 |
|
|
 |
 Interferon-a (IFN-a) Application Versus Tumor Necrosis Factor-a Antagonism for Ocular Behçet's Disease: Focusing More on IFN To the Editor: We read with interest the article by Ohno, et al1, on the efficacy of infliximab in 13 patients with Behçet's disease (BD) and refractory uveitis and the corresponding editorial by Rosenbaum2 in the same issue. Ohno, et al present the first open label trial in a "larger" group of patients with BD and cyclosporin A (CSA) and glucocorticoid resistant uveoretinitis. There have been case reports on infliximab for this indication before2-5. The number of ocular attacks decreased significantly during the 51-day (median) observation period. However, some points must be addressed: The dosage chosen (5 mg and 10 mg/kg body weight) was high (standard dosage for rheumatoid arthritis would be 3 mg/kg bw) and hence treatment becomes very expensive. Neutralizing anti-mouse-antibodies were measured positive in 7 patients; these probably will develop in a relatively high number of patients considering the high dosages given. Adverse events were quite common, about one-third of patients experienced diarrhea, cold, nausea or vomiting, and changes in blood pressure. In one patient latent tuberculosis was reactivated. In 2 patients in the 10 mg group, antinuclear antibodies without clinically overt symptoms of autoimmune disease developed. The extraocular manifestations of BD did not respond as well; especially folliculitis and oral aphthous ulcers in individual patients did not respond to treatment. Finally, patients relapsed when infliximab was discontinued for more than 12 weeks. It remains to be determined if these relapses can be prevented by longterm administration and if infliximab can ever be discontinued without relapses of ocular attacks. Thus, when comparing these results to those from our own open label study on interferon-a2a (IFN-a2a) for treatment resistant posterior or panuveitis in BD6,7, they seem very similar with respect to the rate of response, which was 92% in our 50 patients. There were similar adverse events at comparable frequency; however, due to the different mode of action of IFN, which is more immunomodulatory than immunosuppressive, infections were not observed. In contrast, psoriasis occurred and autoimmune thyroiditis was seen in 2 and 3 patients, respectively, with IFN-a2a. With IFN-a2a we also observed differential efficacy, meaning that although ocular manifestations dramatically improved, oral aphthae did not7. Visual acuity improved from 0.56 to 0.84 after 24 weeks. In more than 60% of the patients (unpublished data, at the time of publication 40%) IFN has been stopped without relapse. This has not been shown for any other treatment of BD uveitis up to now. We recently published the first results for the visual acuity after 5 years, and were able to show that the improved visual acuity after IFN treatment was preserved -- the 5-year data after IFN are significantly better when compared to those for immunosuppressants8. Thus, considering and comparing the data published until now (and we are not the only group with positive experiences with IFN-a for ocular BD -- Wechsler, et al from Paris and Krause, et al from Berlin published similar results9,10), IFN-a appears to be at least as effective as infliximab, providing quick responses (time to response 2 weeks) and having similar, possibly less serious side effects. The main advantage of IFN-a is the possibility of discontinuation of treatment without relapse and the preservation of visual acuity. Prof. Rosenbaum states in the corresponding editorial to the article of Ohno, et al11 that he would certainly prefer TNF antagonists to IFN for the treatment of resistant ocular BD. This is his personal opinion, which he explains with his own experience, being much better for 9 patients treated with infliximab and inferior for an unnamed number of IFN treated patients. He may have used IFN in combination with immunosuppressants, which is counterintuitive, because most immunosuppressants, especially glucocorticoids, block exactly those signal transduction pathways IFN utilizes for its diverse effects on the immune system and thus diminish its efficacy. We, too, treated 2 patients who did not respond adequately to IFN with infliximab, and achieved remission of ocular inflammation. In our experience, when using it as a monotherapy, IFN-a2a is effective in over 90% of the cases, and this has not changed after publication of the data on 50 patients in 2003. As IFN can be discontinued without relapse in at least 50% of the patients and is much cheaper than infliximab in a dosage of 5 to 10 mg/kg, and the number of studies and case reports on IFN for BD, and thus the number of published patients treated, is much higher for IFN-a (more than 300, summarized in12) than for infliximab (about 40), in these times of evidence-based medicine, we would primarily treat our treatment-resistant patients with ocular BD with IFN, and in case of inefficacy, switch them to infliximab. As Prof. Rosenbaum states, a randomized controlled trial is necessary, but first, each of the agents discussed here (IFN-a2a and infliximab) should be tested against the standard immunosuppressive regimen (e.g., CSA plus steroids) and then, in a second step, when proven superior to or at least adequate to the standard, against each other. We have just started a national randomized, single-blind trial of IFN-a2a versus CSA in Germany and hope that a similar trial will be done for infliximab. INA KÖTTER, MD, Internal Medicine/Rheumatology/Haematology/ Oncology, University Hospital, Department of Internal Medicine II; CHRISTOPH DEUTER, MD; NICOLE STÜBIGER, MD; MANFRED ZIERHUT, MD, University Hospital, Department of Ophthalmology, Tübingen, Germany. REFERENCES 1. Ohno S, Nakamura S, Hori S, et al. Efficiacy, safety, and pharmacokinetics of multiple administration of infliximab in Behçet's disease with refractory uveoretinitis. J Rheumatol 2004;31:1362-8. 2. Sfikakis PP, Theossiadis PG, Katsari CG, Kaklamanis P, Markomichelakis NN. Effect of infliximab on sight-threatening panuveitis in Behçet's disease. Lancet 2001;58:295-6. 3. Triolo G, Vadala M, Accardo-Palumbo A, et al. Anti-tumour necrosis factor monoclonal antibody treatment for ocular Behçet's disease. Ann Rheum Dis 2002;61:560-1. 4. Sfikakis PP, Kaklamanis PH, Elezoglu A, et al. Infliximab for recurrent, sight-threatening ocular inflammation in Adamantiades-Behçet disease. Ann Intern Med 2004;140:404-6. 5. Gulli S, Arrigo C, Bocchino L, et al. Remission of Behçet's disease with anti-tumour necrosis factor monoclonal antibody therapy: a case report. BMC Musculoskelet Disord 2003;4:19. 6. Kötter I, Zierhut M, Eckstein AK, et al. Human recombinant interferon alfa 2a for the treatment of Behçet's disease with sight threatening posterior or panuveitis. Br J Ophthalmol 2003; 87:423-31. 7. Kötter I, Vonthein R, Zierhut M, et al. Differential efficacy of human recombinant interferon-alpha 2a on ocular and extraocular manifestations of Behçet's disease: results of an open 4-center-trial. Semin Arthritis Rheum 2004;33:311-9. 8. Deuter CME, Kötter I, Günaydin I, Zierhut M, Stübiger N. Augenbeteiligung bei Morbus Behçet: erste 5-Jahres Ergebnisse zur Visusentwicklung nach Therapie mit Interferon alfa-2a. Ophthalmologe 2004;101:129-34. 9. Wechsler B, Bodaghi B, Huong DL, et al. Efficacy of interferon-alfa-2a in severe and refractory uveitis associated with Behçet's disease. Ocul Immunol Inflamm 2000;8:293-301. 10. Krause L, Turnbull JR, Torun N, Pleyer U, Zouboulis CC, Foerster MH. Interferon-alfa 2a in the treatment of ocular Adamantiades-Behçet disease. Adv Exp Med Biol 2003;528:511-9. 11. Rosenbaum JT. Blind insight: eyeing anti-tumor necrosis factor treatment in uveitis associated with Behçet's disease. J Rheumatol 2004;31:1241-3. 12. Kötter I, Günaydin I, Zierhut M, Stübiger N. The use of interferon alpha in Behçet disease: Review of the literature. Semin Arthritis Rheum 2004;33:320-35.
|