Department of Rheumatology, University Hospital of Schleswig-Holstein, Campus Luebeck, and Rheumaklinik Bad Bramstedt, Ratzeburger Allee 160, 23538 Luebeck, Germany
We should like to address some of the points raised by Dr Rozin's comment on our article [1]. First of all, refractory Wegener's granulomatosis and rheumatoid arthritis are different diseases. Full-blown Wegener's granulomatosis is a potentially hazardous, organ- and/or life-threatening autoimmune disease characterized by granulomatous lesions and a small vessel vasculitis affecting multiple organs [2]. It cannot be expected that any previously published treatment regimens for infliximab in rheumatoid arthritis will prove to be of the same efficacy and no modifications of dosage and/or intervals between infusions be necessary when applied in Wegener's granulomatosis. An indirect reflection of the higher inflammatory activity in refractory Wegener's granulomatosis may have been the observation that a higher dosage of infliximab (5 mg/kg) seemed to be more effective [1]. We did not observe any decrease of efficacy with the regimen reported [1] and no reduction of efficacy upon reinstitution of infliximab therapy in one patient who had a relapse after 12 months of maintenance therapy with azathioprine during follow-up of that patient group [3]. We and others have published data on the efficacy of different treatments for the maintenance of remission in Wegener's granulomatosis such as methotrexate [4, 5]. In contrast to some reports on rheumatoid arthritis and infliximab therapy we have not observed so far any rebound phenomena of inflammatory activity after discontinuation of infliximab therapy and switch to maintenance treatment [1, 3]. However, it seems unlikely that after infliximab therapy the efficacy of maintenance regimens will be principally different from what has previously been reported.
The dosage of corticosteroids was already high (20250 mg prednisolone/day for weeks) and ineffective before we started with the infliximab therapy. Only then a stable remission was induced. We discussed the role of possible additive effects of previous or concomitant treatments as well as adverse effects of concomitant treatments such as in case 3 in our article [1].
It may have escaped Dr Rozin's attention, but we addressed the role of excess TNF- production in Wegener's granulomatosis by mentioning that granuloma formation and the development of vasculitis are sustained by TH1-like cytokines and TNF-
and that disruption of this process by targeting TNF-
[1, 3, 6] may explain the response to infliximab treatment and point to a central role of TNF-
in the pathogenesis of Wegener's granulomatosis [1]. The expansion of circulating T cells lacking the costimulatory molecule CD28 independent of age and immunosuppressive regimen, and interferon-
and tumor necrosis factor (TNF)-
secretion by circulating peripheral blood as well as granuloma CD4+CD28T cells, point to a major role of this TNF-
producing T-cell population in the pathogenesis of Wegener's granulomatosis [7, 8]. Phenotypic alterations of this expanded CD4+CD28T-cell population are reminiscent of so-called late or effector memory T cells and suggest a general alteration of the cellular immune response in Wegener's granulomatosis [8, 9]. Moreover, monocytes also show an increased TNF-
production during disease activity, but not in remission [10]. Thus, there is plenty of evidence for the role of TNF-
in the pathogenesis of Wegener's granulomatosis from several studies. In contrast, the cytokine profile as well as the phenotype of T cells in systemic lupus erythematosus is different from Wegener's granulomatosis [11]. Therefore, one should be cautious in drawing conclusions from autoimmune diseases with different cytokine profiles on the role of any vicious cycles' and concentrate on the study of TNF-
in Wegener's granulomatosis itself.
Notes
Correspondence to: P. Lamprecht. E-mail: lamprecht{at}rheuma-zentrum.de
References