Wegener's Granulomatosis: Evolving Concepts in Treatment

Abstract

Wegener's granulomatosis (WG), the most common of the pulmonary granulomatous vasculitides, typically involves the upper respiratory tract, lower respiratory tract (bronchi and lung), and kidney, with varying degrees of disseminated vasculitis. Major histological features include a necrotizing vasculitis involving small vessels, extensive "geographic" necrosis, and granulomatous inflammation. Clinical manifestations of WG are protean; virtually any organ can be involved. Further, the spectrum and severity of the disease is heterogeneous, ranging from indolent disease involving only one site to fulminant, multiorgan vasculitis leading to death. The pathogenesis of WG has not been elucidated, but both cellular and humoral components are involved. Circulating antineutrophil cytoplasmic antibodies (cANCA) likely play a role in the pathogenesis and often correlate with activity of the disease. Treatment strategies are evolving. Cyclophosphamide (CYC) plus corticosteroids (CS) is the mainstay of therapy for generalized, multisystemic WG. Historically, the combination of CYC plus CS was used for a minimum of 12 months, but concern about late toxicities associated with CYC has led to novel treatment approaches. Currently, short-course (3-6 months) induction treatment with CYC plus CS, followed by maintenance therapy with less toxic agents (e.g., methotrexate, azathioprine) is recommended. Further, recent studies suggest that methotrexate combined with CS may be adequate for limited, non-life threatening WG. The role of other immunomodulatory agents (including trimethoprim-sulfamethoxazole) is also explored.

B-Cell Depletion in Wegener’s Granulomatosis

“…Currently, cyclophosphamidesparing treatment regimens are often used-using cyclophosphamide as an "induction" agent and, once remission is present, transition to a methotrexate-or azathioprinebased "maintenance" regimen [29]. Both methotrexate and azathioprine have been shown to be useful and possibly equipotent to cyclophosphamide for remission maintenance, but their role for remission induction is less well defined [30][31][32].…”

Treatment of Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

“…Studies have found remission rates between 70% and 100% and early mortality rates of less than 20% 9,28,29,37,39,[44][45][46][47][48][49] with increased treatment-related morbidity. 8,44,[50][51][52][53] Therefore, research centered on searching for equally effective but safer treatments, including changing the route of administration and dosage of cyclophosphamide and testing a monthly intravenous regimen.…”

Diagnostic Approach to Diffuse Parenchymal Lung Disease

“…but these disorders do not affect extrapulmonary organs. By contrast, sarcoidosis [29], vasculitis [48], CVD [30], LAM [11,12,49], and LCG [13] may be associated with extrapulmonary manifestations. Pulmonary complications of CVD are protean and include: fibrosing alveolitis; diffuse alveolar damage (DAD); cellular or follicular bronchiolitis; obliterative bronchiolitis (with or without organizing pneumonia); alveolar hemorrhage [50,51].…”