Antineutrophil cytoplasmic antibodies (ANCA) have had important clinical applications in GPA, although their role in pathogenesis remains uncertain. Two types of ANCA have been identified in patients with vasculitis: ANCA directed against proteinase-3 (PR3), which causes a cytoplasmic immunofluorescence pattern (cANCA) on ethanol-fixed neutrophils, and ANCA directed against myeloperoxidase (MPO), which results in a perinuclear immunofluorescence pattern (pANCA). In order to interpret ANCA results, positivity by immunofluorescence should be confirmed with testing for antibodies to PR3 and MPO. In GPA, 75% to 90% of patients have PR3-cANCA, 5% to 20% have MPO-pANCA, and up to 20% may be ANCA negative. Although ANCA has diagnostic utility in settings in which the likelihood of GPA would be high (sinusitis, an active urine sediment, and noninfectious pulmonary disease), for clinical features where GPA would have a lower prevalence, the predictive value of ANCA is insufficient to initiate therapy in the absence of a biopsy-proven diagnosis. ANCA levels do not correlate well with relapse, and a rising ANCA value alone should not be used as the basis to start or increase immunosuppressive therapy.

Biopsies in GPA may demonstrate granulomatous inflammation, necrosis, with necrotizing or granulomatous vasculitis. The highest positive yield of greater than 90% comes from surgical biopsies of affected lung, with biopsies of the upper airways being diagnostic less than 20% of the time. Renal histology is that of a focal, segmental, necrotizing, crescentic glomerulonephritis with few to no immune complexes.

Treatment/Prognosis. Active GPA is potentially life threatening, and initial treatment requires glucocorticoids combined with another immunosuppressive agent. Patients who have active severe GPA should initially be treated with cyclophosphamide in combination with prednisone at 1 mg/kg/day. After 4 weeks of treatment, if there is improvement, the prednisone is tapered with a goal of discontinuation by 6 to 12 months. Cyclophosphamide may either be given orally as 2 mg/kg/day taken all at once in the morning or intravenously as 15 mg/kg every 2 weeks for 3 doses and every 3 weeks thereafter. It has a significant side effect profile that includes infection, cytopenia, bladder toxicity, infertility, and myelodysplasia. To prevent leukopenia, blood cell counts should be measured every 1 to 2 weeks for as long as the patient is taking cyclophosphamide. The drug is given for 3 to 6 months to induce remission, after which time it is stopped and therapy is switched to either methotrexate, 20 to 25 mg/wk, or azathioprine, 2 mg/kg/day, for remission maintenance. Rituximab (anti-CD20), 375 mg/M²/wk for 4 weeks, combined with glucocorticoids has been found to be as effective as cyclophosphamide to induce remission and represents another treatment option for patients with severe disease. In patients who have active but nonsevere disease, prednisone given together with methotrexate, 20 to 25 mg/wk, can effectively induce and then maintain remission. In the absence of side effects, maintenance therapy is given for at least 2 years, after which time consideration may be made on an individual basis whether to continue the maintenance agent or to taper therapy to discontinuation.

Before the introduction of treatment, patients with GPA had a mean survival time of 5 months. Current regimens induce remission in 75% to 100% of GPA patients and carry the potential for long-term survival. However, relapse occurs in 50% to 70% of patients and disease-related organ damage is common.

MICROSCOPIC POLYANGIITIS

Epidemiology/Clinical Manifestations. MPA is characterized by necrotizing vasculitis with few or no immune deposits affecting small vessels. It lacks granulomatous inflammation, which differentiates it from GPA. The most common clinical features of MPA include glomerulonephritis (80%-95%), peripheral nerve disease (60%-70%), lung disease, including pulmonary hemorrhage (25%-55%), cutaneous vasculitis (30%-40%), and gastrointestinal disease (30%).

Diagnosis. The essential laboratory studies in MPA, particularly the important role of urinalysis, are similar to those in GPA. Approximately 75% to 85% of MPA patients have MPO-pANCA, with 5% to 10% being positive for PR3-cANCA and 0 to 20% being ANCA negative. Biopsies in MPA show necrotizing vasculitis of the small vessels or small to medium-sized arteries and the absence of granulomas on immunofluorescence. Like GPA, the renal histology is a focal segmental necrotizing glomerulonephritis with few to no immune complexes.