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Drs. Sari and Akkoc reply To the Editor: We appreciate Bhatia and Kast's interest in our case report and welcome their valuable comments. They argue that etanercept treatment can sometimes lead to increased tumor necrosis factor-a (TNF-a) concentrations that may occasionally contribute to occurrence of TNF mediated disease, as in the case we described1. They state there have been at least 7 studies showing an increase in TNF levels during etanercept treatment2-8. One report7 actually reviewed the results of another study that was cited by them and also in our case report6. This study suggested an increase in the number of interferon-g (IFN-g) and TNF-a-secreting T cells after nonspecific antigen stimulation after etanercept therapy in patients with ankylosing spondylitis. However, no data of serum TNF levels were given in that study. The rest of the studies were mostly performed in patients with nonrheumatic conditions including myeloma5, breast cancer2, or renal transplant8, or in healthy volunteers given endotoxin4. These studies and another3 conducted in patients with TNF-receptor associated periodic syndrome (TRAPS)3 all reported increased levels of immunoreactive TNF. In 3 of these studies TNF bioactivity was measured by cytotoxicity assays and was found not to be increased3,4,8. Preclinical and clinical studies have demonstrated that etanercept prolongs the half-life of TNF8,9, and increased TNF levels observed in these studies are probably due to the carrier effect of etanercept. Bhatia and Kast claim that etanercept-bound soluble TNF may sometimes exert its physiological signaling effects either by dissociation from etanercept or while still retained by it. However, this is very unlikely considering that TNF must be present for extended periods of time to achieve maximal biologic activity10. The development of psoriasis in our patient in the presence of marked improvement of arthritic symptoms (which are certainly also TNF mediated) also contradicts their hypothesis, suggesting a role for increased TNF levels in the circulation in the occurrence of psoriasis in our patient1. Occurrence of psoriasis or psoriasiform lesions after anti-TNF therapy, despite a good clinical response in arthritic symptoms, has also been observed by others10a. Psoriasis has been reported not only with etanercept therapy, but also with infliximab and adalimumab, which have not been shown to lead to increased TNF levels in the serum. Interestingly, our patient who developed psoriasis after etanercept therapy did not develop any psoriatic lesion after infliximab within a followup of 15 months. We pointed out in our report that etanercept6, but not infliximab11, has been shown to upregulate local secretions of TNF-a and IFN-g, and proposed that this differential effect of the 2 TNF inhibitors could provide an explanation for the occurrence of psoriasis in our patient under treatment with etanercept, but not infliximab. However, there are reports of other cases that developed psoriasis with infliximab but not with etanercept1. It is likely that different mechanisms may play a role in different patients. We agree that etanercept treatment may be associated with other TNF mediated diseases, such as Crohn's12, in which infliximab is efficacious13. Uveitis is another condition that can be successfully treated with infliximab, but that can occur as an adverse effect of etanercept14. However, worsening of congestive heart failure (CHF) has been reported with both TNF inhibitors15. The review Bhatia and Kast cite describing 4 cases of new-onset CHF associated with etanercept use in patients under age 50 also reports 6 cases associated with infliximab therapy16. Moreover, a randomized controlled trial with infliximab for treatment of CHF was also stopped early due to increased morbidity and mortality17. We believe the increased TNF levels reported in some studies cannot alone explain the occurrence of the paradoxical adverse effects such as psoriasis that have been reported not only with etanercept, but also with the other TNF inhibitors. We believe monitoring patients under etanercept therapy for detectable TNF levels is of questionable clinical value at best, and probably not necessary. ISMAIL SARI, MD, Specialist of Internal Medicine; NURULLAH AKKOC, MD, Professor of Internal Medicine, Department of Internal Medicine, Division of Rheumatology, Dokuz Eylul University School of Medicine, Izmir, Turkey. Address reprint requests to Dr. N. Akkoc, Dokuz Eylul Universitesi Tip Fakultesi, Ic Hastaliklari AD, Romatoloji BD, 35340 Inciralti, Izmir, Turkey. E-mail: nurullah.akkoc@deu.edu.tr REFERENCES 1. Sari I, Akar S, Birlik M, Sis B, Onen F, Akkoc N. Anti-tumor necrosis factor-alpha-induced psoriasis. J Rheumatol 2006;33:1411-4. [MEDLINE] 2. Madhusudan S, Foster M, Muthuramalingam SR, et al. A phase II study of etanercept (Enbrel), a tumor necrosis factor alpha inhibitor in patients with metastatic breast cancer. Clin Cancer Res 2004;10:6528-34. [MEDLINE] 3. Nowlan ML, Drewe E, Bulsara H, et al. Systemic cytokine levels and the effects of etanercept in TNF receptor-associated periodic syndrome (TRAPS) involving a C33Y mutation in TNFRSF1A. Rheumatology Oxford 2006;45:31-7. [MEDLINE] 4. Suffredini AF, Reda D, Banks SM, Tropea M, Agosti JM, Miller R. Effects of recombinant dimeric TNF receptor on human inflammatory responses following intravenous endotoxin administration. J Immunol 1995;155:5038-45. [MEDLINE] 5. Tsimberidou AM, Waddelow T, Kantarjian HM, Albitar M, Giles FJ. Pilot study of recombinant human soluble tumor necrosis factor (TNF) receptor (p75) fusion protein (TNFR:Fc; Enbrel) in patients with refractory multiple myeloma: increase in plasma TNF alpha levels during treatment. Leukemia Res 2003;27:375-80. [MEDLINE] 6. Zou J, Rudwaleit M, Brandt J, Thiel A, Braun J, Sieper J. Upregulation of the production of tumour necrosis factor alpha and interferon gamma by T cells in ankylosing spondylitis during treatment with etanercept. Ann Rheum Dis 2003;62:561-4. [MEDLINE] 7. Zou JX, Braun J, Sieper J. Immunological basis for the use of TNF-a-blocking agents in ankylosing spondylitis and immunological changes during treatment. Clin Exp Rheumatol 2002;20 Suppl 28:S34-7. 8. Eason JD, Pascual M, Wee S, et al. Evaluation of recombinant human soluble dimeric tumor necrosis factor receptor for prevention of OKT3-associated acute clinical syndrome. Transplantation 1996;61:224-8. [MEDLINE] 9. Mohler KM, Torrance DS, Smith CA, et al. Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists. J Immunol 1993;151:1548-61. [MEDLINE] 10. Engelberts I, Moller A, Leeuwenberg JF, van der Linden CJ, Buurman WA. Administration of tumor necrosis factor alpha (TNF alpha) inhibitors after exposure to TNF alpha prevents development of the maximal biological effect: an argument for clinical treatment with TNF alpha inhibitors. J Surg Res 1992;53:510-4. [MEDLINE] 10a. Kary S, Worm M, Audring H, et al. New onset or exacerbation of psoriatic skin lesions in patients with definite rheumatoid arthritis receiving tumour necrosis factor alpha antagonists. Ann Rheum Dis 2006;65:405-7. [MEDLINE] 11. Zou J, Rudwaleit M, Brandt J, Thiel A, Braun J, Sieper J. Down-regulation of the nonspecific and antigen-specific T cell cytokine response in ankylosing spondylitis during treatment with infliximab. Arthritis Rheum 2003;48:780-90. [MEDLINE] 12. Oh J, Arkfeld DG, Horwitz DA. Development of Crohn's disease in a patient taking etanercept. J Rheumatol 2005;32:752-3. [MEDLINE] 13. Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. New Engl J Med 1997;337:1029-35. [MEDLINE] 14. Taban M, Dupps WJ, Mandell B, Perez VL. Etanercept (enbrel)-associated inflammatory eye disease: case report and review of the literature. Ocul Immunol Inflamm 2006;14:145-50. [MEDLINE] 15. Mann DL. Targeted anticytokine therapy and the failing heart. Am J Cardiol 2005;95:9C-16C; 38C-40C. [MEDLINE] 16. Kwon HJ, Cote TR, Cuffe MS, Kramer JM, Braun MM. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med 2003;138:807-11. [MEDLINE] 17. Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate to severe heart failure: results of the Anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 2003;107:3133-40. [MEDLINE]
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