Generalized or severe disease generally requires aggressive therapy. Since introduced by Fauci et al in the 1970s, oral cyclophosphamide in combination with high-dose glucocorticoids (ie, prednisone 1mg/kg/day) has been the criterion standard for induction of remission in AAV.
Eventually, intravenous cyclophosphamide was investigated as an alternative to oral cyclophosphamide in an effort to decrease treatment-associated toxicities, and, while the emphasis has been placed on optimizing treatment by minimizing exposure to cyclophosphamide and seeking alternative comparable therapies, the combination of cyclophosphamide (intravenous or oral) and glucocorticoids remained the recommended therapy for induction of remission in generalized/severe GPA for years. 
In 2011, however, the US Food and Drug Administration (FDA) approved the use of rituximab (a monoclonal antibody that targets B cells), in combination with glucocorticoids, as an alternative to cyclophosphamide for induction of remission in AAV (GPA and microscopic polyangiitis).
Cyclophosphamide can be given either by a daily oral route or intermittent intravenous route in combination with high-dose glucocorticoids. The recommended daily oral dose of cyclophosphamide is 2 mg/kg/day (not to exceed 200 mg/day). Pulsed (intravenous) cyclophosphamide (15 mg/kg every 2 weeks for the first 3 pulses, then every 3 weeks for the next 3-6 pulses) is an alternative to daily oral cyclophosphamide; it results in less cumulative exposure to cyclophosphamide and, therefore, theoretically causes fewer adverse effects.
Pulsed cyclophosphamide has been shown to be as effective as daily oral cyclophosphamide in inducing remission.  A study found, however, that there was a trend toward higher relapse rates with pulsed cyclophosphamide later in the maintenance phase of treatment. Nonetheless, this study was not intended to detect a difference between the 2 groups; more studies are needed. [5, 59]
Cyclophosphamide doses are reduced as needed for renal function and age. Cyclophosphamide therapy is usually continued until significant disease improvement or remission occurs, typically 3-6 months. The patient is then transitioned to a less toxic medication for maintenance of remission. Cyclophosphamide toxicity manifests as hemorrhagic cystitis (in 15-43% of cases after oral treatment), bladder cancer (30-fold increased incidence as compared with controls), increased risk of other malignancies, cytopenias, infertility, and opportunistic infections, typically occurring during cyclophosphamide-induced leukopenia.
Patients receiving pulse cyclophosphamide should also be given oral or intravenous 2-mercaptoethanesulfonate sodium (Mesna), which binds to acrolein, the toxic metabolite of cyclophosphamide responsible for hemorrhagic cystitis. Once bound to acrolein, the toxic metabolite can no longer bind to cell-surface proteins in the bladder, limiting the risk of local cyclophosphamide-associated toxicity. Mesna may also be beneficial in patients receiving continuous oral cyclophosphamide.
The recommended IV dosing of mesna is equal to 20% (weight/weight) of the IV cyclophosphamide dose, divided into 3 equal doses. The first dose of IV mesna is administered 15-30 minutes prior to IV cyclophosphamide. The 2 remaining doses are then given 4 hours and 8 hours following IV cyclophosphamide. Peak urinary concentrations with IV mesna dosing occur in 1 hour. 
The dose of oral mesna should be equal to 40% of the cyclophosphamide doses (oral or IV), based on a 50% oral bioavailability, and divided into 3 equal doses. The first dose of oral mesna should be given 2 hours before cyclophosphamide (oral or IV). The second and third oral doses can still be given 4 hours and 8 hours after cyclophosphamide, as with IV mesna dosing. The bioavailability is not affected by food intake, and peak urinary concentrations occur in 3 hours. 
Frequent urinalyses should be performed while the patient is receiving either intravenous or oral cyclophosphamide, and should also be performed throughout the patient’s life to screen for the development of bladder cancer. Urine cytology can also be considered. Additionally, complete blood count (CBC) monitoring should be performed every 1-2 weeks throughout the course of daily oral cyclophosphamide to detect and prevent leukopenia. CBC counts should be performed on day 10 and 14 after each intravenous pulse and immediately before the next intravenous dose as well.
Finally, infertility may be of great concern to both male and female patients who desire future childbearing. A study of 42 women in the WGET trial, aged 14 to 46 years (mean age 35 years), found that daily oral cyclophosphamide, even when administered for less than 6 months, was associated with diminished ovarian reserve, as evidenced by decreased anti-Müllerian hormone (AMH).  If there is time prior to the initiation of cyclophosphamide therapy, men may wish to pursue sperm banking and women of childbearing age should consider oral contraceptives and gonadotropin-releasing hormone analogues (ie, leuprolide) to help preserve fertility. 
Rituximab combined with high-dose glucocorticoids represents an alternative to cyclophosphamide for induction of remission in GPA; it is the first treatment ever approved by the FDA for AAV. 
The evidence for this approval came from the Stone et al's RAVE (Rituximab in Antineutrophil Cytoplasmic Antibody ̶ Associated Vasculitis) trial.  Rituximab is a chimeric monoclonal anti-CD20 IgG1 antibody that induces apoptosis of B cells, with the exception of plasma cells and pre-B cells. Infusion of rituximab typically causes a 6-month depletion of circulating B cells and therefore may decrease the production of autoantibodies such as ANCAs.
The RAVE trial, which showed the noninferiority of rituximab compared with the cyclophosphamide control group, suggested that rituximab may be better for induction of relapsing disease. There were no significant differences between the treatment groups in the number or severity of adverse events.
The RITUXVAS trial, by The European Vasculitis Study Group (EUVAS), examined the use of rituximab in severe GPA with renal involvement in older patients and found rituximab was not superior to cyclophosphamide and was associated with a similar number of adverse events, although the rituximab group also received cyclophosphamide.  Both studies confirmed the efficacy and superiority of rituximab over cyclophosphamide in reducing ANCA positivity. 
Further studies may address whether rituximab is effective for limited disease, which is typically associated with more granulomatous features than vasculitic ones. Rituximab is typically thought to be more effective in the vasculitic phase rather than the granulomatous phase, but small studies have shown good results even in limited disease. [65, 66]
Adverse effects associated with rituximab include infusion reactions, mucocutaneous reactions, increased risk of infections (to include opportunistic infections such as progressive multifocal leukoencephalopathy), cytopenias, and malignancy. In rheumatoid arthritis patients, hypogammaglobulinemia before rituximab seemed to be more closely associated with risk of infection than during or after rituximab.  Whether rituximab-associated hypogammaglobulinemia is associated with risk of infection in AAV remains to be determined, although a retrospective study did not show an association.  Late-onset neutropenia has also been associated with rituximab in GPA; appropriate laboratory monitoring should be considered. 
Historically, glucocorticoid monotherapy prolonged median survival in GPA by only 7.5 months. There have been no clinical trials evaluating the role or dosing of glucocorticoids in AAV, but every clinical trial has used glucocorticoids in combination with other immunosuppressants. Thus, corticosteroids remain the cornerstone of treatment for AAV, especially for the induction of remission. 
One meta-analysis sought to answer the question of comparing glucocorticoid regimens in AAV. The authors found that studies with a longer course of glucocorticoids (ie, nonzero target dose) were associated with fewer relapses. Another retrospective study by McGregor et al found that once remission is reached for at least 1 month, glucocorticoid therapy beyond 6 months was associated with a greater risk of infection without a significantly reduced risk of relapse.  Further studies are still needed to define the best regimen with respect to glucocorticoid dose and duration of therapy. 
Glucocorticoids are usually given orally. If a rapid response is needed, however, such as in the case of rapidly progressive glomerulonephritis and/or alveolar hemorrhage, intravenous pulse methylprednisolone (0.5-1 g/day for 3 consecutive days) can be used and then followed by oral prednisone.
Initial high-dose glucocorticoids (1 mg/kg/day) should be continued for at least 1 month. Doses should not be reduced to less than 15 mg/day within the first 3 months. The dose should then be slowly tapered to a maintenance dose of 10 mg/day or less during remission.  Methods to prevent glucocorticoid-induced osteoporosis should be followed.
Pneumocystis pneumonia has an annual incidence of 1% but is a potentially deadly complication of immunosuppressive therapy in patients with GPA, especially with prolonged lymphocytopenia.
Prophylaxis against Pneumocystisjiroveci pneumonia should be instituted while patients are taking cyclophosphamide and corticosteroids (particularly high-dose corticosteroids). Typically, trimethopim-sulfamethoxazole (TMP-SMZ) at 160/800 mg 3 times weekly is used. If the patient has a sulfa allergy, dapsone 100 mg daily can be substituted. Pneumocystis prophylaxis has also been recommended during rituximab treatment and for at least 6 months following the last rituximab infusion.
Reports have examined TMP-SMZ use in isolation without other immunosuppressive medications in the induction phase of treatment in patients with very limited disease; however, prospective trials of TMP-SMZ as monotherapy have been disappointing.
In adults, TMP-SMZ has been shown to prevent relapses of GPA in remission.  This action of TMP-SMZ may be due to anti-inflammatory action or decrease in infections, particularly respiratory tract infections.
Plasma exchange may be considered in patients with rapidly progressive renal disease (serum creatinine level >5.65mg/dL) in order to preserve renal function.  Additionally, plasma exchange, along with aggressive immunotherapy, may be helpful in DAH.  Plasma exchange is used with daily oral cyclophosphamide and glucocorticoids, usually pulse methylprednisolone. Plasma exchange has not been shown to improve overall survival rates or relapse rates but has been associated with improved long-term survival, free of hemodialysis. [72, 73]
Jayne et al reported improved renal outcomes in adults with GPA or microscopic polyangiitis with severe renal failure (creatinine >5.8 mg/dL) who were treated with plasma exchange, when compared with intravenous methylprednisolone.  The patients in this multicenter European trial were also treated with oral prednisone and oral cyclophosphamide at the time of enrollment.
The proposed mechanism of action of plasma exchange in AAV includes removal of pathologic circulating factors (eg, ANCA, activated lymphocytes), removal of excess physiologic factors (eg, complement, coagulation factors, cytokines/chemokines), replacement of deficient plasma factors, and other, less well-defined mechanisms. Potential adverse events associated with plasma exchange include electrolyte disturbances, anaphylaxis, hemorrhage, and transfusion-related lung injury. 
Localized, milder disease generally requires less aggressive therapy. A combination of methotrexate (oral or subcutaneous) and glucocorticoids can be considered as a less-toxic alternative to cyclophosphamide for the induction of remission of non–organ-threatening or non–life-threatening GPA. 
Methotrexate (20-25 mg/wk, oral or subcutaneous) can be used in patients with normal renal function. It may take longer to reach remission with methotrexate than with cyclophosphamide, but methotrexate has been shown to be equal to cyclophosphamide in terms of its capacity to induce remission in early AAV.  Daily folic acid 1 mg/day is recommended to lessen some of the adverse effects of methotrexate.
Azathioprine for induction of remission has not been shown to be effective. 
A 47-year-old Caucasian woman came to the emergency department at Baylor University Medical Center complaining of a 3-week history of sinus congestion and drainage with a sore throat. Her primary care physician had prescribed a 5-day course of azithromycin 250 mg. Since she did not improve, the doctor prescribed moxifloxacin and steroids. Symptoms improved temporarily but then returned. She sought care in the emergency department after two episodes of coughing with hemoptysis. She also complained of generalized malaise, myalgias, headache, nausea, anorexia, and left chest wall tenderness. The patient denied exposure to tuberculosis or sick contacts.
Her previous medical history was unremarkable. Her only regular medication was atorvastatin, 10 mg daily, for hypercholesterolemia. She denied using alcohol, tobacco, or illicit drugs.
Physical examination revealed an ill-appearing patient. She had mild bibasilar crackles in her lungs. Her vital signs and results of the remaining physical examination were normal. Laboratory tests obtained in the emergency department are shown in Table 1. A radiograph and computed tomography (CT) scan of her chest revealed a large confluent density in the periphery of the left midlung and two smaller nodules in the right midlung as well as multiple reactive mediastinal lymph nodes (Figure 1). A peripheral blood smear showed hypochromasia, polychromasia, and rouleaux.
(a) Chest radiograph showing a confluent density in the left midlung and two smaller pulmonary nodules in the right midlung. (b) Computed tomography scan showing the same nodular findings with the addition of mediastinal lymphadenopathy.
Significant laboratory test results
Her presenting problems were hemoptysis with an abnormal chest radiograph and CT scan, upper respiratory symptoms, renal insufficiency, hematuria, proteinuria, anemia, hyponatremia, and hypoalbuminemia. A differential diagnosis that encompasses these symptoms includes forms of glomerulonephritis associated with systemic diseases such as systemic lupus erythematosus, vasculitis, Wegener granulomatosis, microscopic polyangiitis, and Goodpasture syndrome.
The middle lobe lung infiltrate increased the probability of an atypical pneumonia. However, the infectious disease workup was negative. Urinalysis revealed the presence of red cell casts. Analysis of serum and urine protein electrophoresis for proteinuria revealed only acute-phase changes without evidence of any monoclonal spike. Positive rheumatologic test results included the following: antinuclear antibody titer, 1:160 with a speckled fluorescence pattern; rheumatoid factor titer, 1:80; and cytoplasmic–antineutrophil cytoplasmic antibody (C-ANCA) titer, 1:64.
Bronchoscopy and transbronchial biopsies showed mixed inflammatory infiltrates but no evidence of malignancy. Studies showed no Pneumocystis carinii pneumonia, virus, or fungus. A kidney biopsy showed acute necrotizing and pauci-immune acute crescentic glomerulonephritis consistent with Wegener granulomatosis 1(Figure 2). Renal biopsy immunofluorescence was negative for immunoglobulin (Ig)G, IgA, IgM, complement, and kappa and lambda light chains, with normal albumin backgrounds. Electron microscopy showed no electron-dense deposits. Light microscopy showed perivascular granulomas, which are typically seen in lung or sinus tissue biopsies but rarely in kidney biopsies.
Results of the patient's kidney biopsy. (a) The hypercellular and proliferative glomeruli, showing crescent formation (arrow). (b) The granuloma with a giant cell (arrow), encompassed by several arterioles and vascular areas.
These findings led us to a diagnosis of Wegener granulomatosis. The treatment included methylprednisolone 1 gm intravenously (started before the kidney biopsy) and then prednisone 80 mg orally, cyclophosphamide, and sulfamethoxazole and trimethoprim after we determined the definitive diagnosis. The patient tolerated the treatment well, leading to her subsequent discharge from the hospital. She continues outpatient follow-up care with a nephrologist to monitor treatment with cyclophosphamide and prednisone. Shortly after discharge, her creatinine level decreased to 1.5 mg/dL; currently, her creatinine level is 1.0 mg/dL, and she continues to improve.
Wegener granulomatosis, or granulomatous vasculitis, is a disease that produces inflammation of the medium and small arteries and venules (2–4). Necrotizing and crescentic changes are found in the glomeruli (1). The process typically affects the upper and lower airways and kidneys.
The prevalence of the disease is about 3 in 100,000, with a slightly higher prevalence in men than in women (3:2). The peak incidence of the disease is at 50 to 60 years of age.
This patient presented with the classic clinical triad of Wegener granulomatosis: upper respiratory, pulmonary, and kidney involvement (2, 3). Other organ systems that can be affected include the joints, eyes, skin, central nervous system, and, less commonly, the gastrointestinal tract, parotid gland, heart, thyroid, liver, and breast (5–7) (Table 2).
Common presenting symptoms of Wegener granulomatosis
Wegener granulomatosis is considered a probable autoimmune disorder because of the frequent presence of high-titer antibodies against neutrophilic peptides (ANCA). Most characteristic is C-ANCA directed against proteinase 3 present in the primary granules of neutrophils and monocytes. These antibodies are important for the diagnosis of the disease and may also play a major pathogenic role (4, 8–10). Experimental studies indicate that they can cause tissue damage and vasculitis (Figure 3). Ninety percent of patients with active generalized disease are ANCA positive. However, in patients with milder, limited forms of the disease, the ANCA test may be negative up to 40% of the time (10). A positive perinuclear (P)-ANCA result is less specific. Other frequent but nonspecific laboratory findings include leukocytosis, thrombocytosis, an elevated erythrocyte sedimentation rate, and a normocytic, normochromic anemia (11).
Antineutrophilic cytoplasmic antibodies (ANCA) under fluorescence. (a) In C-ANCA (cytoplasmic), the cytoplasm lights up. (b) In P-ANCA (perinuclear), a green halo appears on the cytoplasm and the nucleus lights up.
A tissue biopsy is essential for the definitive diagnosis of Wegener granulomatosis. Upper respiratory tract biopsies show acute and chronic inflammation with granulomatous changes. Kidney biopsies typically show segmental necrotizing pauci-immune and often angiocentric glomerulonephritis (1). Lung biopsies show vasculitis and granulomatous inflammation.
Confirmation of the diagnosis is important because therapy is often very toxic. Initial therapy generally consists of cyclophosphamide and glucocorticoids (12). This regimen is maintained until the patient is in stable remission, usually 3 to 6 months. Various alternative regimens include 1) intravenous monthly cyclophosphamide instead of daily, oral cyclophosphamide; 2) methotrexate instead of cyclophosphamide in patients with mild disease, limited bone marrow reserve, or bladder toxicity; and 3) plasmapheresis, especially when anti–glomerular basement membrane antibodies are present or when severe pulmonary hemorrhage occurs (13).
Maintenance therapy is usually given for 12 to 18 months after the initial remission to prevent relapse. Cyclophosphamide is continued for approximately 12 months. However, corticosteroids are not shown to have any added benefit in maintenance therapy; thus, they should be tapered rapidly after the disease stabilizes (12). Several drugs are given for prophylaxis for potential side effects from treatment medications (14, 15) (Table 3).
Medications used for treatment side effects
Most adverse, nonfatal outcomes are related to the treatment of Wegener granulomatosis. These include side effects from glucocorticoids, increased risk of malignancy, and progressive organ failure. Patients with Wegener granulomatosis have an increased risk of deep vein thrombosis and pulmonary embolism, probably because of the nature of the vasculitis. Progressive renal failure with kidney involvement and respiratory failure with pulmonary involvement can occur. Untreated patients have a low survival rate of only 20% at 2 years. However, the 2-year survival rate for treated patients is about 90%.
1. Haas M, Eustace JA. Immune complex deposits in ANCA-associated crescentic glomerulonephritis: a study of 126 cases. Kidney Int. 2004;65(6):2145–2152.[PubMed]
2. Manganelli P, Fietta P, Carotti M, Pesci A, Salaffi F. Respiratory system involvement in systemic vasculitides. Clin Exp Rheumatol. 2006;24(2 Suppl 41):S48–S59.[PubMed]
3. Duna GF, Galperin C, Hoffman GS. Wegener's granulomatosis. Rheum Dis Clin North Am. 1995;21(4):949–986.[PubMed]
4. Seo P, Stone JH. The antineutrophil cytoplasmic antibody–associated vasculitides. Am J Med. 2004;117(1):39–50.[PubMed]
5. Harper SL, Letko E, Samson CM, Zafirakis P, Sangwan V, Nguyen Q, Uy H, Baltatzis S, Foster CS. Wegener's granulomatosis: the relationship between ocular and systemic disease. J Rheumatol. 2001;28(5):1025–1032.[PubMed]
6. Daoud MS, Gibson LE, DeRemee RA, Specks U, el-Azhary RA, Su WP. Cutaneous Wegener's granulomatosis: clinical, histopathologic, and immunopathologic features of thirty patients. J Am Acad Dermatol. 1994;31(4):605–612.[PubMed]
7. Ozdogu H, Boga C, Bolat F, Ertorer ME. Wegener's granulomatosis with a possible thyroidal involvement. J Natl Med Assoc. 2006;98(6):956–958.[PMC free article][PubMed]
8. Hagen EC, Daha MR, Hermans J, Andrassy K, Csernok E, Gaskin G, Lesavre P, Ludemann J, Rasmussen N, Sinico RA, Wiik A, van der Woude FJ, EC/BCR Project for ANCA Assay Standardization Diagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies in idiopathic systemic vasculitis. Kidney Int. 1998;53(3):743–753.[PubMed]
9. Bosch X, Guilabert A, Font J. Antineutrophil cytoplasmic antibodies. Lancet. 2006;368(9533):404–418.[PubMed]
10. Morgan MD, Harper L, Williams J, Savage C. Anti-neutrophil cytoplasm–associated glomerulonephritis. J Am Soc Nephrol. 2006;17(5):1224–1234.[PubMed]
11. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, Rottem M, Fauci AS. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992;116(6):488–498.[PubMed]
12. White ES, Lynch JP. Pharmacological therapy for Wegener's granulomatosis. Drugs. 2006;66(9):1209–1228.[PubMed]
13. Levy JB, Hammad T, Coulthart A, Dougan T, Pusey CD. Clinical features and outcome of patients with both ANCA and anti-GBM antibodies. Kidney Int. 2004;66(4):1535–1540.[PubMed]
14. Ognibene FP, Shelhamer JH, Hoffman GS, Kerr GS, Reda D, Fauci AS, Leavitt RY. Pneumocystis carinii pneumonia: a major complication of immunosuppressive therapy in patients with Wegener's granulomatosis. Am J Respir Crit Care Med. 1995;151(3 Pt 1):795–799.[PubMed]
15. Somers EC, Marder W, Christman GM, Ognenovski V, McCune WJ. Use of a gonadotropin-releasing hormone analog for protection against premature ovarian failure during cyclophosphamide therapy in women with severe lupus. Arthritis Rheum. 2005;52(9):2761–2767.[PubMed]