Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Large Vessel Vasculitis and Kawasaki Disease in Japan

Based on studies comparing the prevalence of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) between Japan and Europe, we have learned that the difference may be due to genetic background and environmental factors, but not to diagnosis or ELISA system for myeloperoxidase and proteinase-3 ANCA. In Japan, microscopic polyangiitis is the most common among AAV, but Wegener’s granulomatosis was present in less than 2 per million patients. Also, one study from Hokkaido reported only 16 patients in a 27-year time frame. A recent retrospective study of renal vasculitis between 2000 and 2004 from Miyazaki prefecture in Japan reported an incidence of microscopic polyangiitis of 14.8 per million, but no patients with Wegener’s granulomatosis or Churg-Strauss syndrome. In the present review, we focus on ANCA-related vasculitis in Japan: (1) AAV and large vessel vasculitis – Takayasu’s arteritis and giant cell arteritis; (2) primary renal vasculitis; (3) epitopes of myeloperoxidase-ANCA in vasculitis in the JapaPublished online: November 10, 2010 Kazuo Suzuki, PhD Inflammation Program, Department of Immunology Chiba University Graduate School of Medicine Inohana 1-8-1, Chuo-ku, Chiba 260-8670 (Japan) Tel. +81 43 221 0831, Fax +81 43 221 0832, E-Mail ksuzuki @ faculty.chiba-u.jp © 2010 S. Karger AG, Basel 1420–4096/10/0336–0442$26.00/0 Accessible online at: www.karger.com/kbr D ow nl oa de d by : 54 .1 91 .4 0. 80 9 /1 6/ 20 17 8 :3 1: 11 P M AAV, Large Vessel Vasculitis and Kawasaki Disease in Japan Kidney Blood Press Res 2010;33:442–455 443 bution of vasculitis phenotypes and ANCA specificities would vary with latitude has not been confirmed or refuted [3] . Japan is located between the latitude 26° to 45° North [4] . There exist interesting concordance and discordance of clinical features of vasculitis between Japan and Europe/USA. The differences will be reviewed here. Vasculitis is much more heterogeneous in its clinical features such as incidence, phenotype and/or genotype among areas. As few giant cell arteritis (GCA) patients have been reported in Japan, compared with Europe and the USA [5] , the prevalence of GCA in studies in Japan will be also reviewed and discussed. Moreover, differences in renal involvement in WG and MPA between the UK and Japan [6] will also be discussed. These area differences will be reviewed in association with human leukocyte antigen (HLA) such as cANCA-positive WG in 1996 [7] , and autoreactive T cell response MPO fragments [8, 9] . A good correlation between the extent of crescent formation and the MPO-ANCA titer has been demonstrated [10] . Differences in reactivity suggest differences of binding to MPO epitopes by MPO-ANCA. The titer of MPOANCA does not always reflect disease activity, and this inconsistency may be attributable to differences in epitopic specificity by MPO-ANCA between patients. We also review the analyses of the epitopes in MPO-ANCA in the Japanese population. Epitopes on MPO recognized by MPO-ANCA from patients with MPO-ANCA-associated vasculitis in the Japanese population have been analyzed using recombinant MPO fragments [11] . Differences in binding specificity may influence the pathogenic potential of the antibodies. The immunodominant epitopes have not been precisely defined. Erdbrügger et al. [12] reported that PR3-ANCA and MPO-ANCA do not interfere with the enzymatic activity of MPO. The differences in binding specificity may influence the pathogenic potential of the antibodies [13] . Van der Geld et al. [14] demonstrated that noncontiguous amino acids are important to the structure of epitopes. In this review, the epitopes in patients with vasculitis in Japan will be discussed. Concomitantly, ELISA systems for three kinds of MPO-ANCA and PR3-ANCA used in Japan have been compared with those commonly used in Europe. The report of Ito-Ihara et al. [15] that described ANCA ELISA systems in Japan will mainly be reviewed. Finally, we will review Kawasaki disease (KD), a systemic vasculitis in childhood prevailing in Japan that was first described in 1967 by Dr. Tomisaku Kawasaki. The nationwide surveys for KD conducted every 2 years show that the number of KD patients has been increasing [16] . KD is now appearing all over the world, but is most prevalent in Japan and Asian countries [16, 17] . Thus, in this review, we describe ANCA-associated vasculitis (AAV) and other vasculitis including large vessel vasculitis (Takayasu’s arteritis, TAK) and GCA and KD in Japan. Epitopes of MPO-ANCA in vasculitis in the Japanese population and a comparison of ANCA-ELISA systems in Japan and Europe are also described. Vasculitides in Japan and Europe/USA Differences in the Clinical Presentation of Vasculitis between Japan and Other Countries It is important to study and understand the concordance and discordance of clinical features of vasculitis between populations in Japan and Europe and the USA. Compared to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), vasculitis is much more heterogeneous in its clinical features, such as incidence, phenotype and/or genotype among areas and/or countries. TAK and GCA are two types of vasculitis where inflammation occurs in the large vessels, and their granulomatous vasculitis with the presence of giant cells [18, 19] . Compared with Europe and the USA, fewer GCA patients and a higher incidence of TAK patients are reported in Japan. The point prevalence of GCA in studies from Japan in 1997 was 690 patients (95% CI 400–980) [5] . The prevalence of patients aged more than 50 years was 1.48/ million compared with 200 in the USA and 60 in Spain [20, 21] . We have been asking ourselves why there are so few GCA patients in Japan. One factor leading to this question is the fact that we do not frequently see patients with ankylosing spondylitis in Japan, which is not the case in Korea and China. The incidence of HLA-B27 in Japan is only 0.3% compared with about 5% in Korea and China and 7–14% in the USA and Europe [22] . Therefore, genetic factors affecting the incidence of the disease must be unique even among far eastern countries. HLADRB1 * 0401 or HLA-DRB1 * 0404 are predominantly (60%) detected in patients with GCA in the USA; however, HLA-DRB1 * 0401 and HLA-DRB1 * 0404 are less frequent, 2.9 and 0.7%, respectively, as determined in 493 Japanese healthy individuals compared with 15.9 and 3.2%, respectively, in 60 healthy individuals in the USA [19] . This is one of the reasons why the incidence and/or prevalence of GCA is not high in Japan. In Japan, TAK is predominant in young female patients and mainly affects the aortic arch (type I), as determined D ow nl oa de d by : 54 .1 91 .4 0. 80 9 /1 6/ 20 17 8 :3 1: 11 P M Kobayashi /Fujimoto /Takahashi /Suzuki Kidney Blood Press Res 2010;33:442–455 444 by angiography. The patients show significantly high levels of HLA-B52 (56%) and HLA-B39 (17%) compared with healthy controls (25 and 6%, respectively) [23] . However, it was reported that a larger number of patients with TAK in India and other East Asian countries are middle-aged males with affected abdominal aortas (type III), and who have HLA-B39 [23] . A nationwide point prevalence survey in the form of a retrospective, hospital-based study was conducted in 1994 and 1998 ( table 1 ). Although the data are not new and do not show the real incidence, the prevalence of vasculitis/vasculopathy in Japan understandable. Buerger’s disease and TAK are common, but WG and GCA are not frequently observed in Japan. In 1997, we conducted a retrospective, hospital-based, nationwide survey on Japanese patients with AVV. The survey reported 63 MPA, 28 WG and 12 Churg-Strauss syndrome (CSS) patients and 104 patients with undifferentiated AAV (most patients were renal-limited vasculitis of MPA analyzed by the records). The point prevalence of AVV in the 1997 survey demonstrated that MPA is the most common AVV in Japan. Among 207 AVV patients, PR3-cANCA and MPO-pANCA were demonstrated in 26.3 and 80.8%, respectively. Among 28 WG patients, PR3-cANCA and MPO-pANCA were shown in 86 and 14%, respectively; and among 63 patients with MPA in 22 and 87% of patients, respectively. For MPA, prominent manifestations were renal involvement (87.3%), mainly rapidly progressive glomerulonephritis (RPGN), and pulmonary involvement (63.5%) including interstitial pneumonia/pulmonary fibrosis (33.3%) and pulmonary hemorrhage (22.2%). Patients with MPA having only a pulmonary localized lesion have been reported. In addition, 93% of Japanese WG patients demonstrated the ear, nose and throat (ENT) features, whereas only 39% demonstrated renal involvement. Compared to WG patients in Europe and the USA, renal involvements are not common in Japanese WG patients. Furthermore, positive rate and titer of PR3-/cANCA are relatively low in WG patients who have localized ENT lesions. These results were included in the annual report for the Research Committee of Intractable Vasculitis, the Ministry of Health and Welfare, Japan, in 1998 by Hashimoto and colleagues. The question why MPA is more common than WG in Japan while WG is the most common AVV in Europe and the US is important. This question led us to start an epidemiological study on Japanese patients with AVV in collaboration with the European Systemic Vasculitis Study Group (EUVAS) members Drs. D. Jayne, R. Watts, D. Scott, N. Rasmussen and U. Specks. The understanding of differences will lead to new insights into the etiology and pathogenesis of vasculitides. Latitude of Japan Japan is located between the latitude 26–45° North. Asahikawa city (43.5° North) on Hokkaido island is close to the latitude of Lugo, Spain (42°N). This is compatible with the latitude theory of AAV [4] ( fig. 1 ). Since we had to update old epidemiological data for AAV and determine the present incidence of AAV in Japan, we are glad to have started the new epidemiological study with UK/EUVAS members. Results of incidence of AAV in Miyazaki Prefecture are described in the section ‘Primary Renal Vasculitis in Japan’. It is interesting to note that a study from Beijing, China, demonstrated that 60.7% (54/89) of patients with WG were MPO-ANCA positive, 38.2% (34/89) were PR3ANCA positive, and patients with MPO-ANCA had multisystem involvement and elevated initial serum creatinine level as compared with PR3-ANCA-positive WG patients [24, 25] . Table 1. Point prevalence of vasculitis patients in Japan Year of investigation Disease Estimated number of patients Average age of patients at the time of study, years Male/ female 1993 Takayasu’s arteritis 4,800 35–65 1/1