Wegener’s granulomatosis (WG) is characterized by granulomatous lesions and vasculitic disease manifestations. Granulomatous lesions are found in the upper and lower respiratory tract (eg, granulomatous sinusitis, orbital masses, and pulmonary granuloma), whereas vasculitic manifestations occur frequently in lung (alveolar hemorrhage) and kidney (glomerulonephritis). Vasculitis is typically associated with antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3. WG has been traditionally associated with a poor outcome and increased mortality as documented by numerous studies; however, recent cohort studies report an improved outcome, probably a consequence of increased awareness leading to an earlier diagnosis, and to improved treatment strategies derived from evidence from controlled trials. Treatment regimens for WG, adapted to disease stage and activity, are reviewed and discussed in this article.
Wegener’s granulomatosis (WG) is a rare autoimmune disorder of unknown etiology that is characterized by granulomatous inflammation and antineutrophil cytoplasmic antibodies (ANCA)-associated small-vessel vasculitis (AAV). WG has a broad clinical spectrum that ranges from predominantly granulomatous manifestations restricted to the respiratory tract (localized disease) to severe, life-threatening necrotizing vasculitis affecting many organs, with a predilection for lung and kidney involvement (alveolar hemorrhage and crescentic glomerulonephritis). In WG, ANCA are mainly directed against Proteinase 3 (PR3); there is strong evidence from in vitro studies that ANCA play a crucial role in the mediation of small-vessel vasculitis. It has been hypothesized that WG starts as localized disease of the respiratory tract with granulomatous inflammation that later generalizes into small-vessel vasculitis. This concept has been endorsed by the EULAR (European League Against Rheumatism)/EUVAS (European Vasculitis Study Group) definition of disease stages to facilitate consistent conduct of clinical trials and to provide evidence-based guidelines for stage-adapted therapy regimens. As a result of EUVAS and other trials, recommendations for therapy for AAV have been published recently, but new data are constantly available, providing evidence for the use of new therapies to reduce treatment toxicity and improve patients’ outcome.
Clinical manifestations
Classification Criteria, Epidemiology, Disease Stages, and Outcome
Incidence rates of 6 to 12 per million per year are reported for the United Kingdom, Germany, and Norway, which have been confirmed at stable rates for the United Kingdom and Germany. Lower rates have been found in Southern Europe, such as in Spain (2.95/million/year). In a recent United Kingdom study, the annual prevalence was reported to have increased from 28.8 per million in 1990 to 64.8 per million in 2005, suggesting that survival is increasing due to improved therapy and care. WG is even more common in southern Sweden, with a point prevalence on January 1, 2003 of 160 per million. Additional detailed data on the incidence and prevalence of WG are provided in the article by Holle and colleagues elsewhere in this issue.
Of interest is that a Japanese study reported an overall incidence of ANCA-associated renal vasculitis similar to that in Europe, but all patients were classified as microscopic polyangiitis (MPA); no cases of renal WG and Churg-Strauss syndrome were detected. Nevertheless, there is evidence of WG occurring in Japan as described by Japanese ear/nose/throat (ENT) units. Thus, Japanese patients may show a special phenotype of WG that does not progress to generalized renal vasculitis. Whether this phenotype corresponds to the definition of localized disease remains to be clarified.
According to a concept proposed by Fienberg, WG starts as granulomatous disease and subsequently progresses to generalized vasculitis; this concept has been incorporated in the definition of disease stages introduced in 1995, which has been updated several times. In the current definitions ( Table 1 ), the localized stage, defined as manifestations restricted to the upper and/or lower respiratory tract with no signs of systemic vasculitis, is differentiated from the systemic disease stages (early systemic, generalized, and severe disease). The early systemic stage is considered nonlife threatening, whereas in generalized disease organ function is at risk of compromise. In the severe disease stage, organ failure has already occurred (creatinine >500 μmol/L or approximately 5.7 mg/dL). Definitions of activity stages have also been updated lately and are intended to facilitate the conduct of clinical trials, and are very useful for treatment decisions in everyday practice. Controlled trials initiated by the EUVAS have been performed for remission induction and maintenance for several disease stages in AAV and provide valuable evidence for stage-adapted therapy, and may also have an impact on the outcome of AAV.
| Clinical Subgroup | Systemic Vasculitis Outside ENT and Lung | Threatened Vital Organ Function | Other Definitions | Serum Creatinine (μmol/L) |
|---|---|---|---|---|
| Localized | No | No | no B-symptoms ANCA typically neg | <120 |
| Early systemic | Yes | No | B-symptoms ANCA neg or pos | <120 |
| Generalized | Yes | Yes | ANCA pos | <500 |
| Severe | Yes | Organ failure | ANCA pos | >500 |
| Refractory | Yes | Yes | Refractory to standard therapy | Any |
Older age (>50 years), kidney involvement (with impaired renal function), pulmonary manifestations at diagnosis, and absence of ENT involvement are associated with an adverse outcome and increased mortality. Whereas several studies published in the 1990s showed an increased mortality in WG patients compared with the general population with standardized mortality ratios (SMR) of 3.7 to 4.8, a decrease in the SMR at 5 years’ disease duration was reported from a recent Swedish population-based cohort of WG and MPA diagnosed before 1996 and after 1996 (from 2.5 to 1.6, respectively). In addition, in a recent study assessing a population of patients with various vasculitides with disease onset in the 1990s, no increased SMR was reported for women younger than 60 years.
The rate of end-stage renal disease (ESRD) varies among cohort studies, ranging from 23% of patients at 15 months to 23% at 10 years. A decline in the rate of end-stage renal failures was reported in a recent study, which may contribute to a reduction of mortality.
Shorter periods of remission induction and the increasing use of intravenous instead of oral cyclophosphamide (Cyc) or alternative treatments may account for a reduction in the cumulative Cyc dose as reported by Eriksson and colleagues and to a reduction of Cyc-related side effects such as infections and malignancy. Using the current definition of remission, this stage is achieved by 90% to 94% of patients, which highlights the efficacy of standard therapy for the induction of remission. Time to remission is usually less than 6 months, but relapse is frequent (18%–40% at 24 months in WG) and remains a major issue: Eriksson and colleagues found no decline in relapse rates in patients diagnosed before 1996 compared with after 1996.
Yet, an increased awareness of AAV may be a factor for improved survival, as a significant shortening of the interval from first symptoms to diagnosis was reported by recent studies.
Localized Disease Manifestations/Upper and Lower Respiratory Tract Involvement
Upper respiratory tract involvement affecting the nasal and oral cavity, sinuses, trachea, and bronchi is reported to occur in 75% to 93% of patients at diagnosis and in up to 99% of patients during the course of the disease. Rhinosinusitis is the typical manifestation of WG leading to nasal bloody discharge, crusting, and epistaxis. Nasal crusting (“golden crusts”) is a typical finding of endoscopic evaluation ( Fig. 1 ), although it is not specific for WG. A standardized assessment to rate endonasal activity does not yet exist but is under investigation. Granulomatous inflammation/masses may also be found in the nasal cavity and sinuses, and may lead to bone erosion and cartilage destruction causing saddle nose deformity, which is reported in up to 28% of patients ( Fig. 2 ). Conductive hearing loss may be caused by direct involvement of the middle ear mucosa, or by dysfunction of the Eustachian tube due to mucosal involvement of the nasopharynx. The most dreaded granulomatous manifestation in localized disease is orbital granuloma/masses (seen in up to 15% of cases ). Orbital granuloma/masses may develop from inflammatory tissue invading from the sinuses, or may develop as a retroorbital mass in isolation. Orbital granuloma/masses are associated with severe complications such as infiltration or entrapment of ocular muscles and impairment of ocular motility, as well as optic nerve compression and atrophy with subsequent blindness. Orbital granuloma/masses are usually unilateral (>80%), but may affect both orbits in up to 14% of patients. Some patients develop orbital socket contracture, probably as a result of scar formation or fibrosis following immunosuppressive therapy. Orbitonasal fistulas may also develop. Oral manifestations are rare and occur as ulcerative stomatitis (up to 10% ) or hyperplastic gingivitis; subglottic stenosis is the typical laryngeal involvement (12%–15%) ; and stenosis of smaller bronchi and mucosal ulcers of the tracheobronchial tree may also occur.
The overall incidence of pulmonary involvement is between 60% and 85%. The characteristic manifestations are granulomatous masses, alveolitis, and capillaritis, leading to diffuse alveolar hemorrhage (DAH). Pulmonary nodules and/or granuloma have been described on conventional radiography in around 60% of patients. Alveolitis is related to diffuse or interstitial infiltrates. Active disease is associated with an increased neutrophil count in the bronchoalveolar lavage fluid (BAL fluid) and diffuse infiltrates; an elevation of CD4+ T lymphocytes may also be found, mainly in conjunction with interstitial infiltrate. DAH has been reported to occur in 7% to 45% of WG patients. Typically, hemoptysis and dyspnea are common symptoms, however, a significant proportion of patients have no history of hemoptysis. Chest radiographs usually reveal bilateral alveolar shadowing ( Fig. 3 ); a ground-glass pattern is typically seen on computed tomography (CT). DAH can be confirmed by fiberoptic bronchoscopy, which shows diffuse bleeding arising from the pulmonary parenchyma with increasingly bloody lavage fluid and hemosiderin-laden macrophages. Bleeding may be severe, leading to hypovolemic shock and respiratory insufficiency. Mortality of DAH is estimated at 60%.
In general, high-resolution CT (HRCT) may be a useful adjunctive diagnostic procedure to follow pulmonary manifestations. Cavitating nodules/masses with a diameter of greater than 3 cm on HRCT and parenchymal opacification are considered active lesions.
Kidney Involvement
Glomerulonephritis is reported in 38% to 70% of patients and is the hallmark of generalized disease ( Fig. 4 ). Initial renal function may predict renal survival. Approximately 10% to 20% of patients develop end-stage renal failure requiring hemodialysis despite immunosuppressive therapy. Renal involvement/impairment is associated with poorer survival. Diagnosis of renal involvement should be confirmed by biopsy, which usually reveals focal necrotizing glomerulonephritis with both intra- and extracapillary deposits.
