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Wegener granulomatosis: a case report and update.

Abstract: Wegener granulomatosis (WG) is a systemic disease of unknown etiology characterized by necrotizing granulomatous inflammation, tissue necrosis, and variable degrees of vasculitis in small and medium-sized blood vessels. The classic clinical pattern is a triad involving the upper airways, lungs and kidneys. Ninety percent of patients present with symptoms involving the upper and/or lower airways, and 80% will eventually develop renal disease. WG should be suspected in any patient with progressive or unresponsive sinus disease, glomerulonephritis, pulmonary hemorrhage, mono-neuritis multiplex or unexplained multisystem disease. Before the routine use of glucocorticoids and cyclophosphamide, the one year mortality was 82%. However in 1973, Fauci and Wolf discovered that daily prednisone and cyclophosphamide induced complete remission in 75% of patients. The continued use of prednisone and cyclophosphamide for 1 year past remission leads to marked improvement in more than 90% of patients; however, is also associated with serious toxicities. Depending on the disease severity, current treatments employ induction with short-term cyclophosphamide followed by less toxic agents such as methotrexate to maintain disease remission. Although it is a rare disorder, it is pertinent to internists because it is a multisystem disease that presents in a variety of ways. We describe a 63-year-old white male with WG who presented with progressively worsening headaches, bilateral eye redness, epistaxis, hemoptysis and an unintentional 20 pound weight loss, and review the current treatment recommendations.

Key Words: Wegener granulomatosis, ANCA, cyclophosphamide, vasculitis, methotrexate

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Wegener granulomatosis (WG) is a multisystemic disease of unknown etiology that classically involves clinical disease of the upper airways, lungs and kidneys. Although it is an uncommon condition, it is relevant to internists because it can present in a variety of ways. We describe a 63-year-old white male with WG who presented with progressively worsening headaches, bilateral eye redness, epistaxis, hemoptysis and a 20 pound unintentional weight loss, and review the current treatment recommendations.

Case Report

A 63-year-old white male with a history of hypertension, diabetes mellitus, hyperlipidemia, and ischemic heart disease was admitted with 2 months of progressively worsening headaches, bilateral eye redness, epistaxis, bloody sputum and a 20 pound unintentional weight loss. The patient, a retired construction worker who hunted and skinned coyotes, was well until 2 months before admission. He developed an intermittent frontal headache which became severe, constant, diffuse and associated with retro-orbital discomfort. These headaches did not worsen with coughing or change in position, nor were they relieved by over-the-counter analgesics (acetaminophen, ibuprofen, etc.). He also developed bilateral eye redness with mild photophobia, nasal congestion, mild epistaxis and the "feeling of fullness" in both ears with decreased hearing. One month before admission, he developed a slightly purulent cough streaked with blood, subjective fevers, night sweats, malaise, easy fatigability and anorexia.

His home medications included aspirin, metoprolol, metformin, Monopril, atorvastatin and Fioricet (acetaminophen + butalbital + caffeine). The patient had a 40-pack year smoking history, although he quit 20 years before the admission. He denied excessive alcohol intake, illicit drug use, and use of herbal medicines. He denied travel or exposure to tuberculosis. There was no history of rhinorrhea, otorrhea, excessive lacrimation, change in visual acuity, chest pain, dyspnea, asthma, allergic rhinitis, abdominal pain, hematuria, arthritis, skin lesions or paresthesias. There was no family history of vasculitis or connective tissue disease.

The patient was a well-developed male who appeared ill. On physical examination, his temperature was 101.3[degrees] Fahrenheit, heart rate was 98 per minute, respirations were 18 per minute, blood pressure was 146/80 mm Hg and oxygen saturation was 98% on room air.

He had bilateral conjunctival injection without retinal exudates, rash or lymphadenopathy. His lung, cardiovascular, abdominal, extremity, musculoskeletal and neurologic examinations were normal except for a 1/6 systolic heart murmur.

His laboratory data at admission included a hemoglobin of 11.2 g/dL (normal range 11.3-15.4 g/dL), white blood cell count of 8,400 per [mm.sup.3] (normal range 3.4-9.2), platelet count of 835,000 per [mm.sup.3] (normal range 142-405 thousand), and an erythrocyte sedimentation rate of 113 mm per hour (normal range 0-15). His albumin level was 2 g/dL (normal range 3.5-5.0 g/dL), aspartate aminotransferase 49 (normal range 5-34 u/L), alanine aminotransferase 82 (normal range 5-55 u/L), C-reactive protein 4.72 mg/dL (normal range 0.0-0.5 mg/dL) and his urinalysis contained 10 to 20 white cells, 10 to 20 red cells and cellular casts. In addition, his proteinuria estimated by spot urine protein and creatinine was 0.5 g/24 hours. The blood levels of urea nitrogen, creatinine, electrolytes, glucose, total bilirubin and thyroid stimulating hormone levels were normal.

A computed tomographic (CT) scan of the head with contrast (not shown) was negative for mass effect, hemorrhage, or brain lesion. Posteroanterior and lateral chest x-rays indicated a new, approximately 3 X 4.5 cm ovoid opacity in the lateral right upper lobe. Enhanced CT scan of the thorax demonstrated bilateral poorly marginated pulmonary parenchymal lesions; the largest being 4 cm and pleural-based in the anterior segment of the right upper lobe (Fig. 1). Purified protein derivative skin test and sputum smears and cultures for acid-fast bacilli were negative. Blood and urine cultures were sterile and urine histoplasma antigen, serum brucella, tularemia, leptospira, coccidioidomycosis and blastomycosis antibody tests were negative. Tests for human immunodeficiency virus, hepatitis A, B and C viruses were also negative. A transesophageal echocardiogram was normal. A bronchoscopic examination showed that the airways were normal and that there were no abnormal secretions. The bronchoalveolar lavage fluid had no malignant cells and was sterile.

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Otorhinolaryngology evaluation identified golden crusty lesions in the nasal cavities with friable mucosa. CT scan of the sinuses showed mucoperiosteal thickening of maxillary, sphenoid and frontal sinuses without paranasal sinus fluid levels (Fig. 2). Ophthalmologic evaluation suggested subacute conjunctivitis only. Tests for antinuclear antibodies and antiglomerular basement membrane antibodies were negative but an antineutrophil cytoplasmic antibody was positive at a titer of 1:160 with a cytoplasmic pattern. Antiproteinase-3 antibody level detected by an antigen-specific enzyme-linked immunoassay was 82.1 U (normal range < 5 U).

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A left nasal septum biopsy was nondiagnostic. Therefore, the patient underwent a wedge resection of the right upper lobe lung lesion. The histopathological examination revealed diffuse thickening of alveolar walls that contained moderate numbers of mononuclear cells and occasional eosinophils. Many of the large- and medium-sized arteries were noted to have mononuclear cells, eosinophils and occasional multinucleated giant cells within their walls, mostly concentrated in the intima. A frequent dense fibrosis and chronic inflammation was noted around these vessels and the adjacent bronchioles. The alveoli contained numerous macrophages, some with hemosiderin, type II pneumocytes and occasional multinucleated giant cells. Small areas of organizing pneumonia and necrosis were noted. Periodic acid-Schiff stain, Giemsa and acid-fast bacilli smear failed to reveal fungi or acid-fast organisms. These histologic findings were consistent with those seen in Wegener granulomatosis (Fig. 3-5).

The patient was treated with intravenous (IV) methylprednisolone 1 g daily for 3 days followed by prednisone 60 mg daily and continuous daily cyclophosphamide 50 mg per day. In addition, he was started on trimethoprim-sulfamethoxazole one double-strength tablet three times weekly for Pneumocystis jiroveci pneumonia prophylaxis and discharged home in stable condition.

Discussion

Wegener granulomatosis (WG) is a systemic disease of unknown etiology characterized by necrotizing granulomatous inflammation and variable degrees of vasculitis in small and medium-sized blood vessels. It was first described by Heinz Klinger in 1931, followed by other investigators, including Rossle in 1933, Friedrich Wegener in 1936 and 1939, and Ringertz in 1947. (1-3) It affects about 3 in 100,000 people, with equal sex distribution. (4) Although known to affect all ethnic groups, it has a strong tendency to affect Caucasians (98% of all patients) particularly of northern European descent. The majority of the patients are typically in their fourth or fifth decade (median 41 yr) at the time of diagnosis. Fewer than 15% of cases occur in children.

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The classic clinical pattern is a triad involving the upper airways, lungs and kidneys. (4,5) Constitutional symptoms including fever, fatigue and weight loss are often part of the initial presentation. Upper airway disease, including sinusitis, oral ulcers, gingivitis, otitis media and conductive and/or sensorineural hearing loss is the most common presenting feature of WG. Nasal inflammation may present as nasal pain, stuffiness, rhinitis, epistaxis, or brown or bloody crusts and may lead to septal erosions and perforation and, in extreme cases, to nasal bridge collapse (saddle-nose deformity) (Fig. 6). Subglottic tracheal stenosis resulting from tracheal inflammation is manifested by hoarseness, pain, cough and/or wheezing. However, some patients present with the subacute onset of respiratory stridor, a potentially life-threatening complication that needs urgent otorhinolaryngologist referral.

Pulmonary involvement is one of the cardinal features occurring in 85% of cases of WG. (4) Patients may present with cough, hemoptysis, dyspnea or may be asymptomatic (1/3 of cases). Radiographic studies commonly show bilateral nodular pulmonary infiltrates, and may show thin-walled and thick-walled cavities, and "ground glass" infiltrates from alveolar hemorrhage.

Although only 20% of patients have renal disease on initial presentation, glomerulonephritis eventually develops in about 80% of patients. Microscopic hematuria with dysmorphic red blood cells, red blood cell casts and non-nephrotic range proteinuria are clues to renal involvement which may be initially asymptomatic, but can progress rapidly to renal failure. (4,6,7)

Ocular manifestations have been reported to occur in 56% of patients and almost any ocular structure can be affected. (4,8) Keratitis, conjunctivitis, episcleritis, necrotizing scleritis, uveitis, retro-orbital masses leading to proptosis, and nasolacrimal duct obstruction are seen commonly. Retinal vessel occlusion, optic neuritis and vision loss have been reported in as many as 8% of patients. (4) CT or magnetic resonance imaging of the orbit and sinuses may provide useful anatomic information. About two-thirds of patients develop myalgias, arthralgias or frank arthritis. Skin is involved in 46% of patients, with wart-like lesions particularly around the elbows that can mimic rheumatoid nodules, palpable purpura, leukocytoclastic vasculitis, subcutaneous nodules, ulcers, digital infarctions, gangrene and splinter hemorrhages. Neurologic manifestations including mononeuritis multiplex, cranial or sensory neuropathies, mass lesions and pachymeningitis are seen in approximately 8% of patients. (9) WG may also mimic giant cell arteritis, with prominent headaches and symptoms that resemble polymyalgia rheumatica. Pericarditis and cerebral vasculitis are rare but serious complications affecting less than 5% of patients. (9) Other unusual presentations of WG include salivary gland, gastrointestinal, and cardiac involvement.

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Diagnosis

The diagnosis of Wegener granulomatosis is suggested from the clinical and laboratory findings and from the presence of circulating antineutrophil cytoplasmic antibodies (ANCA). Wegener granulomatosis should be suspected in patients with chronic sinusitis unresponsive to treatment with antibiotics, decongestants, or nasal steroids, pulmonary abnormalities, glomerulonephritis, mononeuritis multiplex resulting in wrist or foot drop, migratory arthralgias or arthritis and unexplained multisystem disease. (10) A thorough history and physical examination with particular attention to eyes, nasal membranes, skin, joints, and nerves can reveal signs of active disease. A chest x-ray can detect an abnormality in one third of the patients with no pulmonary signs or symptoms. The diagnosis is challenging because it is important to distinguish it from other diseases, especially those which worsen when treated with immunosuppressants (infections) (Table 1). While biopsy may not be required for confirmation of the diagnosis if the classic triad of upper airway, pulmonary, and renal disease is present and a test for c-ANCA directed against PR3 is positive, in the majority of cases, biopsy is needed to confirm the diagnosis and begin therapy.

Because the histologic changes may be patchy, the first biopsy may not provide the diagnosis. However, large tissue samples increase the yield. Biopsy of the ear, nose and throat is positive only in 20% of cases, mostly showing nonspecific acute and chronic inflammation. (10) Similarly, skin pathology seen in WG can be found in other diseases; therefore, skin biopsy is usually not sufficient for the diagnosis. Transbronchial biopsy obtained via bronchoscopy provides only a small amount of tissue and is positive only in 7% of cases. (10) The highest yield (91%) comes from open or thoracoscopic biopsy of the pulmonary parenchymal lesions. (10) Characteristic pathologic features include palisading granulomatous inflammation in the lung parenchyma, granulomatous vasculitis and areas of irregular eosinophilic necrosis referred to as 'geographic necrosis'. Since similar histologic findings can also be seen with infection, it is crucial to rule out microorganisms with special stains and cultures. The typical renal lesion of WG is a focal, segmental necrotizing glomerulonephritis with crescent formation but few or no immune deposits; hence the term 'pauci-immune' glomerulonephritis. It is unusual to find granulomatous inflammation in renal biopsies. The renal biopsy findings, though not diagnostic of Wegener, certainly indicate systemic necrotizing vasculitis and are helpful in establishing the diagnosis when other clinical, radiologic and serologic data are compatible with WG.

Laboratory abnormalities may include anemia of chronic disease, thrombocytosis, elevated erythrocyte sedimentation rate and C-reactive protein, active urine sediment with dysmorphic red blood cells and red blood cell casts and non-nephrotic range proteinuria, rise in serum creatinine and positive serum ANCA.

Diagnostic Value of ANCA

Antibodies directed against antigens within the primary granules of neutrophils and monocytes were first linked with WG in 1985. (11) The two methods commonly used to detect ANCA by commercial laboratories are indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA) testing for specific target antigen. IIF on ethanol-fixed neutrophils shows two major immunofluorescent patterns: the cytoplasmic pattern (c-ANCA) and perinuclear pattern (p-ANCA). The two relevant target antigens in ANCA positive vasculitides are proteinase 3 (PR3) and myeloperoxidase (MPO). ANCA with target specificities for PR3 and MPO are called PR3-ANCA and MPO-ANCA, respectively. The antiproteinase 3(PR3) antibodies that produce a cytoplasmic pattern on IIF (c-ANCA) are strongly associated with WG (75-90%). Antibodies directed against myeloperoxidase (MPO) occur in 5 to 20% of WG patients and produce a perinuclear staining pattern (p-ANCA) on IIF. Approximately 90% of patients with active, generalized Wegener granulomatosis are ANCA positive. However, small subsets of patients with active, generalized WG and up to 40% of patients with limited forms of the disease (such as subsets with predominant upper respiratory tract disease and no renal involvement) may be ANCA negative. Thus, the absence of ANCA does not exclude the diagnosis of Wegener granulomatosis. Other vasculitides associated with p-ANCA and c-ANCA include microscopic polyangiitis (MPA), renal-limited vasculitis presenting as pauci-immune crescentic glomerulonephritis, and Churg-Strauss syndrome, as well as other diseases. While p-ANCA is more commonly seen in microscopic polyangiitis, Churg-Strauss syndrome and renal-limited vasculitis, the strongest association is between c-ANCA and Wegener granulomatosis. In certain diseases, c-ANCA or p-ANCA tests can be positive while tests for antiproteinase 3 or antimy-eloperoxidase antigens are negative (Table 2). Therefore a positive ANCA test by IIF should be confirmed by antigen-specific ELISA test. Table 3 shows the prevalence of the ANCAs in connective tissue diseases, the vasculitides, and other diseases. Other diseases reported with ANCA include bronchogenic carcinoma, colon carcinoma, endocarditis, Goodpasture syndrome, HIV, mucovisicidosis, sclerosing cholangitis, and ulcerative colitis (p-ANCA). (12)

ANCA levels vary in an individual patient over time and patients with active disease are more likely to have a positive ANCA test and higher titers of the antibody. However, the correlation with disease activity is not strong enough to be used as a basis of preemptive therapy. In two studies, more than 40% of patients who had a fourfold rise in titer did not relapse. Among those who did relapse, the relapse sometimes occurred more than a year after the increase in the antibody titer. (13,14) Plasma ANCA titers can parallel the course of the vasculitis in individual patients. However, a rise in ANCA titer is not consistently predictive of a disease flare, and another study showed inconsistency between the ANCA titers and disease activity in as many as one-third of patients. (15) Furthermore, many patients in complete clinical remission remain ANCA positive. Hence, it is not recommended to initiate or adjust treatment based solely upon ANCA titers. While the ANCA assay provides an important aid to diagnosis, the cornerstone of diagnosis in WG remains the combination of typical clinical features and histopathological findings on biopsy of the involved organ.

Treatment

Fifty years ago, Wegener granulomatosis was considered a fatal illness due to lack of effective therapy, and patients died as a result of pulmonary or renal failure after a median of 5 months (mortality rate 82% at 1 yr). (16) The use of glucocorticoids, which was first reported in the mid-1960s, prolonged survival time to 12.5 months. (17) In 1973, Fauci and Wolff introduced a regimen that significantly improved outcome: prednisone 1 mg/kg daily; tapered and stopped after 6 to 9 months, plus cyclophosphamide (CYC) 2 mg/kg daily continued for 1 year beyond remission. (6,7) This regimen induced complete remission in 75% of patients, marked improvement in 91%, and survival in 80%. (4) The majority of patients (77%) achieve remission in 3 months and some (16%) may take up to 6 months to achieve remission. (18,43) Unfortunately, at least half of patients who have a successful remission subsequently have a relapse. (4) Moreover, treatment with this regimen causes serious morbidity in 42% of patients (Table 4). To reduce CYC toxicity, various strategies have been tried. Current choices for treatment are based on the classification of patients into the categories of either 'severe' or 'limited' disease. In addition, limiting total cyclophosphamide exposure with the induction of short-term CYC treatment (oral daily or monthly pulse therapy) followed by substitution with less toxic agents to maintain disease remission, has been investigated.

Severe Disease

Severe Wegener constitutes an immediate threat to either the patient's life or the function of a vital organ. Examples of severe disease include rapidly progressive glomerulonephritis with a serum creatinine greater than 1.7 mg/dL at presentation, the presence of red blood cell casts, severe hemoptysis, alveolar hemorrhage, intestinal ischemia, cerebral infarction due to vasculitis, orbital pseudotumor, necrotizing scleritis and rapidly progressive vasculitic neuropathy. These patients should be treated with oral cyclophosphamide 2 mg/kg daily and prednisone 1 mg/kg daily. The prednisone is tapered and discontinued over 6 to 9 months. Continuation of CYC for one full year after remission, defined by an absence of active disease in any organ system, is the strategy used by the Fauci and Wolff regimen. As noted earlier, although this treatment protocol is a major breakthrough in the management of WG, it is associated with substantial toxicity. In an attempt to reduce CYC toxicity, methotrexate (MTX) and azathioprine (AZA) have been used in randomized trials for maintaining remission.

Methotrexate. In a randomized, open-label study in 42 patients with WG, methotrexate (MTX) was substituted for CYC after remission was induced. The rate of relapse (52%) was similar to that typically seen with CYC maintenance, and the rate of serious toxicity was 10%. (19,20) In another study of 71 patients with WG treated with MTX after successful induction with CYC, only 26 relapses (36%) were seen after a mean time of 19 months; however, there was an unexpectedly high rate of renal involvement in 16 of 26 relapses (61%). (21) An unblinded randomized controlled trial (Non-Renal Wegner Granulomatosis Treated Alternatively with Methotrexate [NORAM]) compared methotrexate and cyclophosphamide for both induction and remission of ANCA-associated vasculitis. (22) The trial enrolled 89 patients with newly diagnosed Wegener granulomatosis (94%) and 6 with microscopic polyangiitis. Those with severe systemic disease as manifested by a serum creatinine greater than 1.7 mg/dL, red blood cell casts, severe hemoptysis, cerebral infarction due to vasculitis, orbital pseudotumor, or rapidly progressive neuropathy were excluded. The patients were assigned to methotrexate (20-25 mg per week orally) or cyclophosphamide (2 mg/kg per day orally); all received prednisolone. Therapy was gradually tapered and withdrawn by 12 months. At 6 months, 89.8 and 93.5% of patients in the methotrexate and cyclophosphamide arms, respectively, achieved remission. At follow-up at 18 months (6 mo after complete discontinuation of therapy) the relapse rate was high in both groups, but was significantly higher in the methotrexate group (69.5 versus 46.5% with cyclophosphamide), suggesting that some form of immunosuppressive treatment should be continued beyond 12 months for the maintenance of remission. The side effects of MTX are bone marrow suppression, pneumonitis, hepatic fibrosis, mucositis, and nausea. It is contraindicated in patients with renal insufficiency (creatinine concentration > 2.0 mg/dL), hepatic disease (or alcoholism) or severe chronic pulmonary impairment. MTX is a structural analog of folic acid that can competitively inhibit the binding of dihydrofolic acid to the enzyme dihydrofolate reductase. Folic acid 1 to 2 mg/d or folinic acid 2.5 to 5 mg per week should be given concurrently to reduce potential toxicity. Thus, MTX may be reasonably effective in maintaining a remission in patients who are initially treated with cyclophosphamide with relapse rates comparable to CYC maintenance. Treatment with MTX as an induction and maintenance agent is associated with higher relapse rates in patients with severe disease manifestations and is not recommended in this setting.

Azathioprine. Azathioprine, a purine antimetabolite, can be used in the setting of renal insufficiency. In a recent study conducted by the European Vasculitis Study Group (EUVAS), 155 patients with generalized ANCA-associated vasculitis (61% had WG) were initially treated with prednisone and CYC, and those who went into remission after 3 to 6 months were randomized either to continue CYC for a total of 12 months or to switch to azathioprine. After 12 months, the CYC group was also switched to azathioprine and followed for a further 6 months. Rates of relapse during the 18-month period were similar with both therapies (15.5 versus 13.7% in the azathioprine and cyclophosphamide groups, respectively (CYCAZAREM). (18) The French vasculitis study group recently presented preliminary data from a prospective multi-center randomized trial comparing azathioprine (2 mg/kg/d) with methotrexate (0.3 mg/kg/wk) for remission maintenance in 114 patients with WG or MPA after the successful induction of remission with cyclophosphamide pulses, suggesting that both agents are similarly effective for the maintenance of remission. (23) A trend toward a higher frequency of treatment-related adverse events was noted in the methotrexate arm; however, the difference was not statistically significant. Serious side effects of azathioprine include bone marrow suppression, infection, severe allergic reaction, gastrointestinal intolerance, and in transplant recipients, a 1 to 2% rate of leukemia and lymphoma. The results of these trials (18,19,20,23) suggest that cyclophosphamide exposure should be limited to phases of active disease, and should be replaced by less toxic agents as soon as remission is accomplished.

Intermittent IV cyclophosphamide. Another strategy to reduce the total exposure to cyclophosphamide is by the administration of intermittent IV pulses. The use of intermittent IV cyclophosphamide (monthly) in WG is associated with higher rates of relapse. (24-26) A meta-analysis published in 2001 based upon three prospective randomized studies of a total of 143 patients found that IV and oral cyclophosphamide had similar efficacy in terms of inducing remission. (27) IV therapy was associated with less toxicity but a trend toward a higher relapse rate. An ongoing large randomized controlled trial from Europe (CYCLOPS) including patients with Wegener granulomatosis and microscopic polyangiitis is directly comparing pulsed versus oral cyclophosphamide. (28) A preliminary survival analysis was recently presented (29) and showed that the disease-free periods did not differ significantly between patients receiving oral compared with pulse cyclophosphamide therapy. Until complete data from CYCLOPS is published, including a subgroup analysis for patients with WG only, it seems premature to conclude that intermittent IV cyclophosphamide is as effective as daily oral therapy.

Leflunomide. Leflunomide inhibits responses of activated T and B cells by inhibiting pyrimidine synthesis. In an open-label trial involving 20 patients with WG, leflunomide 30 mg/d was substituted for cyclophosphamide after successful induction. During a median follow up of 21 months, one major relapse required treatment with cyclophosphamide and 8 minor relapses were successfully treated by increasing the leflunomide dose to 40 mg a day. (30) In a multicenter randomized controlled trial (LEM) by the German rheumatology network, leflunomide 30 mg/d was compared with methotrexate 20 mg/wk in patients with WG after induction of remission with cyclophosphamide. Higher rates of severe relapses in the methotrexate group (n = 7) compared with leflunomide (n = 1) were noted, suggesting that leflunomide is promising for maintenance therapy and warrants further studies. (31)

Mycophenolate mofetil. Mycophenolate mofetil was well tolerated in 2 small open-label trials to maintain remission in WG patients after initial treatment with CYC. (32,33) The relapse rate was 43% in one study. (21)

Limited disease

Limited WG consists of disease manifestations that are not organ- or life-threatening in the short term. These include upper airway disease, conductive hearing loss, skin lesions, arthritis/arthralgias, pulmonary nodules and infiltrates that do not significantly compromise lung function. This spectrum of disease has shown good response to the combination of MTX (up to 25 mg/wk) and corticosteroids, (4,34,35) with 75% of patients achieving complete remissions. Sneller et al, (34) in an open-label trial, treated 42 patients who had active but not severe disease with combined methotrexate (20-25 mg once a week) and prednisone (1 mg/kg daily with taper) and reported rates of remission of 79%, survival of 93%, relapse of 58%, and serious toxicity of 17%.

Role Of Trimethoprim-sulfamethoxazole In Wegener Granulomatosis

It is suggested that trimethoprim-sulfamethoxazole (T/S) may help patients with upper airway disease. It is uncertain whether the benefit is due to its antimicrobial action which decreases secondary bacterial sinusitis which may be difficult to distinguish from WG. It can be considered for the treatment of isolated upper airway disease, but should never be used alone to treat major organ disease. These patients should be closely monitored for the emergence of other disease features. Stegeman et al randomized 81 patients who were in remission to receive either T/S or placebo, and found that while the recurrence rate of nasal and upper airway lesions was lower with drug therapy, there was no difference in the relapse rate of major organ disease. (36) T/S should, however, be given to patients on corticosteroids and cytotoxic therapy for the prevention of Pneumocystis jiroveci pneumonia (previously called Pneumocystis carinii pneumonia, which occurs in 10% of patients receiving induction therapy and has a 35% mortality rate) at a dose of one double-strength tablet 3 times per week. For patients who are allergic to sulfa drugs, either dapsone, inhaled pentamidine or atovaquone can be used for Pneumocystis jiroveci pneumonia prophylaxis.

Alternative Treatment Regimens

Several other therapies, such as plasmapheresis, IV immunoglobulin, cyclosporin, chlorambucil, and 15-desoxyspergualin have been tried in case reports and small series with variable results. These therapies should be considered only when standard medications have failed or are contraindicated because of concerns about toxicity.

Plasmapheresis

There is no overall benefit from plasmapheresis in patients with Wegener granulomatosis or related disorders. However, those with concurrent anti-GBM antibody disease, severe pulmonary hemorrhage, and those who present with dialysis-dependent renal failure appear to benefit from plasmapheresis. (37-39) This strategy is based upon the theoretical benefit of removing potentially pathogenic ANCA antibodies with plasma exchange, and the observed efficacy of plasmapheresis in patients with pulmonary hemorrhage due to anti-GBM antibody disease. Preliminary results from the MEPEX randomized controlled trial appear to confirm a benefit to plasmapheresis in addition to standard immunosuppression in patients with significant ANCA-associated renal disease. In this trial, over 150 patients with severe renal disease (serum creatinine above 5.7 mg/dL) were treated with either plasma exchange or IV methylprednisolone, in addition to oral steroids and cyclophosphamide. At three months of follow up, renal recovery from dialysis was approximately 70% with plasmapheresis compared with 50% with standard therapy. (37) The overall high mortality reported in this study possibly reflects severe disease in this patient subgroup. The final results of the MEPEX trial are expected in 2006.

15-deoxyspergualin

15-deoxyspergualin is a synthetic analog of spergualin, a natural product of the bacterium Bacillus lactosporus, which has immunosuppressive properties and is licensed in Japan for the treatment of recurrent renal transplant rejection. In an open-label study of 20 patients with refractory ANCA-associated vasculitis (19 had WG), a clinical response was seen in 70% of patients, and 6 of 20 patients achieved complete remission. (40) A large multicenter phase II trial in refractory WG is in progress.

Tumor Necrosis Factor Alpha Inhibitors In Wegener Granulomatosis

Studies have shown that tumor necrosis factor alpha (TNF[alpha]) plays an important role in the pathogenesis of Wegener granulomatosis.

Infliximab. Infliximab is a chimeric monoclonal antibody that binds to TNF[alpha], and has been studied in new and refractory patients with systemic vasculitis including Wegener granulomatosis in small clinical trials. Remission was seen in 81% of patients. Sustained remission for up to a year was seen in 85% of the patients who achieved initial remission. Relapse rate was at least 12%. (41-42)

Etanercept. Etanercept is a fusion protein that binds to soluble TNF[alpha] and prevents it from binding to receptors on cells. In the randomized, double-blind Wegener's Granulomatosis Etanercept Trial (WGET), 180 patients were treated with standard therapy plus etanercept or placebo. There was no difference between the etanercept and placebo groups in the rates of sustained remission, time to sustained remission, or numbers of disease flares. (43) Based on the findings of this study, the use of etanercept in either the induction or the maintenance of remission in patients with Wegener granulomatosis can not be supported.

Rituximab. Rituximab is a chimeric monoclonal antibody that depletes B cells by binding to the CD-20 antigen found on their surface. B cells are the precursors of plasma cells that produce antibodies such as ANCA and cytokines, and interact with T-cells and function as antigen-presenting cells and hence, are potential targets in chronic inflammatory and autoimmune diseases. Rituximab has shown promising results in refractory WG patients who achieved temporary remission. (44-45) A larger trial is ongoing to determine if rituximab can induce remission as effectively as cyclophosphamide.

Nonmedical Management of Upper Airway Involvement

Stenotic lesions of the tracheobronchial tree can cause a variety of problems and can lead to respiratory failure or postobstructive pneumonia. Treatment options for these problems include airway dilation with or without stenting. Subglottic stenosis is frequently unresponsive to systemic immunosuppressive therapy, largely because of fibrotic scarring following inflammation. It is treated with mechanical dilation of the trachea and stent placement and/or intratracheal injection of a long-acting glucocorticoid. Tracheostomy may be necessary in some patients before the dilation of a severe subglottic stenosis. In patients with nasosinus disease, daily saline irrigations help to minimize accumulation of secretions and crusts and reduce the incidence of secondary infections. Reconstructive surgery using grafts prepared from a patient's costal or auricular cartilage, iliac or other bone or dura may provide a functional airway and can restore a more nearly normal-appearing nose.

Cyclophosphamide Refractory Disease

True cyclophosphamide resistance is rare in Wegener granulomatosis, but does occur. In approximately 10% of cases, the administration of cyclophosphamide and corticosteroids alone is insufficient to control disease activity completely. In the management of the patient suspected of being cyclophosphamide-resistant, it is crucial to ensure that the clinical abnormalities are not due to drug toxicity, inadequate dosing, noncompliance, chronic inactive disease, infection, and/or pathogenic processes other than ongoing inflammation. A repeat tissue biopsy may be required to accurately assess the underlying cause of an apparent resistance. Patients with orbital pseudotumor and subglottic stenosis (as noted earlier) may be relatively unresponsive to immunosuppressive therapy and may respond best to local therapies such as triamcinolone injections and dilation procedures. Patients who appear to be failing initial therapy with monthly IV pulse cyclophosphamide sometimes respond better to daily oral therapy. An alternative agent should be tried if optimal CYC dosing is ultimately ineffective or not tolerated.

Monitoring and Treatment of Relapse

Although 90% of the patients with WG achieve remission with treatment, more than half experience a relapse at periods ranging from 3 months to 16 years, affecting same or different organs than the initial presentation. Risk factors for relapse include rapid tapering or discontinuation of glucocorticoids, prior flares, persistent ANCA positivity during a period of clinical remission, ANCA positivity after a period of ANCA negativity, or rising ANCA titers. In a recent study that examined predictors of treatment resistance and relapse in subjects with ANCA-associated small-vessel vasculitis, researchers found that patients who were female, black, or had severe kidney disease, had an increased risk for treatment resistance. The data also showed that lung disease, upper respiratory tract disease, and antiproteinase-3 seropositivity were associated with an increased risk for relapse. (46) Patients with rising ANCA titers should be monitored more closely for early signs of clinical relapse. It is also important to confirm that the recurrent symptoms or signs are due to active Wegener granulomatosis. This may be straightforward if there is clear evidence of new active inflammation manifested by a new rise in the serum creatinine concentration, and recurrence of red blood cells and red cell casts in the urine sediment; however, tissue biopsy may be required in some patients to verify recurrent vasculitis rather than, for example, pulmonary infection or nonimmunologic progression of renal disease from glomerular ischemia and subsequent glomerulosclerosis during the healing phase or from nephron loss from glomerular hypertrophy and intraglomerular hypertension in the remaining functioning glomeruli. The treatment of recurrent vasculitis is largely similar to that of the primary disease; however, if a relapse occurs while the patient is on maintenance therapy, a different drug should be considered.

Management of Patients with End-stage Renal Failure and Transplantation

Between 55 to 90% of patients who present with renal failure severe enough to require dialysis during the acute phase of the disease will recover enough function to come off dialysis; (47) however, in whom there is no evidence of return of renal function after two to three months of immunosuppressive drug therapy, excessive therapy in the absence of active extrarenal disease should be avoided to minimize treatment-related morbidity and mortality.

The optimal treatment of patients with end-stage renal failure who require chronic dialysis and/or renal transplantation is not known. Relapses occur at similar rates as in those who do not require chronic dialysis. Because of increased risk of infection and severe bone marrow suppression in this patient population, cyclophosphamide must be used with great caution. In general, the treatment of chronic dialysis patients with Wegener granulomatosis is the same as for those who do not require maintenance dialysis, and the therapeutic regimen is based on the severity of disease manifestation. If transplantation is considered, it should be delayed for at least six months from the time of initial presentation or most recent relapse. Although less common, disease flares after renal transplantation (including recurrences in the allograft) have been reported among patients with ANCA-associated vasculitis and usually require the use of CYC, based on the severity of the organ involvement.

Wegener Granulomatosis in Pregnancy

The peak incidence of WG occurs in the fourth and fifth decades, and thus is rarely diagnosed in women of childbearing age and is uncommonly encountered during pregnancy. There are only a few reports of de novo WG or relapse in a known patient during pregnancy. Three of the seven cases that were initially diagnosed during pregnancy were treated with cyclophosphamide (after completion of the first trimester) and normal deliveries eventually resulted. (48-50) Therapeutic abortion was performed in two cases followed by treatment with prednisone and cyclophosphamide. (51-52) Treatment with azathioprine resulted in maternal and fetal death in another case. (53) Although conventional treatment with steroids and CYC controls disease activity in more than 90% of patients, the associated teratogenicity of such a regimen warrants careful consideration. Women with significant active disease during pregnancy can undergo therapeutic abortion before cyclophosphamide, particularly in the first trimester. There are few reports of successful remission induction with the use of IV immunoglobulin and steroids during pregnancy. (54) As in nonpregnant patients, pregnant patients with limited disease can be treated with steroids and azathioprine.

Morbidity and Mortality

The morbidity and mortality associated with WG results from the disease itself or its treatment. As noted earlier, after achieving successful remission, up to 50% of patients relapse, leading to more organ damage as well as requiring repeat treatment. Nearly 90% of patients develop clinically important disease-related morbidity despite adequate therapy. Forty-two percent of patients eventually develop permanent renal insufficiency; 20 to 25% progress to end-stage renal disease. Common extrarenal complications include hearing loss (35%), cosmetic and functional nasal deformities (28%), tracheal stenosis (13%), and venous thrombotic events (29%). Serious treatment-related morbidity occurs in 42% of patients treated with long-term prednisone and cyclophosphamide. To date, 6% of patients treated with cyclophosphamide are reported to have transitional cell carcinoma of the bladder and some estimate that this figure may rise to 16% after 15 years of exposure to the drug. (55) Death related to WG or its treatment occurred in 12 and 13% of patients in two large series. (4,56) The major causes of death in Wegener granulomatosis are renal and respiratory failure, infection, malignancy, and less often, from heart failure and myocardial infarction.

Conclusion

Wegener granulomatosis is a multisystem disease with diverse presentation. The regimen of prednisone and cyclophosphamide for one year beyond induction of remission leads to marked improvement in more than 90% of patients, however, with serious toxicities. Current treatment standards employ induction with short-term treatment with daily cyclophosphamide followed by substitution with less toxic agents (mainly methotrexate or azathioprine) to maintain disease remission in a severe disease category, and less toxic agents in limited disease with equal efficacy and much less toxicity. Despite recent progress, the prevention of relapses and treatment of refractory cases (approximately 10%) remain the greatest challenges in the treatment of Wegener granulomatosis. Further investigations are needed with agents that directly target specific immunologic components to reduce drug toxicity, prevent relapse, and induce long-term remission of Wegener granulomatosis.

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Eisha Mubashir, MD, M. Mubashir Ahmed, MD, Samina Hayat, MD, Shahnila Latif, MD, Maureen Heldmann, MD, and Seth Mark Berney, MD

From the Center of Excellence for Arthritis and Rheumatology and Section of Rheumatology, and the Departments of Medicine, Pathology and Radiology, Louisiana State University Health Sciences Center, Shreveport, LA.

Reprint requests to Dr. M. Mubashir Ahmed, 1501 Kings Highway, Shreveport, LA. Email: mahmed3@lsuhsc.edu

First two authors contributed equally.

Accepted April 13, 2006.

RELATED ARTICLE: Key Points

* Wegener granulomatosis is a vasculitis of the small and medium-sized blood vessels that presents in a variety of ways.

* It should be suspected in any patient with progressive or unresponsive sinus disease, glomerulonephritis, pulmonary hemorrhage, mononeuritis multiplex or unexplained multisystemic disease.

* Biopsy is needed to confirm the diagnosis and begin therapy in the majority of cases.

* Antineutrophil cytoplasmic antibody titers are not reliable indicators of disease activity.

* Current treatment standards employ induction with short-term treatment with daily cyclophosphamide followed by substitution to less toxic agents to maintain disease remission in severe disease categories, and use less toxic agents in limited disease with equal efficacy and much less toxicity.
Table 1. Differential diagnosis of Wegener granulomatosis

Infection
Neoplasms (especially lymphoproliferative disease)
Connective tissue disease (eg, systemic lupus erythematosus, rheumatoid
 arthritis)
Other granulomatous disease (eg, sarcoidosis)
Other causes of glomerulonephritis (eg, antiglomerular basement membrane
 disease, poststreptococcal nephritis)

Reprinted with permission from Langford CA. Update on Wegener
granulomatosis. Cleve Clin J Med 2005;72:689-697.

Table 2. A positive antineutrophil cytoplasmic antibodies (ANCA) by
immunofluorescence should be confirmed by antigen-specific ELISA

Test results Associated conditions

Positive c-ANCA by IIF, and positive Wegener granulomatosis
 antiproteinase 3 by ELISA Microscopic polyangiitis
 Churg-Strauss syndrome
Positive c-ANCA by IIF, and negative Mostly infection in case reports
 antiproteinase 3 by ELISA
Positive p-ANCA by IIF, and positive Wegener granulomatosis
 antimyeloperoxidase by ELISA Microscopic polyangiitis
 Churg-Strauss syndrome
 Idiopathic crescentic
 glomerulonephritis
Positive p-ANCA by IIF, and negative Inflammatory bowel disease
 antimyeloperoxidase by ELISA Other autoimmune disease
 Infection
 Medications

c-ANCA, cytoplasmic pattern of antineutrophilic cytoplasmic antibodies;
IIF, indirect immunofluorescence; ELISA, enzyme-linked immunosorbent
assay; p-ANCA, perinuclear pattern of antineutrophilic cytoplasmic
antibodies.
Reprinted with permission from Langford CA. Update on Wegener
granulomatosis. Cleve Clin J Med 2005;72:689-697.

Table 3. Prevalence of antineutrophilic cytoplasmic antibodies in
connective tissue disease and vasculitis

 c-ANCA p-ANCA

Connective tissue disease
 Rheumatoid arthritis 0/241 6/241
 Psoriatic arthritis 0/32 5/32
 SLE 0/109 4/109
 Felty syndrome 0/14 3/14
 Polymyositis 0/10 1/10
 Ankylosing spondylitis 0/50 0/50
 MCTD 0/32 0/32
 Scleroderma 0/43 0/43
 Reiter syndrome 0/29 0/29
 SLE vasculitis 0/21 0/21
Vasculitis
 Wegener granulomatosis 295/383 20/383
 Polyarteritis nodosa 14/49 2/49
 Unclassified vasculitis 8/110 9/110
 Churg-Strauss syndrome 4/13 1/13
 Polymyalgia rheumatica 0/62 5/62
 Temporal arteritis 0/24 2/24
 Behcet syndrome 0/21 0/21
 Henoch-Schonlein purpura 0/18 0/18
 Takayasu arteritis 0/3 0/3
Other*: Bronchogenic carcinoma, colon carcinoma, endocarditis,
Goodpasture syndrome, HIV, mucoviscidosis, sclerosing cholangitis, and
ulcerative colitis (p-ANCA)

c-ANCA, cytoplasmic staining; MCTD, mixed connective tissue disease;
p-ANCA, perinuclear staining; SLE, systemic lupus erythematosus.
*Data were compiled from case reports.
Reprinted with permission from Gross WL, Schmitt WH, Csernok E.
Antineutrophil cytoplasmic autoantibody-associated diseases: a
rheumatologist's perspective. Am J Kidney Dis 1991;18:175-179.

Table 4. Complications of prednisone plus cyclophosphamide treatment for
Wegener granulomatosis

Complication % of patients

Sterility > 50
Major infection 46
Cystitis 43
Cataracts 21
Fractures 11
Bladder cancer 3
Avascular necrosis 3
Lymphoma 2
Myelodysplasia 2

Data from Hoffman GS, Kerr GS, Leavitt RY, et al Wegener granulomatosis:
an analysis of 158 patients. Ann Intern Med 1992;116:488-498.
Reprinted with permission from Langford CA. Update on Wegener
granulomatosis. Cleve Clin J Med 2005;72:689-697.
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