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A novel patient cluster in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) may be identified in Japan. We performed multiple correspondence and cluster analysis regarding 427 clinically diagnosed AAV patients excluding eosinophilic granulomatosis with polyangiitis. Model 1 included the ANCA phenotype, items of the Birmingham Vasculitis Activity Score, and interstitial lung disease; model 2 included serum creatinine (s-Cr) and C-reactive protein (CRP) levels with model 1 components. In seven clusters determined in model 1, the ANCA-negative (n = 8) and proteinase 3-ANCA-positive (n = 41) groups emerged as two distinct clusters. The other five myeloperoxidase-ANCA-positive clusters were characterized by ear, nose, and throat (ENT) (n = 47); cutaneous (n = 36); renal (n = 256), non-renal (n = 33); and both ENT and cutaneous symptoms (n = 6). Four clusters in model 2 were characterized by myeloperoxidase-ANCA negativity (n = 42), without s-Cr elevation (< 1.3 mg/dL) (n = 157), s-Cr elevation (≥ 1.3 mg/dL) with high CRP (> 10 mg/dL) (n = 71), or s-Cr elevation (≥ 1.3 mg/dL) without high CRP (≤ 10 mg/dL) (n = 157). Overall, renal, and relapse-free survival rates were significantly different across the four clusters in model 2. ENT, cutaneous, and renal symptoms may be useful in characterization of Japanese AAV patients with myeloperoxidase-ANCA. The combination of s-Cr and CRP levels may be predictive of prognosis.

Among antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), granulomatosis with polyangiitis (GPA) and proteinase 3-ANCA-positive AAV (PR3-AAV) are prevalent in European populations, while microscopic polyangiitis (MPA) and myeloperoxidase-ANCA-positive AAV (MPO-AAV) are predominant in the Japanese. We previously demonstrated association of DRB1*09:01-DQB1*03:03 haplotype, a haplotype common in East Asians but rare in the European populations, with MPA/MPO-AAV, suggesting that a population difference in HLA-class II plays a role in the epidemiology of this disease. To gain further insights, we increased the sample size and performed an extended association study of DRB1 and DPB1 with AAV subsets in 468 Japanese patients with AAV classified according to the European Medicines Agency algorithm (MPA: 285, GPA: 92, eosinophilic GPA [EGPA]: 56, unclassifiable: 35) and 596 healthy controls. Among these patients, 377 were positive for MPO-ANCA and 62 for PR3-ANCA. The significance level was set at α = 3.3x10-4 by applying Bonferroni correction. The association of DRB1*09:01 with MPO-AAV was confirmed (allele model, P = 2.1x10-4, odds ratio [OR] = 1.57). Protective association of DRB1*13:02 was detected against MPO-AAV (allele model, P = 2.3x10-5, OR = 0.42) and MPA (dominant model, P = 2.7x10-4, OR = 0.43). A trend toward increased frequency of DPB1*04:01, the risk allele for GPA in European populations, was observed among Japanese patients with PR3-AAV when conditioned on DRB1*13:02 (Padjusted = 0.0021, ORadjusted = 3.48). In contrast, the frequency of DPB1*04:01 was decreased among Japanese patients with MPO-AAV, and this effect lost significance when conditioned on DRB1*13:02 (Padjusted = 0.16), suggesting that DRB1*13:02 or other allele(s) in linkage disequilibrium may be responsible for the protection. The differential association of DPB1*04:01 with PR3-AAV and MPO-AAV and difference in DPB1*04:01 allele frequencies between populations supported the hypothesis that the HLA-class II population difference may account in part for these epidemiologic characteristics. Furthermore, taken together with our previous observations, the haplotype carrying DRB1*13:02 was suggested to be a shared protective factor against multiple autoimmune diseases.

Background Neutrophil extracellular traps (NETs) are critically involved in microscopic polyangiitis (MPA) pathogenesis, and some patients with MPA possess anti-NET antibody (ANETA). Anti-myosin light chain 6 (MYL6) antibody is an ANETA that affects NETs. This study aimed to determine the significance of anti-MYL6 antibody in MPA. Methods The influence of anti-MYL6 antibody on NET formation and actin rearrangement necessary for NET formation was assessed by fluorescent staining. An enzyme-linked immunosorbent assay was established to detect serum anti-MYL6 antibody, and the prevalence of this antibody in MPA was determined. Furthermore, the disease activity and response to remission-induction therapy of MPA were compared between anti-MYL6 antibody-positive and anti-MYL6 antibody-negative MPA patients. Results Anti-MYL6 antibody disrupted G-actin polymerization into F-actin, suppressing phorbol 12-myristate 13-acetate-induced NET formation. Serum anti-MYL6 antibody was detected in 7 of 59 patients with MPA. The Birmingham vasculitis activity score (BVAS) of anti-MYL6 antibody-positive MPA patients was significantly lower than anti-MYL6 antibody-negative MPA patients. Among the nine BVAS evaluation items, the cutaneous, cardiovascular, and nervous system scores of anti-MYL6 antibody-positive MPA patients were significantly lower than anti-MYL6 antibody-negative MPA patients, although other items, including the renal and chest scores, were equivalent between the two groups. The proportion of patients with remission 6 months after initiation of remission-induction therapy in anti-MYL6 antibody-positive MPA patients was significantly higher than in anti-MYL6 antibody-negative MPA patients. Conclusions Collective findings suggested that anti-MYL6 antibody disrupted actin rearrangement necessary for NET formation and could reduce the disease activity of MPA.

Background Interstitial lung disease (ILD) is a severe complication with poor prognosis in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Prevalence of AAV-associated ILD (AAV-ILD) in Japan is considerably higher than that in Europe. Recently, we reported that a MUC5B variant rs35705950, the strongest susceptibility variant to idiopathic pulmonary fibrosis (IPF), was strikingly increased in AAV-ILD patients but not in AAV patients without ILD; however, due to the low allele frequency in the Japanese population, the MUC5B variant alone cannot account for the high prevalence of AAV-ILD in Japan. In this study, we examined whether other IPF susceptibility alleles in TERT and DSP genes are associated with susceptibility to AAV subsets and AAV-ILD. Methods Five hundred and forty-four Japanese patients with AAV and 5558 controls were analyzed. Among the AAV patients, 432 were positive for myeloperoxidase (MPO)-ANCA (MPO-AAV). A total of 176 MPO-AAV patients were positive and 216 were negative for ILD based on CT or high-resolution CT. Genotypes of TERT and DSP variants were determined by TaqMan SNP Genotyping Assay, and their association was tested by chi-square test. Results When the frequencies of the IPF risk alleles TERT rs2736100A and DSP rs2076295G were compared between AAV subsets and healthy controls, both alleles were significantly increased in microscopic polyangiitis (MPA) ( TERT P  = 2.3 × 10 −4 , P c  = 0.0023, odds ratio [OR] 1.38; DSP P  = 6.9 × 10 −4 , P c  = 0.0069, OR 1.32) and MPO-AAV ( TERT P  = 1.5 × 10 −4 , P c  = 0.0015, OR 1.33; DSP P  = 0.0011, P c  = 0.011, OR 1.26). On the other hand, no significant association was detected when the allele frequencies were compared between MPO-AAV patients with and without ILD. Conclusions Unexpectedly, TERT and DSP IPF risk alleles were found to be associated with MPA and MPO-AAV, regardless of the presence of ILD. These findings suggest that TERT and DSP may be novel susceptibility genes to MPA/MPO-AAV and also that some susceptibility genes may be shared between IPF and MPA/MPO-AAV.

Rapidly progressive glomerulonephritis (RPGN) has been known to have a poor prognosis. Although evidence across adult RPGN cases has accumulated over many years, the number of case series in adolescents and young adults has been limited, requiring further studies. A total of 1,766 cases from 1989 to 2007 were included in this nationwide questionnaire survey, led by Intractable (former name, Progressive) Renal Diseases Research, Research on intractable disease, from the Ministry of Health, Labour and Welfare of Japan. To elucidate age-related differences in 2-year patient and renal survival rates, the cases were divided into the following four groups: children (0-18 years), young adults (19-39 years), the middle-aged (40-64 years), and the elderly (over 65 years). Of the 1,766 total RPGN cases, antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis comprised 1,128 cases (63.9% of all RPGN cases), showing a tendency to increase with age. Two-year patient survival for RPGN was 93.9% among children, 92.6% in young adults, 83.2% in the middle-aged, and 68.8% in the elderly. The younger group (children plus young adults) showed a clearly higher survival rate compared to the older group (middle-aged plus elderly) (p<0.05). ANCA-associated glomerulonephritis also showed similar age-related results with all RPGN cases. The comparison of renal prognosis showed no statistically significant differences both in RPGN and in ANCA-associated GN. The present study described the age-dependent characteristics of the classification of RPGN, especially focusing on a better prognosis of the younger group in patient survival both in RPGN and in ANCA-associated GN.

Disease relapse remains a major problem in the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In European populations, is associated with both susceptibility and relapse risk in proteinase 3-ANCA positive AAV. In a Japanese population, we previously reported an association between and with susceptibility to, and with protection from, myeloperoxidase-ANCA positive AAV (MPO-AAV). Subsequently, the association of , which is in strong linkage disequilibrium with and , with MPO-AAV susceptibility was reported in a Chinese population. However, an association between these alleles and risk of relapse has not yet been reported. Here, we examined whether is associated with the risk of relapse in MPO-AAV. First, the association of with susceptibility to MPO-AAV and microscopic polyangiitis (MPA) and its relationship with previously reported and were examined in 440 Japanese patients and 779 healthy controls. Next, the association with risk of relapse was analyzed in 199 MPO-ANCA positive, PR3-ANCA negative patients enrolled in previously reported cohort studies on remission induction therapy. Uncorrected P values (P ) were corrected for multiple comparisons in each analysis using the false discovery rate method. The association of with susceptibility to MPO-AAV and MPA was confirmed in a Japanese population (MPO-AAV: P =5.8x10 , odds ratio [OR] 1.74, 95% confidence interval [CI] 1.40-2.16, MPA: P =1.1x10 , OR 1.71, 95%CI 1.34-2.17). was in strong linkage disequilibrium with and , and the causal allele could not be determined using conditional logistic regression analysis. Relapse-free survival was shorter with nominal significance in carriers of (P =0.049, Q=0.42, hazard ratio [HR]:1.87), (P =0.020, Q=0.22, HR:2.11) and (P =0.043, Q=0.48, HR:1.91) than in non-carriers in the log-rank test. Conversely, serine carriers at position 13 of HLA-DRβ1 (HLA-DRβ1_13S), including carriers, showed longer relapse-free survival with nominal significance (P =0.010, Q=0.42, HR:0.31). By combining and HLA-DRβ1_13S, a significant difference was detected between groups with the highest and lowest risk for relapse (P =0.0055, Q=0.033, HR:4.02). is associated not only with susceptibility to MPO-AAV but also with risk of relapse in the Japanese population.

Introduction This study aims to elucidate the prognosis and the effectiveness of current treatments for Japanese patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). Methods Patients with newly diagnosed MPA and GPA were enrolled in a nationwide, prospective, inception cohort study from 22 tertiary Japanese institutions, and treatment patterns and responses were evaluated for 24 months. Primary outcome measures were rates of remission (Birmingham Vasculitis Activity Score, 0) and remission with low-dose glucocorticoids (GC) (prednisolone ≤ 10 mg) (GC remission). Results Of 156 enrolled patients, 78 MPA patients and 33 GPA patients were included. Concomitant cyclophosphamide (CY) was used in 24 MPA (31 %) and 20 GPA (60 %) patients during the initial 3 weeks of treatment. After 6 months, remission was achieved in 66 MPA (85 %) and 29 GPA (87 %) patients, while GC remission was obtained in only 31 MPA (40 %) and 13 GPA (39 %) patients. During the 24-month period, 14 MPA patients and 2 GPA patients died; end stage renal disease (ESRD) was noted in 13 MPA patients but no GPA patients. Patients with severe disease, according to the European Vasculitis Study Group (EUVAS) classification, showed poorer ESRD-free and overall survival rates than those with generalized disease (p < 0.0001). There were no differences in relapse-free survival rates between GPA and MPA, among EUVAS-defined disease severity categories, and between anti-neutrophil cytoplasmic antibody subspecialties. Conclusions The majority of Japanese patients with MPA and GPA received treatment with high-dose GC and limited CY use, and showed high remission and relapse-free survival rates but low GC remission rates in clinical practice. Trial registration University Hospital Medical Information Network Clinical Trials Registry UMIN000001648 . Registered 28 February 2009.

Background\\nMicroscopic polyangiitis (MPA), which is classified as an anti-neutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitis, is one of the most frequent primary vasculitides in Japan. We earlier nominated 16 genes (IRF7, IFIT1, IFIT5, OASL, CLC, GBP-1, PSMB9, HERC5, CCR1, CD36, MS4A4A, BIRC4BP, PLSCR1, DEFA1/DEFA3, DEFA4, and COL9A2) as predictors of response to remission induction therapy against MPA. The aim of this study is to determine the accuracy of prediction using these 16 predictors.\\nMethods\\nThirty-nine MPA patients were selected randomly and retrospectively from the Japanese nationwide RemIT-JAV-RPGN cohort and enrolled in this study. Remission induction therapy was conducted according to the Guidelines of Treatment for ANCA-Associated Vasculitis published by the Ministry of Health, Labour, and Welfare of Japan. Response to remission induction therapy was predicted by profiling the altered expressions of the 16 predictors between the period before and 1 week after the beginning of treatment. Remission is defined as the absence of clinical manifestations of active vasculitis (Birmingham Vasculitis Activity Score 2003: 0 or 1 point). Persistent remission for 18 months is regarded as a \"good response,\" whereas no remission or relapse after remission is regarded as a \"poor response.\"\\nResults\\n\"Poor\" and \"good\" responses were predicted in 7 and 32 patients, respectively. Five out of 7 patients with \"poor\" prediction and 1 out of 32 patients with \"good\" prediction experienced relapse after remission. One out of 7 patients with \"poor\" prediction was not conducted to remission. Accordingly, the sensitivity and specificity to predict poor response was 85.7% (6/7) and 96.9% (31/32), respectively.\\nConclusions\\nResponse to remission induction therapy can be predicted by monitoring the altered expressions of the 16 predictors in the peripheral blood at an early point of treatment in MPA patients.

BackgroundThe life prognosis of elderly patients with myeloperoxidase–anti-neutrophil cytoplasmic antibodies-associated vasculitis (MPO-AAV) has been improved by reducing the corticosteroid or cyclophosphamide dose to avoid opportunistic infection. However, many elderly MPO-AAV patients experience recurrence and renal death. An effective and safer maintenance treatment method is necessary to improve the renal prognosis of MPO-AAV.MethodsPatients with MPO-AAV who reached complete or incomplete remission after induction therapy were prospectively and randomly divided into mizoribine (MZR; n = 25) and control (n = 28) groups. The primary endpoint was relapse of MPO-AAV. The patients’ serum MZR concentration was measured before (C0) and 3 h after taking the MZR. The maximum drug concentration (Cmax) and the serum MZR concentration curves were determined using population pharmacokinetics parameters. We also assessed the relationship between the MZR concentrations and adverse events. The observation period was 12 months.ResultsFifty-eight MPO-AAV patients from 16 hospitals in Japan were enrolled. Ten patients relapsed (MZR group, n = 6; control group, n = 4; a nonsignificant between-group difference). Changes in the serum MZR concentration could be estimated for 22 of the 25 MZR-treated patients: 2 of the 11 patients who reached a Cmax of 3 μg/mL relapsed, whereas 4 of the 11 patients who did not reach this Cmax relapsed. The treatment of one patient with C0 > 1 μg/mL was discontinued due to adverse events. No serious adverse events occurred.ConclusionThere was no significant difference in the recurrence rate of MPO-AAV between treatment with versus without MZR.

Background This study was conducted to standardize treatment and determine patient and renal outcome in Japanese anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis/rapidly progressive glomerulonephritis (AAV/RPGN) patients, because the prognosis of AAV/RPGN patients in Japan had been poor compared with that of other countries. Methods The participants in this retrospective cohort study were 824 ANCA-positive RPGN patients, 705 of whom were only myeloperoxidase (MPO)-ANCA positive. Results Among the early-years cohort (group A; cases diagnosed between 1988 and 1998), patients frequently died due to opportunistic infection. Therefore, we recommended a reduced dose of prednisolone (oral prednisolone dose <0.8 mg/kg/day) with or without cyclophosphamide for initial treatment of Japanese RPGN patients. After this recommendation, 1-year survival of the patients improved: 75% in group A, 79% in group B (between 1999 and 2002), and 81% in group C (after 2003). During the entire observation period, average serum creatinine level at the start of treatment decreased, and improvement of 1-year renal survival was also found (72% in group A, 83% in group B, and 83% in group C), while the recurrence rate was significantly increased in group C (0.05/patient-year in group A, 0.07/patient-year in group B, and 0.13/patient-year in group C). Conclusions Oral prednisolone dose <0.8 mg/kg/day with or without cyclophosphamide as an initial treatment could improve patient survival in older Japanese AAV/RPGN patients. However, maintenance treatment avoiding relapse should be established to improve renal outcomes.