B, DRB1 and -DQB1 alleles using polymerase chain reaction with sequence-specific oligonucleotide and primers. AChR+MG was classified into the three subgroups: early-onset MG (EOMG; n=11), late-onset MG (LOMG; n=20), and thymoma-associated MG (n=27). Healthy volunteers (n=100) served as controls. RESULTS A significant positive association was observed between MuSK+MG with the DRB1*14 [57.1%, MuSK+MG vs. 18.0%, healthy controls (HC); odds ratio (OR): 6.1] and DQB1*05 [78.6%, MuSK+MG vs. 30.0%, HC; odds ratio (OR): 8.5]. We found a negative association between LOMG and DQB1*04 [5.0%, LOMG vs. 37.0%, HC; OR: 0.09]. There was no association between other MG subgroups and HLA alleles. CONCLUSION HLA-DRB1*14 and DQB1*05 were associated with MuSK+MG, therefore these alleles may play important roles in developing MuSK+MG across the races.

Changes in inflammatory cytokine networks in myasthenia gravis

Myasthenia gravis (MG) is an autoimmunological inflammatory disorder of the neuromuscular junction. Inflammation could be a key player for understanding the pathogenesis of MG. We measured the serum levels of 24 inflammatory cytokines in 43 patients with anti-acetylcholine receptor antibody-positive MG and 25 healthy controls. In patients with MG, serum levels of a proliferation-inducing ligand (APRIL), IL-19, IL-20, IL-28A and IL-35 were significantly increased as compared with controls (p < 0.05). Among them, IL-20, IL-28A and IL-35 were significantly decreased after treatment (p < 0.05). In clinical subtype analyses, APRIL and IL-20 were increased in patients with late-onset MG and IL-28A levels were increased in patients with thymoma-associated MG compared with healthy controls (p < 0.01). The results of the present study demonstrate both anti-inflammatory and inflammatory cytokines are upregulated in MG, reflecting the importance of cytokine-mediated inflammation and its regulation in MG pathophysiology.

Increased serum peroxiredoxin 5 levels in myasthenia gravis.

Extracellular peroxiredoxin 5 (PRX5) is known to be an inflammatory mediator. The serum PRX5 levels of 40 patients with anti-acetylcholine receptor antibody-positive MG and those of 40 controls were measured. PRX5 levels in patients with MG were higher than those in the controls (P=0.045). Thymoma-associated MG patients showed higher PRX5 levels than late-onset MG patients and controls (P<0.05). There were significant associations between the serum PRX5 levels and high mobility group box 1 levels. PRX5 elevation in MG could be related to the neuromuscular junction breakdown and plays a pivotal role in the pathogenic inflammation of MG.

Adequate tacrolimus concentration for myasthenia gravis treatment

A single, oral dose of 3 mg/day tacrolimus, approved for myasthenia gravis (MG) treatment in Japan, was shown to reduce steroid dose and anti‐acetylcholine receptor (AChR) antibody titers as well as to improve MG symptoms. However, no studies have investigated the association between tacrolimus concentration and its clinical efficacy in MG. In this study, we aimed to determine the optimal tacrolimus concentration for MG treatment.

Predictive score for oral corticosteroid-induced initial worsening of seropositive generalized myasthenia gravis

BACKGROUND Initial worsening of symptoms after the start of corticosteroid administration is a major concern in the treatment of myasthenia gravis (MG). However, the risk factors or specific patient backgrounds related to this issue have not been fully understood. We aimed to determine the risk factors and developed a scoring system for predicting initial worsening in generalized MG. METHODS We enrolled 62 generalized MG patients with anti-acetylcholine receptor antibody. Initial worsening was defined as an increment of three points in the Quantitative MG score within 2 weeks after the start of steroid treatment. A multivariate logistic regression model was used to determine the risk factors, and predictive scores were assigned. Bootstrap resampling was applied to evaluate the risk score models internal validity. RESULTS Steroid-induced initial worsening occurred in 26% of MG patients and was correlated with thymoma-associated or early-onset MG (p = 0.018), initial prednisolone doses ≥40 mg/day (p = 0.029), and upper limb weakness (p = 0.039). Stepwise multivariate logistic regression identified these three clinical factors for predicting initial worsening in MG. A predictive score of 0-3 points had a bootstrapping area under the curve of 0.770 (0.625-0.878). CONCLUSIONS Our scoring system based on three clinical characteristics can predict the likelihood of steroid-induced initial worsening in MG.

A clinical predictive score for postoperative myasthenic crisis

Myasthenia gravis (MG) is an autoimmune disease mostly caused by autoantibodies against acetylcholine receptor associated with thymus abnormalities. Thymectomy has been proven to be an efficacious treatment for patients with MG, but postoperative myasthenic crisis often occurs and is a major complication. We aimed to develop and validate a simple scoring system based on clinical characteristics in the preoperative status to predict the risk of postoperative myasthenic crisis.

Relationship between damage-associated molecular patterns and cytokines in myasthenia gravis

Damage‐associated molecular patterns (DAMP) and cytokines can play a crucial role in inflammation at neuromuscular junctions in myasthenia gravis (MG). However, the relationship between DAMP and cytokine levels in MG pathogenesis remains unknown. To clarify this, we examined the relationship between serum levels of DAMP and cytokines in MG patients.