Background

This disease is characterized by necrotizing granulomas and vasculitis involving multiple organs. It usually presents in the 5-6th decades with symptoms localized to the upper respiratory tract, such as persistent rhinorrhea and sinus pain. It frequently involves the kidneys with a focal necrotizing glomerulonephritis, the lungs, and the skin in 30-50% of cases. The skin lesions are papulo-necrotic and symmetrically distributed over the elbows, knees, and buttocks.

A limited form may be dominated by pulmonary lesions without renal lesions. This variant has a better prognosis and skin lesions are less frequent. A protracted superficial form has multiple mucosal and cutaneous lesions. Regardless of the form of the disease, it is fatal unless immunosuppressive treatment is started.

One of the characteristic serologic findings is the presence of antineutrophil cytoplasmic antibodies (ANCA). The term ANCA associated disease describes a spectrum of disease ranging from Wegener's to microscopic polyarteritis, to renal limited disease (crescentic glomerulonephritis).

A necrotizing vasculitis is present in the skin in about 20% of cases. Occasionally palisading necrobiotic granulomas with intense eosinophilia, similar to Churg-Strauss syndrome, may be present. In other organs, necrobiotic granulomas and poorly defined granulomas associated with vasculitis may be present.

The pathologist faced with these histologic changes needs to exclude an infectious etiology by routine microbiologic stains. In addition, other granulomatous and necrotizing vasculitides such as polyarteritis nodosa and collagen vascular diseases should be excluded.

OUTLINE

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
PEDIATRIC
Clinical features in 17 paediatric patients with Wegener granulomatosis. Belostotsky VM, Shah V, Dillon MJ. Great Ormond Street Hospital for Children and Institute of Child Health, London WC1N 1EH, UK	Pediatr Nephrol. 2002 Sep;17(9):754-61 Abstract quote The aim of this report was to describe childhood patients with Wegener granulomatosis (WG) from one centre, to analyse the variety of clinical manifestations seen and compare the data with other published paediatric and adult series. The records of 17 patients with WG who were under the care of Great Ormond Street Hospital for Children (GOSH) from 1981 to 1998 were reviewed. We analysed presenting features before admittance to GOSH and the clinical signs observed whilst the children were under the care of the hospital. Of 17 patients, 13 were females and there was a male/female ratio of 1:3.25. Among the patients there were 2 sisters. The age of the patients at disease onset varied from 2 weeks to 14 years. The median/mean age was 6/6.3 years. American College of Rheumatology criteria for diagnosing WG were fulfilled in 11 of 17 patients. The frequency of different system involvement was: respiratory 87%, kidneys 53%, sinuses 35%, joints 53%, eyes 53%, nervous system 12%, skin 53%. cANCA was positive in 10 patients (59%), but pANCA was negative in all measured sera. Kidneys were involved in 2 of 8 patients (25%) with the disease onset from 0 to 5 years and in 7 of 9 patients (78%) with the disease onset from 6 to 14 years ( P<0.05). cANCA was positive in 7 of 9 patients with kidney disease (78%) and in 2 of 8 patients (25%) without kidney involvement ( P<0.05). Colchicine as a supplement to prednisolone and cytotoxic/immunosuppressant drugs was used effectively in 5 patients.

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
Diabetes insipidus secondary to Wegener's granulomatosis: report and review of the literature. Rosete A, Cabral AR, Kraus A, Alarcon-Segovia D. Department of Immunology and Rheumatology, Instituto Nacional de la Nutricion Salvador Zubiran, Mexico City, Mexico.	J Rheumatol 1991 May;18(5):761-5 Abstract quote We describe a 51-year-old woman with Wegener's granulomatosis who developed diabetes insipidus 7 months after the onset of her granulomatous disease and despite apparently good clinical response to prednisone and trimethoprim-sulphametoxazole treatment. A brain computerized tomographic scan taken soon after the onset of polyuria disclosed an enlarged pituitary gland that completely returned to its normal size after 5 months of cyclophosphamide therapy. We review 6 other published cases of diabetes insipidus secondary to Wegener's granulomatosis and discuss the potential pathogenetic mechanisms of this rare combination.
Lack of association between antiphospholipid antibodies and thrombocytopenia in patients with Wegener's granulomatosis. Meyer MF, Schnabel A, Schatz H, Gross WL Department of Rheumatology, Medical University of Lubeck, Germany.	Semin Arthritis Rheum 2001 Aug;31(1):4-11 Abstract quote BACKGROUND AND OBJECTIVE: In patients with Wegener's granulomatosis (WG), thrombocytopenia is less common than thrombocytosis. An increased prevalence of antiphospholipid antibodies (aPL), which is associated with thrombocytopenia, has been noted in patients with WG. The aim of this study was to examine the relationship between thrombocytopenia and aPL in patients with WG. METHODS: Thrombocytopenic episodes were searched for in a random sample of 83 patients with WG. Stored sera obtained during thrombocytopenia, which was defined as platelet count below 130 x 10(9)/L, were examined by 2 different enzyme-linked immunosorbent assays (ELISA) for IgG and IgM anticardiolipin antibodies (aCL) and for IgG antiphosphatidylserine antibodies (aPS). Screening for lupus anticoagulant was performed by use of activated partial thromboplastin time (aPTT). Results were compared with the prevalence of aPL in 20 consecutive nonthrombocytopenic patients with WG. RESULTS: Six cases with thrombocytopenic episodes were found in the group of 83 patients with WG. Increased IgG and IgM aCL were detected in 1 patient, who also had elevated IgG aPS. A positive test result solely for IgM aCL was found in another patient. These findings were consistent in both ELISA for aPL. Five patients were being treated with cyclophosphamide when thrombocytopenia occurred. In the group of nonthrombocytopenic patients with WG, elevated IgG aCL and IgG aPS were consistently detected in 1 patient in both ELISA. Three other patients had positive results in single tests, which were not confirmed by the second assay. In all patients, aPTT was normal. CONCLUSIONS: Thrombocytopenia is a rare finding in patients with WG. A similar prevalence of aPL in thrombocytopenic and nonthrombocytopenic patients with WG provides no evidence that aPL play a major role in the pathogenesis of these events. Thrombocytopenia in WG is more likely caused by the myelotoxic effect of preceding cyclophosphamide treatment. We found a frequency of aPL in WG that exceeds frequencies seen in the general population but does not approximate those detected in systemic lupus erythematosus and closely related disorders.

 

PATHOGENESIS	CHARACTERIZATION
Possible autoimmune disease	J Pathol 2000;190:349-359 May be triggered by infection followed by priming of neutrophils and endothelial cells allowing ANCA to further activate neutrophils with more endothelial damage
	Thorax 2000;54:629-637 Reactivation and relapse may be secondary to antigen-specific memory T-cells which persist after remission
Role of ANCA	J Pathol 2000;190:349-359 Probably doesn't have primary role in the pathogenesis Interactions between ANCA and neutrophils are probably important in the early phase of the disease while interactions between ANCA and monocytes are important in the later phase
Expression of the chemokine RANTES in pulmonary wegener's granulomatosis Aurore Coulomb-L'Hermine, etal.	Hum Pathol 32:320-326. (Abstract quote) Wegener's granulomatosis (WG) is an inflammatory, destructive, angiotropic lesion. The inflammatory process involves accumulation of macrophages, lymphocytes, and polymorphonuclear neutrophils. We studied 6 lung biopsy specimens from patients with WG to characterize the cellular infiltrate and to analyze the mechanism of immune cell recruitment. We show that lymphocytes accumulating in WG lesions are mostly memory CD4+CD45RO+ T lymphocytes and, although less numerous, CD8+CD45RO+ T lymphocytes. Few if any B lymphocytes or natural killer cells are present within lesions. The chemokine RANTES (regulated upon activation in normal T cells, expressed and secreted) has been reported to recruit memory T lymphocytes and macrophages selectively. We used reverse-transcription polymerase chain reaction, in situ hybridization, and immunohistochemistry to study its production in WG. RANTES was expressed at a higher level in WG lungs than in normal controls, especially around microabscesses. As visualized immunohistochemically in serial sections with anti-RANTES monoclonal antibody, RANTES production was produced mainly by macrophages. Expression of the gene coding for interferon- (IFN-), a potent RANTES inducer, was also studied. Its expression was also much stronger in WG than in controls. Our observations are consistent with a cascade of events leading to the recruitment of immune cells in WG, sequentially involving production of IFN- by T lymphocytes and RANTES production by macrophages, leading to the homing of memory T-helper lymphocytes and macrophages.

 

LABORATORY/ RADIOLOGY	CHARACTERIZATION
RADIOLOGY
Thoracic manifestation of Wegener's granulomatosis: CT findings in 30 patients. Lee KS, Kim TS, Fujimoto K, Moriya H, Watanabe H, Tateishi U, Ashizawa K, Johkoh T, Kim EA, Kwon OJ. Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Ilwon-Dong, Kangnam-Ku, Seoul 135-710, Korea	Eur Radiol. 2003 Jan;13(1):43-51 Abstract quote Our objective was to describe the CT findings of thoracic Wegener's granulomatosis. At presentation, both conventional and thin-section CT scans were available in 30 patients with Wegener's granulomatosis. Serial CT scans (range of intervals: 1-25 months, mean 4.5 months) were available in 20 patients. The initial and follow-up CT scans were analyzed retrospectively by two observers in terms of pattern and extent of parenchymal and airway lesions. Positive CT findings were seen in 29 of 30 (97%) patients at initial presentation. The most common pattern was nodules or masses seen in 27 of 30 (90%) patients. They were multiple in 23 of 27 (85%) patients, bilateral in 18 (67%), subpleural in 24 (89%), and peribronchovascular in 11 (41%) in distribution. Bronchial wall thickening in the segmental or subsegmental bronchi was seen in 22 (73%) patients. Large airways were also abnormal in 9 (30%) patients. Patchy areas of consolidation and ground-glass opacity were seen in 7 (23%) patients, respectively. In 17 of 20 (85%) patients in whom follow-up CT scans were available, the parenchymal or airway lesion showed complete or partial improvement with treatment. The CT findings of Wegener's granulomatosis, although multiple and variable, consist mainly of bilateral subpleural or peribronchovascular nodules or masses and bronchial wall thickening in the segmental or subsegmental bronchi. Parenchymal and airway lesions improve with treatment in most patients.
Active disease and residual damage in treated Wegener's granulomatosis: an observational study using pulmonary high-resolution computed tomography. Komocsi A, Reuter M, Heller M, Murakozi H, Gross WL, Schnabel A. Poliklinik fur Rheumatologie, Universitat Lubeck, Ratzeburger Allee 160, 23538 Lubeck, Germany.	Eur Radiol. 2003 Jan;13(1):36-42. Abstract quote The purpose of this study was to determine to what extent high-resolution computed tomography (HRCT) of the lungs can distinguish active inflammatory disease from inactive cicatricial disease in patients treated for Wegener's granulomatosis (WG). Twenty-eight WG patients with active pulmonary disease underwent a first HRCT examination immediately before standard immunosuppressive treatment and a second examination after clinical remission had been achieved. Lesions remaining after treatment were categorized as residual damage and were compared with findings during active disease to see by what features active and cicatricial disease can be distinguished. During active disease 17 patients had nodules/masses, 12 had ground-glass opacities, 6 had septal lines and 6 had non-septal lines. After treatment, ground-glass opacities had resolved completely. Nodules/masses had resolved in 8 patients and had diminished in 7 patients. Residual nodules were distinguished from nodules/masses in active disease by lack of cavitation and a diameter of mostly <15 mm. In one-third of patients lines resolved, but in 8 instances new lines evolved during immunosuppression. During a follow-up period of a median 26.5 months (range 20.0-33.8), patients with residual nodules or lines had no more relapses than patients with completely cleared lungs. Treated pulmonary WG leaves substantial residual damage. High-resolution CT does assist in the distinction between active and inactive lesions. Ground-glass opacities, cavitating nodules/masses and masses measuring more than 3 cm represent active disease ordinarily. Non-cavitary small nodules and septal or non-septal lines can be either active or cicatricial lesions. The nature of these lesions needs to be clarified by longitudinal observation.
ANCA
Image analysis: a novel approach for the quantification of antineutrophil cytoplasmic antibody levels in patients with Wegener's granulomatosis. Boomsma MM, Damoiseaux JG, Stegeman CA, Kallenberg CG, Patnaik M, Peter JB, Cohen Tervaert JW. Department of Internal Medicine, Division of Clinical Immunology, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.	J Immunol Methods. 2003 Mar 1;274(1-2):27-35. Abstract quote. Rises in antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3) have predictive potential for a relapse of Wegener's granulomatosis (WG). To assess the value of image analysis for monitoring ANCA levels, we measured PR3-ANCA in a cohort of PR3-ANCA positive patients with WG that were prospectively followed in our clinic and compared findings with other techniques. ANCA levels were measured serially by quantitative image analysis, titration in indirect immunofluorescence (IIF), two different directly coated antigen-specific enzyme-linked immunosorbent assays (ELISA), and a capture ELISA using a PR3-specific monoclonal antibody in 16 consecutive WG patients prior to a renal relapse, and in 16 age- and sex-matched patients with inactive WG. The positive predictive value (PPV) of an increase in ANCA titers by image analysis for relapse was 69% (11 of 16). The PPV of an increase in ANCA was 61% (11 of 18) by IIF, 71% (12 of 17) by a commercial direct ELISA, 63% (12 of 19) by in-house direct ELISA, and 75% (12 of 16) by capture ELISA. The negative predictive value (NPV) of the absence of an increase in ANCA titers by image analysis for relapse was 69% (11 of 16). The NPV of the absence of an increase in ANCA was 64% (9 of 14) by IIF, 73% (11 of 15) by a commercial direct ELISA, 63% (9 of 13) by in-house direct ELISA, and 75% (12 of 16) by capture ELISA. In conclusions, quantitative image analysis is a novel technique based on the principle of IIF to quantify ANCA levels in a single dilution in a patient sample. No major differences were observed between image analysis and the other techniques in their capacity to predict relapses of disease activity.

 

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
General
Classic	Am J Surg Pathol 1991;15:539-543 Involving upper and lower respiratory tracts
Major	Vasculitis, in arteries, veins, capillaries, showing acute, chronic, necrotizing or nonnecrotizing granulomatous, fibrinoid necrosis, cicatricial changes Parenchymal necrosis; micro or macroabscesses, geographic necrosis Granulomatous inflammation and mixed inflammatory infiltrates; granulomatous inflammation around microabscess, palisading histiocytes, scattered hyperchromatic giant cells, poorly-formed granulomas, few or no sarcoid-like granulomas
Minor	Parenchymal; nodular interstitial fibrosis, endogenous lipid pneumonia, alveolar hemorrhage, organizing intraluminal fibrosis, lymphoid aggregates, tissue eosinophils, xanthogranulomatous lesions, alveolar macrophage collections Bronchial/bronchiolar; acute and chronic bronchiolitis, bronchopneumonia, bronchiolitis obliterans or BOOP, bronchocentric granulomatosis, follicular bronchiolitis, bronchial stenosis, squamous metaplasia
MAJOR VARIANTS
Limited Pulmonary
Protracted Superficial	Chronic ulcerative disease mainly involving nasal and sinus mucosa
Diffuse Alveolar Hemorrhage
Glomerulonephritis	Isolated GN without extrarenal disease
VARIANTS
EAR
Otologic manifestations of Wegener's granulomatosis. Takagi D, Nakamaru Y, Maguchi S, Furuta Y, Fukuda S. Department of Otolaryngology--Head and Neck Surgery, Hokkaido University Graduate Shool of Medicine, Sapporo, Japan.	Laryngoscope. 2002 Sep;112(9):1684-90. Abstract quote OBJECTIVE/HYPOTHESIS: To evaluate the clinical features, treatment, and outcomes of otologic manifestations in Wegener's granulomatosis (WG) treated at Hokkaido University Graduate School of Medicine, Sapporo, Japan. STUDY DESIGN: We retrospectively reviewed 15 cases of WG with ear involvement. METHODS: Twenty-five patients with WG were treated at Hokkaido University Graduate School of Medicine between 1992 and 2001. Fifteen of these patients had otologic symptoms. We evaluated the clinical course, method of therapy, and outcomes in all cases. Diagnosis of WG was made when the patients had clinical findings and a positive titer of cytoplasmic pattern antineutrophil cytoplasmic antibodies (c-ANCA), or when there were clear histologic findings. We also present three case reports. RESULTS: In 15 cases, the most frequent finding was chronic otitis media. Sensorineural hearing loss was present in 2 patients. In 7 patients whose otologic manifestations were the primary involvement of WG, all were confirmed positive for c-ANCA and were treated with glucocorticoids and immunosuppressive drugs. Three patients who could be treated within 1 month of symptom onset showed marked improvement. CONCLUSIONS: In localized cases, biopsy specimens are often small, and it is frequently difficult to make a histologic diagnosis. The prognosis for hearing was poor when appropriate treatment was not given in the early stages of the disease. Therefore, WG should be included in the differential diagnosis in cases of atypical inflammatory states of the ear. Early diagnosis and appropriate treatment are important to prevent irreversible changes in the middle ear and inner ear.
HEART
Cardiac Wegener's granulomatosis masquerading as left atrial myxoma. Herbst A, Padilla MT, Prasad AR, Morales MC, Copeland JG. University of Ulm, Ulm, Germany.	Ann Thorac Surg. 2003 Apr;75(4):1321-3. Abstract quote A 56-year-old woman was referred with mitral regurgitation, left ventricular dysfunction, and a sessile mass on the anterior leaflet of her mitral valve. The initial impression from echocardiography was that she had a left atrial myxoma. At operation, we found an intense inflammatory process diagnosed as Wegener's granulomatosis. It also involved the aortic valve and contiguous myocardium.
PLEURAL EFFUSION
Pleural effusions in Wegener's granulomatosis: report of five patients and a brief review of the literature. Bambery P, Sakhuja V, Behera D, Deodhar SD. Department of Internal Medicine, Postgraduate Institute of Medical Education, Chandigarh, India.	Scand J Rheumatol 1991;20(6):445-7 Abstract quote Wegener's granulomatosis (WG) is an uncommon disease of unknown aetiology which is characterised histologically by a necrotising granulomatous angiitis. The airway, lungs and the kidneys are predominantly involved, but the disease has been documented to affect virtually every organ system. The clinical course is variable and ranges from a short, rapidly fatal illness at one end of the spectrum to indolent involvement compatible with several years of survival at the other. A majority of patients have pulmonary disease evidenced clinically by cough, sputum production and haemoptysis and radiologically by infiltrates, nodules and cavitation. Pleural effusions, however, are rare. No detailed information regarding the nature and clinical behaviour of these effusions is available and only a recent French study has listed the nature of the fluid in passing. We have observed pleural effusions in five patients with WG who are the basis of this report.
LUNGS, SOLITARY LESION
Solitary lung lesions in Wegener's granulomatosis. Pathologic findings and clinical significance in 25 cases. Katzenstein AL, Locke WK. Department of Pathology, State University of New York (SUNY) Health Science Center at Syracuse, USA.	Am J Surg Pathol 1995 May;19(5):545-52 Abstract quote We describe 25 cases of Wegener's granulomatosis presenting with solitary lung lesions to compare the clinical and pathologic findings in these cases with those of the more common multifocal disease and also to evaluate the clinical significance of solitary lung lesions occurring in the absence of extrapulmonary disease. The clinical findings in our patients with solitary Wegener's were similar to those in generalized disease. Men were affected slightly more often than women, and the average age of onset was 53 years. Likewise, no major pathologic differences were found between solitary and multifocal disease. Classic necrotizing granulomatous inflammation and necrotizing vasculitis were the most common findings, although other variants were occasionally encountered, including the eosinophilic variant (two cases), the bronchocentric variant (one case), and small-vessel vasculitis and capillaritis (one case). Three cases had prominent areas of bronchiolitis obliterans-organizing pneumonia. Progressive disease occurred in all seven patients who manifested solitary lung lesions without extrapulmonary involvement and were not treated because the diagnosis was initially unrecognized. Pathologists need to be alert to the possibility of Wegener's granulomatosis causing solitary lung lesions because treatment should be promptly instituted.

 

HISTOLOGICAL TYPES	CHARACTERIZATION
General
Interpretation of head and neck biopsies in Wegener's granulomatosis. A pathologic study of 126 biopsies in 70 patients. Devaney KO, Travis WD, Hoffman G, Leavitt R, Lebovics R, Fauci AS. Department of Pathology, Bethesda Naval Hospital, Maryland.	Am J Surg Pathol 1990 Jun;14(6):555-64 Abstract quote The majority of patients with classic Wegener's granulomatosis present with symptoms of head and neck disease; accordingly, accurate interpretation of biopsy specimens from these sites is essential. This report details the histologic findings in 126 head and neck biopsy specimens from 70 patients (36 male and 34 female). Tissues were obtained from the following sites: 60 nasal, 27 paranasal sinuses, 17 laryngeal, five periorbital, five oral, four middle ear, three mastoid, two external ear, and three salivary gland. Vasculitis, necrosis, and granulomatous inflammation together were seen in only 16% of all head and neck biopsy specimens. Both vasculitis and granulomatous inflammation were seen in 21% and vasculitis and necrosis in 23% of the biopsy specimens reviewed. We discuss the problems in differential diagnosis, particularly the importance of excluding granulomatous infectious processes, which can imitate the histopathologic features of Wegener's granulomatosis. Based on this study, we propose criteria for the diagnosis of Wegener's granulomatosis based on biopsy specimens from the head and neck region.
Diagnostic usefulness of nasal biopsy in Wegener's granulomatosis. Del Buono EA, Flint A. Department of Pathology, University of Michigan, Ann Arbor.	Hum Pathol 1991 Feb;22(2):107-10 Abstract quote Wegener's granulomatosis (WG) frequently involves the upper respiratory tract, and nasal mucosal biopsy is often initially used to establish the diagnosis. To evaluate the diagnostic efficacy of nasal biopsy in WG, we reviewed the pathologic features of 30 such biopsy specimens from 17 patients with well-documented WG. Active vasculitis (granulomatous or nongranulomatous) was identified in seven of the patients (41%). The presence of extravascular foci of necrosis in lung biopsy samples has recently received attention as a characteristic feature of WG. Similar foci were found in the nasal samples from six of our patients, although vasculitis was absent in the samples from two of them. If extravascular foci of necrosis are regarded as characteristic or even diagnostic of WG, two additional patients in our series could be regarded as having had diagnostic nasal biopsies (nine of 17 patients). Nasal biopsy could thus be considered as diagnostic in 53% of the patients. Samples larger than 5 mm in greatest dimension were more likely to contain diagnostic features than were smaller samples (P = 0.002).
Treated Wegener's granulomatosis: distinctive pathological findings in the lungs of 20 patients and what they tell us about the natural history of the disease. Mark EJ, Flieder DB, Matsubara O. Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.	Hum Pathol 1997 Apr;28(4):450-8 Abstract quote Patients with an established diagnosis of Wegener's granulomatosis (WG) sometimes undergo lung biopsy when the disease does not behave in the expected manner. Treatment affects the tissue reaction. The microscopic recognition of partially treated disease is important, as the absence of expected lesions may lead to nonspecific diagnoses and inappropriate management. The appearance of treated disease over time may offer insight into its histogenesis and natural history. We correlated clinical features and pulmonary histology in 20 patients with WG after they had been treated with corticosteroids or cyclophosphamide or both. All patients had inflammatory or fibrotic pulmonary disease resulting from WG, but only 4 (20%) had macronodular necrosis typical of WG. Serum antineutrophil cytoplasmic antibody (ANCA) was elevated in all patients in whom it was measured. We divided the pathological findings into (1) vasculitis, (2) extravascular necrosis, (3) bronchiolitis, and (4) other lesions, and further divided them into (a) diagnostic for active disease, (b) suspicious for active disease, (c) suspicious for healing disease, (d) suspicious for residual disease, and (e) possible disease. Diagnostic or suspicious vascular lesions occurred in 15 patients (75%) and included granulomatous vasculitis, capillaritis or suspicious capillaritis, and neutrophilic vasculitis. Diagnostic or suspicious extravascular lesions occurred in 12 patients (60%) and included palisading granuloma, microabscess, macronodular pathergic necrosis, giant cell nodules, and micronodular scars. The giant cell nodules and nodular scars were an unusual healing pattern of palisading granulomas. Diagnostic bronchiolar lesions occurred in 1 patient (6%) and suspicious lesions in 13 patients (65%), including three novel patterns of bronchiolitis fibrosa (BF): (1) BF with giant cells, (2) BF with hemosiderin, and (3) BF with micronodular scars. Other features related to WG included diffuse alveolar damage, peculiar alveolar fibrin, interstitial fibrosis, pneumonitis resembling usual interstitial pneumonitis, and lipoid pneumonia. Classic necrotic nodules and vasculitis of WG should not be anticipated after therapy, but the diagnosis of pulmonary WG after treatment may be made if the effects of treatment on histology are considered. Changes in anticipated histology are found after therapy as short as 6 days. The histology typically has muted features. BF develops in most patients and may reflect a salutary effect of therapy. Palisading granuloma may convert to giant cell nodule or micronodular scar. Interstitial fibrosis is common, and pneumonitis resembling usual interstitial pneumonitis can develop. If only healing or residual disease is encountered, one should search further clinically and pathologically for active disease. Dampened inflammatory lesions represent smoldering disease that presumably needs additional therapy. Scarring presumably represents successfully treated but permanent disease.
VARIANTS	VASA 1997;26:261-270 Am J Surg Pathol 1990;14:555-564
SKIN	Leukocytoclastic vasculitis and granulomatous angiitis Nonspecific ulceration or chronic inflammation Extravascular palisading granulomas Pyoderma gangrenosum Erythema nodosum Granuloma annulare Necrotizing granuolomatosis with giant cells
Cutaneous manifestations of Wegener's granulomatosis: a clinicopathologic study of 17 patients and correlation to antineutrophil cytoplasmic antibody status. Comfere NI, Macaron NC, Gibson LE. Department of Dermatology, Mayo Clinic, Rochester, MN, USA.	J Cutan Pathol. 2007 Oct;34(10):739-47. Abstract quote Background: Wegener's granulomatosis (WG), a systemic vasculitis, can be associated with cutaneous signs and symptoms before, during or after the diagnosis of systemic disease. Methods: We reviewed clinical and histologic features of cutaneous lesions from 17 patients with WG. The temporal relationship between development of cutaneous symptoms and onset of systemic disease was determined, and antineutrophil cytoplasmic antibody (ANCA) status of the patients was also established. Results: In six patients, systemic and cutaneous disease developed concurrently. In eight patients, cutaneous disease developed after patients received the diagnosis of systemic disease. In three patients, cutaneous disease preceded systemic disease. Cytoplasmic ANCA or proteinase-3-ANCA [c-ANCA/proteinase 3 (PR3)-ANCA] serologic test results were negative for one patient when cutaneous disease developed, and one patient had c-ANCA/PR3-ANCA seroconversion a year before systemic disease developed. Histopathologic features of cutaneous WG were not limited to leukocytoclastic vasculitis; they also included acneiform perifollicular and dermal granulomatous inflammation and palisaded neutrophilic and granulomatous inflammation. Conclusions: Patients with WG can present initially with cutaneous symptoms. Histopathologic patterns vary, but leukocytoclastic vasculitis is most commonly noted. Patients with WG and skin lesions are likely to have positive c-ANCA/PR3-ANCA serologic test results.
Cutaneous manifestations of Wegener granulomatosis. Hu CH, O'Loughlin S, Winkelmann RK.	Arch Dermatol 1977 Feb;113(2):175-82 Abstract quote In a series of 19 patients (15 male and 4 female) who had Wegener granulomatosis with specific cutaneous histopathologic findings, the skin was only involved at onset in two. Four distinct histologic subgroups were defined as follows: necrotizing vasculitis (11 patients); necrotizing palisading granuloma (Churg-Strauss lesion) 2 patients); granulomatous vasculitis (2 patients); and lymphomatoid granulomatosis (4 patients). The 11 patients with necrotizing vasculitis had purpuric and hemorrhagic lesions, and the presence of vesicles and ulceration correlated with the severity of onset and extent of disease. The remaining eight patients had papular and nodular lesions. The patients with necrotizing vasculitis and lymphomatoid granulomatosis had a worse prognosis that did those with a predominant granulomatous reaction.
Eosinophilic angiocentric fibrosis and Wegener's granulomatosis: a case report and literature review. Loane J, Jaramillo M, Young HA, Kerr KM. Department of Pathology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZD, UK.	J Clin Pathol 2001 Aug;54(8):640-1 Abstract quote This report presents a case of eosinophilic angiocentric fibrosis in a man with Wegener's granulomatosis, the first report of a possible association between the two conditions. This association suggests a possible mechanism for its pathogenesis.
CNS	Grossly mimicking brain abscesses with extensive necrosis, necrotizing granulomatosis histologically
Orbit	Microabscesses and nonspecific inflammation
GI tract	Ulceration or perforation usually found after a bowel resection for bleeding
Urogenital tract in men	Prostate and/or bladder involvement
Spleen	Grossly mimic multifocal large or small infarcts; histologically necrotizing granulomatosis and necrotizing or granulomatous vasculitis
Heart	Mostly focal, sometimes widespread, granulomatous inflammation involving contractile myocardium, conduction myocardium, and/or valves
Breast	Usually an incidental finding during breast cancer work-up
Salivary gland	Geographic necrosis, poorly formed granulomas, scattered giant cells and microabscesses
Urogenital tract in women	Uterus or vaginal involvement
LUNGS
Diffuse pulmonary hemorrhage. An uncommon manifestation of Wegener's granulomatosis. Travis WD, Carpenter HA, Lie JT.	Am J Surg Pathol 1987 Sep;11(9):702-8 Abstract quote We report two cases of Wegener's granulomatosis with the unusual manifestation of diffuse alveolar hemorrahge. One patient with well-documented Wegener's granulomatosis developed alveolar hemorrhage 4 weeks after leukopenia necessitated the discontinuation of cyclophosphamide. The second patient presented with pulmonary hemorrhage and died 10 days after an open-lung biopsy in which histologic features of Wegener's granulomatosis were overshadowed by alveolar hemorrhage. Lung biopsies in both cases showed marked alveolar hemorrhage and pulmonary capillaritis. The importance of recognizing capillaritis and other subtle histologic features of Wegener's granulomatosis are emphasized.
The pulmonary biopsy in the early diagnosis of Wegener's (pathergic) granulomatosis: a study based on 35 open lung biopsies. Mark EJ, Matsubara O, Tan-Liu NS, Fienberg R. Department of Pathology, Massachusetts General Hospital, Boston 02114.	Hum Pathol 1988 Sep;19(9):1065-71 Abstract quote We reviewed open lung biopsies from 35 patients with Wegener's (pathergic) granulomatosis in order to study the histogenesis of the pulmonary lesions and to identify the early lesions. The process of pathergic necrosis is fundamental in the production of extravascular and vascular lesions and was divided into micronecrotic and macronecrotic types. Micronecrosis, usually with neutrophils (microabscesses), constitutes the early phase in the development of the pathognomonic organized palisading granuloma. The palisading granuloma differs from the compact granuloma of tuberculoid type, which occurs in infections and sarcoidosis but not in Wegener's (pathergic) granulomatosis. There is a progression of disease from micronecrosis to macronecrosis (widespread necrosis) and then to fibrosis. Macronecrosis surrounded by palisading histiocytes or diffuse granulomatous tissue indicates active disease, whereas necrosis surrounded by fibrous tissue indicates previously active disease. Most cases have a combination of micronecrosis, and fibrosis. We established the relative diagnostic value of various histologic features. Arteritis and phlebitis as classically described in Wegener's granulomatosis were present in most but not all cases. We believe that Wegener's granulomatosis primarily affects both vascular and extravascular collagen and reticulum and that vasculitis represents a primary necrosis of walls of blood vessels. We believe that the concept of Wegener's granulomatosis as a vasculitis is too restrictive and does not include many cases with only extravascular histologic changes.
Surgical pathology of the lung in Wegener's granulomatosis. Review of 87 open lung biopsies from 67 patients. Travis WD, Hoffman GS, Leavitt RY, Pass HI, Fauci AS. Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.	Am J Surg Pathol 1991 Apr;15(4):315-33 Abstract quote We report the pulmonary pathologic features in 87 open lung biopsies from 67 patients with Wegener's granulomatosis (WG) who were treated at a single institution from 1968 to 1990. At the time of open lung biopsy, 48 patients (72%) had classical WG with renal involvement; 19 (28%) had limited WG without renal involvement. The pathologic features were divided into major and minor manifestations. In the 82 specimens demonstrating no infectious organism, the three major pathologic manifestations of classical WG observed were also useful diagnostic criteria and included: (a) parenchymal necrosis, (b) vasculitis, and (c) granulomatous inflammation accompanied by an inflammatory infiltrate composed of a mixture of neutrophils, lymphocytes, plasma cells, histiocytes, and eosinophils. Parenchymal necrosis was found in 84% of biopsy specimens either as neutrophilic microabscesses (65% of specimens) or as large (67%) or small (69%) areas of geographic necrosis. Areas of geographic necrosis were usually surrounded by palisading histiocytes and giant cells. Additional granulomatous lesions consisted of microabscesses surrounded by giant cells (69%), poorly formed granulomas (59%), and scattered giant cells (79%). Sarcoid-like granulomas were uncommon (4%), and in only one specimen (1%) appeared within an inflammatory lesion of WG. Vascular changes were identified in 94% of biopsy specimens. Vascular inflammation was classified as chronic (37% arterial, 64% venous), acute (37% arterial, 29% venous), non-necrotizing granulomatous (22% arterial, 9% venous), and necrotizing granulomatous (22% arterial, 10% venous). Fibrinoid necrosis was relatively uncommon (11% arterial, 6% venous). Cicatricial changes were found in arteries in 41% of biopsy specimens and in veins in 16%. Capillaritis was present in 31% of specimens. Minor pathologic lesions were commonly observed in biopsy specimens associated with classical WG lesions, but they were usually inconspicuous and not useful diagnostic criteria. These included interstitial fibrosis (26%), alveolar hemorrhage (49%), tissue eosinophils (100%), organizing intraluminal fibrosis (70%), endogenous lipoid pneumonia (59%), lymphoid aggregates (37%), and a variety of bronchial/bronchiolar lesions including acute and chronic bronchiolitis (51% and 64%), follicular bronchiolitis (28%), and bronchiolitis obliterans (31%). These minor lesions were often found at the periphery of typical nodules of WG. However, in 15 specimens (18%) a minor pathologic feature represented the dominant or major finding: pulmonary fibrosis (six specimens, 7%), diffuse pulmonary hemorrhage (six specimens, 7%), lipoid pneumonia (one specimen, 1%), acute bronchopneumonia (one specimen, 1%), and chronic bronchiolitis, bronchiolitic obliterans with organizing pneumonia (BOOP), and bronchocentric granulomatosis (one specimen, 1%)
Bronchiolitis obliterans-organizing pneumonia (BOOP)-like variant of Wegener's granulomatosis. A clinicopathologic study of 16 cases. Uner AH, Rozum-Slota B, Katzenstein AL. Department of Pathology, SUNY Health Science Center at Syracuse, USA.	Am J Surg Pathol 1996 Jul;20(7):794-801 Abstract quote The classic histologic features of Wegener's granulomatosis (WG) in lung include necrotizing granulomatous inflammation and necrotizing vasculitis. Recently, several histologic variants have been recognized, including cases characterized by bronchocentric inflammation, a marked eosinophil infiltrate, alveolar hemorrhage, and capillaritis or interstitial fibrosis. We report 16 cases of another variant in which bronchiolitis obliterans-organizing pneumonia (BOOP)-like fibrosis represents the main histologic finding. The extensive geographic necrosis characteristic of Wegener's granulomatosis was absent in all cases, although small suppurative granulomas, minute foci of bland necrosis, and microabscesses were common. All cases showed the typical necrotizing vasculitis of Wegener's granulomatosis. Other frequent findings included darkly staining multinucleated giant cells, prominent acute inflammation, aggregates of epithelioid histiocytes, hemosiderin-filled macrophages, and areas of nonspecific parenchymal fibrosis. The clinical and radiographic features of this variant of Wegener's granulomatosis appear to be indistinguishable from the classic type. Pathologists need to be aware that Wegener's granulomatosis can occasionally manifest histologic changes suggestive of BOOP. The diagnosis will not be overlooked if additional features, especially vasculitis, suppurative granulomas, tiny necrotic zones, microabscesses, and multinucleated giant cells, are appreciated.

 

SPECIAL STAINS/IMMUNOPEROXIDASE/OTHER

CHARACTERIZATION

Clinical spectrum associated with positive ANCA titres in 94 consecutive patients: is there a relation with PR-3 negative c-ANCA and hypergammaglobulinaemia? Blockmans D, Stevens E, Marien G, Bobbaers H. Department of Internal Medicine, University Hospital, Leuven, Belgium.

Ann Rheum Dis 1998 Mar;57(3):141-5 Abstract quote OBJECTIVE: To calculate the positive predictive value (ppv) of cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCAs) and anti-proteinase 3 (PR 3) antibodies for Wegener's granulomatosis (WG) and to evaluate their association with other diseases. METHODS: The clinical files of all 94 patients who had a positive c- or perinuclear (p)-ANCA test, or both, in the laboratory of the University Hospital, Leuven between April 1995 and March 1996 and who attended the Internal Medicine Department of the hospital were retrospectively studied. RESULTS: Of the 94 patients with ANCAs (fluorescence titre > or = 1/40), 57 were c-ANCA positive and 45 p-ANCA positive (eight were simultaneously c- and p-ANCA positive). Of the 57 c-ANCA positive patients, 23 had WG. The ppv for WG thus was 40%. This value did not increase by defining a higher threshold for a positive ANCA. There was not a good relation between ANCA titres and disease activity in the WG patients, nor was there a relation between anti-PR 3 antibody levels and WG disease activity. The ppv of anti-PR 3 antibodies for WG however was very high (85%). There was a positive correlation between the level of (hyper) gammaglobulinaemia and c-ANCA titres in those patients with final diagnoses not known to be associated with c-ANCA. Forty five patients had positive p-ANCAs. The largest group were those with inflammatory bowel disease (n = 20, of whom the majority had colitis ulcerosa or primary sclerosing cholangitis, or both); the great majority of these patients had no anti-myeloperoxidase antibodies. Vasculitis was present in eight patients, of whom two had WG (both were also c-ANCA positive). CONCLUSION: There is a low ppv of c-ANCAs for WG, caused by a high percentage of PR 3 negative, positive c-ANCA determinations, possibly related to hypergammaglobulinaemia. Anti-PR 3 antibodies have a high ppv for WG. However, neither c-ANCA titre, nor the level of anti-PR 3 antibodies correlated with the activity of the disease.

ANCA	Microscopic Polyangiitis	Wegener's Granulomatosis	Churg-Strauss Syndrome
PR3-ANCA	40%	75%	10%
MPO-ANCA	50%	20%	60%
Negative	10%	5%	30%

 

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
ANCA ASSOCIATED GLOMERULONEPHRITIS
Histologic and immunohistologic study and clinical presentation of ANCA-associated glomerulonephritis with correlation to ANCA antigen specificity. Vizjak A, Rott T, Koselj-Kajtna M, Rozman B, Kaplan-Pavlovcic S, Ferluga D. Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.	Am J Kidney Dis. 2003 Mar;41(3):539-49. Abstract quote BACKGROUND: The major antigen specificities of antineutrophil cytoplasmic antibodies (ANCA) are for proteinase 3 (PR3) and myeloperoxidase (MPO). Only a limited number of studies have systematically assessed renal pathology with respect to ANCA antigen specificity. METHODS: The authors evaluated renal biopsy light microscopy and immunofluorescence findings, clinical presentation, and outcome in 135 patients with ANCA-associated vasculitides. RESULTS: Patients were divided into 3 groups: PR3-ANCA (n = 55), MPO-ANCA (n = 74), and ANCA of other specificities (n = 6). The mean duration of renal disease at biopsy was significantly longer in patients with MPO-ANCA than in those with PR3-ANCA (6.9 v 3.0 months). Immunofluorescence results showed mostly pauci-immune glomerulonephritis (n = 129) and rarely diffuse granular glomerular immune deposits suggesting immune complex deposition (n = 6). A focal form of crescentic glomerulonephritis was more frequent (P < 0.001), and glomerular necrosis was more prominent (P = 0.013) in the PR3-ANCA group, whereas diffuse crescentic glomerulonephritis, glomerulosclerosis, and interstitial fibrosis predominated in the MPO-ANCA group (P < 0.001). Extraglomerular vasculitis, present in 22.2%, and chronic vascular lesions indicative of previous vasculitis, present in 11.9% of patients, correlated with systemic involvement. CONCLUSION: The evolution of the pathologic lesions of PR3-ANCA and MPO-ANCA-associated glomerulonephritis seems to be similar. Differences in histopathology could be explained by the observation that in patients with PR3-ANCA, kidney biopsy was performed soon after renal involvement appeared, and focal active lesions were prevalent, whereas in patients with MPO-ANCA, kidney biopsy was done late in the course of the disease, and diffuse chronic sclerotic lesions predominated. Renal extraglomerular small vessel vasculitis appeared to be predictive of systemic involvement.
TRIGEMINAL TROPHIC SYNDROME
Trigeminal trophic syndrome mimicking Wegener's granulomatosis. A case report with a review of the literature. Datta RV, Zeitouni NC, Zollo JD, Loree TR, Hicks WL Jr. Department of Head and Neck Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.	Ann Otol Rhinol Laryngol 2000 Mar;109(3):331-3 Abstract quote Trigeminal neuropathy with nasal ulceration, called trigeminal trophic syndrome, is an unusual complication of anesthesia in the trigeminal area. We present a case to illustrate the diagnostic and management problems that this syndrome presents.

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS
GENERAL
Baseline features and initial treatment as predictors of remission and relapse in Wegener's granulomatosis. Koldingsnes W, Nossent JC. Department of Rheumatology, Institute of Clinical Medicine, University of Tromso, Norway.	J Rheumatol. 2003 Jan;30(1):80-8. Abstract quote OBJECTIVE: To describe the course of disease activity and determine predictors of remission and relapse in a population based cohort of patients with Wegener's granulomatosis (WG). METHODS: Retrospective cohort study of 56 patients (median age 50 yrs) followed for 42.5 months. Disease activity was assessed by Birmingham Vasculitis Activity Score (BVAS-1) and permanent organ damage by Vasculitis Damage Index (VDI). Induction therapy consisted of prednisolone (Pred) 0.5-1 mg/kg and cyclophosphamide (CYC) daily orally 2 mg/kg (19 patients) or intravenous pulses 15 mg/kg every 2nd week (32 patients). Baseline clinical and laboratory features and cumulative treatment during the first 6 months were recorded. Multiple Cox and logistic regression analyses were used to find risk factors for remission and relapse. RESULTS: All patients surviving > 1 month achieved either complete (85%) or partial remission (15%). Higher baseline BVAS-1 increased the likelihood of achieving complete remission [BVAS-1 > 23, relative hazard (RH) 2.94, 95% confidence interval (CI) 1.48-5.85]. Relapse occurred in 31 patients (60%) after a median period of 18 months. The risk of relapse was increased in patients having received < 10 g CYC during the first 6 months (RH 2.83, 95% CI 1.33-6.02), in patients having received Pred > 20 mg/day for < 2.75 months (RH 2.41, 95% CI 1.12-5.21), and in patients with initial heart involvement (RH 2.87, 95% CI 1.09-7.58). A higher Pred dose during the first 6 months was associated with severe infections. Therapy resistance (no complete remission) was associated with baseline organ damage (VDI increase by 1, OR 1.53, 95% CI 1.03-2.27). CONCLUSION: Initial high disease activity increased and the presence of baseline organ damage reduced the likelihood for complete remission in WG. Relapse was associated with less intensive initial treatment in terms of lower CYC doses and shorter time taking Pred > 20 mg/day.
Predictors of survival and organ damage in Wegener's granulomatosis. Koldingsnes W, Nossent H. Department of Rheumatology, Institute of Clinical Medicine, University of Tromso, Norway.	Rheumatology (Oxford). 2002 May;41(5):572-81 Abstract quote OBJECTIVE: To determine survival, organ damage and predictors of these outcomes in a population-based, longitudinal cohort study of patients with Wegener's granulomatosis (WG). METHODS: In a retrospective study, 56 WG patients (median age 50 yr) were followed for 56.5 months. Clinical and laboratory data, disease activity, organ involvement and the Vasculitis Damage Index (VDI) were recorded at baseline (start of treatment) and at a research visit after 42.5 months. The Kaplan-Meier method was used to estimate survival and Cox proportional hazards and linear regression models were used to study predictors of outcome. RESULTS: Duration of symptoms before the start of treatment (baseline) was 6 months (1-102 months) and 21 patients (37.5%) had organ damage (VDI > or = 1) at baseline. Baseline organ damage was associated with delay in the start of treatment and an elevated serum creatinine concentration. Fifty-five patients received prednisolone (Pred) and 53 patients received cyclophosphamide by intravenous pulse (CYCiv) or as a daily oral dose (CYCpo). CYCiv patients received lower cumulative doses of CYC and spent less time on Pred >20 mg/day than CYCpo patients. Thirteen patients died during the study period. Ten-year patient survival was 75%. Baseline predictors of reduced survival were higher age, dialysis-dependence and the presence of organ damage. Chronic, end-stage renal failure developed in 10 patients overall and was associated with reduced renal function at baseline. Severe organ damage (VDI > or = 5) developed in 71% of the patients and new damage occurred mainly during the first 6 months. Increased time (months) on Pred >20 mg/day during follow-up increased the last VDI [beta=0.5, 95% confidence interval (CI) 0.3 to 0.8], P<0.001), whereas increased time on CYC during the first 6 months reduced the last VDI (beta=-0.6, 95% CI -1.1 to -0.02, P=0.04). CONCLUSION: Treatment with CYC and corticosteroid led to a 10-yr survival rate of 75% in WG but did not prevent severe organ damage. The presence of baseline organ damage was a marker of poor outcome. There was an association between damage and treatment given.
Analysis of factors predictive of survival based on 49 patients with systemic Wegener's granulomatosis and prospective follow-up. Mahr A, Girard T, Agher R, Guillevin L. Service de Medecine Interne, Hopital Avicenne, Universite Paris-Nord, 125, route de Stalingrad, 93009 Bobigny Cedex, France.	Rheumatology (Oxford). 2001 May;40(5):492-8. Abstract quote OBJECTIVES: This prospective study attempted to determine factors predictive of survival in systemic Wegener's granulomatosis (WG) based on 49 patients. Patients and methods. All patients had previously untreated systemic WG. Treatment was with oral or pulse cyclophosphamide plus corticosteroids. Univariate and multivariate analyses of survival were performed using 13 parameters evaluated at diagnosis. RESULTS: The mortality rate was 37% during a mean follow-up period of 1.9 yr. Among the 13 parameters evaluated, univariate analysis selected the following factors as predictors of a poor outcome: serum creatinine > or =18.1 mg/dl, age > or =57 yr, and erythrocyte sedimentation rate (ESR) > or =90 mm/1st h. The absence of ear, nose and throat (ENT) involvement also tended to predict a greater risk of mortality. Glomerulonephritis, when present and regardless of creatininaemia, and pulmonary involvement had no significant effect. Multivariate analysis retained serum creatinine > or =18.1 mg/dl and age > or =57 yr as significant predictors of poor prognosis. CONCLUSIONS: Our results suggest that impaired renal function and older age are independent factors predicting poor outcome in WG. ESR proved to be a good marker of disease severity. Conversely, univariate analysis indicated that patients with ENT involvement tended to have a better outcome, suggesting a more benign evolution of granulomatous disease compared with more aggressive vasculitis.
ANCA TITERS
Limited prognostic value of changes in antineutrophil cytoplasmic antibody titer in patients with Wegener's granulomatosis. Kerr GS, Fleisher TA, Hallahan CW, Leavitt RY, Fauci AS, Hoffman GS. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892.	Arthritis Rheum 1993 Mar;36(3):365-71 Abstract quote OBJECTIVE. To assess the correlation and prognostic value of antineutrophil cytoplasmic antibody (cANCA) titers with disease activity in patients with Wegener's granulomatosis (WG). METHODS. One hundred six patients with WG had serum ANCA determinations; 72 had serial titers obtained routinely at 1-3-month intervals. One hundred twelve subjects (19 of whom were healthy donors) served as controls. All serum samples were tested for cANCA by an indirect immunofluorescence technique. A prospective analysis of disease activity and cANCA values was performed. Disease activity was assessed according to clinical, laboratory, radiographic, and histopathologic findings. RESULTS. Positivity for cANCA was a sensitive (88%) marker of active WG. However, changes in serial titers temporally correlated with a change in disease status in only 64% of patients. Furthermore, an increase in the cANCA titer preceded clinical exacerbation of disease in only 24% of patients who had been in remission or had low-grade, smoldering disease. CONCLUSION. A rise in cANCA titer alone should not be considered adequate evidence of an impending clinical exacerbation, and therefore does not justify initiating or increasing immunosuppressive therapy.
Prediction of relapses in Wegener's granulomatosis by measurement of antineutrophil cytoplasmic antibody levels: a prospective study. Boomsma MM, Stegeman CA, van der Leij MJ, Oost W, Hermans J, Kallenberg CG, Limburg PC, Cohen Tervaert JW. University Hospital Groningen, The Netherlands. O	Arthritis Rheum 2000 Sep;43(9):2025-33 Abstract quote OBJECTIVE: Prediction of relapses in Wegener's granulomatosis (WG) by measuring levels of antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3) or myeloperoxidase (MPO) remains a controversial issue. To assess the value of serial quantification of ANCA by indirect immunofluorescence (IIF) and antigen-specific enzyme-linked immunosorbent assay (ELISA) for monitoring disease activity in patients with WG, a prospective observational study was conducted in patients with WG attending an outpatient clinic in the Netherlands. METHODS: One hundred patients with WG (85 with PR3-ANCA, 15 with MPO-ANCA) were studied prospectively from 1996 to 1998. Serum samples were obtained and analyzed every 2 months for ANCA levels. Disease activity was prospectively assessed without knowledge of the ANCA levels. RESULTS: Relapses occurred in 37 of 100 patients (37%). Thirty-four (92%) of the 37 patients showed a rise in the level of ANCA preceding their relapse, as detected by ELISA or IIF. The predictive value of an increase in ANCA titers for relapse was 57% (17 of 30) for cytoplasmic/classic ANCA (cANCA; by IIF), 71% (27 of 38) for PR3-ANCA (by ELISA), and 100% (3 of 3) for MPO-ANCA (by ELISA). The predictive value of a rise in ANCA as measured by ELISA or IIF did not substantially improve following concomitant measurement of the IgG3 subclass of PR3-ANCA. Forty-three percent of patients who showed a rise in cANCA (by IIF) and 29% with a rise in PR3-ANCA (by ELISA) did not subsequently experience a relapse. CONCLUSION: Serial measurement of ANCA levels is valuable for the early prediction of relapses in patients with WG.
RECURRENCE	50% or remissions are associated with one or more relapses
RENAL DISEASE
Wegener's granulomatosis: clinical course in 108 patients with renal involvement. Aasarod K, Iversen BM, Hammerstrom J, Bostad L, Vatten L, Jorstad S. Department of Medicine, University Hospital of Trondheim, The Norwegian Kidney Register.	Nephrol Dial Transplant. 2000 May;15(5):611-8. Abstract quote BACKGROUND: The aim of this study was to evaluate the clinical course of patients with Wegener's granulomatosis and renal involvement, with special reference to relapse rate, renal and patient survival and morbidity from serious infections. METHODS: A retrospective analysis was carried out of 108 patients presenting with Wegener's granulomatosis and active renal disease in eight hospitals in Norway between 1988 and 1998. Multivariate analysis was used to investigate whether selected variables predicted relapse, renal and patient survival and serious infections. RESULTS: Median follow-up was 41.5 months. Twenty-two patients (20.4%) were admitted with a need for dialysis. Complete remission was obtained in 81.5% after a median of 4 months, and 54.7% relapsed after a median of 22. 5 months. Two- and five-year renal survival was 86 and 75%, respectively, and 22.8% developed end-stage renal disease (ESRD). Two- and five-year patient survival was 88 and 74%, respectively, and the cumulative mortality was 3.8 times higher than expected. The relative risk of relapse increased with the use of intravenous pulse cyclophosphamide compared with daily oral cyclophosphamide. Initial renal function predicted renal survival, and low serum albumin and high age at treatment start increased the mortality risk. Thirty one per cent of the patients were hospitalized for serious infections during follow-up. Old age increased the risk of having an infection. CONCLUSIONS: The current treatment of Wegener's granulomatosis does not prevent relapse, development of ESRD and serious treatment-induced infections in a considerable fraction of the patients. Alternative strategies for the management of this disease will be an important objective for further studies.
SURVIVAL	Thorax 2000;54:629-637 Mean survival without treatment is 5 months and 12. 5 months in patients treated with glucocorticoids alone
	Ann Intern Med 1992;116:488-494 Combined cyclophosphamide with glucocorticoids: 91% with symptomatic improvement 75% remission rate 87% survival rate varying from 6 months to 24 years
TREATMENT	Combined treatment with cyclophosphamide and prednisone
	Alternative regimens: Intravenous pulse cyclophosphamide Methotrexate Bactrim Azathioprine
	Thorax 2000;54:629-637 IVIG Cyclosporine Etoposide Anti-T-cell antibodies Tumor necrosis factor inhibitors
CYCLOPHOSPHAMIDE
Use of a cyclophosphamide-induction methotrexate-maintenance regimen for the treatment of Wegener's granulomatosis: extended follow-up and rate of relapse. Langford CA, Talar-Williams C, Barron KS, Sneller MC. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.	Am J Med. 2003 Apr 15;114(6):463-9. Abstract quote PURPOSE: To determine the relapse rate and outcome in patients with Wegener's granulomatosis treated with daily cyclophosphamide and glucocorticoids to induce remission followed by methotrexate for remission maintenance. METHODS: We performed an open-label prospective study in 42 patients with active Wegener's granulomatosis. All patients were treated with a standardized regimen. Outcomes were assessed using predetermined definitions based on clinical characteristics and pathologic, laboratory, and radiographic findings. RESULTS: All patients achieved disease remission. The median time to remission was 3 months, and the median time to discontinuation of glucocorticoids was 8 months. During a median of 32 months of follow-up, 1 patient died (of a myocardial infarction not related to vasculitis). Two patients (5%) had to withdraw from the study because of medication toxicity. Twenty-two patients (52%) relapsed, with glomerulonephritis occurring in 16 patients. Of these 16 patients, 4 had an increase of >0.2 mg/dL in serum creatinine level. All 4 patients returned to their prior level of renal function with treatment. None of the 22 relapses met the criteria for severe disease. CONCLUSION: The use of cyclophosphamide and glucocorticoids for induction and methotrexate for maintaining remission is an effective and well-tolerated therapeutic approach in patients with active Wegener's granulomatosis.
A staged approach to the treatment of Wegener's granulomatosis: induction of remission with glucocorticoids and daily cyclophosphamide switching to methotrexate for remission maintenance. Langford CA, Talar-Williams C, Barron KS, Sneller MC. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.	Arthritis Rheum. 1999 Dec;42(12):2666-73. Abstract quote OBJECTIVE: To determine the efficacy of a daily cyclophosphamide (CYC) and glucocorticoid induction and methotrexate (MTX) remission-maintenance regimen for the treatment of Wegener's granulomatosis (WG). METHODS: An open-label, prospective, standardized trial for the treatment of WG was performed using CYC and glucocorticoids for remission induction and MTX for remission maintenance. Thirty-one patients were enrolled in this study. Outcome was assessed using predetermined definitions based on clinical characteristics and pathologic, laboratory, and radiographic findings. RESULTS: The use of CYC and glucocorticoids for remission induction and MTX for remission maintenance resulted in disease remission for all 31 patients. The median time to remission was 3 months and the median time to discontinuation of glucocorticoids was 8 months. No patients have died, and 5 patients (16%) have had disease relapses at a median of 13 months after achieving remission. Only 2 patients (6%) have had to withdraw from the trial as a result of medication toxicity. CONCLUSION: The use of CYC and glucocorticoids for remission induction and MTX for remission maintenance was shown by this study to be an acceptable alternative therapy for patients with active WG, including those with severe disease at onset.
A prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized Wegener's granulomatosis. Guillevin L, Cordier JF, Lhote F, Cohen P, Jarrousse B, Royer I, Lesavre P, Jacquot C, Bindi P, Bielefeld P, Desson JF, Detree F, Dubois A, Hachulla E, Hoen B, Jacomy D, Seigneuric C, Lauque D, Stern M, Longy-Boursier M. Hopital Avicenne, Bobigny, France.	Arthritis Rheum. 1997 Dec;40(12):2187-98. Abstract quote OBJECTIVE. To investigate the effectiveness and side effects of oral versus pulse cyclophosphamide (CYC) in combination with corticosteroids (CS) in the treatment of systemic Wegener's granulomatosis (WG). METHODS. Patients with newly diagnosed systemic WG were enrolled in a prospective, randomized trial. At the time of diagnosis, prior to randomization, every patient received a daily injection of methylprednisolone for 3 days, followed by daily oral prednisone (1 mg/kg/day) and a 0.7-gm/m2 pulse of CYC. Patients were then randomly assigned to receive either prednisone plus intravenous pulse CYC (group A) or prednisone plus oral CYC (group B) as first-line treatment. CYC was given for at least 1 year and was then progressively tapered and discontinued. RESULTS. Fifty patients were included in the study: 27 in group A and 23 in group B. At 6 months, 24 group A patients (88.9%) were in remission, versus 18 group B patients (78.3%). At the end of the trial, 18 group A patients (66.7%) and 13 group B patients (56.5%) were in remission. In group A, 66.7% of the patients experienced side effects, versus 69.6% in group B. Infectious side effects were significantly more frequent in group B (69.6%) than in group A (40.7%) (P < 0.05). The incidence of Pneumocystis carinii pneumonia was higher in oral CYC-treated patients (30.4%) than in pulse CYC-treated patients (11.1%). Nine group A patients (33.3%) and 10 group B patients (43.5%) died. Actuarial curves showed that relapses were significantly more frequent in group A (59.2%) than in group B (13%) (P = 0.02). CONCLUSION. Our results indicate that pulse CYC is as effective as oral CYC in achieving initial remission of WG and is associated with fewer side effects and lower mortality. However, in the long term, treatment with pulse CYC does not maintain remission or prevent relapses as well as oral CYC.

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