Various Forms of Life in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

IN RESPONSE:

Hogan and colleagues have restated their belief that the 4 diseases included in their study under the rubric of “ANCA vasculitis” are “phenotypic variants of a single entity, small-vessel vasculitis.” This assertion ignores abundant evidence of important differences among these diseases that influence presentation, complications, selection of treatment strategies, and outcomes.

These disease entities have unique clinical differences. Consider, for example, the patient with Wegener granulomatosis who presents with chronic ear, nose, throat, or tracheal damage, none of which are complications of microscopic polyangiitis or renal-limited pauci-immune glomerulonephritis and rarely emerge in the context of the Churg–Strauss syndrome. The strategies to treat such complications extend beyond deciding which cytotoxic agent to add to corticosteroid therapy. In Wegener granulomatosis, one must consider whether chronic otitis media and conductive hearing loss may require placement of tympanotomy tubes, whether nasal complications require debridement of crusts or measures to improve moisturization, and whether subglottic or large bronchus stenosis requires surgical interventions. Unlike microscopic polyangiitis or renal-limited disease, active Wegener granulomatosis can also present with inflammatory mass lesions that may appear in any organ and must be differentiated from a comorbid malignancy or abscess. Although asthma and peripheral eosinophilia are infrequently found in Wegener granulomatosis, microscopic polyangiitis, and renal-limited disease, they are characteristic manifestations of the Churg–Strauss syndrome that can influence clinical decision making.

Microscopic characteristics of lesions also demonstrate striking histopathologic differences that provide further testimony to the distinct nature of these diseases. Whereas the renal histopathologic characteristics of all 4 diseases are similar, lesions in other organs are quite distinct. Nonspecific inflammation and granulomatous lesions are common in Wegener granulomatosis and are often present in the absence of vasculitis. However, granulomatous changes are not pathologic characteristics in microscopic polyangiitis or renal-limited disease. Biopsies from patients with the Churg–Strauss syndrome usually show an abundance of eosinophils, which is not characteristic for the other disease entities.

Hogan and colleagues argue that these diseases may be characterized within a common spectrum on the basis of patient responses to broad-based immunosuppressive therapy. We find this analytic approach to be no more sound than to argue that rheumatoid arthritis and inflammatory bowel disease are more similar than different because both diseases respond to similar treatment regimens.

Hogan and associates also note that the ideal treatment duration remains uncertain for patients with Wegener granulomatosis, microscopic polyangiitis, and the Churg–Strauss syndrome. We agree that large clinical trials will be required to best determine duration of treatment after induction of remission for each disease (and perhaps even for subsets within each disease). However, until such studies have been performed, our previously cited data support the notion that relapses can be diminished with more prolonged therapy and that such therapy need not include cyclophosphamide. The findings of De Groot (1) and Jayne and colleagues (2) and the European Vasculitis Study Group resulted from trials that were conducted in a prospective, standardized manner. Furthermore, other researchers who support the withdrawal of maintenance therapies have acknowledged increased rates of relapse with this management strategy (3, 4).

We believe that it is not wise to assume that these diseases are phenotypic variants of ANCA-associated small-vessel vasculitis. Despite important and insightful investigations of these antibodies that have come from in vitro studies and murine models, we lack definitive evidence to prove that ANCA seropositivity is crucial to disease pathogenesis in humans. The absence of ANCA in many patients with Wegener granulomatosis and the Churg–Strauss syndrome supports the notion of a nonessential role. However, it does not rule out the possibility that ANCA, when present, may influence disease expression in certain organs. Vasculitis is not a constant feature of lesions in Wegener granulomatosis or the Churg–Strauss syndrome. To think of these disease entities as merely expressions of small-vessel vasculitis is an oversimplification that does not serve to inform discussions of pathogenesis. We conclude that differences in disease presentation, organ involvement, and complications that require unique treatment strategies make this debate clinically relevant and not one that should be dismissed as being merely a matter of “academic haggling.”