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Difference in relapse-rate and clinical phenotype by autoantibody-subtype in Japanese patients with anti-neutrophil cytoplasmic antibody-associated vasculitis

Difference in relapse-rate and clinical phenotype by autoantibody-subtype in Japanese patients... Abstract Objective: To correlate the serotype specificity to myeloperoxidase (MPO) and proteinase-3 (PR3) with clinical characteristics in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Methods: Clinical characteristics and outcomes of patients with AAV in our division from 2005 to 2014 were retrospectively compared on the basis of ANCA subtype. Results: We collected the data from 88 patients with MPO–ANCA vasculitis, and 17 with PR3-ANCA vasculitis. Patients with PR3-ANCA vasculitis were younger, and had higher involvement-rates in the eye, nose, and ear. In both MPO- and PR3-ANCA vasculitis, the most frequently involved organ was the respiratory system. Interstitial pneumonia was more frequent in MPO-ANCA vasculitis (52.3% versus 5.9%, p < 0.01), whereas nodular shadow was more frequent in PR3-ANCA vasculitis (9.1% versus 58.8%, p < 0.01). Multivariable Cox proportional hazard regression analysis showed that the hazard ratio of PR3-ANCA for relapse was 2.48 (95% confidence interval 1.14–5.42, p = 0.02). There was no difference in the survival and the progression to end-stage kidney disease and respiratory failure between the two vasculitides. Conclusion: MPO-ANCA vasculitis was a predominant form of AAV in Japan. Classification based on ANCA subtype would be clinically relevant in the prediction of organ involvement and relapse. ANCA-associated vasculitis, MPO-ANCA, PR3-ANCA, Relapse, Survival Introduction Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA, formerly known as Wegener’s granulomatosis), and eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as the Churg–Strauss syndrome) [1]. AAV is pathologically characterized by systemic necrotizing vasculitis in small- to medium-sized vessels. The diagnosis of MPA, GPA, and EGPA has been made on the basis of the clinical, laboratory, and histopathological features specific to each disease. Patients with AAV have overlapping features in the respiratory, peripheral nerves, and renal systems, and have high mortality rate [2]. Because MPA and GPA share similar clinical manifestations, their treatment was investigated under the same disease entity mainly in Western countries. The dominant target antigens of ANCA are myeloperoxidase (MPO) and proteinase-3 (PR3), which are major proteins found in neutrophil azurophilic granules. ANCA is a useful diagnostic marker and may have a certain pathogenesis in vasculitis because both MPO-ANCA and PR3-ANCA can activate neutrophils in vitro [3], and the transfer of MPO-ANCA induces vasculitis in animal model [4]. MPO-ANCA or PR3-ANCA is detectable in a majority of patients with MPA or GPA, but the relationship of these two vasculitides to ANCA subtype is not strictly defined. A recent genome-wide association study showed the evidence of genetic contribution to ANCA specificity [5]. MPO-ANCA was associated with HLA-DQ, and PR3-ANCA with HLA-DP and genes encoding α1-antitrypsin and PR3. This result strongly indicates that MPO-ANCA and PR3-ANCA vasculitides are genetically distinct. Thus, a study demonstrated that the disease classification based on ANCA subtype was useful to distinguish clinical phenotypes and better predict a relapse of AAV [6]. There are ethnic and geographic differences in the incidence of AAV and phenotype of MPA. MPO-ANCA vasculitis is a predominant form of AAV in China and Japan compared to Western countries [7–9]. Because of the predominance of MPO-ANCA vasculitis, clinical studies such as the JMAAV study in Japan focused on MPO-ANCA vasculitis [10,11]. In Europe, the incidences of MPO-ANCA and PR3-ANCA vasculitis differ between northern and southern parts [12,13]. In addition, the type of respiratory involvement of MPA was different between UK and Japan [7]; interstitial lung disease is predominant in Japan whereas alveolar hemorrhage is predominant in UK. The difference in the incidence of AAV and phenotype of MPA by country may be due to the distinct genetic and environmental factors. In this study, we aimed to correlate ANCA subtype with clinical phenotype and outcome of patients with AAV in Japan and compare them with those in Western countries on the basis of literatures. Patients and methods This is a single center retrospective observational study on the clinical phenotypes and outcomes of patients with newly and established diagnosis of AAV. Patients positive for ANCA in our division from 2005 to 2014 were screened for the presence of vasculitic signs from medical records, and patients diagnosed as having AAV were selected. The diagnosis of vasculitis was based on their pathological findings and clinical signs such as mononeuritis multiplex, renal involvement, respiratory involvement, skin involvement, eye, nose, and ear involvement, and muscle involvement. MPO-ANCA and PR3-ANCA were assayed with an enzyme-linked immunosorbent assay (ELISA, NIPRO (Osaka, Japan) for MPO-ANCA, Euro-Diagnostica (Malmo, Sweden) for PR3-ANCA) before March 2012, and a chemiluminescent enzyme immuno assay (CLEIA (Nagoya, Japan), anchor-ELISA (Nagoya, Japan), MBL) after April 2012. The normal limits of the assays were defined by the manufacturers. We reviewed the demographics of the patients including gender, age at diagnosis, organ involvement, treatment, and outcomes of AAV from their medical records. The CRP level and Birmingham vasculitis activity score (BVAS) version 3 [14] at the diagnosis of vasculitis were used to assess the activity of vasculitis. The diagnosis of respiratory involvement was based on the imaging findings of both chest plain x-ray and computed tomography. Pathological analysis was not included because there were not sufficient histopathological data to compare between MPO-ANCA and PR3-ANCA vasculitis. Outcomes assessed in this study included disease relapse, survival of the patients, progression to end-stage kidney disease (ESKD) and respiratory failure. Relapse was defined as a recurrence/development of any organ damage or exacerbation of inflammatory response after the previous treatment, and when treating doctors considered that treatment intensification was needed. Relapse was assessed in only patients whose disease activity subsided by the initial treatment and the disease course could be followed. Survival was defined by excluding death of any cause in all patients. ESKD was defined as an irreversible renal function with estimated glomerular filtration rate less than 15 ml/min for at least three months. Respiratory failure was defined as the irreversible condition that required the introduction of home oxygen therapy (HOT), tracheotomy, or death due to respiratory failure. The progression to ESKD and respiratory failure was assessed in patients who had renal and respiratory involvement specific to AAV. Patients were censored at the time of the last scheduled follow-up visit for the analysis of death and at the time of last scheduled follow-up visit or death for the analysis of relapse and the progression to ESKD and respiratory failure. Patients with AAV were reviewed by ANCA subgroups (MPO-ANCA vasculitis and PR3-ANCA vasculitis) and clinical disease subgroups (MPA, GPA, EGPA, and undifferentiated) based on their clinical data and pathological findings defined by the criteria of Chapel Hill Consensus Conference [15]. We compared the clinical phenotypes, treatment, and outcomes including survival, relapse, and the progression to ESKD and respiratory failure between MPO-ANCA and PR3-ANCA vasculitis. In addition, we compared the clinical phenotype between MPA and GPA. This study was conducted in compliance with the Helsinki Declaration. The institutional review board admitted that informed consents from individual patients were not required as there were no pharmacological or other interventions involved. Instead, it recommended that the explanation of this study be presented at the web homepage of Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University, Japan. Statistical analyses were performed by the Mann–Whitney U test for continuous variables with non-normal distribution, and by χ2 test or Fisher’s exact test (if the cell size was less than five) for categorical variables. We compared relapse, survival, and the progression to ESKD and respiratory failure between MPO-ANCA and PR3-ANCA vasculitis using the Kaplan–Meier survival curves. The curves were compared by log rank test, and the probability of survival or event-free by the Kaplan–Meier curve was calculated at three years for relapse and 10 years for survival and progression to ESKD and respiratory failure. Multivariable Cox proportional hazard regression analysis was performed to reveal factors associated with relapse. Explanatory variables were selected by stepwise backward selection based on p values less than 0.05. A two-sided p value less than 0.05 was considered significant. These statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama Japan), which is a graphical user interface for R version 3.1.1 (The R Foundation for Statistical Computing, Vienna, Austria). EZR is a modified version of R commander version 2.1-2 designed to add statistical function used in biostatistics [16]. Results Screening of AAV The in-patients and out-patients from 2005 to 2014 in our division were screened if they were assayed for ANCA. There were 1501 and 1339 patients who were assayed for MPO-ANCA and PR3-ANCA, respectively. From the list of these patients, we found 126 MPO-ANCA positive and 65 PR3-ANCA positive patients. Among these ANCA positive patients, 88 and 17 patients were diagnosed as having MPO-ANCA vasculitis and PR3-ANCA vasculitis, respectively. Ten patients were both MPO-ANCA and PR3-ANCA positive, and their clinical diagnosis included four MPA, two propylthiouracil-induced vasculitis, one systemic lupus erythematosus (SLE), one ulcerative colitis, one rheumatoid arthritis, and one undiagnosed case. The four patients with MPA double positive for MPO-ANCA and PR3-ANCA were not included in this study. The diagnoses of MPO-ANCA or PR3-ANCA single positive patients without vasculitic signs (non-AAV) were as follows: rheumatoid arthritis, 7 and 11; SLE, 2 and 8; systemic sclerosis, 2 and 3; polymyalgia rheumatica, 1 and 2; polymyositis or dermatomyositis, 2 each; drug induced, 3 and 0; giant cell arteritis, 1 and 0; IgA vasculitis, 0 and 2; primary Sjögren syndrome, 0 and 3; mixed connective tissue disease, 0 and 2; reactive arthritis, 0 and 1; infectious endocarditis, 0 and 1; interstitial pneumonia, 1 and 0; and undiagnosed cases, 19 and 13, respectively. When the titers of MPO-ANCA and PR3-ANCA assayed by ELISA were compared between patients with AAV and non-AAV (MPO-ANCA, 54 versus 21 patients; PR3-ANCA, 10 versus 27 patients), those in patients with AAV were significantly higher than those in patients with non-AAV (median titers were 61.5 versus 20.5 U/ml in MPO-ANCA and 26.1 versus 5.0 U/ml in PR3-ANCA, each p value was <0.01). These median titers of ANCA in MPO-ANCA or PR3-ANCA vasculitis represent the levels of ANCA at the onset of vasculitis as ANCA was assayed at the diagnosis of AAV in most of patients. Patient demographics The demographic data of MPO-ANCA and PR3-ANCA vasculitis are shown in Table 1. MPO-ANCA vasculitis was more frequent than PR3-ANCA vasculitis in this study. There was no gender difference in frequency between them. The median age was higher in patients with MPO-ANCA than in those with PR3-ANCA vasculitis (p < 0.01). The CRP levels and BVAS new/worse were not different between MPO-ANCA and PR3-ANCA vasculitis, but BVAS persistent was higher in MPO-ANCA vasculitis. The clinical diagnosis of MPO-ANCA vasculitis included 71 MPA, 8 GPA, 8 EGPA, and 1 undifferentiated vasculitis, and that of PR3-ANCA vasculitis included 13 GPA, 2 MPA, and 2 undifferentiated vasculitis (p < 0.01). The median follow-up periods were 28 months (range, 0.5–159 months) in patients with MPO-ANCA vasculitis and 36 months (range, 5–314 months) in patients with PR3-ANCA vasculitis. Table 1. Patient characteristics. Type of vasculitis MPO-ANCA PR3-ANCA p Value Number of patients 88 17 Gender, female, no. (%) 59 (67.0) 11 (64.7) 1.0 Age at the diagnosis, median (IQR) years 70 (64–76) 55 (44–66) <0.01 CRP, median (IQR) mg/dL* 5.7 (2.3–10.8) 5.0 (2.1–10.5) 0.79 BVAS new/worse, median (IQR)* 14.5 (11–21) 15 (12.75–20) 0.56 BVAS persistent, median (IQR)* 1 (0–2) 0 (0–0) <0.01 Number of patients diagnosed with (%)† <0.01  MPA 71 (80.7) 2 (11.8)  GPA 8 (9.1) 13 (76.4)  EGPA 8 (9.1) 0 (0)  Undifferentiated 1 (1.1) 2 (11.8) Type of vasculitis MPO-ANCA PR3-ANCA p Value Number of patients 88 17 Gender, female, no. (%) 59 (67.0) 11 (64.7) 1.0 Age at the diagnosis, median (IQR) years 70 (64–76) 55 (44–66) <0.01 CRP, median (IQR) mg/dL* 5.7 (2.3–10.8) 5.0 (2.1–10.5) 0.79 BVAS new/worse, median (IQR)* 14.5 (11–21) 15 (12.75–20) 0.56 BVAS persistent, median (IQR)* 1 (0–2) 0 (0–0) <0.01 Number of patients diagnosed with (%)† <0.01  MPA 71 (80.7) 2 (11.8)  GPA 8 (9.1) 13 (76.4)  EGPA 8 (9.1) 0 (0)  Undifferentiated 1 (1.1) 2 (11.8) *These are at the diagnosis of vasculitis. The numbers of patients with PR3-ANCA vasculitis whose BVAS calculated was 16. †There was a difference in the ratio of clinical diagnosis between MPO-ANCA and PR3-ANCA vasculitis (p < 0.01). IQR: interquartile range; BVAS: Birmingham vasculitis activity score. Open in new tab Table 1. Patient characteristics. Type of vasculitis MPO-ANCA PR3-ANCA p Value Number of patients 88 17 Gender, female, no. (%) 59 (67.0) 11 (64.7) 1.0 Age at the diagnosis, median (IQR) years 70 (64–76) 55 (44–66) <0.01 CRP, median (IQR) mg/dL* 5.7 (2.3–10.8) 5.0 (2.1–10.5) 0.79 BVAS new/worse, median (IQR)* 14.5 (11–21) 15 (12.75–20) 0.56 BVAS persistent, median (IQR)* 1 (0–2) 0 (0–0) <0.01 Number of patients diagnosed with (%)† <0.01  MPA 71 (80.7) 2 (11.8)  GPA 8 (9.1) 13 (76.4)  EGPA 8 (9.1) 0 (0)  Undifferentiated 1 (1.1) 2 (11.8) Type of vasculitis MPO-ANCA PR3-ANCA p Value Number of patients 88 17 Gender, female, no. (%) 59 (67.0) 11 (64.7) 1.0 Age at the diagnosis, median (IQR) years 70 (64–76) 55 (44–66) <0.01 CRP, median (IQR) mg/dL* 5.7 (2.3–10.8) 5.0 (2.1–10.5) 0.79 BVAS new/worse, median (IQR)* 14.5 (11–21) 15 (12.75–20) 0.56 BVAS persistent, median (IQR)* 1 (0–2) 0 (0–0) <0.01 Number of patients diagnosed with (%)† <0.01  MPA 71 (80.7) 2 (11.8)  GPA 8 (9.1) 13 (76.4)  EGPA 8 (9.1) 0 (0)  Undifferentiated 1 (1.1) 2 (11.8) *These are at the diagnosis of vasculitis. The numbers of patients with PR3-ANCA vasculitis whose BVAS calculated was 16. †There was a difference in the ratio of clinical diagnosis between MPO-ANCA and PR3-ANCA vasculitis (p < 0.01). IQR: interquartile range; BVAS: Birmingham vasculitis activity score. Open in new tab Organ involvement in AAV The organ involvement of the patients is shown in Table 2. There was a significant difference in the eye, nose, and ear involvement between MPO-ANCA and PR3-ANCA vasculitis (p value was <0.01, <0.01, and 0.01). The respiratory system was the most frequently involved organ in both MPO-ANCA and PR3-ANCA vasculitis (83.0% and 88.2%, respectively), with no difference in their incidence (p = 0.73). However, the type of respiratory involvement was different; interstitial lung disease was more frequent in MPO-ANCA vasculitis (p < 0.01), and nodular shadow in PR3-ANCA vasculitis (p < 0.01). In other organs, there was no difference in their incidence of organ involvement between MPO-ANCA and PR3-ANCA vasculitis. When limited to 73 patients with MPA (71 patients with MPO-ANCA vasculitis and 2 patients with PR3-ANCA vasculitis), 44 (60.3%) and 3 (4.1%) patients had interstitial lung disease and alveolar hemorrhage, respectively. When we compared the clinical characteristics between MPA and GPA (Table 3), the results were similar to those of comparison between MPO-ANCA and PR3-ANCA vasculitis. The incidences of nodular lesion in MPO-ANCA positive GPA and PR3-ANCA positive GPA were 4 of 8 (50%) and 9 of 13 (69%), respectively (p = 0.65). Table 2. Type and incidence of organ involvement. Organ involvement, no. (%) MPO-ANCA vasculitis (n = 88) PR3-ANCA vasculitis (n = 17) p Value Kidney* 60 (68.2) 9 (52.9) 0.27 Respiratory system† 73 (83.0) 15 (88.2) 0.73  Interstitial lung disease 46 (52.3) 1 (5.9) <0.01  Nodular shadow 8 (9.1) 10 (58.8) <0.01  Pleuritis 3 (3.4) 1 (5.9) 0.51  Consolidation 5 (5.7) 2 (11.8) 0.32  Airway disease 11 (12.5) 0 (0) 0.21  Emphysema 7 (8.0) 0 (0) 0.60  Alveolar hemorrhage 5 (5.7) 3 (17.6) 0.12  Asthma 9 (10.2) 2 (11.8) 1.0 Peripheral nerves 34 (38.6) 6 (35.3) 1.0 Central nervous system 9 (10.2) 1 (5.9) 1.0 Eye‡ 7 (8.0) 7 (41.2) <0.01 Nose, paranasal sinus 15 (17.0) 10 (58.8) <0.01 Ear§ 18 (20.5) 9 (52.9) 0.01 Skin 19 (21.6) 7 (41.2) 0.12 Gastro-intestinal and hepatobiliary systems 16 (18.2) 3 (17.6) 1.0 Cardiovascular system 6 (6.8) 0 (0) 0.59 Organ involvement, no. (%) MPO-ANCA vasculitis (n = 88) PR3-ANCA vasculitis (n = 17) p Value Kidney* 60 (68.2) 9 (52.9) 0.27 Respiratory system† 73 (83.0) 15 (88.2) 0.73  Interstitial lung disease 46 (52.3) 1 (5.9) <0.01  Nodular shadow 8 (9.1) 10 (58.8) <0.01  Pleuritis 3 (3.4) 1 (5.9) 0.51  Consolidation 5 (5.7) 2 (11.8) 0.32  Airway disease 11 (12.5) 0 (0) 0.21  Emphysema 7 (8.0) 0 (0) 0.60  Alveolar hemorrhage 5 (5.7) 3 (17.6) 0.12  Asthma 9 (10.2) 2 (11.8) 1.0 Peripheral nerves 34 (38.6) 6 (35.3) 1.0 Central nervous system 9 (10.2) 1 (5.9) 1.0 Eye‡ 7 (8.0) 7 (41.2) <0.01 Nose, paranasal sinus 15 (17.0) 10 (58.8) <0.01 Ear§ 18 (20.5) 9 (52.9) 0.01 Skin 19 (21.6) 7 (41.2) 0.12 Gastro-intestinal and hepatobiliary systems 16 (18.2) 3 (17.6) 1.0 Cardiovascular system 6 (6.8) 0 (0) 0.59 *The kidney involvement includes patients with pathological findings, elevation of serum creatinine level, proteinuria, and hematuria indicating glomerulonephritis. †The numbers indicate the total number of patients with respiratory involvement. There are overlaps in the respiratory involvement. The respiratory involvement is classified based on the CT imaging and clinical findings. ‡The eye involvement includes scleritis, episcleritis, conjunctivitis, and uveitis. §The ear involvement includes exudative otitis, and sensorineural, conductive, and combined hearing loss. Open in new tab Table 2. Type and incidence of organ involvement. Organ involvement, no. (%) MPO-ANCA vasculitis (n = 88) PR3-ANCA vasculitis (n = 17) p Value Kidney* 60 (68.2) 9 (52.9) 0.27 Respiratory system† 73 (83.0) 15 (88.2) 0.73  Interstitial lung disease 46 (52.3) 1 (5.9) <0.01  Nodular shadow 8 (9.1) 10 (58.8) <0.01  Pleuritis 3 (3.4) 1 (5.9) 0.51  Consolidation 5 (5.7) 2 (11.8) 0.32  Airway disease 11 (12.5) 0 (0) 0.21  Emphysema 7 (8.0) 0 (0) 0.60  Alveolar hemorrhage 5 (5.7) 3 (17.6) 0.12  Asthma 9 (10.2) 2 (11.8) 1.0 Peripheral nerves 34 (38.6) 6 (35.3) 1.0 Central nervous system 9 (10.2) 1 (5.9) 1.0 Eye‡ 7 (8.0) 7 (41.2) <0.01 Nose, paranasal sinus 15 (17.0) 10 (58.8) <0.01 Ear§ 18 (20.5) 9 (52.9) 0.01 Skin 19 (21.6) 7 (41.2) 0.12 Gastro-intestinal and hepatobiliary systems 16 (18.2) 3 (17.6) 1.0 Cardiovascular system 6 (6.8) 0 (0) 0.59 Organ involvement, no. (%) MPO-ANCA vasculitis (n = 88) PR3-ANCA vasculitis (n = 17) p Value Kidney* 60 (68.2) 9 (52.9) 0.27 Respiratory system† 73 (83.0) 15 (88.2) 0.73  Interstitial lung disease 46 (52.3) 1 (5.9) <0.01  Nodular shadow 8 (9.1) 10 (58.8) <0.01  Pleuritis 3 (3.4) 1 (5.9) 0.51  Consolidation 5 (5.7) 2 (11.8) 0.32  Airway disease 11 (12.5) 0 (0) 0.21  Emphysema 7 (8.0) 0 (0) 0.60  Alveolar hemorrhage 5 (5.7) 3 (17.6) 0.12  Asthma 9 (10.2) 2 (11.8) 1.0 Peripheral nerves 34 (38.6) 6 (35.3) 1.0 Central nervous system 9 (10.2) 1 (5.9) 1.0 Eye‡ 7 (8.0) 7 (41.2) <0.01 Nose, paranasal sinus 15 (17.0) 10 (58.8) <0.01 Ear§ 18 (20.5) 9 (52.9) 0.01 Skin 19 (21.6) 7 (41.2) 0.12 Gastro-intestinal and hepatobiliary systems 16 (18.2) 3 (17.6) 1.0 Cardiovascular system 6 (6.8) 0 (0) 0.59 *The kidney involvement includes patients with pathological findings, elevation of serum creatinine level, proteinuria, and hematuria indicating glomerulonephritis. †The numbers indicate the total number of patients with respiratory involvement. There are overlaps in the respiratory involvement. The respiratory involvement is classified based on the CT imaging and clinical findings. ‡The eye involvement includes scleritis, episcleritis, conjunctivitis, and uveitis. §The ear involvement includes exudative otitis, and sensorineural, conductive, and combined hearing loss. Open in new tab Table 3. Patient demographics based on clinical diagnosis. Type of vasculitis MPA GPA p Value Number of patients 73 21 Gender, female, no. (%) 49 (67.1) 14 (66.7) 1.0 Age at the diagnosis, median (IQR) years 70 (66–76) 60 (52–69) <0.01 MPO-ANCA positive, no. (%) 71 (97.3) 8 (38.1) <0.01 PR3-ANCA positive, no. (%) 2 (2.7) 13 (61.9) <0.01 CRP, median (IQR) mg/dL* 6.5 (2.3–11.5) 5.7 (1.8–9.0) 0.89 BVAS new/worse, median (IQR)* 14 (11–20) 15 (11.5–19.25) 0.69 BVAS persistent, median (IQR)* 0 (0–2) 0 (0–1) 0.40 Organ involvement, no (%) Kidney 57 (78.0) 12 (57.1) 0.09 Respiratory system 63 (86.3) 17 (81.0) 0.51  Interstitial lung disease 44 (60.3) 1 (4.8) <0.01  Nodular shadow 3 (4.1) 13 (61.9) <0.01  Alveolar hemorrhage 4 (5.5) 3 (14.3) 0.18  Asthma 1 (1.4) 2 (9.5) 0.12 Peripheral nerves 26 (35.6) 8 (38.1) 1.0 Central nervous system 8 (11.0) 2 (9.5) 1.0 Eye 7 (9.6) 6 (28.6) 0.07 Nose, paranasal sinus 10 (13.7) 12 (57.1) <0.01 Ear 16 (21.9) 11 (52.4) 0.01 Type of vasculitis MPA GPA p Value Number of patients 73 21 Gender, female, no. (%) 49 (67.1) 14 (66.7) 1.0 Age at the diagnosis, median (IQR) years 70 (66–76) 60 (52–69) <0.01 MPO-ANCA positive, no. (%) 71 (97.3) 8 (38.1) <0.01 PR3-ANCA positive, no. (%) 2 (2.7) 13 (61.9) <0.01 CRP, median (IQR) mg/dL* 6.5 (2.3–11.5) 5.7 (1.8–9.0) 0.89 BVAS new/worse, median (IQR)* 14 (11–20) 15 (11.5–19.25) 0.69 BVAS persistent, median (IQR)* 0 (0–2) 0 (0–1) 0.40 Organ involvement, no (%) Kidney 57 (78.0) 12 (57.1) 0.09 Respiratory system 63 (86.3) 17 (81.0) 0.51  Interstitial lung disease 44 (60.3) 1 (4.8) <0.01  Nodular shadow 3 (4.1) 13 (61.9) <0.01  Alveolar hemorrhage 4 (5.5) 3 (14.3) 0.18  Asthma 1 (1.4) 2 (9.5) 0.12 Peripheral nerves 26 (35.6) 8 (38.1) 1.0 Central nervous system 8 (11.0) 2 (9.5) 1.0 Eye 7 (9.6) 6 (28.6) 0.07 Nose, paranasal sinus 10 (13.7) 12 (57.1) <0.01 Ear 16 (21.9) 11 (52.4) 0.01 *These are at the diagnosis of vasculitis. The numbers of patients with GPA whose BVAS was calculated was 20. Open in new tab Table 3. Patient demographics based on clinical diagnosis. Type of vasculitis MPA GPA p Value Number of patients 73 21 Gender, female, no. (%) 49 (67.1) 14 (66.7) 1.0 Age at the diagnosis, median (IQR) years 70 (66–76) 60 (52–69) <0.01 MPO-ANCA positive, no. (%) 71 (97.3) 8 (38.1) <0.01 PR3-ANCA positive, no. (%) 2 (2.7) 13 (61.9) <0.01 CRP, median (IQR) mg/dL* 6.5 (2.3–11.5) 5.7 (1.8–9.0) 0.89 BVAS new/worse, median (IQR)* 14 (11–20) 15 (11.5–19.25) 0.69 BVAS persistent, median (IQR)* 0 (0–2) 0 (0–1) 0.40 Organ involvement, no (%) Kidney 57 (78.0) 12 (57.1) 0.09 Respiratory system 63 (86.3) 17 (81.0) 0.51  Interstitial lung disease 44 (60.3) 1 (4.8) <0.01  Nodular shadow 3 (4.1) 13 (61.9) <0.01  Alveolar hemorrhage 4 (5.5) 3 (14.3) 0.18  Asthma 1 (1.4) 2 (9.5) 0.12 Peripheral nerves 26 (35.6) 8 (38.1) 1.0 Central nervous system 8 (11.0) 2 (9.5) 1.0 Eye 7 (9.6) 6 (28.6) 0.07 Nose, paranasal sinus 10 (13.7) 12 (57.1) <0.01 Ear 16 (21.9) 11 (52.4) 0.01 Type of vasculitis MPA GPA p Value Number of patients 73 21 Gender, female, no. (%) 49 (67.1) 14 (66.7) 1.0 Age at the diagnosis, median (IQR) years 70 (66–76) 60 (52–69) <0.01 MPO-ANCA positive, no. (%) 71 (97.3) 8 (38.1) <0.01 PR3-ANCA positive, no. (%) 2 (2.7) 13 (61.9) <0.01 CRP, median (IQR) mg/dL* 6.5 (2.3–11.5) 5.7 (1.8–9.0) 0.89 BVAS new/worse, median (IQR)* 14 (11–20) 15 (11.5–19.25) 0.69 BVAS persistent, median (IQR)* 0 (0–2) 0 (0–1) 0.40 Organ involvement, no (%) Kidney 57 (78.0) 12 (57.1) 0.09 Respiratory system 63 (86.3) 17 (81.0) 0.51  Interstitial lung disease 44 (60.3) 1 (4.8) <0.01  Nodular shadow 3 (4.1) 13 (61.9) <0.01  Alveolar hemorrhage 4 (5.5) 3 (14.3) 0.18  Asthma 1 (1.4) 2 (9.5) 0.12 Peripheral nerves 26 (35.6) 8 (38.1) 1.0 Central nervous system 8 (11.0) 2 (9.5) 1.0 Eye 7 (9.6) 6 (28.6) 0.07 Nose, paranasal sinus 10 (13.7) 12 (57.1) <0.01 Ear 16 (21.9) 11 (52.4) 0.01 *These are at the diagnosis of vasculitis. The numbers of patients with GPA whose BVAS was calculated was 20. Open in new tab Treatment We retrospectively reviewed the treatment for AAV. The use of glucocorticoid and its dose were not different between MPO-ANCA and PR3-ANCA vasculitis, whereas the use of cyclophosphamide was different. Intravenous or oral cyclophosphamide was administered in 28 (31.8%) and 15 (88.2%) patients with MPO-ANCA and PR3-ANCA vasculitis, respectively. Rituximab was administered in six patients with PR3-ANCA vasculitis (35.3%) for the relapses of AAV, whereas there was only one patient with MPO-ANCA vasculitis (1.1%) who was treated with rituximab for the relapse. Analysis of relapse, survival, ESKD, and respiratory failure We compared outcomes between MPO-ANCA and PR3-ANCA vasculitis (Figure 1a–d). When assessed by the Kaplan-Meier curve, relapse-free rate was lower in PR3-ANCA than in MPO-ANCA vasculitis (log rank analysis, p = 0.02, Figure 1a). The probability of relapse-free in MPO-ANCA and PR-3 ANCA vasculitis at three years were 0.62 and 0.34, respectively. Multivariable Cox proportional hazard regression analysis using explanatory variables including age, sex, ANCA subtype, respiratory involvement, and renal involvement showed that PR3-ANCA positivity was associated with relapse (hazard ratio 2.48, 95% confidence interval 1.14–5.42, p = 0.02) (Table 4). In contrast, there was no difference in survival, ESKD-free, and respiratory failure-free between MPO-ANCA and PR3-ANCA vasculitis by Kaplan–Meier curves (Figure 1b–d). The probabilities of survival, ESKD-free, and respiratory failure-free in MPO-ANCA and PR3-ANCA vasculitis at 10 years were 0.60 versus 0.89, 0.92 versus 0.80, and 0.51 versus 0.86, respectively. The cause of death included six exacerbation of AAV (four respiratory failure due to interstitial lung disease and two gastrointestinal involvements), three infections (one Pneumocystis pneumonia, one sepsis, and one unknown organism), and two unknown causes in MPO-ANCA, and one suicide in PR3-ANCA vasculitis. Respiratory failure included introduction of HOT in five, death due to exacerbation of lung disease in three, tracheotomy due to bilateral recurrent nerve palsy in one, Pneumocystis pneumonia in one, and respiratory failure related to pleuritis in one with MPO-ANCA vasculitis, and introduction of HOT in one with PR3-ANCA vasculitis. Figure 1. Open in new tabDownload slide Kaplan–Meier curves of relapse (a), survival (b) and the progression to end-stage kidney disease (c) and respiratory failure (d). The probabilities of survival or event-free at three years (a) or 10 years (b–d) are shown. Relapse was assessed in patient with AAV in whom remission was introduced, the progression to end-stage kidney disease or respiratory failure was assessed in patients who had kidney or respiratory disease. The curves in each subfigure are compared by log rank test, and the p values are shown in each figure. Figure 1. Open in new tabDownload slide Kaplan–Meier curves of relapse (a), survival (b) and the progression to end-stage kidney disease (c) and respiratory failure (d). The probabilities of survival or event-free at three years (a) or 10 years (b–d) are shown. Relapse was assessed in patient with AAV in whom remission was introduced, the progression to end-stage kidney disease or respiratory failure was assessed in patients who had kidney or respiratory disease. The curves in each subfigure are compared by log rank test, and the p values are shown in each figure. Table 4. Cox proportional hazard regression analysis for relapse. Hazard ratio 95% CI p Value Multivariable analysis*  Age 1.02 0.99–1.06 0.21  Female 0.79 0.40–1.55 0.50  PR3-ANCA positive 3.71 1.36–10.20 0.01  Respiratory involvement 1.51 0.45–5.12 0.51  Renal involvement 0.60 0.29–1.26 0.14 Multivariable analysis†  PR3-ANCA positive 2.48 1.14–5.42 0.02 Hazard ratio 95% CI p Value Multivariable analysis*  Age 1.02 0.99–1.06 0.21  Female 0.79 0.40–1.55 0.50  PR3-ANCA positive 3.71 1.36–10.20 0.01  Respiratory involvement 1.51 0.45–5.12 0.51  Renal involvement 0.60 0.29–1.26 0.14 Multivariable analysis†  PR3-ANCA positive 2.48 1.14–5.42 0.02 *All explanatory variables listed below were forcedly entered. †Explanatory variables were selected by stepwise backward selection with p value <0.05. CI: confidence interval. Open in new tab Table 4. Cox proportional hazard regression analysis for relapse. Hazard ratio 95% CI p Value Multivariable analysis*  Age 1.02 0.99–1.06 0.21  Female 0.79 0.40–1.55 0.50  PR3-ANCA positive 3.71 1.36–10.20 0.01  Respiratory involvement 1.51 0.45–5.12 0.51  Renal involvement 0.60 0.29–1.26 0.14 Multivariable analysis†  PR3-ANCA positive 2.48 1.14–5.42 0.02 Hazard ratio 95% CI p Value Multivariable analysis*  Age 1.02 0.99–1.06 0.21  Female 0.79 0.40–1.55 0.50  PR3-ANCA positive 3.71 1.36–10.20 0.01  Respiratory involvement 1.51 0.45–5.12 0.51  Renal involvement 0.60 0.29–1.26 0.14 Multivariable analysis†  PR3-ANCA positive 2.48 1.14–5.42 0.02 *All explanatory variables listed below were forcedly entered. †Explanatory variables were selected by stepwise backward selection with p value <0.05. CI: confidence interval. Open in new tab Discussion The clinical characteristics of AAV were compared on the basis of their clinical diagnosis: MPA, GPA, and EPGA. However, at present, there are no established diagnostic criteria of AAV for clinical practice. There are classification criteria of American College of Rheumatology for GPA and EGPA, but no criteria for MPA. The criteria of Chapel Hill Consensus Conference and the European Medicines Agency classification system for AAV are currently used [15,17]. However, they were made for the definition or classification for epidemiological studies. MPO-ANCA or PR3-ANCA is detected in a majority of cases with these vasculitic syndromes, and it would be reasonable to classify AAV on the basis of ANCA subtype because ANCA specificity is closely linked to genetic background. In this study, we correlated clinical characteristics with ANCA subtype in Japanese patients with AAV. There were differences in the age and the incidence in the eye, nose, and ear involvement in the two ANCA subtypes. Although there was no difference in the incidence of overall respiratory involvement, the incidence of interstitial lung disease was higher and that of nodular shadow was lower in MPO-ANCA than in PR3-ANCA vasculitis. Except for interstitial lung disease, the result in our study was quite comparable to the report from USA which described that the incidence of respiratory involvement in MPO-ANCA and PR3-ANCA vasculitis is similar, and the incidence of the eye, nose, and ear involvement and lung nodule or cavity is higher in PR-3 ANCA vasculitis [6]. This indicates that PR3-ANCA is a universal marker of the eye, nose, and ear involvement and lung nodule or cavity regardless of genetic or environmental differences. BVAS version 3 is a useful tool for the assessment and follow-up of vasculitis activity [18]. In this study, BVAS new/worse and the CRP levels were not different, but BVAS persistent was different between MPO-ANCA and PR3-ANCA vasculitis. The difference may be partly due to preexisting organ damage such as interstitial pneumonia in MPO-ANCA vasculitis. The results of comparison of clinical characteristics based on serological subtypes were similar to those based on clinical diagnosis. Because the clinical diagnosis of AAV is sometimes difficult due to difficulties in obtaining sufficient pathological specimens or variation in diagnostic criteria, classification of AAV based on ANCA subtype would be an easier way of diagnosis in clinical practice. With regard to the pathogenesis of nodular lesion, we speculate that factors other than ANCA may be involved in the formation of nodular lesion because patients not only with PR3-ANCA positive GPA but also with MPO-ANCA positive GPA showed nodular lesion with approximately the similar incidence. In contrast, the incidence of MPO-ANCA vasculitis was five times higher than that of PR3-ANCA vasculitis, and the incidence of interstitial lung disease was 15 times higher than that of alveolar hemorrhage in MPA in Japan. These results were comparable to those from reports in Japan, but were different from those in Western countries [7,19,20]; ANCA subtype predominance is not observed, and alveolar hemorrhage is more frequent than interstitial lung disease in UK. A similar incidence of AAV is shown in China as in Japan [9]. The difference in the ratio of clinical diagnosis in AAV and the type of respiratory involvement in MPA by country may be due to the difference in genetic or environmental factors. It would be important to clarify the difference in the outcomes of AAV on the basis of ANCA subtype. It is reported that as much as 50% of patients with AAV have a relapse [21–23]. Factors such as PR-3 ANCA, respiratory involvement, cardiac involvement, elevation of serum creatinine level, age, and tapering-pace of prednisolone are reported as the predictors of relapse in AAV [24–28], and the hazard ratio of relapse in PR3-ANCA vasculitis is 1.89 compared to MPO-ANCA vasculitis [6]. Similar to these reports, we found that the relapse rate was higher in PR-3 ANCA than in MPO-ANCA vasculitis with the hazard ratio of 2.48. The reason or pathological mechanism of higher relapse rate in PR3-ANCA vasculitis is not clear, but this finding will be critical in clinical practice because relapse may lead to the impairment of activity of daily living or organ damage. We now utilize rituximab in patients with PR3-ANCA vasculitis with high probability of relapse even after cyclophosphamide use. Rituximab, which targets CD20 molecules on B cell surface, is one of the treatment drugs expected to have a more potent ability to prevent relapse in PR3-ANCA vasculitis [29]. In Japan, rituximab was approved for the treatment of MPA and GPA with high disease activity or refractory to glucocorticoid in 2014. The optimal maintenance therapy with rituximab, the effectiveness of rituximab to prevent relapse, and the safety of rituximab treatment in Japanese patients with AAV remain to be established. Classification by ANCA subtype may be useful to guide the use of immunosuppression in AAV because patients with PR-3 ANCA vasculitis responded rituximab better than cyclophosphamide [30]. In contrast to relapse, there was no difference in survival and progression to respiratory failure and ESKD between MPO-ANCA and PR3-ANCA vasculitis assessed by Kaplan–Meier curves. Our result about survival was comparable to the report that classification based on ANCA subtype is not useful in distinguishing mortality. However, with regard to the kidney involvement, there are conflicting reports that the incidence of kidney involvement is lower in PR3-ANCA vasculitis [6], and PR3-ANCA vasculitis is associated with higher mortality [31] and faster deterioration of renal function [32]. The discrepancy might be due to the difference in genetic or environmental factors or referral bias. Since the number of patients with PR3-ANCA vasculitis is small in Japan, further study would be needed to validate the results on this. Our study was done under retrospective observational design. The decision of relapse and drugs employed were not standardized and completely at the discretion of each treating physicians. In addition, the use rate of cyclophosphamide was lower compared to that in Western countries. We acknowledge that there is a possibility that the variation in cyclophosphamide use affected the survival rate and the progression to respiratory or renal failure. The number of the patients with PR3-ANCA vasculitis was small; patients with PR3-ANCA vasculitis are rare in Japan. There may be a referral bias that patients with severe respiratory or renal failure had admitted to divisions of respiratory medicine or nephrology. Some of these drawbacks would be overcome only by prospective multi-institutional study which is definitely needed. There were some ANCA-positive patients who were not diagnosed as AAV, namely, false positive patients. We speculate that one of the reasons may be ANCA assays by ELISA or CLEIA were used as screening test not only for patients with vasculitic signs but also for patients with non-vasculitic signs including fever of unknown origin. It would be important to raise prior probability of vasculitis to avoid the advent of ANCA-false positive patients when utilizing ANCA assays. In conclusion, the results obtained in our study suggest that classification based on ANCA subtype would be useful to distinguish the clinical phenotypes, and to predict relapse of AAV. In addition, there seems to be a difference in the incidence and type of respiratory involvement of AAV with respect to country. Conflicts of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. References Lally L , Spiera R Current landscape of antineutrophil cytoplasmic antibody-associated vasculitis: classification, diagnosis, and treatment. Rheum Dis Clin North Am . 2015 ; 41 : 1 – 19 . Google Scholar Crossref Search ADS PubMed WorldCat Guillevin L , Pagnoux C, Seror R, et al. . The Five-Factor Score revisited: assessment of prognoses of systemic necrotizing vasculitides based on the French Vasculitis Study Group (FVSG) cohort. Medicine . 2011 ; 90 : 19 – 27 . 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Google Scholar Crossref Search ADS PubMed WorldCat © 2016 Japan College of Rheumatology This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Modern Rheumatology Oxford University Press

Difference in relapse-rate and clinical phenotype by autoantibody-subtype in Japanese patients with anti-neutrophil cytoplasmic antibody-associated vasculitis

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1439-7595
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10.1080/14397595.2016.1192760
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Abstract

Abstract Objective: To correlate the serotype specificity to myeloperoxidase (MPO) and proteinase-3 (PR3) with clinical characteristics in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Methods: Clinical characteristics and outcomes of patients with AAV in our division from 2005 to 2014 were retrospectively compared on the basis of ANCA subtype. Results: We collected the data from 88 patients with MPO–ANCA vasculitis, and 17 with PR3-ANCA vasculitis. Patients with PR3-ANCA vasculitis were younger, and had higher involvement-rates in the eye, nose, and ear. In both MPO- and PR3-ANCA vasculitis, the most frequently involved organ was the respiratory system. Interstitial pneumonia was more frequent in MPO-ANCA vasculitis (52.3% versus 5.9%, p < 0.01), whereas nodular shadow was more frequent in PR3-ANCA vasculitis (9.1% versus 58.8%, p < 0.01). Multivariable Cox proportional hazard regression analysis showed that the hazard ratio of PR3-ANCA for relapse was 2.48 (95% confidence interval 1.14–5.42, p = 0.02). There was no difference in the survival and the progression to end-stage kidney disease and respiratory failure between the two vasculitides. Conclusion: MPO-ANCA vasculitis was a predominant form of AAV in Japan. Classification based on ANCA subtype would be clinically relevant in the prediction of organ involvement and relapse. ANCA-associated vasculitis, MPO-ANCA, PR3-ANCA, Relapse, Survival Introduction Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA, formerly known as Wegener’s granulomatosis), and eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as the Churg–Strauss syndrome) [1]. AAV is pathologically characterized by systemic necrotizing vasculitis in small- to medium-sized vessels. The diagnosis of MPA, GPA, and EGPA has been made on the basis of the clinical, laboratory, and histopathological features specific to each disease. Patients with AAV have overlapping features in the respiratory, peripheral nerves, and renal systems, and have high mortality rate [2]. Because MPA and GPA share similar clinical manifestations, their treatment was investigated under the same disease entity mainly in Western countries. The dominant target antigens of ANCA are myeloperoxidase (MPO) and proteinase-3 (PR3), which are major proteins found in neutrophil azurophilic granules. ANCA is a useful diagnostic marker and may have a certain pathogenesis in vasculitis because both MPO-ANCA and PR3-ANCA can activate neutrophils in vitro [3], and the transfer of MPO-ANCA induces vasculitis in animal model [4]. MPO-ANCA or PR3-ANCA is detectable in a majority of patients with MPA or GPA, but the relationship of these two vasculitides to ANCA subtype is not strictly defined. A recent genome-wide association study showed the evidence of genetic contribution to ANCA specificity [5]. MPO-ANCA was associated with HLA-DQ, and PR3-ANCA with HLA-DP and genes encoding α1-antitrypsin and PR3. This result strongly indicates that MPO-ANCA and PR3-ANCA vasculitides are genetically distinct. Thus, a study demonstrated that the disease classification based on ANCA subtype was useful to distinguish clinical phenotypes and better predict a relapse of AAV [6]. There are ethnic and geographic differences in the incidence of AAV and phenotype of MPA. MPO-ANCA vasculitis is a predominant form of AAV in China and Japan compared to Western countries [7–9]. Because of the predominance of MPO-ANCA vasculitis, clinical studies such as the JMAAV study in Japan focused on MPO-ANCA vasculitis [10,11]. In Europe, the incidences of MPO-ANCA and PR3-ANCA vasculitis differ between northern and southern parts [12,13]. In addition, the type of respiratory involvement of MPA was different between UK and Japan [7]; interstitial lung disease is predominant in Japan whereas alveolar hemorrhage is predominant in UK. The difference in the incidence of AAV and phenotype of MPA by country may be due to the distinct genetic and environmental factors. In this study, we aimed to correlate ANCA subtype with clinical phenotype and outcome of patients with AAV in Japan and compare them with those in Western countries on the basis of literatures. Patients and methods This is a single center retrospective observational study on the clinical phenotypes and outcomes of patients with newly and established diagnosis of AAV. Patients positive for ANCA in our division from 2005 to 2014 were screened for the presence of vasculitic signs from medical records, and patients diagnosed as having AAV were selected. The diagnosis of vasculitis was based on their pathological findings and clinical signs such as mononeuritis multiplex, renal involvement, respiratory involvement, skin involvement, eye, nose, and ear involvement, and muscle involvement. MPO-ANCA and PR3-ANCA were assayed with an enzyme-linked immunosorbent assay (ELISA, NIPRO (Osaka, Japan) for MPO-ANCA, Euro-Diagnostica (Malmo, Sweden) for PR3-ANCA) before March 2012, and a chemiluminescent enzyme immuno assay (CLEIA (Nagoya, Japan), anchor-ELISA (Nagoya, Japan), MBL) after April 2012. The normal limits of the assays were defined by the manufacturers. We reviewed the demographics of the patients including gender, age at diagnosis, organ involvement, treatment, and outcomes of AAV from their medical records. The CRP level and Birmingham vasculitis activity score (BVAS) version 3 [14] at the diagnosis of vasculitis were used to assess the activity of vasculitis. The diagnosis of respiratory involvement was based on the imaging findings of both chest plain x-ray and computed tomography. Pathological analysis was not included because there were not sufficient histopathological data to compare between MPO-ANCA and PR3-ANCA vasculitis. Outcomes assessed in this study included disease relapse, survival of the patients, progression to end-stage kidney disease (ESKD) and respiratory failure. Relapse was defined as a recurrence/development of any organ damage or exacerbation of inflammatory response after the previous treatment, and when treating doctors considered that treatment intensification was needed. Relapse was assessed in only patients whose disease activity subsided by the initial treatment and the disease course could be followed. Survival was defined by excluding death of any cause in all patients. ESKD was defined as an irreversible renal function with estimated glomerular filtration rate less than 15 ml/min for at least three months. Respiratory failure was defined as the irreversible condition that required the introduction of home oxygen therapy (HOT), tracheotomy, or death due to respiratory failure. The progression to ESKD and respiratory failure was assessed in patients who had renal and respiratory involvement specific to AAV. Patients were censored at the time of the last scheduled follow-up visit for the analysis of death and at the time of last scheduled follow-up visit or death for the analysis of relapse and the progression to ESKD and respiratory failure. Patients with AAV were reviewed by ANCA subgroups (MPO-ANCA vasculitis and PR3-ANCA vasculitis) and clinical disease subgroups (MPA, GPA, EGPA, and undifferentiated) based on their clinical data and pathological findings defined by the criteria of Chapel Hill Consensus Conference [15]. We compared the clinical phenotypes, treatment, and outcomes including survival, relapse, and the progression to ESKD and respiratory failure between MPO-ANCA and PR3-ANCA vasculitis. In addition, we compared the clinical phenotype between MPA and GPA. This study was conducted in compliance with the Helsinki Declaration. The institutional review board admitted that informed consents from individual patients were not required as there were no pharmacological or other interventions involved. Instead, it recommended that the explanation of this study be presented at the web homepage of Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University, Japan. Statistical analyses were performed by the Mann–Whitney U test for continuous variables with non-normal distribution, and by χ2 test or Fisher’s exact test (if the cell size was less than five) for categorical variables. We compared relapse, survival, and the progression to ESKD and respiratory failure between MPO-ANCA and PR3-ANCA vasculitis using the Kaplan–Meier survival curves. The curves were compared by log rank test, and the probability of survival or event-free by the Kaplan–Meier curve was calculated at three years for relapse and 10 years for survival and progression to ESKD and respiratory failure. Multivariable Cox proportional hazard regression analysis was performed to reveal factors associated with relapse. Explanatory variables were selected by stepwise backward selection based on p values less than 0.05. A two-sided p value less than 0.05 was considered significant. These statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama Japan), which is a graphical user interface for R version 3.1.1 (The R Foundation for Statistical Computing, Vienna, Austria). EZR is a modified version of R commander version 2.1-2 designed to add statistical function used in biostatistics [16]. Results Screening of AAV The in-patients and out-patients from 2005 to 2014 in our division were screened if they were assayed for ANCA. There were 1501 and 1339 patients who were assayed for MPO-ANCA and PR3-ANCA, respectively. From the list of these patients, we found 126 MPO-ANCA positive and 65 PR3-ANCA positive patients. Among these ANCA positive patients, 88 and 17 patients were diagnosed as having MPO-ANCA vasculitis and PR3-ANCA vasculitis, respectively. Ten patients were both MPO-ANCA and PR3-ANCA positive, and their clinical diagnosis included four MPA, two propylthiouracil-induced vasculitis, one systemic lupus erythematosus (SLE), one ulcerative colitis, one rheumatoid arthritis, and one undiagnosed case. The four patients with MPA double positive for MPO-ANCA and PR3-ANCA were not included in this study. The diagnoses of MPO-ANCA or PR3-ANCA single positive patients without vasculitic signs (non-AAV) were as follows: rheumatoid arthritis, 7 and 11; SLE, 2 and 8; systemic sclerosis, 2 and 3; polymyalgia rheumatica, 1 and 2; polymyositis or dermatomyositis, 2 each; drug induced, 3 and 0; giant cell arteritis, 1 and 0; IgA vasculitis, 0 and 2; primary Sjögren syndrome, 0 and 3; mixed connective tissue disease, 0 and 2; reactive arthritis, 0 and 1; infectious endocarditis, 0 and 1; interstitial pneumonia, 1 and 0; and undiagnosed cases, 19 and 13, respectively. When the titers of MPO-ANCA and PR3-ANCA assayed by ELISA were compared between patients with AAV and non-AAV (MPO-ANCA, 54 versus 21 patients; PR3-ANCA, 10 versus 27 patients), those in patients with AAV were significantly higher than those in patients with non-AAV (median titers were 61.5 versus 20.5 U/ml in MPO-ANCA and 26.1 versus 5.0 U/ml in PR3-ANCA, each p value was <0.01). These median titers of ANCA in MPO-ANCA or PR3-ANCA vasculitis represent the levels of ANCA at the onset of vasculitis as ANCA was assayed at the diagnosis of AAV in most of patients. Patient demographics The demographic data of MPO-ANCA and PR3-ANCA vasculitis are shown in Table 1. MPO-ANCA vasculitis was more frequent than PR3-ANCA vasculitis in this study. There was no gender difference in frequency between them. The median age was higher in patients with MPO-ANCA than in those with PR3-ANCA vasculitis (p < 0.01). The CRP levels and BVAS new/worse were not different between MPO-ANCA and PR3-ANCA vasculitis, but BVAS persistent was higher in MPO-ANCA vasculitis. The clinical diagnosis of MPO-ANCA vasculitis included 71 MPA, 8 GPA, 8 EGPA, and 1 undifferentiated vasculitis, and that of PR3-ANCA vasculitis included 13 GPA, 2 MPA, and 2 undifferentiated vasculitis (p < 0.01). The median follow-up periods were 28 months (range, 0.5–159 months) in patients with MPO-ANCA vasculitis and 36 months (range, 5–314 months) in patients with PR3-ANCA vasculitis. Table 1. Patient characteristics. Type of vasculitis MPO-ANCA PR3-ANCA p Value Number of patients 88 17 Gender, female, no. (%) 59 (67.0) 11 (64.7) 1.0 Age at the diagnosis, median (IQR) years 70 (64–76) 55 (44–66) <0.01 CRP, median (IQR) mg/dL* 5.7 (2.3–10.8) 5.0 (2.1–10.5) 0.79 BVAS new/worse, median (IQR)* 14.5 (11–21) 15 (12.75–20) 0.56 BVAS persistent, median (IQR)* 1 (0–2) 0 (0–0) <0.01 Number of patients diagnosed with (%)† <0.01  MPA 71 (80.7) 2 (11.8)  GPA 8 (9.1) 13 (76.4)  EGPA 8 (9.1) 0 (0)  Undifferentiated 1 (1.1) 2 (11.8) Type of vasculitis MPO-ANCA PR3-ANCA p Value Number of patients 88 17 Gender, female, no. (%) 59 (67.0) 11 (64.7) 1.0 Age at the diagnosis, median (IQR) years 70 (64–76) 55 (44–66) <0.01 CRP, median (IQR) mg/dL* 5.7 (2.3–10.8) 5.0 (2.1–10.5) 0.79 BVAS new/worse, median (IQR)* 14.5 (11–21) 15 (12.75–20) 0.56 BVAS persistent, median (IQR)* 1 (0–2) 0 (0–0) <0.01 Number of patients diagnosed with (%)† <0.01  MPA 71 (80.7) 2 (11.8)  GPA 8 (9.1) 13 (76.4)  EGPA 8 (9.1) 0 (0)  Undifferentiated 1 (1.1) 2 (11.8) *These are at the diagnosis of vasculitis. The numbers of patients with PR3-ANCA vasculitis whose BVAS calculated was 16. †There was a difference in the ratio of clinical diagnosis between MPO-ANCA and PR3-ANCA vasculitis (p < 0.01). IQR: interquartile range; BVAS: Birmingham vasculitis activity score. Open in new tab Table 1. Patient characteristics. Type of vasculitis MPO-ANCA PR3-ANCA p Value Number of patients 88 17 Gender, female, no. (%) 59 (67.0) 11 (64.7) 1.0 Age at the diagnosis, median (IQR) years 70 (64–76) 55 (44–66) <0.01 CRP, median (IQR) mg/dL* 5.7 (2.3–10.8) 5.0 (2.1–10.5) 0.79 BVAS new/worse, median (IQR)* 14.5 (11–21) 15 (12.75–20) 0.56 BVAS persistent, median (IQR)* 1 (0–2) 0 (0–0) <0.01 Number of patients diagnosed with (%)† <0.01  MPA 71 (80.7) 2 (11.8)  GPA 8 (9.1) 13 (76.4)  EGPA 8 (9.1) 0 (0)  Undifferentiated 1 (1.1) 2 (11.8) Type of vasculitis MPO-ANCA PR3-ANCA p Value Number of patients 88 17 Gender, female, no. (%) 59 (67.0) 11 (64.7) 1.0 Age at the diagnosis, median (IQR) years 70 (64–76) 55 (44–66) <0.01 CRP, median (IQR) mg/dL* 5.7 (2.3–10.8) 5.0 (2.1–10.5) 0.79 BVAS new/worse, median (IQR)* 14.5 (11–21) 15 (12.75–20) 0.56 BVAS persistent, median (IQR)* 1 (0–2) 0 (0–0) <0.01 Number of patients diagnosed with (%)† <0.01  MPA 71 (80.7) 2 (11.8)  GPA 8 (9.1) 13 (76.4)  EGPA 8 (9.1) 0 (0)  Undifferentiated 1 (1.1) 2 (11.8) *These are at the diagnosis of vasculitis. The numbers of patients with PR3-ANCA vasculitis whose BVAS calculated was 16. †There was a difference in the ratio of clinical diagnosis between MPO-ANCA and PR3-ANCA vasculitis (p < 0.01). IQR: interquartile range; BVAS: Birmingham vasculitis activity score. Open in new tab Organ involvement in AAV The organ involvement of the patients is shown in Table 2. There was a significant difference in the eye, nose, and ear involvement between MPO-ANCA and PR3-ANCA vasculitis (p value was <0.01, <0.01, and 0.01). The respiratory system was the most frequently involved organ in both MPO-ANCA and PR3-ANCA vasculitis (83.0% and 88.2%, respectively), with no difference in their incidence (p = 0.73). However, the type of respiratory involvement was different; interstitial lung disease was more frequent in MPO-ANCA vasculitis (p < 0.01), and nodular shadow in PR3-ANCA vasculitis (p < 0.01). In other organs, there was no difference in their incidence of organ involvement between MPO-ANCA and PR3-ANCA vasculitis. When limited to 73 patients with MPA (71 patients with MPO-ANCA vasculitis and 2 patients with PR3-ANCA vasculitis), 44 (60.3%) and 3 (4.1%) patients had interstitial lung disease and alveolar hemorrhage, respectively. When we compared the clinical characteristics between MPA and GPA (Table 3), the results were similar to those of comparison between MPO-ANCA and PR3-ANCA vasculitis. The incidences of nodular lesion in MPO-ANCA positive GPA and PR3-ANCA positive GPA were 4 of 8 (50%) and 9 of 13 (69%), respectively (p = 0.65). Table 2. Type and incidence of organ involvement. Organ involvement, no. (%) MPO-ANCA vasculitis (n = 88) PR3-ANCA vasculitis (n = 17) p Value Kidney* 60 (68.2) 9 (52.9) 0.27 Respiratory system† 73 (83.0) 15 (88.2) 0.73  Interstitial lung disease 46 (52.3) 1 (5.9) <0.01  Nodular shadow 8 (9.1) 10 (58.8) <0.01  Pleuritis 3 (3.4) 1 (5.9) 0.51  Consolidation 5 (5.7) 2 (11.8) 0.32  Airway disease 11 (12.5) 0 (0) 0.21  Emphysema 7 (8.0) 0 (0) 0.60  Alveolar hemorrhage 5 (5.7) 3 (17.6) 0.12  Asthma 9 (10.2) 2 (11.8) 1.0 Peripheral nerves 34 (38.6) 6 (35.3) 1.0 Central nervous system 9 (10.2) 1 (5.9) 1.0 Eye‡ 7 (8.0) 7 (41.2) <0.01 Nose, paranasal sinus 15 (17.0) 10 (58.8) <0.01 Ear§ 18 (20.5) 9 (52.9) 0.01 Skin 19 (21.6) 7 (41.2) 0.12 Gastro-intestinal and hepatobiliary systems 16 (18.2) 3 (17.6) 1.0 Cardiovascular system 6 (6.8) 0 (0) 0.59 Organ involvement, no. (%) MPO-ANCA vasculitis (n = 88) PR3-ANCA vasculitis (n = 17) p Value Kidney* 60 (68.2) 9 (52.9) 0.27 Respiratory system† 73 (83.0) 15 (88.2) 0.73  Interstitial lung disease 46 (52.3) 1 (5.9) <0.01  Nodular shadow 8 (9.1) 10 (58.8) <0.01  Pleuritis 3 (3.4) 1 (5.9) 0.51  Consolidation 5 (5.7) 2 (11.8) 0.32  Airway disease 11 (12.5) 0 (0) 0.21  Emphysema 7 (8.0) 0 (0) 0.60  Alveolar hemorrhage 5 (5.7) 3 (17.6) 0.12  Asthma 9 (10.2) 2 (11.8) 1.0 Peripheral nerves 34 (38.6) 6 (35.3) 1.0 Central nervous system 9 (10.2) 1 (5.9) 1.0 Eye‡ 7 (8.0) 7 (41.2) <0.01 Nose, paranasal sinus 15 (17.0) 10 (58.8) <0.01 Ear§ 18 (20.5) 9 (52.9) 0.01 Skin 19 (21.6) 7 (41.2) 0.12 Gastro-intestinal and hepatobiliary systems 16 (18.2) 3 (17.6) 1.0 Cardiovascular system 6 (6.8) 0 (0) 0.59 *The kidney involvement includes patients with pathological findings, elevation of serum creatinine level, proteinuria, and hematuria indicating glomerulonephritis. †The numbers indicate the total number of patients with respiratory involvement. There are overlaps in the respiratory involvement. The respiratory involvement is classified based on the CT imaging and clinical findings. ‡The eye involvement includes scleritis, episcleritis, conjunctivitis, and uveitis. §The ear involvement includes exudative otitis, and sensorineural, conductive, and combined hearing loss. Open in new tab Table 2. Type and incidence of organ involvement. Organ involvement, no. (%) MPO-ANCA vasculitis (n = 88) PR3-ANCA vasculitis (n = 17) p Value Kidney* 60 (68.2) 9 (52.9) 0.27 Respiratory system† 73 (83.0) 15 (88.2) 0.73  Interstitial lung disease 46 (52.3) 1 (5.9) <0.01  Nodular shadow 8 (9.1) 10 (58.8) <0.01  Pleuritis 3 (3.4) 1 (5.9) 0.51  Consolidation 5 (5.7) 2 (11.8) 0.32  Airway disease 11 (12.5) 0 (0) 0.21  Emphysema 7 (8.0) 0 (0) 0.60  Alveolar hemorrhage 5 (5.7) 3 (17.6) 0.12  Asthma 9 (10.2) 2 (11.8) 1.0 Peripheral nerves 34 (38.6) 6 (35.3) 1.0 Central nervous system 9 (10.2) 1 (5.9) 1.0 Eye‡ 7 (8.0) 7 (41.2) <0.01 Nose, paranasal sinus 15 (17.0) 10 (58.8) <0.01 Ear§ 18 (20.5) 9 (52.9) 0.01 Skin 19 (21.6) 7 (41.2) 0.12 Gastro-intestinal and hepatobiliary systems 16 (18.2) 3 (17.6) 1.0 Cardiovascular system 6 (6.8) 0 (0) 0.59 Organ involvement, no. (%) MPO-ANCA vasculitis (n = 88) PR3-ANCA vasculitis (n = 17) p Value Kidney* 60 (68.2) 9 (52.9) 0.27 Respiratory system† 73 (83.0) 15 (88.2) 0.73  Interstitial lung disease 46 (52.3) 1 (5.9) <0.01  Nodular shadow 8 (9.1) 10 (58.8) <0.01  Pleuritis 3 (3.4) 1 (5.9) 0.51  Consolidation 5 (5.7) 2 (11.8) 0.32  Airway disease 11 (12.5) 0 (0) 0.21  Emphysema 7 (8.0) 0 (0) 0.60  Alveolar hemorrhage 5 (5.7) 3 (17.6) 0.12  Asthma 9 (10.2) 2 (11.8) 1.0 Peripheral nerves 34 (38.6) 6 (35.3) 1.0 Central nervous system 9 (10.2) 1 (5.9) 1.0 Eye‡ 7 (8.0) 7 (41.2) <0.01 Nose, paranasal sinus 15 (17.0) 10 (58.8) <0.01 Ear§ 18 (20.5) 9 (52.9) 0.01 Skin 19 (21.6) 7 (41.2) 0.12 Gastro-intestinal and hepatobiliary systems 16 (18.2) 3 (17.6) 1.0 Cardiovascular system 6 (6.8) 0 (0) 0.59 *The kidney involvement includes patients with pathological findings, elevation of serum creatinine level, proteinuria, and hematuria indicating glomerulonephritis. †The numbers indicate the total number of patients with respiratory involvement. There are overlaps in the respiratory involvement. The respiratory involvement is classified based on the CT imaging and clinical findings. ‡The eye involvement includes scleritis, episcleritis, conjunctivitis, and uveitis. §The ear involvement includes exudative otitis, and sensorineural, conductive, and combined hearing loss. Open in new tab Table 3. Patient demographics based on clinical diagnosis. Type of vasculitis MPA GPA p Value Number of patients 73 21 Gender, female, no. (%) 49 (67.1) 14 (66.7) 1.0 Age at the diagnosis, median (IQR) years 70 (66–76) 60 (52–69) <0.01 MPO-ANCA positive, no. (%) 71 (97.3) 8 (38.1) <0.01 PR3-ANCA positive, no. (%) 2 (2.7) 13 (61.9) <0.01 CRP, median (IQR) mg/dL* 6.5 (2.3–11.5) 5.7 (1.8–9.0) 0.89 BVAS new/worse, median (IQR)* 14 (11–20) 15 (11.5–19.25) 0.69 BVAS persistent, median (IQR)* 0 (0–2) 0 (0–1) 0.40 Organ involvement, no (%) Kidney 57 (78.0) 12 (57.1) 0.09 Respiratory system 63 (86.3) 17 (81.0) 0.51  Interstitial lung disease 44 (60.3) 1 (4.8) <0.01  Nodular shadow 3 (4.1) 13 (61.9) <0.01  Alveolar hemorrhage 4 (5.5) 3 (14.3) 0.18  Asthma 1 (1.4) 2 (9.5) 0.12 Peripheral nerves 26 (35.6) 8 (38.1) 1.0 Central nervous system 8 (11.0) 2 (9.5) 1.0 Eye 7 (9.6) 6 (28.6) 0.07 Nose, paranasal sinus 10 (13.7) 12 (57.1) <0.01 Ear 16 (21.9) 11 (52.4) 0.01 Type of vasculitis MPA GPA p Value Number of patients 73 21 Gender, female, no. (%) 49 (67.1) 14 (66.7) 1.0 Age at the diagnosis, median (IQR) years 70 (66–76) 60 (52–69) <0.01 MPO-ANCA positive, no. (%) 71 (97.3) 8 (38.1) <0.01 PR3-ANCA positive, no. (%) 2 (2.7) 13 (61.9) <0.01 CRP, median (IQR) mg/dL* 6.5 (2.3–11.5) 5.7 (1.8–9.0) 0.89 BVAS new/worse, median (IQR)* 14 (11–20) 15 (11.5–19.25) 0.69 BVAS persistent, median (IQR)* 0 (0–2) 0 (0–1) 0.40 Organ involvement, no (%) Kidney 57 (78.0) 12 (57.1) 0.09 Respiratory system 63 (86.3) 17 (81.0) 0.51  Interstitial lung disease 44 (60.3) 1 (4.8) <0.01  Nodular shadow 3 (4.1) 13 (61.9) <0.01  Alveolar hemorrhage 4 (5.5) 3 (14.3) 0.18  Asthma 1 (1.4) 2 (9.5) 0.12 Peripheral nerves 26 (35.6) 8 (38.1) 1.0 Central nervous system 8 (11.0) 2 (9.5) 1.0 Eye 7 (9.6) 6 (28.6) 0.07 Nose, paranasal sinus 10 (13.7) 12 (57.1) <0.01 Ear 16 (21.9) 11 (52.4) 0.01 *These are at the diagnosis of vasculitis. The numbers of patients with GPA whose BVAS was calculated was 20. Open in new tab Table 3. Patient demographics based on clinical diagnosis. Type of vasculitis MPA GPA p Value Number of patients 73 21 Gender, female, no. (%) 49 (67.1) 14 (66.7) 1.0 Age at the diagnosis, median (IQR) years 70 (66–76) 60 (52–69) <0.01 MPO-ANCA positive, no. (%) 71 (97.3) 8 (38.1) <0.01 PR3-ANCA positive, no. (%) 2 (2.7) 13 (61.9) <0.01 CRP, median (IQR) mg/dL* 6.5 (2.3–11.5) 5.7 (1.8–9.0) 0.89 BVAS new/worse, median (IQR)* 14 (11–20) 15 (11.5–19.25) 0.69 BVAS persistent, median (IQR)* 0 (0–2) 0 (0–1) 0.40 Organ involvement, no (%) Kidney 57 (78.0) 12 (57.1) 0.09 Respiratory system 63 (86.3) 17 (81.0) 0.51  Interstitial lung disease 44 (60.3) 1 (4.8) <0.01  Nodular shadow 3 (4.1) 13 (61.9) <0.01  Alveolar hemorrhage 4 (5.5) 3 (14.3) 0.18  Asthma 1 (1.4) 2 (9.5) 0.12 Peripheral nerves 26 (35.6) 8 (38.1) 1.0 Central nervous system 8 (11.0) 2 (9.5) 1.0 Eye 7 (9.6) 6 (28.6) 0.07 Nose, paranasal sinus 10 (13.7) 12 (57.1) <0.01 Ear 16 (21.9) 11 (52.4) 0.01 Type of vasculitis MPA GPA p Value Number of patients 73 21 Gender, female, no. (%) 49 (67.1) 14 (66.7) 1.0 Age at the diagnosis, median (IQR) years 70 (66–76) 60 (52–69) <0.01 MPO-ANCA positive, no. (%) 71 (97.3) 8 (38.1) <0.01 PR3-ANCA positive, no. (%) 2 (2.7) 13 (61.9) <0.01 CRP, median (IQR) mg/dL* 6.5 (2.3–11.5) 5.7 (1.8–9.0) 0.89 BVAS new/worse, median (IQR)* 14 (11–20) 15 (11.5–19.25) 0.69 BVAS persistent, median (IQR)* 0 (0–2) 0 (0–1) 0.40 Organ involvement, no (%) Kidney 57 (78.0) 12 (57.1) 0.09 Respiratory system 63 (86.3) 17 (81.0) 0.51  Interstitial lung disease 44 (60.3) 1 (4.8) <0.01  Nodular shadow 3 (4.1) 13 (61.9) <0.01  Alveolar hemorrhage 4 (5.5) 3 (14.3) 0.18  Asthma 1 (1.4) 2 (9.5) 0.12 Peripheral nerves 26 (35.6) 8 (38.1) 1.0 Central nervous system 8 (11.0) 2 (9.5) 1.0 Eye 7 (9.6) 6 (28.6) 0.07 Nose, paranasal sinus 10 (13.7) 12 (57.1) <0.01 Ear 16 (21.9) 11 (52.4) 0.01 *These are at the diagnosis of vasculitis. The numbers of patients with GPA whose BVAS was calculated was 20. Open in new tab Treatment We retrospectively reviewed the treatment for AAV. The use of glucocorticoid and its dose were not different between MPO-ANCA and PR3-ANCA vasculitis, whereas the use of cyclophosphamide was different. Intravenous or oral cyclophosphamide was administered in 28 (31.8%) and 15 (88.2%) patients with MPO-ANCA and PR3-ANCA vasculitis, respectively. Rituximab was administered in six patients with PR3-ANCA vasculitis (35.3%) for the relapses of AAV, whereas there was only one patient with MPO-ANCA vasculitis (1.1%) who was treated with rituximab for the relapse. Analysis of relapse, survival, ESKD, and respiratory failure We compared outcomes between MPO-ANCA and PR3-ANCA vasculitis (Figure 1a–d). When assessed by the Kaplan-Meier curve, relapse-free rate was lower in PR3-ANCA than in MPO-ANCA vasculitis (log rank analysis, p = 0.02, Figure 1a). The probability of relapse-free in MPO-ANCA and PR-3 ANCA vasculitis at three years were 0.62 and 0.34, respectively. Multivariable Cox proportional hazard regression analysis using explanatory variables including age, sex, ANCA subtype, respiratory involvement, and renal involvement showed that PR3-ANCA positivity was associated with relapse (hazard ratio 2.48, 95% confidence interval 1.14–5.42, p = 0.02) (Table 4). In contrast, there was no difference in survival, ESKD-free, and respiratory failure-free between MPO-ANCA and PR3-ANCA vasculitis by Kaplan–Meier curves (Figure 1b–d). The probabilities of survival, ESKD-free, and respiratory failure-free in MPO-ANCA and PR3-ANCA vasculitis at 10 years were 0.60 versus 0.89, 0.92 versus 0.80, and 0.51 versus 0.86, respectively. The cause of death included six exacerbation of AAV (four respiratory failure due to interstitial lung disease and two gastrointestinal involvements), three infections (one Pneumocystis pneumonia, one sepsis, and one unknown organism), and two unknown causes in MPO-ANCA, and one suicide in PR3-ANCA vasculitis. Respiratory failure included introduction of HOT in five, death due to exacerbation of lung disease in three, tracheotomy due to bilateral recurrent nerve palsy in one, Pneumocystis pneumonia in one, and respiratory failure related to pleuritis in one with MPO-ANCA vasculitis, and introduction of HOT in one with PR3-ANCA vasculitis. Figure 1. Open in new tabDownload slide Kaplan–Meier curves of relapse (a), survival (b) and the progression to end-stage kidney disease (c) and respiratory failure (d). The probabilities of survival or event-free at three years (a) or 10 years (b–d) are shown. Relapse was assessed in patient with AAV in whom remission was introduced, the progression to end-stage kidney disease or respiratory failure was assessed in patients who had kidney or respiratory disease. The curves in each subfigure are compared by log rank test, and the p values are shown in each figure. Figure 1. Open in new tabDownload slide Kaplan–Meier curves of relapse (a), survival (b) and the progression to end-stage kidney disease (c) and respiratory failure (d). The probabilities of survival or event-free at three years (a) or 10 years (b–d) are shown. Relapse was assessed in patient with AAV in whom remission was introduced, the progression to end-stage kidney disease or respiratory failure was assessed in patients who had kidney or respiratory disease. The curves in each subfigure are compared by log rank test, and the p values are shown in each figure. Table 4. Cox proportional hazard regression analysis for relapse. Hazard ratio 95% CI p Value Multivariable analysis*  Age 1.02 0.99–1.06 0.21  Female 0.79 0.40–1.55 0.50  PR3-ANCA positive 3.71 1.36–10.20 0.01  Respiratory involvement 1.51 0.45–5.12 0.51  Renal involvement 0.60 0.29–1.26 0.14 Multivariable analysis†  PR3-ANCA positive 2.48 1.14–5.42 0.02 Hazard ratio 95% CI p Value Multivariable analysis*  Age 1.02 0.99–1.06 0.21  Female 0.79 0.40–1.55 0.50  PR3-ANCA positive 3.71 1.36–10.20 0.01  Respiratory involvement 1.51 0.45–5.12 0.51  Renal involvement 0.60 0.29–1.26 0.14 Multivariable analysis†  PR3-ANCA positive 2.48 1.14–5.42 0.02 *All explanatory variables listed below were forcedly entered. †Explanatory variables were selected by stepwise backward selection with p value <0.05. CI: confidence interval. Open in new tab Table 4. Cox proportional hazard regression analysis for relapse. Hazard ratio 95% CI p Value Multivariable analysis*  Age 1.02 0.99–1.06 0.21  Female 0.79 0.40–1.55 0.50  PR3-ANCA positive 3.71 1.36–10.20 0.01  Respiratory involvement 1.51 0.45–5.12 0.51  Renal involvement 0.60 0.29–1.26 0.14 Multivariable analysis†  PR3-ANCA positive 2.48 1.14–5.42 0.02 Hazard ratio 95% CI p Value Multivariable analysis*  Age 1.02 0.99–1.06 0.21  Female 0.79 0.40–1.55 0.50  PR3-ANCA positive 3.71 1.36–10.20 0.01  Respiratory involvement 1.51 0.45–5.12 0.51  Renal involvement 0.60 0.29–1.26 0.14 Multivariable analysis†  PR3-ANCA positive 2.48 1.14–5.42 0.02 *All explanatory variables listed below were forcedly entered. †Explanatory variables were selected by stepwise backward selection with p value <0.05. CI: confidence interval. Open in new tab Discussion The clinical characteristics of AAV were compared on the basis of their clinical diagnosis: MPA, GPA, and EPGA. However, at present, there are no established diagnostic criteria of AAV for clinical practice. There are classification criteria of American College of Rheumatology for GPA and EGPA, but no criteria for MPA. The criteria of Chapel Hill Consensus Conference and the European Medicines Agency classification system for AAV are currently used [15,17]. However, they were made for the definition or classification for epidemiological studies. MPO-ANCA or PR3-ANCA is detected in a majority of cases with these vasculitic syndromes, and it would be reasonable to classify AAV on the basis of ANCA subtype because ANCA specificity is closely linked to genetic background. In this study, we correlated clinical characteristics with ANCA subtype in Japanese patients with AAV. There were differences in the age and the incidence in the eye, nose, and ear involvement in the two ANCA subtypes. Although there was no difference in the incidence of overall respiratory involvement, the incidence of interstitial lung disease was higher and that of nodular shadow was lower in MPO-ANCA than in PR3-ANCA vasculitis. Except for interstitial lung disease, the result in our study was quite comparable to the report from USA which described that the incidence of respiratory involvement in MPO-ANCA and PR3-ANCA vasculitis is similar, and the incidence of the eye, nose, and ear involvement and lung nodule or cavity is higher in PR-3 ANCA vasculitis [6]. This indicates that PR3-ANCA is a universal marker of the eye, nose, and ear involvement and lung nodule or cavity regardless of genetic or environmental differences. BVAS version 3 is a useful tool for the assessment and follow-up of vasculitis activity [18]. In this study, BVAS new/worse and the CRP levels were not different, but BVAS persistent was different between MPO-ANCA and PR3-ANCA vasculitis. The difference may be partly due to preexisting organ damage such as interstitial pneumonia in MPO-ANCA vasculitis. The results of comparison of clinical characteristics based on serological subtypes were similar to those based on clinical diagnosis. Because the clinical diagnosis of AAV is sometimes difficult due to difficulties in obtaining sufficient pathological specimens or variation in diagnostic criteria, classification of AAV based on ANCA subtype would be an easier way of diagnosis in clinical practice. With regard to the pathogenesis of nodular lesion, we speculate that factors other than ANCA may be involved in the formation of nodular lesion because patients not only with PR3-ANCA positive GPA but also with MPO-ANCA positive GPA showed nodular lesion with approximately the similar incidence. In contrast, the incidence of MPO-ANCA vasculitis was five times higher than that of PR3-ANCA vasculitis, and the incidence of interstitial lung disease was 15 times higher than that of alveolar hemorrhage in MPA in Japan. These results were comparable to those from reports in Japan, but were different from those in Western countries [7,19,20]; ANCA subtype predominance is not observed, and alveolar hemorrhage is more frequent than interstitial lung disease in UK. A similar incidence of AAV is shown in China as in Japan [9]. The difference in the ratio of clinical diagnosis in AAV and the type of respiratory involvement in MPA by country may be due to the difference in genetic or environmental factors. It would be important to clarify the difference in the outcomes of AAV on the basis of ANCA subtype. It is reported that as much as 50% of patients with AAV have a relapse [21–23]. Factors such as PR-3 ANCA, respiratory involvement, cardiac involvement, elevation of serum creatinine level, age, and tapering-pace of prednisolone are reported as the predictors of relapse in AAV [24–28], and the hazard ratio of relapse in PR3-ANCA vasculitis is 1.89 compared to MPO-ANCA vasculitis [6]. Similar to these reports, we found that the relapse rate was higher in PR-3 ANCA than in MPO-ANCA vasculitis with the hazard ratio of 2.48. The reason or pathological mechanism of higher relapse rate in PR3-ANCA vasculitis is not clear, but this finding will be critical in clinical practice because relapse may lead to the impairment of activity of daily living or organ damage. We now utilize rituximab in patients with PR3-ANCA vasculitis with high probability of relapse even after cyclophosphamide use. Rituximab, which targets CD20 molecules on B cell surface, is one of the treatment drugs expected to have a more potent ability to prevent relapse in PR3-ANCA vasculitis [29]. In Japan, rituximab was approved for the treatment of MPA and GPA with high disease activity or refractory to glucocorticoid in 2014. The optimal maintenance therapy with rituximab, the effectiveness of rituximab to prevent relapse, and the safety of rituximab treatment in Japanese patients with AAV remain to be established. Classification by ANCA subtype may be useful to guide the use of immunosuppression in AAV because patients with PR-3 ANCA vasculitis responded rituximab better than cyclophosphamide [30]. In contrast to relapse, there was no difference in survival and progression to respiratory failure and ESKD between MPO-ANCA and PR3-ANCA vasculitis assessed by Kaplan–Meier curves. Our result about survival was comparable to the report that classification based on ANCA subtype is not useful in distinguishing mortality. However, with regard to the kidney involvement, there are conflicting reports that the incidence of kidney involvement is lower in PR3-ANCA vasculitis [6], and PR3-ANCA vasculitis is associated with higher mortality [31] and faster deterioration of renal function [32]. The discrepancy might be due to the difference in genetic or environmental factors or referral bias. Since the number of patients with PR3-ANCA vasculitis is small in Japan, further study would be needed to validate the results on this. Our study was done under retrospective observational design. The decision of relapse and drugs employed were not standardized and completely at the discretion of each treating physicians. In addition, the use rate of cyclophosphamide was lower compared to that in Western countries. We acknowledge that there is a possibility that the variation in cyclophosphamide use affected the survival rate and the progression to respiratory or renal failure. The number of the patients with PR3-ANCA vasculitis was small; patients with PR3-ANCA vasculitis are rare in Japan. There may be a referral bias that patients with severe respiratory or renal failure had admitted to divisions of respiratory medicine or nephrology. Some of these drawbacks would be overcome only by prospective multi-institutional study which is definitely needed. There were some ANCA-positive patients who were not diagnosed as AAV, namely, false positive patients. We speculate that one of the reasons may be ANCA assays by ELISA or CLEIA were used as screening test not only for patients with vasculitic signs but also for patients with non-vasculitic signs including fever of unknown origin. It would be important to raise prior probability of vasculitis to avoid the advent of ANCA-false positive patients when utilizing ANCA assays. 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Google Scholar Crossref Search ADS PubMed WorldCat © 2016 Japan College of Rheumatology This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

Modern Rheumatology – Oxford University Press

Published: Jan 2, 2017

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