© 2006 American Thoracic Society
Rituximab in Refractory Wegener's Granulomatosis: Favorable or Not?To the Editor:We read with interest the recent article by Keogh and colleagues on rituximab in refractory Wegener's granulomatosis (WG) (1). Of note, we have recently reported on eight patients with refractory WG treated with rituximab with less favorable outcomes (2). Several reasons could account for the differences between the two studies. Although patients with refractory clinical manifestations of granulomatous lesions (subglottic stenosis, retroorbital masses) were included in our study, Keogh and coworkers treated patients with clinical signs of small vessel vasculitis (glomerulonephritis, pulmonary hemorrhage, episcleritis, optic neuritis) (1, 2). Differences in outcome between granulomatous and vasculitic lesions have recently become evident (3). Orbital lesions may be at particular disadvantage for successful treatment due to their anatomic site. Among others, Omdal and coworkers reported unresponsiveness of retroorbital granuloma and sinus masses in two of three cases (4). Granulomatous lesions in WG may be a response to ectopic autoantigen presentation with lymphoid tissue formation (5). While peripheral blood CD20+ B-cell depletion is marked with rituximab, it affects only 30 to 40% of CD20+ B cells in lymphoid tissues. CD20+ B cells functioning as antigen-presenting cells could be affected, but the question remains whether long-lived autoantibody-producing CD20– plasma cells are affected by elimination of CD20+ B-cell precursors with rituximab or cylophosphamide. Recent findings in animal models argue against this assumption (6). WG relapses occurring after peripheral blood CD20+ B-cell reconstitution, as evidenced by Keogh and coworkers (1), seems to be an inevitable consequence with rituximab. Differences in rituximab protocols between Keogh and coworkers (four weekly doses of 375 mg/m2) and our study (375 mg/m2 every 4 wk in combination with other immunosuppressants) are unlikely to explain the differences in outcome (1, 2). In vitro studies suggest a dose–response relationship up to a 10- to 25-mg/ml threshold, after which the curve levels off due to receptor saturation. The half-life of rituximab is about 1 week, but the median persistence of active levels is about 3 months. Against this background, the need to infuse the rituximab at 1-week intervals has been questioned. Further, combination of rituximab with chemotherapy has been shown to have additive or synergistic effects in some lymphoma studies, albeit with differences between lymphoma entities (7). In conclusion, further studies are needed to evaluate the actual effect mediated by rituximab and follow differences in organ involvement. Apart from analyzing CD20+ B-cell responses, plasmablast and autoreactive plasma cell responses should be followed more closely to understand effects of rituximab treatment.
University Hospital Schleswig-Holstein, Bad Bramstedt, Germany FOOTNOTES Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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s granulomatosis lesions? Granulomas as potential lymphoid tissue maintaining autoantibody production. Ann N Y Acad Sci 2005;1051:12–19.