Reply

P. Lamprecht, J. Voswinkel, A. Gause and W. L. Gross

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 (20–250 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-{alpha} production in Wegener's granulomatosis by mentioning that granuloma formation and the development of vasculitis are sustained by TH1-like cytokines and TNF-{alpha} and that disruption of this process by targeting TNF-{alpha} [1, 3, 6] may explain the response to infliximab treatment and point to a central role of TNF-{alpha} 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-{gamma} and tumor necrosis factor (TNF)-{alpha} secretion by circulating peripheral blood as well as granuloma CD4+CD28–T cells, point to a major role of this TNF-{alpha} producing T-cell population in the pathogenesis of Wegener's granulomatosis [7, 8]. Phenotypic alterations of this expanded CD4+CD28–T-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-{alpha} production during disease activity, but not in remission [10]. Thus, there is plenty of evidence for the role of TNF-{alpha} 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-{alpha} in Wegener's granulomatosis itself.

Notes

Correspondence to: P. Lamprecht. E-mail: lamprecht{at}rheuma-zentrum.de Back

References

  1. Lamprecht P, Voswinkel J, Lilienthal T et al. Effectiveness of TNF-{alpha} blockade with infliximab in refractory Wegener's granulomatosis. Rheumatology 2002;41:1303–7.[Abstract/Free Full Text]
  2. Savage CO, Harper L, Adu D. Primary systemic vasculitis. Lancet 1997;349:553–8.[CrossRef][ISI][Medline]
  3. Lamprecht P, Arbach O, Voswinkel J et al. Induction of remission with infliximab in therapy-refractory Wegener's granulomatosis—follow-up of six patients. Dtsch Med Wochenschr 2002;127:1876–80.[CrossRef][ISI][Medline]
  4. Reinhold-Keller E, Fink CO, Herlyn K, Gross WL, De Groot K. High rate of renal relapse in 71 patients with Wegener's granulomatosis under maintenance of remission with low-dose methotrexate. Arthritis Rheum 2002;47:326–32.[CrossRef][Medline]
  5. Langford CA, Talar-Williams C, Sneller MC. Use of methotrexate and glucocorticoids in the treatment of Wegener's granulomatosis. Long-term renal outcome in patients with glomerulonephritis. Arthritis Rheum 2000;43:1836–40.[CrossRef][ISI][Medline]
  6. Stone JH, Uhlfelder ML, Hellmann DB, Crook S, Bedocs NM, Hoffman GS. Etanercept combined with conventional treatment in Wegener's granulomatosis: a six-month open-label trial to evaluate safety. Arthritis Rheum 2001;44:1149–54.[CrossRef][ISI][Medline]
  7. Lamprecht P, Moosig F, Csernok E et al. CD28-negative T-cells are enriched in granulomatous lesions of the respiratory tract in Wegener's granulomatosis. Thorax 2001;56:751–7.[Abstract/Free Full Text]
  8. Komocsi A, Lamprecht P, Cseronk E et al. Peripheral blood- and granuloma CD4+CD28–T-cells are a major source of IFN-{gamma} and TNF-{alpha} in Wegener's granulomatosis. Am J Pathol 2002;160:1717–24.[Abstract/Free Full Text]
  9. Appay V, Dunbar PR, Callan M et al. Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat Med 2002;8:379–85.[CrossRef][ISI][Medline]
  10. Lamprecht P, Kumanovics G, Mueller A et al. Elevated monocytic IL-12 and TNF-{alpha} production in Wegener's granulomatosis is normalized by cyclophosphamide and corticosteroid therapy. Clin Exp Immunol 2002;128:181–6.[CrossRef][ISI][Medline]
  11. Bijl M, Horst G, Limburg PC, Kallenberg CG. Expression of costimulatory molecules on peripheral blood lymphocytes of patients with systemic lupus erythematosus. Ann Rheum Dis 2001;60:523–6.[Abstract/Free Full Text]
Accepted 6 February 2003





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