Vasculitis varieties associated with Antineutrophil Cytoplasmic Antibody (ANCA) include Wegener’s granulomatosis, Churg-Strauss Vasculitis, and microscopic polyangiitis. The description of ANCA and its association with specific vasculitis syndromes have modified our clinical evaluation of vasculitis and proposed pathophysiologic mechanisms. Cytoplasmic immunofluorescence of fixed neutrophils (c-ANCA)— demonstrating human autoantibody binding—is manifest in cases of Wegener’s granulomatosis. Perinuclear staining (p-ANCA) is characteristic in Churg-Strauss syndrome, microscopic polyangiitis, and progressive glomerulonephritis with vasculitis. Exceptions occur with staining patterns. For example, p-ANCA may be seen in about 5% of Wegener’s granulomatosis cases. ANCA occurs in subjects without vasculitis and is absent in some individuals with these conditions. Thus, the detection of ANCA supports but does not establish a diagnosis, and the absence of ANCA does not eliminate the diagnosis of vasculitis of these types. Measuring antibodies to specific neutrophil antigens enhances the specificity of ANCA results and improves the prognostic value of titer changes in predicting changes in disease activity.
Antimyeloperoxidase antibodies are characteristic in microscopic polyangiitis or Churg-Strauss syndrome (associated with p-ANCA), and anti-proteinase 3 is more specific for Wegener’s granulomatosis (associated with c-ANCA). The concentration of ANCA may be used to monitor disease activity and assist decision-making related to therapeutic dose reduction. The addition of monitoring levels of antibodies to specific neutrophil enzymes—such as elastase, proteinase 3 or myeloperoxidase—may enhance the reliability of ANCA changes in predicting changes in disease activity.
ANCA may activate neutrophils, resulting in initiation or augmentation of immunologic response and blood-vessel damage. Therefore, treatments directed toward reducing ANCA may minimize disease activity. The importance of ANCA in the pathophysiology of the associated vasculitis is unproven but suspected.
Wegener’s granulomatosis typically affects the upper airway, lung, and kidney. Involvement of the airway is the main reason that allergists/immunologists will encounter this vasculitic syndrome. Ninety percent or more of affected subjects will have ear, nose, or throat involvement including persistent sinusitis, nasal crusting or bleeding, otitis media, hearing loss, and ear pain. Pulmonary involvement occurs in more than 80% of affected subjects, usually showing nodules, infiltrates, or hemoptysis.
Symptoms of Churg-Strauss vasculitis are likely to help in the differential diagnosis of persistent sinus disease, difficult-to-treat asthma, allergic bronchopulmonary aspergillosis, eosinophilia, and increased blood IgE. Churg-Strauss vasculitis usually occurs in individuals with a history of asthma and allergy or allergic-like disease, overlapping with the majority of patients seen by an allergist or immunologist ().
Microscopic polyangiitis or small-vessel necrotizing vasculitis is characterized by pulmonary involvement, often with hemorrhage. Asthma is not characteristic of microscopic polyangiitis.
Since all three of these syndromes share a tendency for ANCA positivity and airway involvement, allergists/immunologists are likely to encounter individuals in which these syndromes are considered in the differential diagnosis. The prognosis of all three is poor without suitable treatment. So, allergists/immunologists emphasize the need for awareness and prompt diagnosis.
Treatment of ANCA Associated Vasculitis
Mean survival time of untreated subjects with Wegener’s granulomatosis (WG) is 5 months. Allergists/immunologists see more than 90% mortality rate within 2 years of diagnosis for patients without therapy. Similarly, the 5-year prognosis for survival of untreated Churg-Strauss vasculitis and microscopic polyangitis is 25% or less. With treatment, patients in all three vasculitis syndrome groups experience a 5-year survival rate of greater than 70%.
Glucocorticoid therapy alone is marginally effective in suppressing these diseases, with median survival of slightly more than one year for patients with Wegener’s granulomatosis. Controlled trials have demonstrated that a combination of oral prednisone, 1-1.5 mg/kg/day and oral cyclophosphamide, 2mg/kg/day, is effective in inducing remissions and permitting tapering of therapy over several years in the majority of Wegener’s granulomatosis studies. Prednisone dosage is tapered to every other day and the cyclophosphamide gradually also tapered over 6-24 months. Conversion to alternative immunosuppressive therapy, particularly with weekly methotrexate after 6 months of successful induction therapy, may maintain clinical response without increasing the risk of bladder cancer—a side effect of oral cyclophosphamide treatment. Recommendations for therapy of other forms of ANCA-associated vasculitis, such as Churg-Strauss syndrome or microscopic polyangiitis, are less secure because we lack sufficient controlled trials. However, many clinicians use treatments similar to those studied in Wegener’s granulomatosis.
Relapses of Wegener’s granulomatosis after remission, along with the cumulative adverse effects produced by both the prednisone and cyclophosphamide administration, have stimulated the search for alternative treatments. A randomized study demonstrated clinical benefits of monthly, pulse-therapy with cyclophosphamide. This study showed a reduction of side effects and a 57% reduction of total cyclophosphamide dose needed for disease control. The intravenous treatment group experienced significantly fewer infections, less leukopenia, and a possible reduction of gonadal toxicity as a result of decreased levels of follicle-stimulating hormone. Also, intermittent, intravenous cyclophosphamide is associated with less bladder toxicity than daily, oral therapy. Recent onset of disease, presence of renal involvement and absence of granulomas in the lung and airway characterize a cohort of subjects that shows better response to intravenous cyclophosphamide. Daily treatment with oral cyclophosphamide appears to be more effective than monthly treatment with intravenous cyclophosphamide. An oral combination of trimethoprim and sulfamethoxazole reduces relapse rates in Wegener’s granulomatosis, sparing additional cytotoxic and glucocorticoid therapy. Intramuscular, depot-injections of corticosteroid may also reduce corticosteroid side effects without significantly compromising clinical response. Weekly, oral, pulse–administration of methotrexate is also effective in controlling Wegener’s granulomatosis and is a potential consideration if cyclophosphamide toxicity or adverse effect to gonads is an overriding concern. Methotrexate is also recommended after the first 6 months of cyclophosphamide administration to ease tapering of the cyclophosphamide, thereby minimizing bladder toxicity. Methotrexate therapy is not recommended for severe, immediately life-threatening disease. Limited data support the efficacy of mycophenolate mofetil and calcineurin inhibitors, such as cyclosporine and tacrolimus, in the treatment of necrotizing vasculitis. Inhibitors of tumor necrosis factor—such as etanercept—have not been found to be effective in Wegener’s granulomatosis. Intravenous gamma globulin may be of some value in Churg-Strauss vasculitis.
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