DÄ internationalArchive19/2008Stable Incidence of Systemic Vasculitides in Schleswig-Holstein, Germany

Original article

Stable Incidence of Systemic Vasculitides in Schleswig-Holstein, Germany

Dtsch Arztebl Int 2008; 105(19): 355-61. DOI: 10.3238/arztebl.2008.0355

Herlyn, K; Hellmich, B; Gross, W L; Reinhold-Keller, E

Introduction: The authors present data on the incidence of primary systemic vasculitides (PSV) in the northern German state of Schleswig-Holstein from 1998 to 2005.
Methods: Population-based study of all new cases of PSV from 1 January 1998 onward in a region with a population of 2.83 million. The sources of patient data were all hospital departments in the catchment area, including outpatient clinics; all departments of pathology; and the reference immunological laboratories serving the catchment area.
Results: Over this eight-year period, 982 patients with newly diagnosed PSV were identified in Schleswig-Holstein, of whom 273 were diagnosed with ANCA (i.e., anti-neutrophil cytoplasmic antibody)-associated vasculitis (AAV). The incidence of all types of PSV combined was between 38 and 54 cases per million population per year. The incidence of AAV (which includes Wegener's granulomatosis [WG], microscopic polyangiitis [MPA], and Churg-Strauss syndrome [CSS]) was between 9.5 and 16 cases per million per year. WG consistently accounted for two-thirds to three-quarters of all new cases of AAV diagnosed each year.
Discussion: This population-based vasculitis registry designed to capture all new cases of PSV in an eight-year period in a northern German region with 2.83 million inhabitants revealed stable incidence figures for all types of PSV and for AAV. Compared to figures obtained in other studies from small regions or referral centers, the incidence rate of WG (as an illustrative type of AAV) in this study was the same as those in Norway and Sweden, lower than that in the United Kingdom, but higher than those in Spain and in Vilnius (Lithuania). It is unclear whether these differences truly reflect a north-south gradient within Europe or are merely due to methodological differences.
Dtsch Arztebl Int 2008; 105(19): 355–61
DOI: 10.3238/arztebl.2008.0355
Key words: epidemiology, primary systemic vasculitides, ANCA-associated vasculitides, Wegener´s granulomatosis
LNSLNS Primary systemic vasculitides (PSV) are very rare diseases whose epidemiological characteristics have not yet been extensively studied, with the exception of arteritis (15). Most vasculitides have risen in incidence in recent years, particularly giant cell arteritis (GCA) (6).

A number of groups have found an increased incidence of Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), and Churg-Strauss syndrome (CSS) since the mid-1980s. This finding was associated with the discovery of the anti-neutrophilic cytoplasmic antibody (ANCA) and the recognition of its diagnostic importance (7, 8). Thus, a retrospective study in Sweden revealed a significant increase in the incidence of WG from 0.77 new cases per million inhabitants per year in 1975 to 11.9 in 2001 (9). Statistics from the United Kingdom and Spain, however, for the time periods 1988 to 1998 and 1988 to 2001, respectively, have shown practically unchanged incidences for ANCA-associated vasculitides (AAV) (1, 4, 10).

The case registries that have existed until now could often be faulted for being limited to a small, and thus perhaps unrepresentative, target region with a small population, or for referral bias due to monocentric registration (15). This situation motivated the creation of a vasculitis registry in northern and southern Germany, from 1998 onward, within the framework of the BMBF-sponsored joint project "Vasculitides: Their Etiology, Pathogenesis, Treatment, and Epidemiology."

All newly diagnosed primary systemic vasculitides, as defined by the Chapel Hill Consensus Conference, were registered from January 1, 1998, onward in a population-based study with nearly five million persons inhabiting the catchment area (11). The first two years' results showed no difference between northern and southern Germany in the incidence either of primary systemic vasculitides overall, or of any of the individual diseases in this class (12). As two years was too short a time to collect reliable, population-based epidemiological data on rare diseases, the vasculitis registry was kept in operation in the northern German federal state of Schleswig-Holstein (population 2.83 million). An initial report was published with data from the first five years (13). The goal of the present study is to analyze the results from a total of eight years, from 1998 to 2005, with special emphasis on ANCA-associated vasculitides. The Schleswig-Holstein Vasculitis Registry for the first time enables the reliable, prospective determination of the incidence of PSV in Germany and is the largest population-based study to date on the epidemiology of vasculitides.

Methods
Study area and study population
The study area is the state of Schleswig-Holstein, which has 2.83 million inhabitants (table 1 gif ppt). The calculated incidences are based on the population figures of January 1, 2000, and on the updated figures of January 1, 2003 (Statistical Office of the state of Schleswig-Holstein). There was relatively little population change attributable to immigration and emigration, the rates of which were 6% and 7%, respectively; for persons aged 50 and above, these rates were even lower (2% and 3%).

Study period
All newly diagnosed cases of PSV in Schleswig-Holstein from January 1, 1998, to December 31, 2005, were entered into the registry.

Sources
Before the Vasculitis Registry was begun, its creation was announced in regional medical publications and official university bulletins as well as by personal letter to all potential participants. All of the relevant institutions agreed to participate in the registry and designated a contact person within the institution. Data on PSV cases were regularly reported by, or requested from, the following sources:

- all hospital departments, including outpatient clinics,
- all pathology departments,
- and the regional immunological reference laboratory.

All "sources" were contacted by letter every three months (up to three times) and asked to report all newly diagnosed cases in the preceding three months. If all three letters went unanswered, the institutional contact person for the registry was contacted by telephone. All reported cases were re-evaluated by the authors with regard to the diagnosis, site of residence of the patient, and other features.

As required by data protection guidelines, the initial reporting of each case was anonymous but included the postal code of the patient's residence as well as the patient's sex, date of birth, and diagnosis, and the second letters of the patient's first and last names. If the patient consented, further medical data were obtained, e.g., the nature and manner of onset of the initial symptoms, the organs that were affected at the time of diagnosis, the ANCA findings, the histological findings, and the treatment provided.

All newly diagnosed patients were provided with information about the disease and its treatment and complications, as well as suitable literature for patients, patient education sessions, and contact persons in the nationwide Vasculitis Self-Help Group, which has been in existence in Germany since 1994. The study protocol was examined and approved both by the Ethics Committee of the University of Lübeck and by the State Data Protection Authority of Schleswig-Holstein.

Inclusion criteria
The following types of PSV, as defined in the Chapel Hill Consensus Conference (CHCC) of 1992 (11), were included in the registry:

- giant cell arteritis (GCA),
- Takayasu's arteritis (TA),
- Wegener's granulomatosis (WG),
- microscopic polyangiitis (MPA),
- Churg-Strauss syndrome (CSS),
- Henoch-Schönlein purpura (HSP),
- (isolated) cutaneous leukocytoclastic angiitis (CLA),
- (classic) panarteritis nodosa (PAN),
- Kawasaki syndrome.

Cases in which primary vasculitis was definitely present – as confirmed, e.g., by histopathological examination – but could not be assigned any of the above diagnoses were entered into the registry as "unclassifiable vasculitis" (UV). This category included, for example, isolated primary CNS vasculitis.

The diagnosis was required to have been made during the period of the study, and the patient was required to have resided within the study area at this point in time.

Exclusion criteria
Patients were excluded from the registry if they had secondary vasculitis (e.g., in the setting of inflammatory rheumatological diseases), vasculitis associated with an infectious disease (including hepatitis-associated vasculitis), or vasculitis associated with malignancy.

Statistics
The incidence figures were calculated as the number of new cases per million persons per year, and 95% confidence intervals were determined. The latter intervals were obtained by assuming that the incidence of rare diseases (both PSV as a whole and the individual entities that it comprises) follows a Poisson distribution. Furthermore, stratified incidence figures were calculated by age and sex, with separate calculations for the population subgroups above and below age 50. The number of sources reporting each individual case was recorded. For cases of AAV, it was also studied how frequently ANCA testing was performed in the Bad Bramstedt immunological reference laboratory, and what percentages of the patients were treated as either in- or outpatients in the Bad Bramstedt/Lübeck Vasculitis Center.

Results
A total of 1260 cases were reported from 1998 to 2005. 278 cases were excluded from the registry because the diagnosis was made before 1998, because the patient did not reside in the study area, or because the diagnosis did not correspond to the inclusion criteria. Thus, the registry finally included 982 patients (tables 2 and 3 and e-figure). The numbers of cases per year were as follows: in 1998, 152 cases; in 1999, 138 cases; in 2000, 126 cases; in 2001, 111 cases; in 2002, 115 cases; in 2003, 112 cases; in 2004, 107 cases; and in 2005, 121 cases.

Patients were reported by an average of two out of three possible sources (range, 1 to 3). For 406 patients (41%), the following laboratory tests were performed in the German reference laboratory for ANCA diagnostic studies in Bad Bramstedt:

- ANCA autoantibodies (indirect immunofluorescence plus ELISA for proteinase 3 and myeloperoxidase);
- antinuclear antibodies;
- double-stranded DNA antibodies (dsDNA-Ab);
- extractable nuclear antibodies (ENA).

ANCA-associated vasculitides
Over the entire period of the study, 273 patients developed ANCA-associated vasculitides (AAV) (i.e., WG, MPA, and CSS), corresponding to 28% of all vasculitides, with the number of cases per year ranging from 28 (in 1999) to 45 (in 2002) (table 2 gif ppt). In the course of these eight years, 191 patients developed WG, consistently accounting for two-thirds or more of all cases of AAV. The annual figures were as follows: in 1998, 21/29 (72%); in 1999, 18/28 (64%); in 2000, 24/37 (65%); in 2001, 24/33 (73%); in 2002, 33/45 (73%); in 2003, 22/29 (76%); in 2004, 24/38 (63%); in 2005, 25/34 (73%). The distribution of AAV patients by age and sex is shown in table 4 (gif ppt).

136 (50%) of the 273 patients with AAV underwent ANCA testing at the Bad Bramstedt reference laboratory. 143 of them (53%) underwent in- or outpatient treatment at the Bad Bramstedt/Lübeck Vasculitis Center. The regional distribution of all 273 patients with AAV over the entire temporal course of the study is shown in table 3 (gif ppt) and in the e-figure (gif ppt).

Incidences in northern Germany
The overall incidence of PSV of all types in Schleswig-Holstein varied from 38 to 54 new cases per million inhabitants per year over the course of the study. The annual incidence of AAV from 1998 to 2005 ranged from 9.5 to 16 new cases per million inhabitants per year, with a median figure of 12. WG was consistently the most common subtype of AAV, with an incidence ranging from 6 to 12 new cases per million inhabitants per year (median, 8.5). MPA was more common than CSS, the least common type of AAV (table 5 gif ppt).

Age-related incidences
Both PSV overall and AAV were two to five times more common among persons over 50 years of age than in persons under 50 years of age (table 4). The incidence of these conditions rose with age to the same extent in men and women. The mean age at diagnosis for all types of PSV was over 60 years (range, 61 to 66); for WG, 55 to 65 years; for MPA, 63 to 74 years; and for CSS, 43 to 63 years (table 2).

Sex-related incidences
The overall incidence of PSV was nearly the same among men and women (slightly higher among women, but the difference was statistically not significant). AAV were more common in men, again without statistical significance) (table 4).

Discussion
The Schleswig-Holstein Vasculitis Registry for the first time enabled the collection of reliable data on the incidence of PSV in Germany. With a target population of 2.83 million people and an observation period of eight years, it is the largest prospective population-based study performed to date on the epidemiology of vasculitides.

The overall incidence of PSV was found to vary between 38 and 54 new cases per year per million people. It is thus comparable to the incidence of systemic lupus erythematosus (14) and nearly twice as high as that of systemic sclerosis (15) or multiple sclerosis (16). The ANCA-associated vasculitides (WG, MPA, and CSS) occur in Schleswig-Holstein with an incidence ranging from 9.5 to 16 new cases per year per million people (median, 12). WG accounts for up to 75% of this group of patients; among the remaining 25%, MPA is twice as common as CSS.

Data from other European countries are available regarding the epidemiology of AAV (15, 9, 10). There are, however, major methodological differences between the individual studies. The data were often obtained from so-called tertiary centers or in a population-based manner from very small, and therefore unrepresentative, areas (e.g., under-representation of either larger cities or rural areas). Although many of these studies were carried out for long periods of time, some of them recruited a much smaller number of patients; thus, for example, a Norwegian population-based study of the incidence of WG identified only 55 patients with the disease during a period of 15 years. Studies from the United Kingdom and Spain that were carried out for 11 and 15 years, respectively, recruited only 40 (U.K.) and 12 (Spain) patients over the entire period of the study (1, 4, 10). In contrast, there were 191 new cases of WG in Schleswig-Holstein during the eight years of the present study.

In principle, epidemiological studies can be carried out in one of two ways:

- Observation of a small region over a long period of time, with the advantage of a high capture rate
- Observation of a large region over a shorter period of time, with the advantage of a large number of patients in a relatively short time, but with the disadvantage of a potential failure to capture all cases of the disease.

The differences between these two strategies might play a role in the interpretation of a number of the reported findings on vasculitides. In the past 15 to 20 years, there has been increased interest in AAV, and the diagnostic algorithm has changed (17). The most important contributing factors were the introduction of ANCA testing in the late 1980s (18) and the development of classifying criteria and definitions for PSV in the early 1990s. The latter also permit the identification of forms with a relatively benign course that previously would often have escaped detection (19). Thus, comparing the results of this study with those of previous European studies is likely to be difficult.

The authors' study revealed incidence rates of AAV ranging from 9.5 to 16 new cases per million persons per year (median, 12), compared to 22 in the United Kingdom and 12.1 in Spain (1, 4). Classification criteria have a major influence on epidemiological data regarding PSV, particularly as concerns MPA and PAN. In our study, and in the Spanish study as well, the CHCC definitions (11) were used for PSV, because these take immunological and immunohistochemical criteria into account, unlike the classification system of the American College of Rheumatology (ACR) (19). Furthermore, there are as yet no ACR criteria for MPA. The CHCC definitions for the first time enable a clear-cut distinction between MPA and PAN, two entities with presumably very different pathogenetic features.
WG was the most common type of AAV in this study and in the British study, yet, in Spain, the incidence of MPA was more than twice as high as that of WG (1, 4). In our population-based study with a catchment area containing 2.83 million inhabitants, WG consistently accounted for two-thirds to three-quarters of all cases of AAV. The data in the Spanish study, in contrast, were derived from a tertiary center in a region containing only 238 000 people. The importance of methodological differences in epidemiological studies of AAV is also demonstrated by a study from Sweden on the incidence of small-vessel vasculitides (3). This study by Tidman et al., carried out in a nephrology department, also identified far more patients with MPA (n = 70) than with WG (n = 19).

We found an incidence of WG ranging from 6 to 12 new cases per million inhabitants per year, with a median of 8.5 new cases (table 5). The incidence of WG was thus significantly higher in Schleswig-Holstein than in Spain or Lithuania (2.95 and 2.1 cases per million inhabitants per year, respectively), comparable to the incidence in Norway (8.0) and Sweden (7.8), and somewhat lower than the incidence in the United Kingdom (1, 4, 5, 9, 10) (table 6 gif ppt). These differences (with the exception of the figure from Lithuania) might reflect a north-south gradient across Europe, similar to the one that has been described for AT, unless they are entirely due to methodological differences. Preliminary data from an initial study in the Southern Hemisphere regarding the incidence of WG and MPA in Lima, Peru (population 930 306) from 1990 to 2004 surprisingly show a nearly tenfold higher incidence of MPA (4.1 per million persons per year) than of WG (0.5 per million persons per year).

The demographic data on the population of our catchment area and of our study patients (sex distribution, age at diagnosis) remained fairly constant over the period of the study. It is worth noting that the median age at the time of diagnosis of WG remained roughly 60 years over the entire study period (range of ages at diagnosis: 22 to 87), while the median age at diagnosis was much younger (between 40 and 50) in large WG cohorts that were recruited about 20 years earlier (2124), even though the time lag from the initial manifestations to the establishment of the diagnosis has become shorter over the years. In the present study, the median time to diagnosis was 3 months (range, 0 to 48 months), while the comparable figures in earlier WG cohorts were 9 months (range, 0 to 288 months) (23) and 15 months (22). This could be due either to a real increase of the age at diagnosis or to increased attention to small-vessel vasculitis in older persons, or both. A limitation of this study might be a less than total capture of patients that were treated entirely on an outpatient basis (and not in the outpatient clinics of hospital departments) and whose diagnoses were established without any histological examinations or auto-antibody determinations. One can safely assume, however, that such patients are rare among persons with AAV.

Overview
This prospective, population-based vasculitis registry that was kept for eight years in Schleswig-Holstein, an area with 2.83 million inhabitants, revealed an annual incidence of PSV varying from 38 to 54 new cases per million persons per year. ANCA-associated vasculitides had an incidence ranging from 9.5 to 16 new cases per million persons per year and thus accounted for 28% of all vasculitides; their incidence was stable over the eight years of the study. It currently remains unclear whether there are any regional differences in the incidence of WG. The differences that were found might reflect either a true north-south gradient in Europe, perhaps due to different exogenous exposures, or they might merely reflect methodological differences between studies.

Acknowledgements
The authors thank Michaela Beck and Claudia Möck for their collaboration and excellent assistance.

The Vasculitis Registry has had financial support from BMBF (1998–2000) and from the Bad Bramstedt Research Association (Forschungsverein Bad Bramstedt e.V.) (2001–present).

Conflict of interest statement
The authors declare that no conflict of interest exists as defined by the guidelines of the International Committee of Medical Journal Editors.

Manuscript received on 18 June 2007; revised version accepted on
21 December 2007.

Translated from the original German by Ethan Taub, M.D.


Corresponding author
Dr. med. Karen Herlyn, M.P.H.
Poliklinik für Rheumatologie
Universitätsklinikum Schleswig-Holstein, Campus Lübeck
Ratzeburger Allee 160
23538 Lübeck, Germany
Karen.Herlyn@uk-sh.de

e-figure:
www.aerzteblatt-international.de/article08m355
1.
Gonzales-Gay MA, Garcia-Porrua C, Guerrero J, Rodriguez-Ledo P, Llorca J: The epidemiology of the primary systemic vasculitides in northwest Spain: Implications of the Chapel Hill Consensus Conference Definitions. Arthritis Care & Res 2003; 49: 388–93. MEDLINE
2.
Haugenberg G, Bie R, Bendvold A, Strom Larsen A, Johnsen V: Primary vasculitis in a Norwegian Community Hospital: a retrospective study. Clin Rheumatol 1998; 17: 364–8. MEDLINE
3.
Tidman M, Olander R, Svalander C, Danielsson D: Patients hospitalized because of small vessel vasculitides with renal involvement in the period 1975–1995. Organ involvement, ANCA patterns, seasonal attack rates and fluctuation of annual frequencies. J Intern Med; 1998; 244: 133–41. MEDLINE
4.
Watts RA, Gonzales-Gay MA, Lane SE, Garcia-Porrua C, Bentham G, Scott DGI: Geoepidemiology of systemic vasculitis: comparison of the incidence in two regions of Europe. Ann Rheum Dis 2001; 60: 170–172. MEDLINE
5.
Dadoniene J, Kirdaite G, Mackiewicz Z, Rinkevicius A, Haugeberg G: Incidence of primary systemic vasculitides in Vilnius: a universtiy hospital population based study. Ann Rheum Dis 2005; 64: 335–6. MEDLINE
6.
Salvarani C, Gabriel SE, O'Fallon WM, Hunder GG: The incidence of giant cell arteritis in Olmstedt County, Minnesota: apparent fluctuations in a cyclic pattern. Ann Intern Med 1995; 123: 192–4. MEDLINE
7.
Carruthers DM, Watts RA, Symmons DPM, Scott DGI: Wegener's granulomatosis – increased incidence or increased recognition? Br J Rheum 1996; 35: 142–5. MEDLINE
8.
Lane SE, Scott DGI, Heaton A, Watts RA: Primary renal vasculitis in Norfolk – increasing incidence or increasing recognition? Nephrol Dial Transplant 2000; 15: 23–7. MEDLINE
9.
Knight A, Ekbom A, Brandt L, Askling J: Increasing incidence of Wegeners’ granulomatosis in Sweden, 1975–2001. J Rheumatol 2006; 33: 2060–3. MEDLINE
10.
Koldingsnes W, Nossent H: Epidemiology of Wegener's granulomatosis in Northern Norway. Arthritis Rheum 2000; 43: 2481–7. MEDLINE
11.
Jennette JC, Falk RJ, Andrassy K et al.: Nomenclature of systemic vasculitides: proposal of an International Consensus Conference. Arthritis Rheum 1994; 37: 187–92. MEDLINE
12.
Reinhold-Keller E, Herlyn K, Wagner-Bastmeyer R et al.: No differences in the incidences of vasculitides between North and South Germany: first results of the German vasculitis register. Rheumatology 2002; 41: 540–9. MEDLINE
13.
Reinhold-Keller E, Herlyn K, Wagner-Bastmeyer R, Gross WL: Stable incidence of primary systemic vasculitides over five years: results from the German vasculitis register. Arthritis Rheum 2005; 53: 93–9. MEDLINE
14.
Stahl-Hallengren C, Jonsen A, Nived O, Sturfelt G: Incidence studies of systemic lupus erythematosus in Southern Sweden. J Rheumatol 2000; 27: 685–91. MEDLINE
15.
Stehen VD, Oddis CV, Conte CG, Janoski J, Casterline GZ, Medsger TA: Incidence of systemic sclerosis in Allegheny County, Pennsylvania. Arthritis Rheum 1997; 40: 441–5. MEDLINE
16.
Jacobsen DL, Gange SJ, Rose NR, Graham NMH: Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 1997; 84: 223–43. MEDLINE
17.
Hellmich B, Csernok E, Gross WL: 20 Years with ANCA (antineutrophil cytoplasmic antibodies): from seromarker to major pathogenic player in vasculitis. J Leukocyte Biol 2003; 74: 1–2. MEDLINE
18.
Csernok E, Lamprecht P, Gross WL: Diagnostic significance of ANCA in vasculitis. Nat Clin Pract Rheumatol 2006; 2: 174–5. MEDLINE
19.
Fries JF, Hunder GG, Bloch DA et al.: The American College of Rheumatology 1990 criteria for the classification of vasculitis. Arthritis Rheum 1990; 33: 1135–6. MEDLINE
20.
Sanchez AA, Acevedo EM, Sanchez CG et al.: Epidemiology of the primary systemic vasculitides in a Latin-American population. Arthritis Rheum 2006; 54(9) (Suppl): S757.
21.
Anderson G, Coles ET, Crane M, Douglas AC, Gibbs AR, Geddes DM, Peel ET, Wood JB: Wegener's granulomatosis. A series of 265 British cases seen between 1975 and 1985. A report by a sub-committee of the British Thoracic Society Research Committee. Q J Med 1992 83: 427–38. MEDLINE
22.
Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, Rottem M, Fauci AS: Wegener’s granulomatosis: an analysis of 158 patients. Ann Intern Med 1992; 116: 488–98. MEDLINE
23.
Matteson EL, Gold KN, Bloch DA, Hunder GG: Long-term survival of patients with Wegener's granulomatosis from the American College of Rheumatology Wegener's granulomatosis Criteria Cohort. Am J Med 1996; 101: 129–34. MEDLINE
24.
Reinhold-Keller E, Beuge N, Latza U et al.: An interdisciplinary approach to the care of patients with Wegener's granulomatosis: Longterm outcome in 155 patients. Arthritis Rheum 2000; 43: 1021–32. MEDLINE
Poliklinik für Rheumatologie Universitätsklinikum Schleswig-Holstein Campus Lübeck/Rheumaklinik Bad Bramstedt GmbH: Dr. med. Herlyn, MPH, PD Dr. med. Hellmich, Prof. Dr. med. Gross, PD Dr. med. Reinhold-Keller
1. Gonzales-Gay MA, Garcia-Porrua C, Guerrero J, Rodriguez-Ledo P, Llorca J: The epidemiology of the primary systemic vasculitides in northwest Spain: Implications of the Chapel Hill Consensus Conference Definitions. Arthritis Care & Res 2003; 49: 388–93. MEDLINE
2. Haugenberg G, Bie R, Bendvold A, Strom Larsen A, Johnsen V: Primary vasculitis in a Norwegian Community Hospital: a retrospective study. Clin Rheumatol 1998; 17: 364–8. MEDLINE
3. Tidman M, Olander R, Svalander C, Danielsson D: Patients hospitalized because of small vessel vasculitides with renal involvement in the period 1975–1995. Organ involvement, ANCA patterns, seasonal attack rates and fluctuation of annual frequencies. J Intern Med; 1998; 244: 133–41. MEDLINE
4. Watts RA, Gonzales-Gay MA, Lane SE, Garcia-Porrua C, Bentham G, Scott DGI: Geoepidemiology of systemic vasculitis: comparison of the incidence in two regions of Europe. Ann Rheum Dis 2001; 60: 170–172. MEDLINE
5. Dadoniene J, Kirdaite G, Mackiewicz Z, Rinkevicius A, Haugeberg G: Incidence of primary systemic vasculitides in Vilnius: a universtiy hospital population based study. Ann Rheum Dis 2005; 64: 335–6. MEDLINE
6. Salvarani C, Gabriel SE, O'Fallon WM, Hunder GG: The incidence of giant cell arteritis in Olmstedt County, Minnesota: apparent fluctuations in a cyclic pattern. Ann Intern Med 1995; 123: 192–4. MEDLINE
7. Carruthers DM, Watts RA, Symmons DPM, Scott DGI: Wegener's granulomatosis – increased incidence or increased recognition? Br J Rheum 1996; 35: 142–5. MEDLINE
8. Lane SE, Scott DGI, Heaton A, Watts RA: Primary renal vasculitis in Norfolk – increasing incidence or increasing recognition? Nephrol Dial Transplant 2000; 15: 23–7. MEDLINE
9. Knight A, Ekbom A, Brandt L, Askling J: Increasing incidence of Wegeners’ granulomatosis in Sweden, 1975–2001. J Rheumatol 2006; 33: 2060–3. MEDLINE
10. Koldingsnes W, Nossent H: Epidemiology of Wegener's granulomatosis in Northern Norway. Arthritis Rheum 2000; 43: 2481–7. MEDLINE
11. Jennette JC, Falk RJ, Andrassy K et al.: Nomenclature of systemic vasculitides: proposal of an International Consensus Conference. Arthritis Rheum 1994; 37: 187–92. MEDLINE
12. Reinhold-Keller E, Herlyn K, Wagner-Bastmeyer R et al.: No differences in the incidences of vasculitides between North and South Germany: first results of the German vasculitis register. Rheumatology 2002; 41: 540–9. MEDLINE
13. Reinhold-Keller E, Herlyn K, Wagner-Bastmeyer R, Gross WL: Stable incidence of primary systemic vasculitides over five years: results from the German vasculitis register. Arthritis Rheum 2005; 53: 93–9. MEDLINE
14. Stahl-Hallengren C, Jonsen A, Nived O, Sturfelt G: Incidence studies of systemic lupus erythematosus in Southern Sweden. J Rheumatol 2000; 27: 685–91. MEDLINE
15. Stehen VD, Oddis CV, Conte CG, Janoski J, Casterline GZ, Medsger TA: Incidence of systemic sclerosis in Allegheny County, Pennsylvania. Arthritis Rheum 1997; 40: 441–5. MEDLINE
16. Jacobsen DL, Gange SJ, Rose NR, Graham NMH: Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 1997; 84: 223–43. MEDLINE
17. Hellmich B, Csernok E, Gross WL: 20 Years with ANCA (antineutrophil cytoplasmic antibodies): from seromarker to major pathogenic player in vasculitis. J Leukocyte Biol 2003; 74: 1–2. MEDLINE
18. Csernok E, Lamprecht P, Gross WL: Diagnostic significance of ANCA in vasculitis. Nat Clin Pract Rheumatol 2006; 2: 174–5. MEDLINE
19. Fries JF, Hunder GG, Bloch DA et al.: The American College of Rheumatology 1990 criteria for the classification of vasculitis. Arthritis Rheum 1990; 33: 1135–6. MEDLINE
20. Sanchez AA, Acevedo EM, Sanchez CG et al.: Epidemiology of the primary systemic vasculitides in a Latin-American population. Arthritis Rheum 2006; 54(9) (Suppl): S757.
21. Anderson G, Coles ET, Crane M, Douglas AC, Gibbs AR, Geddes DM, Peel ET, Wood JB: Wegener's granulomatosis. A series of 265 British cases seen between 1975 and 1985. A report by a sub-committee of the British Thoracic Society Research Committee. Q J Med 1992 83: 427–38. MEDLINE
22. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, Rottem M, Fauci AS: Wegener’s granulomatosis: an analysis of 158 patients. Ann Intern Med 1992; 116: 488–98. MEDLINE
23. Matteson EL, Gold KN, Bloch DA, Hunder GG: Long-term survival of patients with Wegener's granulomatosis from the American College of Rheumatology Wegener's granulomatosis Criteria Cohort. Am J Med 1996; 101: 129–34. MEDLINE
24. Reinhold-Keller E, Beuge N, Latza U et al.: An interdisciplinary approach to the care of patients with Wegener's granulomatosis: Longterm outcome in 155 patients. Arthritis Rheum 2000; 43: 1021–32. MEDLINE