Diagnosis of Wegener's granulomatosis in the ANCA era.

Wegener’s granulomatosis (WG) is a chronic granulomatous necrotizing vasculitis predominantly affecting the upper and lower respiratory tracts and the kidneys. Other organs less commonly involved include the skin, joints, eyes, heart, and peripheral and central nervous systems. The disease is closely associated with circulating antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3), and less commonly against myeloperoxidase. The etiology of WG remains unknown. Although a genetic predisposition is thought to contribute to the development of the disease, the relevance of the genetic variations reported to date is unclear1. The disease is more common in Caucasian populations, but familial cases are very rare and the disease has not been reported in homozygous twins. A number of environmental factors have been associated with WG. These include respiratory infections, farming, occupational silica and solvent exposures, prior history of allergy to a drug, and history of allergy overall2,3. Rare clusters of cases have been reported, which also suggests environmental factors may contribute to the etiology of the disease4. Whether the higher prevalence of WG seen in Northern Europe5,6 and in New Zealand7 compared with Southern Europe8 reflects the role of environmental influences remains unclear. In recent years, several studies have suggested that the incidence of WG may be increasing5,6. For example, the annual incidence per million population in northern Norway of 5.2 (95% CI 2.7–9.0) during 1984-88 increased to 12.0 (95% CI 8.0–17.3) during 1994-985. Similar trends of a lesser magnitude were seen in the UK, with an incidence of 8.7 (95% CI 5.2–13.8) during 1988–92 and 10.3 (95% CI 6.4–15.5) during 1993-976. In this issue of The Journal, Knight, et al report on the largest published study on the incidence of WG9. Using the population-based Swedish Inpatient Register, which records individual-based information on all hospitalizations nationwide, they identified 1636 individuals discharged with a diagnosis of WG between 1975 and 2001, corresponding to a mean incidence per million of 8.6 among men (95% CI 8.0–9.1) and 7.0 among women (95% CI 6.5–7.6). Of interest, the authors observed a statistically significant increase in the incidence of the disease over the study period from 3.3 (95% CI 2.8–3.9) in 1975-84 to 7.7 (95% CI 6.9–8.5) in 1985-90, and to 11.9 (95% CI 11.2–12.6) in 1991-2001. The time trend was similar among men and women, and the age of the patients at the time of discharge remained stable over the study period. ANCA testing was introduced in some parts of Sweden in 1988, and in the rest of the country in the early 1990s. This raises the question of whether ANCA testing is the main or even the sole explanation for the very significant time trend observed in this and previous studies. Or are we witnessing a true rise in the incidence of the disease? Knight, et al maintain that ANCA testing cannot be the only explanation, since an increase in the incidence of the disease was noted 3 years before the introduction of testing in 1988. Thus the annual incidence of WG was stable until 1985 (4 per million in 1975, and 3/million in 1977, 1979, 1981, and 1983); incidence rose slightly between 1985 and 1987 (5/million in 1985, 7/million in 1986, and 7/million in 1987), and then considerably more after 1988 (9/million in 1989, 12/million in 1995, and 15/million in 2001). Although ANCA testing was not available in Sweden until 1988, increased physician awareness of WG following the discovery of ANCA in 198210 could certainly explain the rise in the incidence of the disease observed between 1985 and 1987. A Medline search using the key term Wegener’s granulomatosis yielded a significant increase in the number of articles on WG published between 1982 and 1987 (540) versus 1976-81 (369) and 1969-75 (385). Further, if we conclude that the rise in the incidence of the disease can be explained entirely by the introduction of ANCA testing and increased physician awareness, the next question is what diagnosis did patients with true WG erroneously receive prior to 1985? It doesn’t appear that patients were misdiagnosed as having polyarteritis nodosa (PAN) because the incidence of PAN was at a similar if not lower level in the decade prior to introduction of ANCA versus the