NDT Advance Access first published online on June 19, 2008
This version published online on June 24, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn354
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Renal vasculitis in Japan and the UK—are there differences in epidemiology and clinical phenotype?
1 School of Medicine, Health Policy and Practice, University of East Anglia 2 Department of Rheumatology, Norfolk and Norwich University Hospital, Norwich 3 Lupus and Vasculitis Clinic, Addenbrookes’ Hospital, Cambridge, UK 4 Department of Nephrology and Cardiovascular Medicine, Louis Pasteur Centre for Medical Research, Graduate School of Medicine, Kyoto University, Kyoto, Japan 5 Department of Clinical Rheumatology, Musculoskeletal Research Group, School of Clinical Medical Sciences, Newcastle University, Newcastle upon Tyne, UK 6 Department of Nephrology and Dialysis, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka 7 First Department of Internal Medicine, Miyazaki Medical College, University of Miyazaki, Miyazaki 8 Department of Otolaryngology, Asahikawa Medical College, Asahikawa 9 Department of Internal Medicine and Rheumatology, Juntendo University, School of Medicine 10 National Institute of Infectious Diseases (NIID-NIH), Tokyo 11 Inflammation Program, Department of Immunology, Chiba University Graduate School of Medicine, Chiba, Japan
Correspondence and offprint requests to: Richard Watts, School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, NR4 7TJ, UK. Tel: +44-160-3593-570; Fax: +44-160-3593-570; E-mail: richard.watts{at}uea.ac.uk
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Abstract |
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Background. The epidemiology of renal vasculitis in different populations is poorly understood. A recent study from Japan suggests that whilst the overall incidence is similar to that reported from Europe, the clinical phenotype is different, with Wegener's granulomatosis being very much less common. The aim of this study was to compare the incidence of renal vasculitis in the UK with recent data from a Japanese population.
Methods. Incident patients with renal vasculitis were identified prospectively between 2000 and 2004 from a well-defined UK population. The case notes were reviewed and clinical features extracted. Classification between Wegener's granulomatosis, microscopic polyangiitis and Churg Strauss syndrome was performed using a predetermined algorithm. Inclusion criteria were (i) new patients with vasculitis with or without histological confirmation, (ii) renal involvement and (iii) positive serology for anti-neutrophil cytoplasmic antibody (ANCA).
Results. We identified 27 cases of renal vasculitis (Wegener's granulomatosis 13, microscopic polyangiitis 11, Churg Strauss syndrome 3) fulfilling the case definition. The overall average age was 63.5 years which is less than those of the Japanese patients. The overall annual incidence of renal vasculitis was 12.2/million similar to Japan. The annual incidence of Wegener's granulomatosis was 5.8/million, microscopic polyangiitis 4.9/million and Churg Strauss syndrome 1.4/million. ENT and neurological involvement were much less common in Japan. No patients with cANCA/PR3 were seen in Japan. Wegener's granumolatosis seems to be much less common in Japan than the UK.
Discussion. Whilst the overall occurrence of renal vasculitis is similar in Japan to the UK, the clinical phenotype is very different with microscopic polyangiitis predominating in Japan.
Keywords: ANCA; epidemiology; microscopic polyangiitis; vasculitis; Wegener's granulomatosis
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Introduction |
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The ANCA-associated vasculitides (AAV) are a group of rare conditions characterized by the occurrence of systemic necrotising vasculitis and the presence of anti-neutrophil cytoplasmic antibody (ANCA) in serum. Over the past 20 years there have been several studies describing the epidemiology in European and American populations. There is a broad consensus that in these populations, (i) the overall annual incidence is
10–20/million, (ii) the peak age of onset is 65–74 years and (iii) they are very rare in childhood [1]. Comparing the incidence and prevalence in different regions of Europe suggests that there are some potentially significant differences in the various subtypes. A comparative study between groups in Norway, England and Spain in which care was taken to try to classify/define the patients in a consistent fashion showed that Wegener's granulomatosis (WG) was more common in North Norway with an annual incidence of 10.5/million compared with Spain (4.9/million), whilst microscopic polyangiitis (MPA) was more common in Spain (11.6/million) than Norway (2.7/million) [2]. There is little data available from outside Europe. Reports from Japan suggest that the majority of patients with AAV are classified as MPA and that MPO-ANCA-associated disease is much more common than PR3-ANCA-associated disease [3]. A recent study of renal vasculitis during 2000–2004 from Miyazaki prefecture in Japan reported an incidence of MPA of 14.8/million [4]. This study was unable to find any patients with WG or Churg Strauss syndrome (CSS). Since 1988 we have maintained a prospective register of all patients presenting with AAV in the Norwich area. A previous study from this cohort reported an annual incidence of renal vasculitis of 18/million in the 1990s using a different case definition [5]. The aim of the present study was to compare the incidence of renal vasculitis in the UK with Japan during the period 2000–2004 using the same case definitions and investigate whether there are differences in disease expression between the two populations. |
Methods |
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UK population
We have since 1988 maintained a prospective register of patients with systemic vasculitis (NORVASC) who attend the Norfolk and Norwich University Hospital (NNUH), which is the single central referral centre for a stable and ethnically homogenous population of
500 000. The study area covers a geographically isolated coastal region in Eastern England allowing the population to be well defined and therefore suitable for epidemiological studies over a prolonged period of time [6]. We have previously described our methods of case ascertainment [7]. All patients attending the NNUH as outpatients, day admissions and hospitalized with a new clinical diagnosis of systemic vasculitis between 1 January 2000 and 31 December 2004 were identified. The computerized records of the histopathology department were searched for patients with a histological appearance on a renal biopsy consistent with renal vasculitis. The case notes were reviewed retrospectively to identify all patients with renal vasculitis either at presentation or developing subsequently. Patients fulfilling the inclusion criteria for the Miyazaki study were identified: (i) patients with a new diagnosis of WG, MPA, CSS or RLV, with or without histological confirmation, between 1 January 2000 and 31 December 2004; (ii) renal involvement with or without other organ involvement attributable to active WG, MPA, CSS or RLV (necrotizing vasculitis and pauci-immune necrotizing, crescentic glomerulonephritis); and (iii) positive serology for ANCA [4]. A negative ANCA was accepted if there was histological evidence of vasculitis.
The recently described European consensus classification algorithm for the classification of vasculitis was used to classify patients [8]. This uses an algorithm to classify vasculitis and utilizes the ACR (1990) criteria and the Chapel Hill Consensus Conference definitions. Using this approach renal limited vasculitis is placed with MPA.
The denominator population was the same as used in previous studies—patients registered with general practitioners in the former Norwich Health Authority [6]. The estimated 2002 population is 445 000 (215 000 males). The population is 95% Caucasian of UK descent, which is lower than the average for England (Watts 2004). Around 9% of the population is aged >75 years, which is higher than the average for England [7]. The gender balance is similar to the UK as a whole.
Age- and gender-specific incidence rates were calculated using the number of incident cases as the numerator and the population as the denominator. Confidence intervals (95%) were calculated using the Poisson distribution. Comparisons between the UK and Japanese studies were made using the chi-square test.
ANCA was determined by indirect immunofluorescence and by ELISA for PR3/MPO specificity using commercial available kits.
The Norwich Local Research Ethics Committee approved the study.
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Results |
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We identified 36 cases of AAV during 2000–2004. There were 27 cases of renal vasculitis (WG = 13, MPA = 11, CSS = 3) fulfilling the case definition. The overall average age was 63.5 years (WG = 63.9, MPA = 65.4, CSS = 54.4), which is less than those of the Japanese patients. The overall annual incidence of renal vasculitis was 12.2/million. The annual incidence of WG was 5.8/million, MPA 4.9/million and CSS 1.4/million. Comparison with the Japanese study is shown in Table 1. The most striking differences are that no patients with WG or CSS were seen in the Japanese study. There were also significant differences in the pattern of ANCA positivity seen. Over 90% of the Japanese patients were pANCA/MPO positive whereas 55% of the UK patients were pANCA/MPO positive. No Japanese patients were found to be cANCA or PR3-ANCA positive. Five patients in Japan were ANCA negative and two in the UK, both in the MPA group. There were also striking differences in the clinical features especially ENT and neurological involvement, which were much less frequent in Japan (Table 1).
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Discussion |
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This study shows for the first time major differences in the frequencies of the subtypes of renal AAV between Japan and the UK. Renal AAV in Japan is almost exclusively MPA, whereas in the UK only 41% of cases of renal AAV have MPA. The overall incidence of renal vasculitis is similar in the two populations. Our present estimate of renal vasculitis is lower than our previous figure possibly because of a tighter case definition for renal vasculitis. We looked for renal vasculitis at presentation; some patients, especially with WG, may present with renal involvement for the first time at relapse, and thus we may have underestimated the occurrence of renal vasculitis.
The aetiology of AAV is unknown, but is generally considered to be the result of an interaction between a trigger agent (as yet unknown) and a genetically predisposed host. As yet relatively little is known about the genetics of AAV in different populations because appropriate international studies using agreed methods of classification and genetic profiling have not been performed. One of the striking differences between the two populations in this study is the lack of cANCA/PR3-positive AAV in the Japanese cohort. It is possible that ANCA expression is different between populations. In Europe, WG appears to be more common in the North compared with MPA, whereas the reverse is true in Southern Europe. A recent study of 426 cases of AAV seen in a renal unit in Beijing also suggests that the ratio cANCA/PR3:pANCA/MPO positivity is 1:5 [9]. In the whole of our cohort from 2000–2004 the ratio is 2:3 and in the renal cohort 3:5. These data suggest that ANCA phenotype expression is dependent on the genetic background. It is possible therefore that the same trigger stimulus to AAV induction could result in different antigen expression in different populations. This also suggests that the tight association seen between PR3-ANCA and WG in European populations may not hold in other populations with a different genetic background.
The clinical phenotype of renal AAV also appears to be different in the two populations. ENT and neurological involvement is less common in Japan. ENT disease is a sine qua non of WG and its relative absence supports the serological lack of PR3 in the Japanese patients.
The major difference between the two studies is that the UK study was conducted prospectively whilst the Japanese study was retrospective and clearly there is the possibility of incomplete case capture. Furthermore, the Japanese study was performed in a renal unit whereas the UK study was performed in a rheumatology unit, and care was also taken to identify patients attending other departments. These confounders would tend to reduce the differences between the populations; however, it is unlikely that this can be solely the explanation for the serological differences seen. The EMEA algorithm was only applied in the UK, but as it employs both the ACR (1990) classification criteria and the Chapel Hill Consensus definitions, we do not, however, believe that this has confounded the results, because the differences in classification are supported by the marked difference in ANCA specificity between the two populations. It should be noted that renal-limited vasculitis is classified as MPA using the EMEA algorithm.
These data led us to hypothesize that the environmental and genetic triggers for renal vasculitis are different from those driving granulomatous disease seen predominately in the upper respiratory tract. There is little data available on the genetic backgrounds of patients with vasculitis and different clinical phenotypes. In Europe, there is a substantial overlap between ENT, renal involvement and PR3-ANCA. In Japan, in contrast, the overlap is much smaller with PR3-ANCA disease being mainly localized to the ENT tract. This could reflect a different genetic background. As yet relatively little is known about the genetics of AAV in different populations because appropriate international studies using agreed methods of classification and genetic profiling have not been performed. There is a significant association with HLA-DRB1*0901 in Japanese patients with MPA [10]; the haplotype DRB1*0901-DQB1*0303 represents the primary genetic risk for MPA within the HLA region in Japanese [11]. However, MPA has not been similarly studied in Europe. A small study (out of 16 patients only 3 had renal disease) in Japan showed an association with HLA-DR9 [12], but this has not been confirmed in Europe. In Europe HLA-DPB1*0401 is associated with an increase in granulomatous disease [13]. Equally, there could be different environmental factors.
These data clearly need to be confirmed in conventional prospective rather than retrospective first studies, but do lead us to hypothesize that there are very different drivers/triggers/aetiologies to renal vasculitis in Japan as compared with the UK and Europe (particularly northern Europe) and suggest, for example, that ENT and renal disease have quite different aetiologies in these populations. The genetic associations of both granulomatous vasculitis and renal vasculitis need to be investigated in large well-characterized cohorts.
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Acknowledgments |
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We thank the Japanese Health Sciences Foundation for supporting this study.
Conflict of interest statement. The authors do not have any conflict of interest. The results described herein have not previously been published.
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References |
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- Watts RA, Scott DGI. Epidemiology of systemic vasculitis. In: Vasculitis—Bridges L, Ball G, eds. (2007) 2nd edn. Oxford University Press, Oxford, UK. 7–21.
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- Fujimoto SU, S, Hisanaga S, Fukudome K, et al. Incidence of ANCA-associated primary real vasculitis in the Miyazaki Prefecture: the first population based, retrospective, epidemiologic survey in Japan. Clin J Am Soc Nephrol (2006) 1:1016–1022.
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[Abstract/Free Full Text] - Tsuchiya N, Kobayashi S, Hashimoto H, et al. Association of HLA-DRB1*0901-DQB1*0303 haplotype with microscopic polyangiitis in Japanese. Genes Immunity (2006) 7:81–84.[CrossRef][Medline]
- Nakamaru Y, Maguchi S, Takizawa M, et al. The association between human leukocyte antigens (HLA) and cytoplasmic-antineutrophil cytoplasmic antibody (cANCA)-positive Wegener's granulomatosis in a Japanese population. Rhinology (1996) 34:163–165.[Medline]
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Accepted in revised form: 30. 5.08
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