Medical Care: The prognosis associated with untreated systemic WG is poor, with up to 90% of patients dying within 2 years, usually from respiratory or renal failure. Long-lasting remissions can be induced in most patients with cytotoxic agents, particularly cyclophosphamide, administered in combination with corticosteroids. Approximately 90% of patients respond to cyclophosphamide, and approximately 75% experience complete remission. Subsequently, 30-50% of those who respond have at least one relapse, requiring another course of therapy.
Current treatment of WG is based on patient classification of either severe or limited disease. Severe WG threatens a vital organ or life and requires urgent treatment, whereas limited WG does not pose this threat.
Results from several randomized controlled trials in patients with WG and other antineutrophil cytoplasm antibody-associated vasculitides have recently been reported. These reports guide evidence-based therapy in these patients. The considerable toxicity of cyclophosphamide had been a concern. Replacing cyclophosphamide with azathioprine after the successful induction of remission has proven effective in preventing relapses. Even low-dose methotrexate can replace cyclophosphamide in patients without critical organ manifestations as induction treatment. However, a prolonged maintenance treatment that lasts 6-12 months is mandatory.
" The 3 phases of treatment of WG are (1) induction of remission, (2) maintenance of remission, and (3) treatment of relapse.
" The treatment of choice for induction therapy of WG is cyclophosphamide and prednisone, especially in patients with renal involvement or severe lung disease. Oral prednisone is started at 1-1.5 mg/kg/d, and oral cyclophosphamide is added at a dose of 2 mg/kg/d. Once control has been established, the dosage of prednisone is gradually tapered over a 2-month period, and cyclophosphamide is maintained for an additional 6-12 months after the last evidence of stability.
" The role of monthly intravenous cyclophosphamide (pulse therapy) is controversial. Several studies, including that by Guillevin et al from 1997, have shown comparable rates of remission; however, other studies, such as that by Gross from 1994, showed decreased efficacy. These conclusions may not be valid because nonresponders had more severe disease compared with responders. Therefore, perhaps intravenous cyclophosphamide should not be used, at least initially, in patients with severe or life-threatening disease.
" In patients who present with rapidly progressive glomerulonephritis, alveolar hemorrhage, or both, intravenous glucocorticoids should be administered at a much higher dose.
" Pulse therapy with methylprednisolone at 0.5-1 g/d for 3 consecutive days is followed by oral prednisone.
" A higher dose of oral cyclophosphamide (4 mg/kg/d) or intravenous cyclophosphamide (0.75 g/m2 of body surface area at intervals of 3-4 wk) is administered.
" In severely ill patients, intravenous gamma globulin has been used at some centers with some success, but this is not a proven therapy. In patients who do not tolerate cyclophosphamide, other cytotoxic agents such as azathioprine, chlorambucil, or methotrexate have been used.
" Methotrexate may be an alternative agent in mild-to-moderately severe disease when patients do not have pulmonary hemorrhage or fulminant renal failure.
" Plasmapheresis generally produces no added benefit, although it may be beneficial in patients who are dependent on dialysis, who have severe pulmonary hemorrhage, or who have concurrent anti-glomerular basement membrane antibody disease.
" Other therapies such as intravenous immunoglobulin, mycophenolate mofetil, leflunomide, and etanercept have been administered to a small number of patients. Data for these and other therapies, including tumor necrosis factor inhibitors, are insufficient to endorse their widespread use.
" Based on recent clinical trials, a new approach to immunosuppression has emerged for patients with WG.
o According to studies by Jayne from 2003 and Langford et al from 1999, a shorter course of induction treatment with cyclophosphamide, usually for a duration of 3-6 months, is recommended. A longer maintenance therapy with less toxic agents (eg, azathioprine, methotrexate) is continued for at least 1 year after remission is achieved. For patients who develop frequent exacerbations, long-term use of low-dose prednisone, methotrexate, or azathioprine may be appropriate.
o Most patients with limited WG may be treated with glucocorticoids and methotrexate alone. Remission could occur in up to 75% of these patients with treatment regimens not including cyclophosphamide.
o The relapse rate following remission ranges from 20-46%, with most relapses occurring within the first year after cessation of immunosuppressive therapy.
o Infections may play a role in relapse by inducing expression of cytoplasmic antigens on the surface of circulating neutrophils, releasing oxygen radicals, and causing vascular injury.
o Relapses generally respond to re-treatment with cyclophosphamide and prednisone. Daily treatment with the antibiotic sulfamethoxazole-trimethoprim has reduced relapse rates in published series. A placebo-controlled study by Stegeman et al published in 1996 demonstrated that 82% of subjects receiving cotrimoxazole remained in remission, compared with 60% of those in the placebo group. The mechanism of its efficacy is unknown. Speculations have been made that the efficacy may be due to either the anti-infective or anti-inflammatory effects of this drug.
o ANCA titers usually parallel the course of vasculitis, especially C-ANCA. Acute phase reactants (eg, erythrocyte sedimentation rate, C-reactive protein level) also parallel the course of WG, although they can rise with concurrent infection without active disease.
o Although decreasing titers of ANCA predict a lower risk for clinical relapse, the relationship between ANCA titers and disease activity is not absolute and may be discordant in one third of patients.
o Studies have shown that a rise in ANCA titers in asymptomatic patients may be used to predict a relapse, but therapy should not be initiated unless early clinical findings of relapse also appear.
o Rituximab, a chimeric anti-CD20 monoclonal antibody, has been shown to be effective in the treatment of immune disorders due to autoantibodies. A recent prospective study of long-term effects of rituximab in 10 patients with ANCA-positive vasculitis refractory to conventional therapy or subsequent relapse was published. Treatment consisted of intravenous infusions of rituximab 375 mg/m2 weekly for 4 consecutive weeks. All patients experienced a rapid clinical improvement following the administration of rituximab. This therapy could be considered in patients with severe WG who fail to respond to standard therapy (Stasi, 2006).
o Etanercept, which blocks tumor necrosis factor-alpha, has been shown to be ineffective in maintenance of remission in patients with WG. Durable remissions were achieved in only a minority of the patients in one prospective study, and the rate of treatment-related complications was high.
Surgical Care: Inflammatory insult leads to tissue necrosis and fibrotic damage to the nose, subglottic areas, trachea, and bronchi. Consider surgical intervention in such situations.
" Saddle nose deformity can be surgically repaired.
" For subglottic stenosis, laser treatment, balloon dilatation, or resection of the stenotic area with reanastomosis (performed as the definitive procedure) may be performed.
" Obstruction of the nasal lacrimal ducts can be corrected by surgical means.
" Recurrent middle ear infections due to dysfunction of the eustachian tube can be treated by introducing ventilating tubes through the tympanic membranes.
" For patients who develop stenosis of the major bronchi, dilatation, placement of silastic stents, or both may be beneficial. Intralesional injections of corticosteroids may also be beneficial in these patients.
" Patients with renal failure should be considered for transplantation. Recurrence of WG in the transplanted kidney has not been reported.