© 2006 American Thoracic Society
Rituximab in Refractory Wegener's Granulomatosis: Favorable or Not?From the Authors:With regard to their comments on our recent article (1), we agree with Drs. Aries, Lamprecht, and Gross that further studies are needed before we fully understand the exact role of rituximab in the management of Wegener's granulomatosis. We did read with interest their recent report (2) suggesting a less favorable response to rituximab in Wegener's granulomatosis than in our studies (1, 3). The authors postulate that this difference in outcomes may be due to primarily vasculitic manifestations in our patients, versus granulomatous manifestations in theirs. We would like to clarify here that the majority of our patients, both in this prospective pilot trial (9/10) (1), and in our initial compassionate use series (5/11) (3), had granulomatous disease manifestations in addition to those caused predominantly by vasculitis affecting small vessels and capillaries. Predominantly granulomatous disease manifestations included nose and sinus inflammation, pulmonary involvement with multiple pulmonary nodules, and retroorbital disease. Both the vasculitic and the granulomatous disease manifestations responded to rituximab in our study populations. Therefore, the primary difference between our studies and that of Aries and colleagues would appear to be our different rituximab dosing regimens rather than differences in disease manifestations. We utilized the standard lymphoma treatment regimen for single-agent rituximab use, which is a weekly dosing schedule (1, 3). Pharmacokinetic studies in lymphoma populations have shown wide individual variability in drug half-life, as well as prolongation of half-life with subsequent infusions following the above protocol. In one study mean half-life measurements varied between 13 and 371 h (4). While varying tumor burden contributes to this via binding and consumption of rituximab, there are likely additional individual factors that may also be relevant to a Wegener's population and could therefore lead to underdosing when rituximab is given on a monthly basis. This may then also allow for the formation of antichimeric molecule antibodies, which may further affect efficacy. We agree with Aries and colleagues that there is a need for further formal prospective study of rituximab in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis. To that end, a randomized, double-blind, double placebo-controlled, multicenter trial is being conducted in 200 patients with ANCA-associated vasculitis. This trial is designed to evaluate the efficacy of rituximab for remission induction in severe Wegener's granulomatosis and microscopic polyangiitis in comparison to cyclophosphamide (www.clinicaltrials.gov). As part of the trial, associated mechanistic studies are being conducted to identify individual patient characteristics, which influence or predict the degree and duration of the therapeutic efficacy of B-cell depletion as well as of standard therapy.
Mayo Clinic College of Medicine, Rochester, Minnesota FOOTNOTES Conflict of Interest Statement: K.A.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. F.C.F. received $90,733 in 2003 from Roche Pharmaceutical and $175,000 in 2005 from Genentech in support of investigator-initiated research grants. U.S. received $32,690 in 2002 and 2003 from Genentech in support of an investigator-initiated research grant. REFERENCES
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
