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The cornerstone of ANCA vasculitis treatment is based on a combination of corticosteroids and cyclophosphamide according to various regimens described in the literature. Since renal prognosis appears to be determined by early treatment, we typically initiate induction therapy with three daily pulses of methylprednisolone (7 mg/kg/day) followed by daily oral prednisone. Prednisone is started at a dose of 1 mg/kg for the first month, and tapered progressively over 3–4 months. Cyclophosphamide is administered either by monthly intravenous pulses (0.5–1 g/m2) or orally (1–2 mg/kg/day). All forms of cyclophosphamide dosage should be titrated to keep the nadir leukocyte count >3000 cells/mm3. When compared to treatment with corticosteroids alone, the use of cyclophosphamide is associated with a 5-fold decrease in the risk of death and a 3-fold decrease in the risk of relapse. Patients treated with either intravenous or oral cyclophosphamide have a long-term remission rate of between 60% and 85%.
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Determining the optimum mode (oral versus intravenous) and duration of treatment with cyclophosphamide depends on several factors and considerations. The short- and long-term complications associated with the use of cyclophosphamide are commensurate with the cumulative dose received. In general, the intravenous regimen allows for a two to three times smaller total dose of cyclophosphamide than the oral regimen. In prospective and retrospective analyses, intravenous therapy was associated with a significant decrease in the rate of clinically significant neutropenia and other complications. In a meta-analysis of three randomized controlled trials comparing pulse versus oral continuous cyclophosphamide, intravenous cyclophosphamide resulted in a statistically higher rate of remission (odds ratio for failure to achieve remission 0.29; 95% CI 0.12–0.73) and lower rates of leukopenia (odds ratio 0.36; 95% CI 0.17–0.78) and infections (odds ratio 0.45; 95% CI 0.23–0.89). The final outcomes of patients (death or ESKD) were no different in the two groups despite a (statistically not significant) lower rate of relapse in the oral cyclophosphamide group.
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The optimum length of therapy with cyclophosphamide has not been determined and is the subject of ongoing controversy. In patients achieving complete remission within 6 months of therapy, treatment can be stopped with the institution of close patient follow-up. In those individuals with persistently active disease at 6 months, it is reasonable to continue cyclophosphamide therapy for a full 12 months. An alternative regimen consists of switching cyclophosphamide to oral azathioprine at the end of 3 months if the patient is in remission. Azathioprine is then continued for 18 months. This regime offers the advantage of a limited use of cyclophosphamide and results in rates of remission and relapse similar to the cyclophosphamide-only-based therapies.
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Patients presenting with pulmonary hemorrhage also benefit from the institution of plasmapheresis in a regimen similar to that used for patients with Goodpasture's disease. Although no controlled data are available, early and aggressive institution of plasmapheresis has substantially diminished the mortality rate associated with massive pulmonary hemorrhage. Plasmapheresis is typically performed daily until the pulmonary hemorrhage ceases and then every other day for a total of seven to ten treatments. The addition of plasma exchange to cyclophosphamide and corticosteroids also improves the chances of recovery of renal function of patients with severe renal dysfunction (serum creatinine >5.6 mg/dL) or needing dialysis at presentation. For patients without profound renal failure or with pulmonary hemorrhage, controlled and observational trials have not demonstrated a beneficial role to the addition of plasmapheresis to cyclophosphamide and corticosteroids.
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Adjunctive, Alternative, and Maintenance Treatment Strategies
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Several other therapies have been evaluated for a potential role in the management of patients with ANCA vasculitis. Considering the generally excellent response rates to treatment with cyclophosphamide and glucocorticoids, the goals of these therapies can conceptually be delineated in the broad categories of adjunctive therapy for patients at risk for treatment resistance; alternatives to the repeat use of cyclophosphamide; or as maintenance therapy aimed at preventing relapses. With a few notable exceptions, the data available in support of these treatments are limited to open-label, uncontrolled studies that are often limited in size. No agent has as yet been established as a clear alternative to cyclophosphamide for the induction therapy of patients with organ- or life-threatening disease. The following sections review the data regarding alternative, adjunctive, or maintenance therapies for ANCA vasculitis.
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Trimethoprim-Sulfamethoxazole
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Trimethoprim-sulfamethoxazole is suggested as the initial treatment of selected patients with Wegener's granulomatosis limited to the upper respiratory tract, reserving corticosteroid therapy for patients who fail antibiotic therapy. In assessing the role of trimethoprim-sulfamethoxazole in the prevention of relapse in patients who were already treated with cyclophosphamide and/or prednisone, a prospective placebo-controlled trial with trimethoprim-sulfamethoxazole was performed in 81 patients with Wegener's granulomatosis. The number of relapses was significantly reduced in the groups assigned to trimethoprim-sulfamethoxazole, although the benefit was limited to relapse involving the upper respiratory tract, not the lower respiratory tract or the kidney. In contrast, “maintenance” therapy with trimethoprim-sulfamethoxazole (after cyclophosphamide treatment) has been associated with an increased rate of relapse when compared to no maintenance treatment (42% versus 29%, respectively).
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Similarly, in a randomized trial of 65 patients with Wegener's granulomatosis comparing methotrexate and trimethoprim-sulfamethoxazole, methotrexate therapy was more effective in maintaining remission than trimethoprim-sulfamethoxazole used alone or in combination with prednisone. Thus, the use of trimethoprim-sulfamethoxazole in patients with Wegener's granulomatosis remains a matter of controversy, and its beneficial effects seem to be limited to the respiratory tract.
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The use of methotrexate (MTX) has been studied almost exclusively in patients with Wegener's granulomatosis, and primarily in patients with “limited,” mild disease, and with little or no renal involvement. MTX has been evaluated as an alternative to cyclophosphamide for the induction of remission in an open-label, uncontrolled trial that revealed a response rate of 76% and a remission rate of 69%. The value of weekly MTX as an induction agent was compared to daily oral cyclophosphamide in a randomized controlled trial in 100 patients with “early” ANCA vasculitis who did not have organ- or life-threatening manifestations or significant renal involvement (patients with creatinine >150 μmol/L, urinary red cell casts, or proteinuria >1.0 g/day were excluded). Although the remission rate at 6 months was not statistically different between the two groups [MTX (89.8%) versus cyclophosphamide (93.5%) (p = 0.041)], remission was delayed among MTX-treated patients with more extensive disease or pulmonary involvement. MTX treatment was associated with a significantly higher rate of relapse than cyclophosphamide (69.5% versus 46.5%) and 45% of the relapses occurred while the patients were still receiving MTX.
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Whether MTX is effective in preventing relapses after induction therapy with cyclophosphamide has also been evaluated in open-label, uncontrolled studies. These studies revealed relapse rates of 37–52% with 61–72% of relapses associated with glomerulonephritis and 69% of relapses involving the upper respiratory tract. In the absence of proper control groups, it is not possible to assess whether maintenance therapy with MTX reduces the rate or severity of relapses.
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In summary, MTX appears to be an option in the treatment of patients with mild ANCA vasculitis and normal or near normal renal function. The data regarding its value for maintenance therapy are currently less convincing. The dose of MTX should be decreased by 50% in patients with renal insufficiency and its use is contraindicated if the Ccr is <10 mL/minute. Trimethoprim-sulfamethoxazole for prophylaxis against Pneumocystis carinii pneumonia cannot be used concomitantly with MTX.
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The role of azathioprine in the management of patients with ANCA vasculitis was examined for the maintenance of remission as an alternative to a prolonged course of cyclophosphamide. In a large multicenter European trial, 144 patients with ANCA vasculitis who attained remission with oral cyclophosphamide and prednisolone were randomized to either a continued course of oral cyclophosphamide for a total of 1 year or switched to oral azathioprine. All patients were switched to oral azathioprine after 12 months. At the end of 12 months of follow-up, the risk of relapse was not significantly different between the two groups (13.7% versus 15.5%, p = 0.65) nor was there a significant difference in the risk of adverse events.
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In the past few years a number of new immunomodulatory agents, targeting T cells, B cells, or both, and a number of proinflammatory pathways have been introduced. Several of these agents have been evaluated in a limited way as adjunctive or maintenance therapy of ANCA vasculitis. These include the inhibitors of lymphocyte proliferation mycophenolate mofetil and leflunomide, the lymphocyte-depleting humanized anti-CD52 antibody alemtuzumab, the B cell-depleting chimeric antibody rituximab, and blockers of the tumor necrosis factor (TNF)-α pathway infliximab and etanercept. All but etanercept were evaluated only as part of small open-label, uncontrolled studies. The possible role of etanercept for the maintenance of remission was evaluated in a randomized, placebo-controlled trial of 180 patients in the Wegener's Granulomatosis Etanercept Trial (WGET). In addition to etanercept or placebo, patients received standard therapy with glucocorticoids plus cyclophosphamide or MTX. After 3–6 months of cyclophosphamide, patients in remission discontinued cyclophosphamide and were treated with etanercept and either MTX or azathioprine (depending on their degree of renal insufficiency). Over a mean follow-up of 27 months, 72% of patients attained a sustained remission, but only 50% of patients remained in remission for the remainder of the trial. There were no significant differences between the etanercept and control groups in the rates of sustained remission (69.7% versus 75.3%, p = 0.39), in the relative risk of disease flares per 100 person-years of follow-up (0.89, p = 0.54), or in the severity of relapses. During the study, 56.2% of patients in the etanercept group and 57.1% of those in the control group had at least one severe or life-threatening adverse event or died (p = 0.90). It was concluded that etanercept was not effective for the maintenance of remission in patients with Wegener's granulomatosis.
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Recurrence of ANCA vasculitis after renal transplantation occurs in about 20% of patients. Time to recurrence varies widely, from a few days to several years posttransplantation. Patients with Wegener's granulomatosis appear more likely to relapse than patients with microscopic polyangiitis or necrotizing crescentic glomerulonephritis alone, whereas the presence of circulating ANCA at the time of transplant does not seem to increase the risk of recurrence after transplantation. If the patient is clinically in remission, it is probably not necessary to delay transplantation until a negative ANCA serology is attained. We believe that transplantation should be delayed in patients with active disease. In the majority of reported cases, recurrent disease after transplantation responded well to treatment with cyclophosphamide and pulse corticosteroids.
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As corticosteroids and cyclophosphamide remain the cornerstone of therapy of ANCA SVV, special effort must be exercised to minimize the short- and long-term complications of treatment. Whenever corticosteroids are used, the development of osteoporosis can be minimized with the early institution of calcium and vitamin D supplementation, and in patients with established osteoporosis, calcitonin or bisphosphonates (if not contraindicated by azotemia or esophagitis). Rigorous control of blood pressure with sodium restriction and antihypertensive therapy is essential to minimize the additive effect of hypertension in loss of renal function following active nephritis. Hormonal manipulation during cytotoxic therapy may allow the preservation of gonadal function. The prevention of cyclophosphamide-induced infertility was reported with the use of testosterone in men and leuprolide in women.
Booth A et al: Prospective study of TNFalpha blockade with
infliximab in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. J Am Soc Nephrol 2004;15:717.
[PubMed: 14978174]
de Groot K et al: Randomized trial of
cyclophosphamide versus
methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2005;52:2461.
Eriksson P: Nine patients with anti-neutrophil cytoplasmic antibody-positive vasculitis successfully treated with
rituximab. J Intern Med 2005;257:540.
[PubMed: 15910558]
Keogh KA et al: Induction of remission by B lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2005;52:262.
[PubMed: 15641078]
Langford CA et al:
Mycophenolate mofetil for remission maintenance in the treatment of Wegener's granulomatosis. Arthritis Rheum 2004;51:278.
[PubMed: 15077273]
Nzeusseu TA et al: Oral
pamidronate prevents high-dose glucocorticoid-induced lumbar spine bone loss in premenopausal connective tissue disease (mainly lupus) patients. Lupus 2005;14:517.