Wegener granulomatosis (granulomatosis with polyangiitis): evolving concepts in treatment

Wegener granulomatosis (WG), the most common of the pulmonary granulomatous vasculitides, typically involves the upper respiratory tract, lower respiratory tract (bronchi and lung), and kidney, with varying degrees of disseminated vasculitis. THE TERM GRANULOMATOSIS WITH POLYANGIITIS (WEGENER) WAS RECENTLY PROPOSED TO REPLACE THE OLDER TERM, WG. THE TERM GRANULOMATOSIS WITH POLYANGIITIS CAN BE ABBREVIATED TO GPA, WITH THE IDEA THAT THE EPONYM WEGENER WOULD BE OMITTED OVER TIME. Cardinal histologic features include a necrotizing vasculitis involving small vessels, extensive "geographic" necrosis, and granulomatous inflammation. Clinical manifestations of WG are protean; virtually any organ can be involved. The spectrum and severity of the disease are heterogeneous, ranging from indolent disease involving only one site to fulminant, multiorgan vasculitis. The pathogenesis of WG has not been elucidated, but both cellular and humoral components are involved. Circulating antibodies against cytoplasmic components of neutrophils [anti-neutrophil cytoplasmic antibodies (c-ANCAs)] likely play a role in the pathogenesis, and often correlate with activity of the disease. Treatment strategies are evolving. Cyclophosphamide (CYC) plus corticosteroids (CSs) is the mainstay of therapy for generalized, multisystemic WG. Historically, the combination of CYC plus CS was used for a minimum of 12 months, but concern about late toxicities associated with CYC has led to novel treatment approaches. Currently, short-course (3 to 6 months) induction treatment with CYC plus CS, followed by maintenance therapy with less toxic agents (e.g., methotrexate, azathioprine) is recommended. Further, methotrexate combined with CS may be adequate for limited, non-life-threatening WG. Recent studies suggest that rituximab may be useful for induction therapy or CYC-refractory WG. The role of other immunomodulatory agents (including trimethoprim-sulfamethoxazole) is also explored.     

Immunosuppressive and cytotoxic therapy: pharmacology, toxicities, and monitoring

Treatment strategies for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) are evolving. Cyclophosphamide (CYC) plus corticosteroids (CSs) is the mainstay of therapy for generalized, multisystemic AAV. Historically, the combination of CYC plus CS was used for a minimum of 12 months, but concern about late toxicities associated with CYC has led to novel treatment approaches. Currently, short-course (3 to 6 months) induction treatment with CYC plus CS, followed by maintenance therapy with less toxic agents (eg, methotrexate, azathioprine, mycophenolate mofetil) is recommended. Further, methotrexate combined with CS may be adequate for limited, non-life-threatening AAV. Recent studies suggest that rituximab may be useful for induction therapy or for CYC-refractory AAV. This article reviews the key agents used to treat AAV, with a focus on pharmacology, toxicities, and monitoring.     

Wegener-Granulomatose und mikroskopische Polyangiitis

Wegener’s granulomatosis (WG) and microscopic polyangiitis (MPA) are primary systemic small vessel vasculitides, associated with a positive C/PR3-ANCA in WG and P/MPO-ANCA in MPA. The most prominently involved organs are the upper (only in WG) and lower respiratory tract and the kidneys. The diagnostic work-up is an interdisciplinary approach assessing disease stage and extent. Treatment is adapted to disease stage and extent and relies on a combination of a cytotoxic plus a tapering regimen of corticosteroids. Induction of remission in “early systemic” disease can be achieved with low-dose methotrexate. In severe generalized vasculitis cyclophosphamide (CYC) is the mainstay of therapy, in rapidly progressive glomerulonephritis in combination with plasmapheresis. After 3–6 months of induction CYC is switched to a maintenance treatment with azathioprine. Alternatives are leflunomide, mycophenolate or methotrexate (creatinine < 150 µmol/l). Age ≥ 50 at diagnosis, renal dysfunction and pulmonary involvement are associated with higher mortality rates. The relapse rate is approximately 50% within 5 years, being higher in WG than MPA.     

Esophageal involvement in wegener's granulomatosis

Wegener's granulomatosis (WG) is characterized by granulomatous vasculitis, renal disease, and upper and lower respiratory tract disease. Although most organ systems can be involved, gastrointestinal (GI) manifestations are notably uncommon. We describe a patient with WG whose presentation was unique for the prominence of odynophagia. Esophagoscopy revealed erosive esophagitis, which on biopsy was shown to be due to direct involvement by the underlying vasculitis. This is first antemortem documentation of esophageal disease secondary to WG. The GI manifestations of WG are reviewed.     

Influence of disease manifestation and antineutrophil cytoplasmic antibody titer on the response to pulse cyclophosphamide therapy in patients with wegener's granulomatosis

Objective. To assess the effectiveness of pulse cyclophosphamide (CYC) in the treatment of Wegener's granulomatosis (WG) and to identify the patients who are responsive to the treatment. Methods. The prospective study included 43 patients with biopsy-proven WG. Clinical, radiographic, laboratory, and immunologic data were evaluated for predicitive values regarding the outcome of pulse CYC therapy. Results. Only 42% of the patients showed complete or partial remission that lasted at least 6 months after cessation of pulse CYC therapy. These responders had a higher frequency of disease activity limited to the upper and lower respiratory tract (39%, versus 8% in the nonresponder group; P < 0.05) and had lower titers of classic antineutrophil cytoplasmic antibody (cANCA) prior to treatment (<1:64 42%, versus 6% in the nonresponder group; P < 0.05). In the 58% of patients who did not respond to pulse CYC treatment, there was both systemic disease involving more than 4 organ systems (mainly, the heart, nervous system, eye, and skin) and constitutional symptoms. Serious side effects induced by pulse CYC occurred in only 1 patient. Conclusion. Based on these findings, pulse CYC therapy appears to be effective in WG patients with moderate disease activity and low titers of cANCA, but of little benefit in patients with severe WG. Pulse CYC should therefore not be used as first-line therapy in patients with severe and rapidly progressing forms of WG associated with high titers of cANCA.     

Wegener's granulomatosis of the prostate gland

Wegener's granulomatosis (WG) is a systemic granulomatous vasculitis affecting medium and small arteries, venules, and arterioles. The upper and lower respiratory tract and kidney are primarily involved. Patients with classic WG essentially present with upper airway and pulmonary involvement. Renal disease is common. Involvement of other organ systems is also relatively frequent, most often heart, joints, muscles, eyes, skin, and central and/or peripheral nervous system. We present a patient in whom WG was diagnosed primarily because of prostate involvement. This seems to be a rare manifestation.     

The treatment of Wegener's granulomatosis with glucocorticoids and methotrexate.

OBJECTIVE. To identify alternatives to daily low-dose cyclophosphamide (CYC) in the treatment of Wegener's granulomatosis (WG). METHODS. An open-label pilot study of weekly low-dose methotrexate (MTX) plus glucocorticoids (GC) for treatment of patients with WG was performed. Twenty-nine patients who did not have immediately life-threatening disease were included. Outcome was determined by clinical characteristics, pathologic findings, course of illness, laboratory and radiographic findings, and successful withdrawal of GC therapy. RESULTS. Weekly administration of MTX (at a mean stable dosage of 20 mg) and GC resulted in marked improvement in 76% of the 29 patients. Remission was achieved in 69% of the patients, 7% improved but had intermittent smoldering disease that precluded total withdrawal of GC, and 17% had progressive disease within 2-6 months of starting the study treatment. Two patients who initially achieved remission later had relapses after GC was discontinued. Of those who remain in remission (mean followup time 14.5 months), 72% have not required GC for a mean period of 10 months. CONCLUSION. Although standard therapy for WG (daily CYC and GC) has dramatically improved outcome in this often-fatal disease, treatment morbidity has led to attempts to identify effective interventions that have less toxicity. Weekly low-dose MTX was shown in this study to be a feasible alternative to CYC in patients whose illness was not immediately life-threatening or in whom prior CYC treatment was ineffective or produced serious toxicity. Although these results are preliminary, they are encouraging and justify further studies in which MTX, CYC, and other alternative therapeutic approaches are compared concurrently.     

Granulomatous vasculitis. Wegener's granulomatosis and Churg-Strauss syndrome

Wegener's granulomatosis and the Churg-Strauss syndrome are both syndromes that appear to begin with a phase of regionally limited symptomatology before they progress at unpredictable rate to a generalized phase characterized by symptoms of systemic vasculitis. The clinical features of atopy, peripheral blood eosinophilia, and tissue eosinophilia distinguish CSS from WG, with its typical necrotizing granulomatous respiratory tract lesions. Whereas in generalized WG with renal involvement the use of cyclophosphamide usually cannot be avoided, the generalized systemic vasculitis phase of CSS appears to respond well to glucocorticoids alone. For the more limited forms of WG, adapted therapy regimens including trimethoprim-sulfamethoxazole have been reported to be successful. Anticytoplasmic autoantibodies (c-ANCA = ACPA) are a new diagnostic serum test with high specificity for WG. Serial determinations of c-ANCA are a promising tool to monitor disease activity.     

Wegener granulomatosis

Wegener granulomatosis (WG) is a necrotizing, granulomatous vasculitis that has a clinical predilection to involve the upper airways, lungs, and kidneys. Although the first case was reported by Klinger in 1931, Friedrich Wegener in 1936 characterized the unique clinical and pathological features of this disease that subsequently came to bear his name. Vascular inflammation and occlusion leading to tissue ischemia is a hallmark of WG. Although strong evidence indicates that such blood vessel damage is immunologically mediated, the mechanisms that initiate this process are still largely unknown. To date, there has been no clearly established association with genetic factors, specific infectious agents, or environmental irritants, although speculation has remained that these may play a role in triggering the onset of disease. Until the introduction of therapy with cyclophosphamide (CYC) and glucocorticoids, WG was uniformly fatal. Although drug toxicity and disease relapse remain of concern with this regimen, it has provided us with a successful means of treatment and the opportunity to better understand this disease through long-term patient follow-up.     

Sinonasal NK/T-cell lymphoma mimicking Wegener's granulomatosis: a case report

In Western population, sinonasal malignant lymphoma is rare and constitutes 1.5% of all non-Hodgkin lymphoma (NHL) and 2.2% of extranodal lymphomas. Wegener's granulomatosis (WG) is the necrotizing vasculitis of small arteries and veins. WG is characterized by granulomatous vasculitis and involves the upper and lower respiratory tract together with glomerulonephritis. But there are some forms of WG named limited WG that involves the upper respiratory tract only without glomerulonephritis and even seronegative without renal involvement. Herein, we present a typical WG with isolated sinonasal tract involvement with clinical, and radiological findings with the final diagnosis of NK/T-cell angiocentric lymphoma by the repeated biopsies. Since both diseases have same clinical and radiological findings differential diagnosis may be difficult.     

Orbital Wegener’s granulomatosis: a case report and review of the literature

Wegener's granulomatosis (WG) is a multisystem granulomatous, necrotizing vasculitis of presumed autoimmune origin that affects small- to medium-sized blood vessels. The respiratory tract and kidneys are typically involved (Gross and Reinhold-Keller, "Clinical features of primary ANCA-associated vasculitis" in Oxford textbook of rheumatology, third edition, 2004). The limited form usually involves the head and neck, lacks renal involvement, and may not progress to generalized disease (Cassan et al., Am. J. Med. 49:366-379, 1970). Ocular involvement, which may be the initial manifestation, is often encountered and can result in significant morbidity and possibly blindness (Pakrou et al., Semin. Arthritis Rheum. 35:284-292, 2006). We report an unusual case of WG presenting as an orbital mass. The diagnostic triad of granulomatous inflammation with multinucleated giant cells, vasculitis, and necrosis was discovered on histopathology (McDonald and Edwards, JAMA 173:1205-1209, 1960).     

The treatment of wegener's granulomatosis with glucocorticoids and methotrexate

Objective. To identify alternatives to daily low-dose cyclophosphamide (CYC) in the treatment of Wegener's granulomatosis (WG). Methods. An open-label pilot study of weekly low-dose methotrexate (MTX) plus glucocorticoids (GC) for treatment of patients with WG was performed. Twenty-nine patients who did not have immediately life-threatening disease were included. Outcome was determined by clinical characteristics, pathologic findings, course of illness, laboratory and radiographic findings, and successful withdrawal of GC therapy. Results. Weekly administration of MTX (at a mean stable dosage of 20 mg) and GC resulted in marked improvement in 76% of the 29 patients. Remission was achieved in 69% of the patients, 7% improved but had intermittent smoldering disease that precluded total withdrawal of GC, and 17% had progressive disease within 2–6 months of starting the study treatment. Two patients who initially achieved remission later had relapses after GC was discontinued. Of those who remain in remission (mean followup time 14.5 months), 72% have not required GC for a mean period of 10 months. Conclusion. Although standard therapy for WG (daily CYC and GC) has dramatically improved outcome in this often-fatal disease, treatment morbidity has led to attempts to identify effective interventions that have less toxicity. Weekly low-dose MTX was shown in this study to be a feasible alternative to CYC in patients whose illness was not immediately life-threatening or in whom prior CYC treatment was ineffective or produced serious toxicity. Although these results are preliminary, they are encouraging and justify further studies in which MTX, CYC, and other alternative therapeutic approaches are compared concurrently.     

A staged approach to the treatment of Wegener's granulomatosis: induction of remission with glucocorticoids and daily cyclophosphamide switching to methotrexate for remission maintenance

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.     

Panhypopituitarism due to Wegener's granulomatosis

Wegener's granulomatosis (WG) is a multi-system necrotizing granulomatous vasculitis which classically affects the upper respiratory tract, lungs and kidneys. Pituitary participation has been described in 24 patients in the literature to date. The aim of this article is to report a case of pituitary involvement in WG, and to present a literature review on this association. We present a female patient with WG who evolved with central diabetes insipidus (CDI), panhypopituitarism, and mild hyperprolactinemia. MRI showed an infiltrative pattern. Pituitary involvement has been reported in around 1% of patients with WG, mostly in women. It is represented by CDI and hypopituitarism. MRI generally shows pituitary enlargement, stalk thickening and loss of hyperintensity of the neurohypophysis. Permanent endocrine therapy is generally needed. WG should be considered in cases of CDI and hypopituitarism, essentially if a vasculitis is suspected and more common sellar disorders have been ruled out.     

Wegener's granulomatosis effectively treated with rituximab: a case study

Wegener's granulomatosis (WG) is a granulomatous disorder associated with systemic necrotizing vasculitis. Wegener's granulomatosis predominantly involves the upper airways, lung and kidneys. The disease is often associated with cytoplasmic antineutrophil cytoplasmic antibodies (cANCA). B lymphocytes are potential cANCA producers and there is an evident correlation between cANCA titre, severity of the disease and response to treatment. Wegener's granulomatosis usually begins with symptoms limited mostly to the upper and/or lower respiratory tracts and may transform into the generalized phase, characterized by systemic necrotizing vasculitis. If left untreated, it can turn fulminant with poor prognosis. The severe form of the disease is usually treated with a combination of cyclophosphamide and corticosteroids. In refractory cases, rituximab that binds to CD20 expressed on B-cells should be considered. We presented a case of a 38-year-old woman with severe form of WG, refractory to standard therapy. Despite the standard treatment with cyclophosphamide and corticosteroids and the addition of infliximab with methotrexate, progression of the disease was observed. Exacerbation affected mainly the lungs and caused the gradual destruction of pulmonary tissue and development of respiratory insufficiency. Rituximab (500 mg) was given intravenously every week in four infusions, causing a partial remission of WG and the arrest of lung deterioration. The following administration of 500 mg was given every two weeks, which induced the remission of WG and enabled the patient to return to her normal activity and work. Such treatment appeared to be successful and prevented severe pulmonary involvement.     

B lymphocyte maturation in Wegener's granulomatosis: a comparative analysis of VH genes from endonasal lesions

BACKGROUND: Anti-neutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3) are highly specific for Wegener's granulomatosis (WG). Evidence for a pivotal role of PR3-ANCA in the induction of vasculitis has been demonstrated. B cell clusters have been observed within endonasal biopsy specimens. OBJECTIVES: To determine whether B cell selection and maturation take place in granulomatous lesions of WG. METHODS: Granulomatous lesions and the immunoglobulin (VH) gene repertoire from nasal tissue of six WG patients-two active and two smouldering localised WG (ANCA negative, restricted to respiratory tract), plus one active and one smouldering PR3-ANCA positive generalised WG-were characterised by immunohistochemistry, polymerase chain reaction, cloning, DNA sequencing and database comparison. RESULTS: B lymphocyte-rich, follicle-like areas were observed proximal to PR3 positive cells and plasma cells in granulomatous lesions; 184 VH genes from these granulomatous lesions were compared with 84 VH genes from peripheral blood of a healthy donor. The mutational pattern of VH genes from active WG resembled memory B cells. Structural homologies of VH genes from granulomatous lesions to PR3-ANCA encoding genes were detected. Significantly more genes (55%, 45%, and 53%, respectively) from active WG compared with the healthy repertoire carried mutations to negatively charged amino acids within the binding site coding regions, favouring affinity to the positively charged PR3. CONCLUSIONS: Selection and affinity maturation of potentially PR3-ANCA producing autoreactive B cells may start in granulomatous lesions, thereby contributing to disease progression from ANCA negative localised to PR3-ANCA positive generalised WG.     

Wegener’s granulomatosis presenting as multiple bilateral renal masses: case report and literature review

Wegener's granulomatosis (WG) is a disease of unknown etiology characterized by necrotizing granulomatous vascularitis. The upper and lower respiratory tract and kidney involvements are very common; however, its presentation as bilateral renal masses is unusual. We report a case of a 59-year-old female patient who presented with multiple bilateral renal masses. The patient presented with sinusal and ocular symptoms suggestive of WG, and positive antineutrophil cytoplasmic antibodies (c-ANCA) with an anti-PR3 pattern. Histopathologic examination of the renal biopsy specimen revealed granulomatous inflammation with vasculitis and fibrinoid necrosis. The patient management, including prednisone and cyclophosphamid, induced a marked improvement of the renal masses. This case illustrates that WG should be considered in the differential diagnosis of renal masses.     

An interdisciplinary approach to the care of patients with Wegener's granulomatosis: long-term outcome in 155 patients

OBJECTIVE: To examine the outcome in 155 consecutive patients with Wegener's granulomatosis (WG) followed up for a median of 7 years. METHODS: Treatment was adapted to the activity and extent of disease, with regular evaluation by an interdisciplinary team accompanied by group education about vasculitis. RESULTS: The estimated median survival time was 21.7 years (95% confidence interval [95% CI] 15.60-27.86). Twenty-two patients died; 19 deaths were attributable to WG and/or its treatment. Significant predictors of survival at diagnosis were age >50 years (hazard ratio [HR] 5.45, 95% CI 1.97-15.02), kidney involvement with impaired renal function (HR 5.42, 95% CI 1.76-16.68), and lung involvement (HR 3.75, 95% CI 1.26-11.16). At some stage, 142 patients received prednisone and cyclophosphamide (CYC), usually as daily CYC plus mesna as uroprotection, 50 patients received trimethoprim/sulfamethoxazole, and 45 received methotrexate. Complete remission was achieved in 83 of the 155 patients. One or more relapses occurred in 99 patients after either complete or partial remission. CYC-induced cystitis and myelodysplastic syndrome occurred in 17 and 11 patients, respectively. A cumulative dose of 100 gm or more of CYC resulted in a 2-fold greater risk of CYC-related morbidity than with lower CYC doses. Serious infections occurred in 41 patients. CONCLUSION: An interdisciplinary approach to the care of 155 WG patients resulted in a median survival of >21 years. Kidney or lung involvement at diagnosis was predictive of a >3-fold higher mortality. Although CYC remains essential in the treatment of WG, it was administered as briefly as possible and under close surveillance to avoid permanent CYC-related morbidity, which can lead to serious therapeutic problems in chronic relapsing WG.     

Substitution of methotrexate for cyclophosphamide in Wegener granulomatosis: a 12-year single-practice experience

We conducted a retrospective review to assess outcomes of therapy in patients with newly diagnosed Wegener granulomatosis (WG) using methotrexate (MTX) for mild to moderate disease and short-term treatment with cyclophosphamide (CYC) followed by MTX for severe disease. Patients with WG were included if their initial plan of therapy and subsequent care were directly supervised by the Cleveland Clinic Center for Vasculitis Care and Research. Severe disease (immediately life-threatening or involving critical organs) was initially treated with CYC and glucocorticoids. Mild to moderate disease was initially treated with MTX and glucocorticoids if serum creatinine was less than 2 mg/dL. Following initial improvement of severe disease, treatment was changed to MTX if serum creatinine was originally less than 2 mg/dL or had diminished to less than 2 mg/dL. Disease activity was determined at each visit and later converted to a Birmingham Vasculitis Activity Score, as modified for Wegener granulomatosis (BVAS/WG). Laboratory monitoring of disease and treatment toxicity was initially weekly and never less than monthly.Eighty-two (32%) of 253 patients with WG referred to the Center for Vasculitis Care and Research met eligibility criteria. Ineligible patients did not have new-onset disease or were not able to be followed principally in our center. Seventy percent of patients (57/82) initially had severe disease and received a short course of CYC for remission induction. In over half of these patients, illness was judged to be severe because of pulmonary hemorrhage; rapidly progressive glomerulonephritis, including need for dialysis; or neurologic abnormalities.All patients improved: remission was achieved in 50% (41/82) of patients within 6 months and in 72% (59/82) within 12 months. Sustained remission (BVAS/WG = 0 for at least 6 consecutive months) was ultimately achieved in 78% (64/82) of patients. Among the 75 (91%) patients who achieved remission of any duration, 45% relapsed within 1 year and 66% relapsed within 2 years following remission. Eighty-two percent of relapsed patients achieved subsequent remissions after additional treatment. About three-quarters of relapses were mild and promptly responded to treatment.Seventeen percent of patients developed serious infections. CYC-associated cystitis or bladder cancer did not occur in any patients. At least 1 form of permanent morbidity from WG alone was noted in 74.0% of patients. Three patients (3.7%) died over a median follow-up period of 4.5 years; no deaths were due to active disease.Although treatment was primarily directed toward achieving clinical improvement and not calculated to achieve marked lymphopenia, patients in whom treatment produced lymphocyte counts of 1000/mm was associated with a hazard ratio for relapse of 3.0, although the latter difference was not statistically significant.In patients with WG, a strategy that limits or avoids CYC therapy produced a frequency of remission comparable to that achieved with conventional CYC protocols, excellent survival, and avoidance of long-term CYC toxicity. However, relapses were common and incremental permanent morbidity occurred in most patients. While not a goal of therapy, when treatment produced marked lymphopenia, prolonged remissions were more likely.     

ANCA-associated vasculitis: diagnostic and therapeutic strategy.

Among small-vessel vasculitides, microscopic polyangiitis (MPA), Wegener's granulomatosis (WG), and allergic granulomatous angiitis (AGA) are known collectively as ANCA-associated vasculitis (AAV) because of the involvement of anti-neutrophil cytoplasmic antibodies (ANCA) as the common pathogenesis. Major target antigens of ANCA associated with vasculitis are myeloperoxidase (MPO) and proteinase 3 (PR3). MPO-ANCA is related to MPA and AGA, and PR3-ANCA is the marker antibody in WG. MPO-ANCA-associated vasculitis is more frequent in Japan, whereas PR3-ANCA-associated vasculitis is more common in Europe and USA. ANCA appears to induce vasculitis by directly activating neutrophils. Therefore, no immunoglobulins or complement components are detected in the vasculitis lesions; hence, AAV is called pauci-immune vasculitis (pauci = few/little). Untreated patients with severe AAV with multi-organ involvement have a poor prognosis, which is improved by combination therapy with cyclophosphamide and high-dose corticosteroid. Randomized controlled trials (RCT) regarding induction and maintenance of remission of AAV indicated that the rate of remission induction by the standard regimen is approximately 90% in 6 months, that maintenance of remission can be achieved with oral azathioprine as well as cyclophosphamide, and that methotrexate can be used only for non-renal mild AAV. As these data were obtained mostly in patients positive for PR3-ANCA, caution must be taken in applying these findings to Japanese patients, most of whom are positive for MPO-ANCA. A prospective study is now underway to clarify the effectiveness of the standard regimen in Japanese patients with MPO-ANCA-associated vasculitis. This article describes the diagnostic criteria and the recent evidence-based therapeutic strategy of AAV.