Mechanisms of Disease: pathogenesis and treatment of ANCA-associated vasculitides

Wegener's granulomatosis and microscopic polyangiitis are idiopathic systemic vasculitides strongly associated with antineutrophil cytoplasmic autoantibodies (ANCA). In Wegener's granulomatosis, ANCA are mostly directed against proteinase 3 (PR3), whereas in microscopic polyangiitis ANCA are directed against myeloperoxidase; increases in levels of these autoantibodies precede or coincide with clinical relapses in many cases. In vitro, ANCA can further activate primed neutrophils to release reactive oxygen species and lytic enzymes, and, in conjunction with neutrophils, can damage and lyse endothelial cells. Patients with Wegener's granulomatosis or microscopic polyangiitis have an increased percentage of neutrophils that constitutively express PR3 on their membrane. These neutrophils can be stimulated by ANCA, without priming. In vivo, transfer of splenocytes from myeloperoxidase-deficient mice immunized with mouse myeloperoxidase into wild-type mice resulted in pauci-immune systemic vasculitis. A similar experiment in PR3-deficient mice did not cause significant vasculitic lesions. Together, clinical, in vitro and in vivo experimental data support a pathogenic role for ANCA in Wegener's granulomatosis and microscopic polyangiitis, although this role is more evident for myeloperoxidase-specific ANCA than for PR3-specific ANCA. Several controlled trials have led to an evidence-based approach for the treatment of ANCA-associated vasculitis, and further studies, based on new insights into pathogenesis, are in progress.     

B-Lymphozyten-Differenzierung in granulomatösen Geweben der Lunge und der Nasenschleimhäute beim Morbus Wegener

Wegener's granulomatosis (WG) starts with granulomatous inflammation of the respiratory tract before it converts into a potentially organ and life threatening systemic vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA).The site of formation of the highly specific ANCA directed against "Wegener's autoantigen" proteinase 3 (PR3) is still unknown. Previously, we have shown that follicle-like B lymphocytic infiltrates in the vicinity to PR3 expressing cells in WG-granulomata. We characterized the immunoglobulin-VH repertoire in lung and nasal granulomata (paraffin embedded) from four WG patients. A total of 115 individual VH genes were characterized and compared to 84 VH genes from the peripheral blood of a healthy donor. We found an increased frequency of mutations with a bias to amino acid exchanges within the antigen binding sites (CDR) 1 and 2 in WG tissue. A large number of mutations led to negatively charged amino acids and may increase affinity to the positively charged PR3. Furthermore, the occurrence of differently mutated members of one B cell clone indicates clonal expansion and intraclonal diversification by an antigen, e.g. PR3. Several WG tissue derived genes displayed similarities to published sequences from peripheral PR3 ANCA producing B cells. Thus, granulomata of the lower and upper respiratory tract contain follicle-like B cell clusters with a selected VH repertoire infiltrate in WG. WG granulomata could be the place of autoantigen presentation and formation of high-affinity ANCA within neoformed ectopic or tertiary lymphoid-like tissue areas.     

Low seroprevalence and poor specificity of antineutrophil cytoplasmic antibodies in tuberculosis

OBJECTIVES: Recently published findings suggested that antineutrophil cytoplasmic antibodies (ANCA), particularly those with a cytoplasmic (C-ANCA) labelling pattern and targeting proteinase 3 (anti-PR3), might be markers of tuberculosis (TB). This is a critical issue, because C-ANCA/anti-PR3 were considered to be a highly specific hallmark of Wegener's granulomatosis or microscopic polyangiitis and because TB may clinically mimic Wegener's granulomatosis. We therefore undertook a study with the aim of investigating further the prevalence and specificity of ANCA in TB. METHODS: We evaluated serum samples from 67 patients diagnosed with culture-proven TB and 10 previously untested control samples from patients known to be ANCA positive (four Wegener's granulomatosis and two microscopic polyangiitides) or negative. All 77 sera were screened for ANCA using commercially available indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA) for anti-PR3 and antimyeloperoxidase (MPO). IIF-positive and anti-PR3- and anti-MPO-negative sera were also tested for bactericidal/permeability-increasing protein, lactoferrin, elastase and cathepsin G specificities with commercially available ELISA. RESULTS: IIF detected ANCA in seven (10%) of the TB sera, including three C-ANCA and four atypical perinuclear-labelling ANCA. Only one IIF-negative specimen was anti-PR3 positive in ELISA. ANCA testing of the control sera yielded IIF and ELISA results concordant with previous findings, except for one borderline ELISA. CONCLUSION: Our results indicate that TB is associated with low ANCA seroprevalence and poor specificity, with no test serum showing combined C-ANCA/anti-PR3 activity. In a clinical setting of Wegener's granulomatosis/TB mimicry, such combined reactivity would seem to be more suggestive of Wegener's granulomatosis.     

Opportunistic infection and antineutrophil cytoplasm antibodies in Wegener's granulomatosis

Antineutrophil cytoplasmic antibodies (ANCA) are of established value in the diagnosis of Wegener's granulomatosis allowing early introduction of therapy. These patients are at risk of opportunistic infection, especially whilst receiving immunosuppressive drugs and this may mimic reactivation of disease. We present three cases of Wegener's granulomatosis complicated by opportunistic infection and assess the value of ANCA detection. Two presented with symptoms compatible with disease reactivation but ANCA were negative. One died with pulmonary infection due to Pneumocystis carinii, Aspergillus fumigatus and Herpes simplex. Transbronchial biopsy in the second case revealed Pneumocystis carinii. A third case had strongly positive serum ANCA at diagnosis but in addition pulmonary infection with Legionella pneumophila. ANCA detection is of value in patients with Wegener's granulomatosis, but the result must be interpreted in the full clinical context.     

Wegener’s Granulomatosis

Wegener's granulomatosis is an organ- and/or life-threatening autoimmune disease of as yet unknown etiology. The classic clinical triad consists of necrotizing granulomatous inflammation of the upper and/or lower respiratory tract, necrotizing glomerulonephritis, and an autoimmune necrotizing systemic vasculitis affecting predominantly small vessels. The detection of antineutrophil cytoplasmic antibodies directed against proteinase 3 (PR3-ANCA) is highly specific for Wegener's granulomatosis. ANCA positivity is found only in about 50% of the patients with localized Wegener's granulomatosis (which is restricted to the respiratory tract and affects < or = 5% of the patients), whereas PR3-ANCA positivity is seen in 95% of the patients with generalized Wegener's granulomatosis. Studies showing an expansion of circulating tumor necrosis factor-(TNF-)alpha-producing Th1-type CD4(+)CD28(-) T-cell effector memory T-cells and their presence as Th1-type cytokine profile- driving cell population within granulomatous lesions provide the rationale for using TNF-alpha-blocking agents in Wegener's granulomatosis refractory to standard induction therapy with cyclophosphamide and corticosteroids ("Fauci's scheme"). Vasculitis is an independent risk factor for diffuse endothelial dysfunction and may be a consequence of TNF-alpha action on endothelial cells. Recently, another study has shown intima-media thickening of the wall of the common carotid artery and bulb, as well as a significantly increased incidence of stroke, myocardial infarction and occlusive artery disease in Wegener's granulomatosis. This study suggests that systemic inflammation and vasculitis contribute to accelerated arteriosclerosis in Wegener's granulomatosis.     

Severe CNS manifestations as the clinical hallmark in generalized Wegener's granulomatosis consistently negative for antineutrophil cytoplasmic antibodies (ANCA). A report of 3 cases and a review of the literature

OBJECTIVE: Antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 are highly specific for Wegener's granulomatosis (WG); their sensitivity for active generalized WG is nearly 100%. There are patients, however, who fulfill both the ACR 1990 criteria and the CHC 1992 definition for WG but who remain ANCA negative. The authors report 3 young patients with biopsy-proven active generalized WG who were consistently negative for ANCA over observation times ranging from 58 to 114 months. METHODS: ANCA titers were determined serially every 3 months. ANCA-negativity was defined by the absence of any fluorescence pattern on IFT plus the absence of any specific ELISA reactions. This included negative results for the antibody classes IgG, IgM and IgA. The sera of all patients were also tested in a capture PR3-ANCA ELISA. At 1- to 6-month intervals each patient underwent a standardized set of interdisciplinary examinations. RESULTS: Although CNS involvement in large WG cohorts is about 10%, severe CNS manifestations were the clinical hallmark in all 3 patients. One patient suffered from both intraspinal and intracerebral disease with fatal outcome; the other 2 had meningeal manifestations that responded favorably to immunosuppressive therapy. CONCLUSION: Severe CNS manifestations could represent a clinical hallmark of patients with generalized Wegener's granulomatosis who are consistently negative for antineutrophil cytoplasmic antibodies (ANCA).     

Pulmonary giant bulla in Wegener's granulomatosis

The association of lung emphysema with severe systemic antineutrophil cytoplasm antibodies (ANCA)-positive vasculitis, such as Wegener's granulomatosis is unusual since only four cases have been described previously. We report the first case of a 30 year-old smoker man presenting with biopsy-proven Wegener's granulomatosis, who developed a bullous emphysema during severe active lung vasculitis, in association with positive ANCA disclosing an anti-myeloperoxydase pattern. Alpha 1-antitrypsin deficiency, a known risk factor of lung emphysema recently found to be associated with anti-proteinase 3-positive vasculitis, was not present in this patient. Cigarette smoking, in association with severe lung vasculitis, might have contributed to the development of this emphysematous lesion.     

Antineutrophil cytoplasmic antibodies (ANCA) and small vessel vasculitis

We report on one patient with Wegener's granulomatosis (WG) and two patients with microscopic polyangiitis (MPA). The patient with WG had signs of a respiratory infection and showed a c-ANCA pattern with proteinase 3 (PR3) specificity. The patients with MPA presented with pulmonary haemorrhage and signs of renal damage and showed a p-ANCA pattern with myeloperoxidase (MPO) specificity. In the three patients histopathological findings confirmed the diagnosis. We discuss the clinical indications of ANCA testing and the current terminology for reporting ANCA results (c-ANCA, p-ANCA, c-ANCA (atypical) and atypical ANCA). The target antigens and diseases associated with these different patterns are considered. Finally we focus on the value of ANCA and more specific PR3-ANCA and MPO-ANCA in the diagnosis of WG and MPA. The new application domain of ANCA in Crohn's disease and ulcerative colitis is also discussed.     

Alternating antineutrophil cytoplasmic antibody specificity: drug-induced vasculitis in a patient with Wegener's granulomatosis

We describe a patient who presented with Wegener's granulomatosis associated with antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3) with a cytoplasmic immunofluorescence pattern (cANCA), whose ANCA type changed to antimyeloperoxidase antibodies with a perinuclear immunofluorescence pattern (pANCA) when treated with propylthiouracil, and changed back to anti-PR3 antibodies with cANCA after the medication was discontinued. The patient developed flares of vasculitis symptoms associated with rises in either type of ANCA. Tests for antimyeloperoxidase ANCA were repeatedly negative before the drug was started, strongly implicating the drug as the cause of the episode. This case demonstrates that patients with idiopathic ANCA-positive vasculitis may quickly develop a superimposed drug-associated ANCA-positive vasculitis. Iatrogenic vasculitis should be suspected when a patient with idiopathic vasculitis with one type of ANCA develops the other type of ANCA.     

A case of Wegener's granulomatosis associated with the syndrome of inappropriate secretion of ADH]

A 68 year-old woman was admitted with fever, productive cough and sore throat. A chest radiograph and a chest computed tomography showed multiple nodules in both lungs. Thoracoscopic lung biopsy was performed. The specimens showed vasculitis and geographic basophilic necrosis with palisading histiocytes, giant cells, and neutrophils. Wegener's granulomatosis was diagnosed. On the 5th hospital day, the serum sodium level was 128 mEq/l. Since secretion of antidiuretic hormone had continued despite a low plasma osmolarity, we diagnosed the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and initiated oral prednisolone and cyclophosphamide. As a result, the symptoms and image findings were improved, and serum sodium level became normal. This case was considered to be SIADH secondary to Wegener's granulomatosis.     

Variations in performance characteristics of commercial enzyme immunoassay kits for detection of antineutrophil cytoplasmic antibodies: what is the optimal cut off?

BACKGROUND: Previous studies have shown considerable variation in diagnostic performance of enzyme linked immunosorbent assays (ELISAs) for measuring antineutrophil cytoplasmic antibodies (ANCA) specific for proteinase 3 (PR3) and myeloperoxidase (MPO). OBJECTIVE: To analyse the performance characteristics of different commercially available direct ANCA ELISA kits. METHODS: ELISA kits for detecting PR3-ANCA and MPO-ANCA from 11 manufacturers were evaluated. Serum samples were taken from patients with Wegener's granulomatosis (15), microscopic polyangiitis (15), other vasculitides (10), and controls (40). RESULTS: were compared with data obtained by indirect immunofluorescence (IFT). The diagnostic performance of the tests was analysed and compared by receiver operating characteristic (ROC) curve analysis.Results: Applying the manufacturers' cut off resulted in great variation in sensitivity of the commercial PR3-ANCA kits for diagnosing Wegener's granulomatosis (ranging from 13.3% to 66.7%), and of the MPO-ANCA kits for diagnosing microscopic polyangiitis (ranging from 26.7% to 66.7%). Specificities were relatively constant (from 96.0% to 100%). IFT was superior to all ELISAs (C-ANCA for Wegener's granulomatosis: sensitivity 73.3%, specificity 98%; P-ANCA for microscopic polyangiitis: sensitivity 86.7%, specificity 98%). The sensitivities of PR3-ANCA and MPO-ANCA ELISA kits were increased by lowering the cut off values. This reduced specificity but increased overall diagnostic performance. CONCLUSIONS: The low sensitivity of some commercial kits reflects the high cut off levels recommended rather than methodological problems with the assays. Comparative analyses using sera from well characterised patients may help identify optimum cut off levels of commercial ANCA ELISA tests, resulting in better comparability of results among assays from different manufacturers.     

Immunoglobulin G antineutrophil cytoplasmic antibodies are produced in the respiratory tract of patients with Wegener's granulomatosis

Wegener's granulomatosis (WG) is a small-vessel vasculitis of unknown etiology that usually involves the upper and lower respiratory tract and the kidneys. Recently, an association has been made between the presence of serum antineutrophil cytoplasmic antibodies (ANCA) and WG. Because WG frequently involves the lung, we sought to evaluate bronchoalveolar lavage (BAL) fluids obtained from 14 patients with WG for the presence of ANCA. Immunoglobulin (Ig) G ANCA was found in the BAL with the same staining patterns as observed in the serum. Patients with active disease had the highest serum and BAL IgG ANCA titers. IgA or IgM ANCA was not detected in the serum or BAL of these patients. Protein analysis of BAL fluid revealed that patients with active, untreated WG had approximately a fourfold elevation in total protein (41.3 versus 10.5 mg/dl), with a disproportionately greater increase in the ratio of IgG to albumin (BAL IgG index = 1.49, normal = 0.74; p = 0.027). The increase of the IgG index in patients with active WG suggests that local production of IgG ANCA occurs in the lungs.     

Antineutrophil cytoplasmic antibodies reacting with the pro form of proteinase 3 and disease activity in patients with Wegener's granulomatosis and microscopic polyangiitis

OBJECTIVE: Antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3) are diagnostic markers for the small vessel vasculitides Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA). Correlation of disease activity with PR3 ANCA levels, as determined by standard methods, is not apparent in every patient. PR3 ANCA react with yet to be identified conformational epitopes. We have identified PR3 ANCA subsets that react differentially with mature recombinant PR3 (rPR3; lacking the N-terminal activation dipeptide) and the pro form of this enzyme (pro-rPR3). The present study was performed to determine the association of these PR3 ANCA subsets with disease activity. METHODS: Sera from 61 PR3 ANCA-positive patients with WG or MPA were assayed by capture enzyme-linked immunosorbent assay using pro-rPR3 and rPR3 as target antigens, and were correlated with disease activity as determined by the Birmingham Vasculitis Activity Score (BVAS). RESULTS: Median levels of PR3 ANCA reacting with pro-rPR3 were higher during active (n = 32) than during inactive (n = 29) disease (P = 0.016). Reactivity with mature rPR3 was not significantly different (P = 0.71). Serial followup in individual patients also indicated better correlation of PR3 ANCA reactivity with pro-rPR3 than with mature rPR3. CONCLUSION: PR3 ANCA subsets reactive with epitopes accessible on pro-PR3 correlate better with disease activity than do subsets reactive with epitopes accessible only on mature PR3. This observation may explain why ANCA levels determined with current standard methods are suboptimal for monitoring disease activity. It raises new questions about the primary target of the PR3 ANCA immune response in patients with small vessel vasculitis.     

Wegener's granulomatosis mimicking paraneoplastic syndrome

Wegener's granulomatosis is a distinct clinico-pathological entity characterised by a triad of upper and lower respiratory disease and renal involvement, although atypical presentations can be seen. These patients characteristically have small vessel vasculitis and or granulomatous vasculitis and are usually anti-neutrophilic cytoplasmic antibody (ANCA) positive. We present a case of Wegener's granulomatosis that clinically mimicked a lung neoplasm with a paraneoplastic syndrome. Biopsy and histopathological evaluation of a readily accessible subcutaneous nodule showed small vessel vasculitis. Correlation with clinical data and ANCA positivity led to a definite diagnosis.     

Prediction of relapses in Wegener's granulomatosis by measurement of antineutrophil cytoplasmic antibody levels: a prospective study

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.     

Functional characterization of antineutrophil cytoplasmic antibodies in patients with cocaine-induced midline destructive lesions

OBJECTIVE: Antineutrophil cytoplasmic antibodies (ANCA) binding to neutrophil elastase (NE) and proteinase 3 (PR3) are detectable in most patients with cocaine-induced midline destructive lesions (CIMDL), but the pathogenic role and antigen specificity of these antibodies are unknown. This study was undertaken to assess the effects of NE ANCA on the enzymatic activity of NE, to determine whether these antibodies interfere with the physiologic effect of secretory leukoprotease inhibitor (SLPI), and to investigate the antigen specificity of both NE and PR3 ANCA in patients with CIMDL. We also compared the binding of PR3 ANCA in patients with CIMDL with that in patients with Wegener's granulomatosis (WG). METHODS: PR3 ANCA and NE ANCA were detected by capture enzyme-linked immunosorbent assays (ELISAs) and by indirect immunofluorescence. IgG was purified from the patients' sera, and the influence of NE ANCA on the enzymatic activity of NE and on the inhibitory activity of SLPI was investigated by determining the hydrolysis of N-methoxysuccinyl-Ala-Ala-Pro-Val p-nitroanilide by NE. RESULTS: IgG from NE ANCA-positive sera of patients with CIMDL inhibited the enzymatic activity of NE and did not interfere with the activity of SLPI. In contrast to the findings in WG sera, measurement of PR3 ANCA in CIMDL sera showed only fair to moderate concordance between the 2 different capture ELISAs. Cross-inhibition experiments demonstrated that NE ANCA and PR3 ANCA represent distinct autoantibodies in patients with CIMDL. CONCLUSION: The functional effects of NE ANCA on the enzymatic activity of NE or on the activity of SLPI cannot be implicated in the pathogenesis of CIMDL. The autoimmune reaction that targets neutrophil serine proteases in patients with CIMDL is frequently directed against more than one antigen. The ANCA response, including the reactivity of PR3 ANCA, in patients with CIMDL differs from what has been described in patients with WG.     

Wegener's granulomatosis--treatment under revision?

A 44-year-old man with nasal and respiratory symptoms combined with positive serum antibodies to neutrophil cytoplasmic antigens (ANCA) suggestive of Wegener's granulomatosis was treated with antibacterial agents. Complete clinical response was achieved with co-trimoxazole, and the titer of ANCA declined. After a 12-month treatment period, the patient contracted fever and respiratory symptoms and fatigue again, and he had proteinuria and hematuria. After the institution of conventional treatment with oral prednisolone and cyclophosphamide, a favorable response was achieved. Wegener's-like granulomatosis is difficult to diagnose at its early stage, but the presence of ANCA may be helpful. We suggest that co-trimoxazole should be considered as a first-line treatment, under careful supervision, for young patients whose disease is limited to the respiratory organ.     

The spectrum of disease associated with a positive ANCA

Summary This is a retrospective analysis of all patients with a raised titre of ANCA in a single centre over a two-year period. Sixty-five patients were identified and clinical data is presented for 58 of these — 34 male and 24 female. The median age is 56 years (13–83). Fourteen patients had Wegener's granulomatosis, 14 microscopic polyarteritis nodosa and 30 had other diagnoses. The patients with unexpectedly positive results are discussed in detail. This study confirms the sensitivity of ANCA in Wegener's granulomatosis and microscopic polyarteritis nodosa but suggests that the test is not as specific as initially claimed.     

Rituximab for refractory Wegener's granulomatosis: report of a prospective, open-label pilot trial

RATIONALE: Standard therapy for Wegener's granulomatosis is fraught with substantial toxicity and not always effective. B lymphocytes have been implicated in the pathogenesis of Wegener's granulomatosis. Their depletion has been proposed as salvage therapy for refractory disease. Earlier encouraging reports are confounded by concomitant immunosuppressive medications and include only limited available biomarker data. OBJECTIVES: To evaluate the efficacy and safety of rituximab for remission induction in refractory Wegener's granulomatosis. METHODS: A prospective open-label pilot trial was conducted with 10 patients monitored for 1 yr. Included were patients with active severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, ANCA positivity, and resistance to (or intolerance of) cyclophosphamide. The remission induction regimen consisted of oral prednisone (1 mg/kg/d) and four weekly infusions of rituximab (375 mg/m(2)). Prednisone was tapered and discontinued over 5 mo. Failure to achieve remission, a clinical flare in the absence of B lymphocytes, and inability to complete the glucocorticoid taper were considered treatment failures. MAIN RESULTS: Three women and seven men (median age, 57 yr; range, 25-72 yr) were enrolled. All had ANCA reacting with proteinase-3. The median activity score at enrollment was 6 (range, 5-10). All patients tolerated rituximab well, achieved swift B-lymphocyte depletion and complete clinical remission (activity score, 0) by 3 mo, and were tapered off glucocorticoids by 6 mo. Five patients were retreated with rituximab alone for recurring/rising ANCA titers according to protocol. One patient experienced a clinical flare after B lymphocyte reconstitution. CONCLUSION: In this cohort, rituximab was a well-tolerated and effective remission induction agent for severe refractory Wegener's granulomatosis.     

Wegener's granulomatosis complicated with intestinal ulceration

We report the case of a 32-year-old man who developed Wegener's granulomatosis complicated with refractory intestinal ulceration. In August 2001, he presented with a high fever, nasal bleeding, and bilateral leg numbness. These symptoms worsened, which prompted him to consult his home doctor on February 18, 2002. In spite of treatment with antibiotics, his symptoms did not improve. Furthermore, abdominal pain and melena occurred as additional symptoms in March 2002. He was admitted to our hospital on April 5, 2002. A deformed nose condition (the so-called saddle nose) was observed at this time. Laboratory data showed a high erythrocyte sedimentation rate (103 mm/h) and a high level of serum C-reactive protein (14.98 mg/dl), and hematuria and proteinuria were also observed. The patient was positive for an antineutrophil cytoplasmic antibody specific for proteinase-3 (PR3-ANCA). A chest computed tomography (CT) scan revealed multiple pulmonary nodules in the lung field. A biopsied-specimen from the nasal mucosa showed necrotizing granulomatosis with giant cells. Together with his symptoms and the laboratory and pathological findings, the patient was diagnosed as having Wegener's granulomatosis. A colon fiberscopy showed multiple ulcerations with bleeding from the terminal ileum to the ascending colon, and nodular lesions at the terminal ileum. We started a combination therapy of prednisolone (60 mg/day) and cylophosphamide (100 mg/day) orally. The patient's gastrointestinal symptoms disappeared and abnormal serological indicators improved. Although Wegener's granulomatosis complicated with refractory intestinal ulceration is rare, this case indicates that the gastrointestinal region is also a target organ of Wegener's granulomatosis.