Indian Journal of Pharmacology Medknow Publications on behalf of Indian Pharmacological Society ISSN: 0253-7613 EISSN: 1998-3751 Vol. 36, Num. 1, 2004, pp. 10-14

Indian Journal of Pharmacology, Vol. 36, No. 1, Feb, 2004, pp. 10-14

Educational Forum

AntiTNF-a strategy: Present status of this therapeutic paradigm

J. Singh, A. Suruchi

Department of Pharmacology, PGIMS, Rohtak - 124001, India.
Correspondence to: J.Singh E-mail: suruchiaditya@rediffmail.com

Received: 10.2.2003
Revised: 17.9.2003
Accepted: 20.9.2003

Code Number: ph03004

Abstract

Tumor necrosis factor-alpha (TNF-a), a proinflammatory cytokine is involved in the pathophysiology of a number of disorders including Crohn's disease, rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. AntiTNF-a strategies target this pathogenic element to provide clinical benefit. The various strategies are in preliminary stage of experimentation and much remains to be elucidated before these are applied clinically. Though antiTNF-a therapy is currently approved only for rheumatoid arthritis and Crohn's disease, the future of this therapeutic paradigm holds much promise. The number of official indications for strategies against this biologic agent are likely to increase to include congestive heart failure, psoriasis, asthma, septic shock, stroke and malignancy. This will make it a truly broad spectrum therapeutic weapon currently available to us.

Key Words: AntiTNF-a therapy, etanercept, infliximab, tumor necrosis factor.

Introduction

Tumor necrosis factor-alpha (TNF-a) is a multi-functional cytokine with important role in immune response, inflammation and response to injury.¹ TNF family is primarily involved in regulation of cell proliferation and apoptosis.¹ TNF-a has also been shown to have an important role in cell death through a variety of mechanisms including second messenger pathways, arachidonate metabolism, protein kinase, oxygen free radicals, nitric oxide, transcription of a variety of cytotoxic genes, regulation of nuclear regulatory factors, ADP-ribosylation and potentially DNA fragmentation.¹ TNF regulates expression of a variety of peptide regulatory factors including IL-1, IL-6, platelet derived growth factor, transforming growth factors-ß as well as a group of eicosanoids and hormones including platelet activating factors and adrenaline.¹ It is now well recognized that TNF-a participates in the pathophysiology of various diseases/conditions including diabetes, multiple sclerosis, autoimmune diseases, cachexia, parasitic infections, AIDS,² asthma,³ stroke,⁴ rheumatoid arthritis (RA),⁵ Crohn's disease,⁶ neurodegenerative disorders and malignancy.⁷ However, the role of TNF-a in the pathogenesis of malignancies remains controversial. Indeed, recent studies have demonstrated a causative role for TNF-a in a group of diseases including septic shock,⁸ pre-eclampsia,⁹ hemolytic uremic syndrome, allograft rejection, regional enteritis, and congestive heart failure.¹⁰ This review describes the role of TNF-a antagonists as a potential therapeutic weapon in various clinical conditions.

Clinical strategies for antiTNF-a therapy

AntiTNF strategies are aimed at blocking activity of TNF-a either through antiTNF-a antibody or administration of soluble TNF receptor to mop up circulating TNF-a. In addition to these, some proteins, TNF secretion/production inhibitors and expression inhibitors are also available^11-24 (Table 1).

AntiTNF-a therapy for rheumatoid arthritis

TNF-a increases in rheumatoid joints and has a potential role in the establishment of rheumatoid synovitis and joint destruction.⁵ The use of TNF-a antagonists has taught us that selective targetting of a pathogenic element can provide substantial benefit, setting a new therapeutic standard for RA.⁵ AntiTNF-a therapy induces a rapid improvement in multiple clinical assessment of disease activity including morning stiffness, pain score, Ritchre articular index and swollen joint count. The clinical benefits are associated with an improvement in some serological parameters and histological features of the synovium.²⁵ Several controlled clinical trials have clearly demonstrated short and middle term efficacy and safety profile of antiTNF-a therapy²⁶ and they will soon become available worldwide. Infliximab and etanercept have been approved in US and Europe for treating RA.²⁷ A multicentric double blind placebo controlled phase III clinical trial on 428 patients with active RA has shown that infliximab (3 mg/kg, every 4-8 weeks or 15 mg/week) + methotrexate for 3 weeks was more efficacious than methotrexate alone in patients with active RA not previously responding to methotrexate.²⁸ However, some questions remain unresolved concerning their place in the general therapeutic strategy against RA, due to uncertainties of their use in the long run. If clinical efficacy is sustained and the safety profile remains benign over long term, TNF-a antagonists may replace methotrexate as a gold standard and become the agent of choice for combination therapy in RA. Further studies are needed to clarify their ultimate position in the therapeutic algorithm. Ankylosing spondylitis has also been successfully treated with infliximab.^29,30 Similarly antiTNF strategies are being targeted at chronic inflammatory arthritides,¹² such as psoriatic arthritis, sarcoidosis arthritis, idiopathic juvenile arthritis and spondyloarthropathy.

AntiTNF-a therapy in Crohn's disease

TNF is considered to be a crucial mediator of Crohn's disease (CD). Inflammatory cells of gastrointestinal lesions produce TNF and its concentration is increased in serum, tissue and stool. Present et al³¹ demonstrated that single i.v. infusion of infliximab (10 mg/kg) decreased the CD activity index score with improvement in colonoscopic evaluation. Infliximab has been found to be very effective in the treatment of fistula in patients with CD.³¹ Similar results have been reported in a controlled trial with etanercept.³²

AntiTNF-a therapy in diabetes

There is complex relationship between TNF-a and diabetic complications. TNF-a related apoptosis inducing ligand (TRAIL) is involved in ß cell damage leading to type I diabetes, causes insulin resistance, interferes with insulin signaling and influence the formation of atherosclerotic vascular lesions in diabetic patients.³³ Increased TNF-a levels in patients with diabetes has been demonstrated and determination of TNF-a levels might offer a diagnostic tool to determine patients at high risk.³⁴ Based on the available data, it can be inferred that antiTNF-a therapy may be beneficial in reducing the complications of diabetes, though no reports are available so far demonstrating them as potential therapeutic candidate.

AntiTNF-a therapy in congestive heart failure

TNF-a and other cytokines have been shown to be elevated in patients with end stage heart failure, heart failure due to myocarditis and ischemic and idiopathic dilated cardiomyopathy (CMP).¹⁰ TNF-a exerts negative inotropic effect, recapitulates cellular and biochemical abnormalities that characterise the failing human heart, uncouples ß-adrenergic receptors from adenylate cyclase, activates metalloproteinases and provokes a hypertrophic growth response in cardiac myocytes.¹⁰ TNF-a expression/production inhibitors have been shown to possess therapeutic utility in the management of patients with CHF. For an antiTNF-a drug to be useful in heart failure, it should not only be highly effective in reducing TNF-a levels but should also have other positive actions and should be orally active and cheap. As yet, no drug fits this description. Davey and Ashrafian¹⁷ demonstrated the therapeutic benefits of thalidomide and its derivatives in management of advanced heart failure. Recently, recombinant soluble TNF-a protein (S TNFR²) have been shown to be safe and capable of reducing raised levels of TNF-a-concomitantly lessening the severity of heart failure in patients with NYHA class III CHF.³⁵ Intravenous infusion of etanercept increased exercise tolerance, ejection fraction and reported life score.³⁵ Despite beneficial effects with antiTNF-a therapy, both hypertrophy and fibrosis persist suggesting early but not late therapy, using anticytokine approaches might benefit patients with CHF.

demonstrated beneficial effect of grepafloxacin (a new fluoroquinolone) in controlling chronic airway inflammatory disease via expression of inhibitory TNF-a induced IL-8 mRNA. Therefore, an inhibitory effect of antiTNF-a therapy on IL-8 production may apply to the treatment of chronic airway inflammatory disease. However, further investigations are needed to clarify this point. Treatment directed specifically at a reduction in TNF-a activity may be useful as a glucocorticoid sparing asthma therapy. AntiTNF-a therapy may also be effective in the treatment of certain allergic conditions including Jarisch-Herxheimer reaction.³⁷ It is well established that recruitment of neutrophils and eosinophils associated with allergic condition is mediated via TNF-a.¹

AntiTNF-a therapy in sepsis and shock

TNF-a is a principal mediator in the pathophysiology of septicemia and elevated levels of TNF-a have been reported in patients with sepsis.^8,11 Attempts to block TNF-a activity have been associated with improved survival in animal models of sepsis and shock.¹¹ In human studies, 7.5 mg/kg, TNF-a monoclonal antibody provided a significant reduction in mortality 30 days after infusion.³⁸ Antibodies have been found effective in reducing early morbidity and mortality but no reduction in 28 days mortality. Drugs that modify TNF in vivo may be an useful component of future management of sepsis either as monotherapy or as part of combined strategy of immunomodulators. Afelimomab has been tested in 7300 patients with septic shock and found to be efficacious and well tolerated.¹¹ However, in sepsis, findings have not been so convincing. The use of antiTNF-a in the wrong patient or at the wrong time may do more harm than good. Although antiTNF-a such as afelimomab may yet prove valuable in treatment of carefully selected patients with severe sepsis, further work is needed to clarify the selection criteria of patients who will be benefited the most.

AntiTNF-a therapy in malignancy

TNF-a promotes cell growth, differentiation, tissue remodeling and tumorigenesis.¹⁶ On the other hand, recombinant TNF-a is reported to be selectively cytotoxic for some tumor cell lines and causes necrosis of certain murine tumors. Although TNF promotes angiogenesis,⁷ antiangiogenic effect on tumor microvasculature has also been reported.³⁹ Therefore, the role of TNF-a in the pathogenesis of malignancies remains controversial. However, direct relationship between the level of TNF expression and tumor grades in ovarian cancer has been reported.⁴⁰ Naylor et al⁴⁰ demonstrated the therapeutic potential of antiTNF therapy in human epithelial ovarian cancer. Monoclonal antibodies against TNF-a have proved successful in ameliorating cachexia of cancer.¹⁶ Skin tumors such as basal cell carcinoma have been shown to be associated with TNF microsatellites.⁴¹ Although a few preliminary studies have demonstrated beneficial effect of antiTNF therapy in ovarian and colorectal cancers, much remains to be elucidated as far as exact place of anti-TNF therapy in cancer treatment is concerned. The TRAIL offers great promise in cancer therapy. Soluble recombinant versions of the TRAIL molecule have exhibited specific tumoricidal activity against a variety of tumors alone, or in combination with other cancer treatments.⁴² The TRAIL effector pathway appears to be a vital component of immunosurveillance of tumor cells, stimulating more hope that manipulating TRAIL activity is a natural path to improved cancer immunotherapy. Lin et al⁴³ found that breast cancer cell lines resistant to chemotherapy or to recombinant TRAIL protein are susceptible to TRAIL gene therapy suggesting that combination of TRAIL gene therapy and chemotherapy is effective in the treatment of metastatic diseases. TRAIL therapy is now being tried in a wide variety of neoplasms.

AntiTNF therapy in dermatology

AntiTNF-a arsenal is an exciting addition to dermatologic therapy. New molecules are expected to enrich the antiTNF-a arsenal. A recently reported double blind trail by Chaudhari et al⁴⁴ showed a greater than 75% improvement in psoriasis, area and severity index score at week 10, in 9 out of 11 (82%) patients receiving infliximab 5 mg/kg at weeks 0, 2 and 6, indicating efficacy and rapidity of onset of therapeutic effect similar to cyclosporine. Etanercept has been shown to possess good efficacy in moderate to severe psoriasis.⁴⁵ Encouraging sporadic results suggest potential indications in Behcets disease, bullous dermatitis, neutrophilic dermatitis, toxic epidermal necrolysis, systemic vasculitis, pyoderma gangrenosum⁴⁶ and pustular dermatitis.⁴⁷ A recent report by Warnnissorn et al⁴⁸ has shown involvement of TRAIL in atopic dermatitis.

AntiTNF-a therapy in other conditions

Beneficial role of antiTNF-a therapy has also been demonstrated in various clinical conditions such as alcoholic hepatitis,⁴⁹ cerebral malaria,⁵⁰ hemolytic uremic syndrome,¹⁶ preeclampsia,⁹ allograft rejection,¹⁶ otitis media,⁵¹ snakebite,⁵² erythema nodosum and other granulomatous diseases.⁵³ Potential new indications include, adult Still's disease, myelodysplastic syndromes,⁵⁴ graft versus host disease⁵⁴ uveitis,⁵⁴ dermatomyositis and polymyositis.⁵⁵

Adverse effects

Early experience with antiTNF-a therapy has identified 7 types of adverse effects that seem to be of particular concern (a) infection including sepsis and tuberculosis (b) malignancies such as lymphoma (c) hematological disorders such as anemia and pancytopenia (d) demyelinating disorders and neuropathy (e) exacerbation of CHF (f) production of autoantibodies and autoimmune responses (immunosuppression) (g) infusion related problems (as hypersensitivity pain, erythema, localized rash and hemorrhage at injection site. Immunocompromised and geriatric patients are at increased risk of severe side effects.^29,30 Blockers of TNF have been associated with occurrence of cutaneous vasculitis also.⁵⁶ Therefore, antiTNF-a therapy can be labeled as a double edged sword.

Conclusion

AntiTNF-a therapy is currently approved for the treatment of rheumatoid arthritis and Crohn's disease. It is clear that the number of official indications for antiTNF-a therapy will increase to include congestive heart failure, psoriasis, malignancy and asthma. However, the compound has already gained a unique niche as a biologic therapy. Exciting pilot studies are being done on TNF-a antibodies to find their utility in clinical conditions such as septic shock, diabetes, stroke and multiple sclerosis. Finally, it may be anticipated that new indications will be discovered for these agents-making it a truly broad-spectrum therapeutic weapon currently available.

References

1. Huang Y, Krein PM, Muruve DA, Winston BW. Complement factor B gene regulation: Synergistic effects of tumor necrosis factor-alpha and interferon-gamma in macrophages. J Immunol 2002;169:2627-35.
2. Berleth ES, Nadadur S, Henn AD, Eppolito C, Shiojiri S, Gurtoo HL, et al. Identification, characterization and cloning of TIP-B1, a noval protein inhibitor of tumor necrosis factor induced lysis. Cancer Res 1999;59:5497-506.
3. Thomas PS. Tumor necrosis factor alpha: The role of this multiple cytokine in asthma. Immunol Coll Biol 2001;79:132-40.
4. Zaremba J. Contribution of tumor necrosis factor alpha to the pathogenesis of stroke. Folia Morphol 2000;59:137-43.
5. Keystone EC. Tumor necrosis factor-alpha blockade in the treatment of rheumatoid arthritis. Rheum Dis Clin North Am 2001;27:427-43.
6. van Balkon BP, Schoon EJ, Stockbrugger RW, Walters FL, van Hogezand RA, van Deventer SJ, Oldenburg B. Effect of antiTNF-a therapy on quality of life in Crohn's disease. Aliment Pharmacol Ther 2002;16:1101-7.
7. Lilli C, Marinucci L, Bellocchio S, Ribatti D, Balducci C, Baroni T, et al. Effects of TGF-ß1 and TNF-alpha on cultured fibroblast from skin fibroma as modulated by toremifene. Int J Cancer 2002;98:824-32.
8. Appoloni O, Dupont E, Vandercruys M, Andriens M, Duchateau J, Vincent JL. Association of TNF-alpha allele with plasma TNF-alpha levels and mortality from septic shock. Am J Med 2001;110:486-8.
9. Kupfermine MJ, Peaceman AM, Wigton TR, Rehnberg KA, Socol ML. Tumor necrosis factor-alpha is elevated in plasma and amniotic fluid of patients with severe preeclampsia. Am J Obstet Gynecol 1994;170:1752-7.
10. Henriksen PA, Newby DE. Therapeutic inhibition of tumor necrosis factora in patients with heart failure: cooling an inflamed heart. Heart 2003;89:14-8.
11. Vincent JL. Afelimomab. Int J Clin Pract 2000;54:190-3.
12. Markhan A, Lamb HM. Infliximab: A review of its use in the management of rheumatoid arthritis. Drugs 2000;59:1341-59.
13. Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, et al. Adalimumab, a fully human antiTNF-a monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: The ARMADA trial. Arthritis Rheum 2003;48:35-45.
14. Sandborn J. Strategies for targeting tumor necrosis factor in inflammatory bowel disease. Best Pract Clin Gastroenterol 2003;17:105-17.
15. Rechless J, Tatalick LM, Grainger DJ. The pan-chemokine inhibitor NR58-3.14.3 abolishes tumour necrosis factor-alpha accumulation and leucocyte recruitment induced by lipopolysaccharide in vivo. Immunology 2001;103: 244-54.
16. Feldman AM, Combes A, Wagner D, Kadakomi T, Kubota T, Li YY, Mc-Tiernan C. The role of tumor necrosis factor in the pathophysiology of heart failure. J Am Coll Cardiol 2000;35:537-44.
17. Davey PP, Ashrafian H. New therapies for heart failure: is thalidomide the answer? QJM 2000;93:305-11.
18. Hashimoto S, Matsumoto K, Gon Y, Maruoka S, Hayashi S, Asai Y, et al. Grepafloxacin inhibits tumor necrosis factor-alpha-induced IL-8 expression in human airway epithelial cells. Life Sci 2000;66:77-82.
19. Van Rijan MML, Metselaar HJ, Hommes M, Ijzermans JN, Tilanus HW, Kwekkeboam J. Mycophenolic acid is a potent inhibitor of the expression of tumor necrosis factor and tumor necrosis factor receptor superfamily costimulatory molecules. Immunology 2003;109:109-16.
20. Gahring LC, Carlson NG, Weiggel WA. Alcohol blocks TNF-alpha but not other cytokine-mediated neuroprotection to NMDA. Alcohol Clin Exp Res 1999;23: 1571-9
21. Zhang XW, Thorlacius H. Inhibitory actions of ropivacaine on TNF-alpha-induced leukocyte adhesion and tissue accumulation in vivo. Eur J Pharmacol 2000;392:1-3.
22. Salas A, Sans N, Soriano A, Reverter JC, Anderson DC,Pique JM, et al. Heparin attenuates TNF-alpha-induced inflammatory response through a CD-11b dependent mechanism. Gut 2000;47:88-96.
23. Chandel NS, Trzyna WC, McClintock DS, Schumacker PT. Role of oxidants in NF-KB activation and TNF-alpha gene transcription induced by hypoxia and endotoxin. J Immunol 2000;165:1013-21.
24. Manna SK, Mukhopadhyay A, Aggarwal BB. Resveratrol suppresses TNF-induced activation of nuclear transcription factor NF-KB, activator protein-1 and apoptosis: Potential role of reactive oxygen intermediates and lipid peroxidation. J Immunol 2000;164:6509-19.
25. Camussi G, Lupia E. The future role of antitumor necrosis factor products in the treatment of rheumatoid arthritis. Drugs 1998;55:613-20.
26. Smith MD. Etanercept treatment of rheumatoid arthritis in the "real world". Ann Rheum Dis 2003;62:95-6.
27. Feldmann M, Maini RN. Anti-TNF-alpha therapy of rheumatoid arthritis: What we have learnt? Ann Rev Immunol 2001;19:163-96.
28. Kavanaugh A, St Clair EW, Mc Cune WJ, Braakman T, Lipsky P. Chimeric antitumor necrosis factor-alpha monoclonal antibody treatment of patients with rheumatoid arthritis receiving methotrexate therapy. J Rheumatol 2001;27: 841-50.
29. Brandt J, Haibel H, Cornely D, Golder W, Gonzalez J, Reddig J, et al. Successful treatment of acute ankylosing spondylitis with antitumor necrosis factor-alpha monoclonal antibody infliximab. Arthritis Rheum 2000;43:1346-52.
30. Braun J, Sieper J, Breban M, Callanles Estevz E, Davis J, Inman R, et al. Antitumor necrosis factor-alpha therapy for ankylosing spondylitis: International experience. Ann Rheumatol Dis 2002;61:51-60.
31. Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, Van-Hogezand RA, et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 1999;340:1398-405.
32. Blam MF, Stein RB, Lichen Stein GR. Integrating antitumor necrosis factor therapy in inflammatory bowel disease. Current and future perspectives. Ann J Gastroenterol 2001; 96:1977-97.
33. Hotamisligil GS. The role of TNF-alpha and TNF-receptors in obesity and insulin resistance. J Intern Med 1999;245:621-5.
34. Lamhamedi-Cherradi SE, Zhengs S, Tisch RM, Chen YH. Critical roles of tumor necrosis factor-related apoptosis-inducing ligand in type I diabetes. Diabetes 2003;52:2274-8.
35. Deswal A, Bozkurt B, Seta Y, Parilti-Eiswirth S, Hayes FA, Blosch C, et al. Safety and efficacy of soluble P75 TNF receptor (enbrel, etanercept) in patients with advanced heart failure. Circulation 1999; 99:3224-6.
36. Venters HD, Dantzer R, Kelley KW. Tumor necrosis factor-alpha-induce neuronal death by silencning survival signals generated by the type I insulin-like growth factor receptor. Ann NY Acad Sci 2000; 917:210-20.
37. Fekade D, Knox K, Hussein K, Melka A, Lalloo DG, Coxon RE, et al. Prevention of Jarisch-Herxheimer reactions by treatment with antibodies against tumor necrosis factor. N Engl J Med 1996;335:311-5.
38. Abraham E, Wunderink R, Silverman H, Peri TM, Nasraway S, Levy H, et al. Efficacy and safety of monoclonal antibody to tumor necrosis factor-alpha in patients with sepsis syndrome. A randomized, controlled, double blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. J Am Med Assoc 1995;273:334-41.
39. Mauceri HJ, Seetharam S, Beckett MA, Lee JY, Gupta VK, Gately S, et al. Tumor production of angiostatin is enhanced after exposure to TNF-alpha. Int J Cancer 2002;97:410-5.
40. Naylor MS, Stamp GW, Foulke WD, Eccles D, Balkwill FR. Tumor necrosis factor and its receptors in human ovarian cancer. Potential role in disease progression. J Clin Invest 1993;91:2194-206.
41. Hajeer AH, Lear JT, Ollier WE, Naves M, Worthington J, Bell DA, et al. Preliminary evidence of association of TNF microsatellites with increased risk of multiple basal cell carcinomas. Br J Dermatol 2000;142:441-5.
42. Smyth MJ, Takeda K, Hayakawa Y, Peschon JJ, van den Brink MR, Yagita H. Nature's TRAIL on a path to cancer immunotherapy. Immunity 2003;18:1-6.
43. Lin T, Zhang L, Davis J, Gu J, Nishizaki M, Ji L, et al. Combination of TRAIL gene therapy and chemotherapy enhances antitumor and antimetastasis effects in chemosensitive and chemoresistant breast cancers. Mol Ther 2003;8:441-8.
44. Chaudhari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: A randomized trial. Lancet 2001;357:1842-7.
45. Camp RD. Updates from the IIIrd international congress on psoriasis. From gene to clinic. Br J Dermatol 2003;148:878-84.
46. Mimouni D, Anhalt GJ, Kauba DJ, Nousari HC. Infliximab for peristomal pyoderma gangrenosum. Br J Dermatol 2003;148:813-6.
47. Voigtlander C, Luftl M, Schuler G, Hertl M. Infliximab (anti TNF-a antibody): a novel highly effective treatment of recalcitrant subcorneal pustular dermatosis (Sneddon-Wilkinson disease). Arch Dermatol 2001;137:1571-4.
48. Warnnissorn P, Nakao A, Suto H, Ushio H, Yamaguchi N, Yagita H, et al. Tumor necrosis factor related apoptosis-inducing ligand expression in atopic dermatitis. Br J Dermatol 2003;148:829-31.
49. Tilg H, Jalan R, Kaser A, Davies NA, Offner FA, Hodges SJ, et al. Anti TNF-a monoclonal antibody therapy in severe alcoholic hepatitis. J Hepatol 2003;38:419-25.
50. McGuire W, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D. Variation in the TNF-a promoter region associated with susceptibility to cerebral malaria. Nature 1994;371:508-10.
51. Jeon EJ, Park YS, Choi YC, Yeo SW, Jung TT. Effect of inhibitor of TNF-a on experimental otitis media with effusion. Ann Otol Rhinol Laryngol 2001;110: 917-21.
52. Szold O, Ben Abraham R, Frolkis I, Sorkine M, Sorkine P. TNF as a mediator of cardiac toxicity following snake envenomation. Crit Care Med 2003;31:1449-53.
53. Labunski S, Posern G, Ludwig S, Kundt G, Brocker EB, Kunz M. Tumor necrosis factor-alpha promoter polymor-phism in erythema nodosum. Acta Derm Venereol 2001;81:18-21.
54. Reimold AM. New indications for treatment of chronic inflammation by TNF-alpha blockade. Am J Med Sci 2003; 325:75-92.
55. Hengstman GJ, van den Hoogen FH, Barrera P, Netea MG, Pieterse A, van de Putte LB, et al. Successful treatment of dermatomyositis and polymyositis with antitumor necrosis factor-alpha: Preliminary observations. Eur Neurol 2003;50: 10-5.
56. Mc Cain ME, Quinet RJ, Davis WE. Etanercept and infliximab associated with cutaneous vasculitis. Rheumatology 2002;41:116-7.

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