Department of Rheumatology, University of Lübeck and Rheumaklinik Bad Bramstedt GmbH
1 Department of Rheumatology and Clinical Immunology, University of Freiburg and
2 Department of Social Medicine, University of Lübeck, Germany
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Abstract |
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Methods. Questionnaires were sent to all hospital departments, all physicians, health insurance providers and pension funds, reference laboratories for autoimmune diseases, and death registries in two catchment areas in northern and southern Germany (combined population 875 983) to identify patients with PSV between 1 January and 31 December 1994. Each catchment area encompassed both an urban and a rural area. Each case was re-evaluated by the authors by applying the definitions of the 1992 Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis.
Results. A total of 180 PSV patients were identified. The overall prevalence of PSV was 216 cases per 1 000 000 inhabitants (95% confidence interval (CI) 173259) in northern Germany vs 195 (95% CI 153236) in southern Germany. The prevalence of PSV was two-fold higher in women than in men, and five-fold higher in people aged 50 yr than in people aged <50 yr. The most frequent type of PSV was giant cell arteritis (GCA), with 87 cases per 1 000 000 in northern and 94 in southern Germany, followed by Wegener's granulomatosis, with 58 and 42 cases respectively. In the population aged
50 yr the prevalence of GCA was 240 per 1 000 000 in northern and 300 in southern Germany. In both northern and southern Germany the prevalence of GCA in this older population was significantly higher in urban than in rural populations (355 per 1 000 000 vs 115 in northern Germany (P<0.01) and 395 vs 220 (P<0.05) in southern Germany). The relative risk for the older urban population having GCA was 2.25-fold higher (95% CI 1.43.6) than in the rural population, and for the female population it was 4.7-fold higher in the urban than in the rural areas (95% CI 2.49.3).
Conclusion. In both northern and southern Germany, GCA was significantly more prevalent in urban than in rural populations, especially among people aged 50 yr and in women. It remains unclear whether this disparity was due to underdiagnosis of GCA in the rural regions associated with differences in the German health-care system in cities vs rural areas. Further studies must examine the role of (chronic) exposure to the environmental factors characteristic of cities.
KEY WORDS: Epidemiology, Vasculitis, Giant cell arteritis, Wegener's granulomatosis.
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Introduction |
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The scarcity of population-based epidemiological studies of PSV and the regional differences reported for the individual types of PSV prompted us to conduct a population-based epidemiological study drawing on eight sources to investigate the prevalence of all types of PSV as defined by the 1992 Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis (CHC) [2] in defined urban and rural populations in northern and southern Germany during the calendar year 1994.
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Methods |
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Study period
The study period encompassed the entire 1994 calendar year.
Sources
Data on the prevalence of PSV were obtained from eight sources: (A) the departments at which the authors are employed: the Department of Rheumatology, University of Lübeck, the Rheumaklinik Bad Bramstedt GmbH (Segeberg), the Department of Rheumatology and Clinical Immunology, University of Freiburg, including their outpatient clinics; (B) all departments of the medical universities, all other hospitals, including their outpatient clinics serving the respective catchment areas; (C) all departments of pathology at both participating universities and all participating hospitals, plus pathologists in private practice; (D) all physicians in private practice; (E) pension funds; (F) health insurance providers; (G) central death registries; and (H) the reference immunology laboratories of both universities serving the respective catchment areas.
All PSV patients treated in 1994 in the institutions comprising source A and living in the catchment areas in 1994 were identified and enrolled. Sources B and D were asked for information on PSV patients receiving medical care for vasculitis or other diseases during 1994. The pathologists (source C) were asked to identify all biopsy specimens for which a diagnosis of vasculitis was given, including kidney biopsies, in 1994. The referring physicians or hospitals were contacted for further information. Health insurance providers and pension funds (sources E and F) were asked to identify PSV patients among their clientele who had received medical care in 1994. The central death registries (source G) were asked to identify PSV patients who had died during 1994, regardless of the immediate cause of death. The reference laboratories for vasculitic diseases located at both participating universities were screened for all PSV cases (either a positive ANCA test result or the diagnosis vasculitis on the request form) living in the catchment areas during 1994 (source H), followed by an additional evaluation of the medical records.
Packets containing a questionnaire, documentation forms and a stamped return envelope were sent to all sources up to three times. When there was no response to all three mailings, the authors contacted the physicians by telephone.
Inclusion criteria/case definition
The following types of PSV, as defined by the 1992 CHC, were studied: GCA (temporal arteritis); Takayasu arteritis; WG; MPA; CSS; HenochSchönlein purpura (HSP); (isolated) cutaneous leukocytoclastic vasculitis (CLA); (classic) polyarteritis nodosa (PAN); and Kawasaki syndrome. The diagnosis of unclassified primary systemic vasculitides (UV) was also included. Patients with one of these vasculitides and living in the catchment areas during the study period were included in the study regardless of their PSV activity status or need of treatment for PSV during the calendar year 1994. The data (medical records were available for most cases) obtained from all sources and the patients medical records were reviewed by two of the authors (ERK and JG).
The study forms documented each patient's unique personal data: date of birth, gender, postal code in 1994, the type of PSV diagnosed and the year of diagnosis.
Exclusion criteria
Patients were excluded if they had secondary vasculitides, e.g. cases of vasculitides secondary to rheumatoid arthritis, systemic lupus erythematosus (SLE) or other connective tissue diseases, or secondary to virus- or malignoma-associated vasculitides. PSV patients who had not resided in one of the catchment areas in 1994 were also excluded.
Ethical approval
Approval for the study was obtained from the ethics committees of the universities of Lübeck and Freiburg. The study was also approved by the data protection agencies of the Federal States of Schleswig-Holstein and Baden-Württemberg.
Statistical analysis
The period prevalence was calculated as the number of PSV cases per 1 000 000 population in 1994 for each type of PSV in the entire populations of the respective catchment areas in northern and southern Germany, as well as separately for the urban and rural populations. The relative risks of having a PSV in urban vs rural populations were also calculated. Gender-standardized prevalence rates were also calculated, and age-adjusted rates for the populations aged 50 yr were calculated to facilitate comparison with other studies. Calculations were based on the population statistics of 30 June 1994. Ninety-five per cent confidence intervals (95% CI) were calculated for the prevalence rates, on the basis of the Poisson distribution.
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Results |
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All hospital departments, including those of both universities, responded to either the written or the telephone inquiries. The rate of written response did not differ between urban physicians outside hospitals (58%) and their rural counterparts (55%). Telephone calls to sources who did not respond in writing led to information from about 75% of all general and internal physicians. Both cities (Lübeck and Freiburg) had 0.06 reported cases per physician and both rural areas (Segeberg and Breisgau) had 0.08 cases per physician. Data from more than one source were obtained in 48 of the 97 cases in northern Germany. Furthermore, immunological tests on 57 of the northern PSV patients, including all cases of ANCA-associated vasculitides (WG, CSS, MPA), were performed in the reference laboratory for vasculitides (source H). Four other northern PSV patients, who had died in 1994, were identified from the central death registry (two with GCA, one with CLA and one with PAN). For 54 of the 83 patients in southern Germany, data were obtained from more than one source. As in the north, the reference laboratory for vasculitides performed immunological tests for vasculitis in 56 southern patients, including all cases with ANCA-associated PSV. Five southern patients were identified from the death registry as having died in 1994 (two with GCA, two with WG and one with CSS).
Characteristics of all PSV patients in northern and southern Germany in 1994
Northern Germany
Sixty-three PSV patients (19 males, 44 females) were identified in the city of Lübeck and 34 (14 males, 20 females) in the rural region Segeberg. The most frequent type of vasculitis was GCA (n=39), followed by WG (n=26). The median age of all patients in 1994 was 66 yr (range 490 yr), and that of the 39 GCA patients was 76 yr (range 5290 yr). In 25 patients the diagnosis of vasculitis was first made in 1994. In the remaining 72 patients the median duration of PSV before 1994 was 3 yr (range 116 yr).
Southern Germany
Forty-four PSV patients (14 males, 30 females) were identified in the city of Freiburg and 39 (12 males, 27 females) in the rural region of Breisgau. Forty patients had GCA and 18 had WG. The median age of southern PSV patients in 1994 was similar to that in the north, namely 69 yr (range 392 yr). The median age of the 40 GCA patients was 76 yr (range 6092 yr). In 28 patients the diagnosis of PSV was first established in 1994. In the remaining 55 patients, the median duration of disease since the diagnosis of vasculitis was 3 yr (range 120 yr).
Prevalence of PSV in northern and southern Germany
The overall prevalence of all types of PSV was 216 per 1 000 000 inhabitants (95% CI 173259) in the north and 195 per 1 000 000 (95% CI 153236) in the south (Table 2). In both areas GCA was the most frequent type of PSV, with a prevalence of 87 per 1 000 000 inhabitants in the north (95% CI 59114) and 94 per 1 000 000 in the south (95% CI 65123). The prevalence of GCA in the population aged
50 yr was 240 per 1 000 000 inhabitants in the north (95% CI 164315) and 300 per 1 000 000 in the south (95% CI 207393). In both areas GCA was followed in order of frequency by WG at 58 per 1 000 000 inhabitants in the north (95% CI 3680) and 42 per 1 000 000 in the south (95% CI 2362) (Table 2
). Neither Takayasu arteritis nor Kawasaki syndrome was observed in either catchment area.
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Prevalences of PSV in cities and rural regions
In both north and south the overall prevalence of PSV was higher in cities than in rural regions (Table 2). The prevalence of PSV in the north was two-fold higher in the city than in the rural region: 290 (95% CI 218362) vs 146 (95% CI 97196) per 1 000 000 (P<0.01). In the southern city of Freiburg the prevalence was 222 per 1 000 000 (95% CI 156287) vs 171 (95% CI 117225) in the corresponding rural region. The differences were most pronounced for GCA (Table 2
), especially in people aged
50 yr (north, 355 per 1 000 000 (95% CI 228482) vs 115 (95% CI 40190) (P<0.01); south, 395 per 1 000 000 (95% CI 237553) vs 220 (95% CI 112328) (P<0.05)). In both cities the relative risk for the elderly with GCA was 2.25-fold higher (95% CI 1.43.6) than for their rural counterparts. The urban/ rural difference was even more marked in females aged
50 yr, whose relative risk for GCA was 4.7-fold higher (95% CI 2.49.3) in the cities than in the rural regions. The prevalence for older men showed no such difference.
Age-adjusted prevalence of PSV
In both catchment areas the prevalence of PSV increased with age, in the north from 87 per 1 000 000 inhabitants aged <50 yr (95% CI 53121) to 442 per 1 000 000 inhabitants aged 50 yr (95% CI 340545) and in the south from 78 (95% CI 46111) to 450 (95% CI 336564) per 1 000 000. Except for HSP, the increase in prevalence with age was observed for all types of PSV (data not shown).
Gender-adjusted prevalence of PSV
The overall prevalence of PSV in the north was 152 per 1 000 000 (95% CI 100204) for males and 275 per 1 000 000 (95% CI 207342) for females; in the south it was 128 per 1 000 000 (95% CI 79177) for males and 256 per 1 000 000 (95% CI 189322) for females. The difference in both areas was mainly caused by the 4-fold higher prevalence of GCA in females
50 yr vs males aged
50 yr (Table 2
).
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Discussion |
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In our study, GCA was the most common type of PSV diagnosed in both northern and southern Germany, with 87 and 94 cases per 1 000 000 respectively. In the populations aged 50 yr, the corresponding frequencies were 240 and 300 cases. Limited information has been published on the prevalence of GCA. Most studies report the incidence of GCA. Huston et al. [21] reported a point prevalence of 1330 per 1 000 000 of the population aged
50 yr in Olmsted County, Minnesota on 1 January 1975, a rate conspicuously higher than our own. In a further study by Machado et al. [22] in the same region, the point prevalence of GCA on 1 January 1984 in the population aged
50 yr was even higher, with 2230 cases per 1 000 000. Neither report provided information on the total number of residents in the catchment areas or on the percentage of the population aged
50 yr. The calculation of their point prevalence was based on 24 patients having GCA on 1 January 1975 in the former and 47 patients on 1 January 1984 in the latter study, markedly fewer patients than the 79 in our study. Furthermore, in contrast to the studies by Huston et al. and Machado et al., we calculated the period prevalence for the entire year 1994. In our study, the additional calculated point prevalence for GCA in the population aged
50 yr on 1 January 1994 was 272 per 1 000 000 in Lübeck and 64 in the rural region of Segeberg (P<0.01). The corresponding data for GCA in Freiburg was 263 cases per 1 000 000 vs only 124 per 1 000 000 in Breisgau (P<0.05). Twenty-six of the 79 GCA patients in our study were first diagnosed in the year 1994, representing about one-third of all GCA cases. In the study of Huston et al. [21] only 15 GCA cases were diagnosed in their study period between 1970 and 1974, and in the study of Machado et al. [22] only 31 were diagnosed between 1980 and 1985. Thus, it can be assumed that the populations examined in their studies were conspicuously smaller than our population. Nevertheless, the reason for the major differences in prevalence between those two studies and our own is unclear. Perhaps general awareness of GCA is greater in Olmsted County, which includes the Mayo Clinic. On the other hand, GCA is often underdiagnosed, as reported by Östberg [23]. Östberg found GCA in 1.7% of 889 consecutive post-mortem biopsies of the temporal arteries. Our results showed 0.02% of the living population aged
50 yr in both areas to be suffering from GCA in 1994. It appears probable that GCA was underdiagnosed in our catchment areas.
Next in order of frequency in our study was WG, with 58 cases per 1 000 000 in the north and 42 per 1 000 000 in the south. Both rates are higher than that reported by Cotch et al. [7] (30 cases per million) in the USA. The latter study, however, included only hospitalized and deceased WG patients. Furthermore, it encompassed the period from 1979 to 1988 and thus, unlike our study, included a long period before the introduction of ANCA in the mid-1980s, which has led to an increase in the rate of diagnosed WG, even of less serious abortive courses [10, 11, 24].
Unlike other epidemiological studies of PSV, our study was population-based, drawing on eight sources. The importance of case-finding methods in epidemiological studies of rare diseases such as PSV was demonstrated by a Swedish study involving cases of small vessel vasculitis [4]. In this study, by a department of nephrology, Tidman et al. considered only in-patients treated at three hospitals over a period of 21 yr. Of 138 patients with small vessel vasculitis treated during this period, 89% had renal involvement. Surprisingly, they found only 19 patients with WG but 70 patients with MPA. In population-based studies, by contrast, WG is four times more common than MPA, as also observed in our study and a study by Scott and Watts [25].
Furthermore, the choice of inclusion criteria can also be important in comparing different studies [26]. Our study included all cases of PSV as defined by the 1992 CHC [2]. Unlike the 1990 American College of Rheumatology (ACR) classification criteria for PSV, this definition incorporates immunological and immunohistochemical findings and makes a clear distinction between MPA and PAN. Moreover, with regard to cutaneous vasculitides, the CHC definitions for CLA and HSP provide clearer distinctions than the ACR criteria [2, 27]. However, our patients with GCA, WG, CSS and HSP fulfilled both the CHC definitions and ACR criteria for these disorders. The ACR criteria do not include MPA as a distinct entity.
The main goal of the present study was to investigate regional differences in the prevalence of PSV between northern and southern Germany and between the urban and rural populations in each of these areas. The overall prevalences of PSV in the north and south did not differ with regard to either the crude prevalences of the different entities or age- and gender-adjusted rates. There were, however, marked differences in the prevalence rates between the respective urban and rural populations. Upon closer examination, these differences were found to be caused by differences in the prevalence of GCA, the most common type of PSV. These differences were significant for the populations aged 50 yr in both the north (355 vs 115 per 1 000 000) and the south (395 vs 220 per 1 000 000), and even more so for women aged
50 yr (north, 545 vs 141 per 1 000 000; south, 602 vs 296 per 1 000 000) (Table 2
). The lack of such differences in the older male populations may be due to the relatively small number of male GCA patients (north, 6 males with GCA vs 33 females; south, 6 males vs 34 females).
Although the overall sex ratio was similar in all four areas, the percentage of females aged 50 yr was higher in all four regions than the percentage of males (Table 1
). Moreover, in the north the percentage of women aged
50 yr was higher in the city than in the rural region (43 vs 36), whereas no such difference existed in the south (35 vs 35). Thus, the differences in the GCA prevalence in urban vs rural regions cannot be explained by demographic differences. On the other hand, regional differences in the German medical care structure [28] were an obvious factor contributing to the differences in the prevalence of GCA in urban vs rural regions (Table 1
). Whereas the northern catchment area contained clinics for rheumatology in both Lübeck and the district of Segeberg, in the south only the city of Freiburg had such a clinic. Furthermore, the ratio of physicians to inhabitants was nearly two-fold higher in both cities than in their corresponding rural regions. The distribution of specialized physicians also varied (Table 1
). Thus, it can be speculated that PSV cases, especially the comparatively mild GCA, were more likely to be underdiagnosed in the rural areas than in the cities. However, the number of reported PSV cases per physician was higher in both rural regions than in the cities.
Finally, the effect of exposure to environmental factors in the cities may also have contributed to the differences in prevalence between the urban and rural populations. Elling et al. [16] found a close association between the occurrence of GCA and/or polymyalgia rheumatica and epidemics of Mycoplasma pneumoniae infections, which were more frequent in cities than rural regions. An association between GCA and infection was also observed by Russo et al. [29], who found that GCA patients were three times more likely than a control group to have infections during a defined period before the occurrence of GCA. In the study on GCA in Olmsted County, Minnesota [9], the peaks in the incidence of GCA every 7 yr may also have been caused by infection epidemics. In addition, chronic long-term exposure to pollutants in cities may help to explain why GCA occurred only in the elderly. Duna et al. [30] found a high rate of self-reported environmental exposure to inhaled substances in WG patients, but similar rates in patients with other chronic inflammatory diseases, and also in healthy controls. Finally, Yashiro et al. [31] reported a close association between an earthquake in Kobe, Japan, and the development of ANCA-associated vasculitides in this region in the following 2 yr. In sum, the reasons for the regional differences in the prevalence of GCA in our study remain unclear. The other types of PSV exhibited no such regional differences, perhaps because the numbers of these cases were too small.
Although this study had a population-based design and used eight different sources of data, it is possible that cases were missed and that the calculated prevalence rates are too low. This could be the case for CLA, a disease that often presents with a transient course and a lack of biopsy as a diagnostic procedure. The prevalence rates for the northern and southern regions are similar for cities and rural areas for all PSVs and for the single entities. Furthermore, for each source the frequency of reports is almost identical in the corresponding regions. We therefore believe that the results for the regions analysed are comparable.
In summary, GCA was found to be the most common type of PSV in the general populations of northern and southern Germany, with a prevalence between 240 and 300 cases per 1 000 000 inhabitants aged 50 yr. In both northern and southern Germany, GCA was conspicuously more common in the urban than in the rural populations. Further studies of larger populations are needed in order to validate these results and to determine the role of (chronic?) exposure to environmental factors in regions of high population density. On the basis of the present findings, a vasculitis registry for all new cases of PSV occurring in large regions in northern and southern Germany and serving about 5 000 000 habitants was established in 1998. This registry is currently being used in a casecontrol study of the role of exposure to environmental factors in the development of PSV.
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Acknowledgments |
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Notes |
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References |
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