Abstract
Blockade of cytokines, particularly of tumour necrosis factor alpha (TNF-α), in immuno-inflammatory diseases, has led to the greatest advances in medicine of recent years. We did a thorough review of the literature with a focus on inflammation models in rodents on modified gene expression or bioactivity for IL-1, IL-6, and TNF-α, and we summarized the results of randomized controlled clinical trials in human disease. What we have learned herewith is that important information can be achieved by the use of animal models in complex, immune-mediated diseases. However, a clear ranking for putative therapeutic targets appears difficult to obtain from an experimental approach alone. This is primarily due to the fact that none of the disease models has proven to cover more than one crucial pathogenetic aspect of the complex cascade of events leading to characteristic clinical disease signs and symptoms. This supports the notion that the addressed human immune-mediated diseases are polygenic and the summation of genetic, perhaps epigenetic, and environmental factors. Nevertheless, it has become apparent, so far, that TNF-α is of crucial importance in the development of antigen-dependent and antigen-independent models of inflammation, and that these results correlate well with clinical success. With some delay, clinical trials in conditions having some relationship with rheumatoid arthritis (RA) indicate new opportunities for blocking IL-1 or IL-6 therapeutically. It appears, therefore, that a translational approach with critical, mutual reflection of simultaneously performed experiments and clinical trials is important for rapid identification of new targets and development of novel treatment options in complex, immune-mediated, inflammatory diseases.
Similar content being viewed by others
References
Dinarello CA (1997) Interleukin-1. Cytokine Growth Factor Rev 8:253–265
Dinarello CA (1996) Biologic basis for interleukin-1 in disease. Blood 87:2095–2147
Arend WP (2002) The balance between IL-1 and IL-1Ra in disease. Cytokine Growth Factor Rev 13:323–340
Ishihara K, Hirano T (2002) IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine Growth Factor Rev 13:357–368
Jones SA (2005) Directing transition from innate to acquired immunity: defining a role for IL-6. J Immunol 175:3463–3468
Feldmann M, Maini RN (2001) Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol 19:163–196
Locksley RM, Killeen N, Lenardo MJ (2001) The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104:487–501
Ibelgaufts H (1995) Dictionary of cytokines. Verlag Chemie, Weinheim
Niki Y, Yamada H, Seki S, Kikuchi T, Takaishi H, Toyama Y, Fujikawa K, Tada N (2001) Macrophage- and neutrophil-dominant arthritis in human IL-1 alpha transgenic mice. J Clin Invest 107:1127–1135
Niki Y, Yamada H, Kikuchi T, Toyama Y, Matsumoto H, Fujikawa K, Tada N (2004) Membrane-associated IL-1 contributes to chronic synovitis and cartilage destruction in human IL-1 alpha transgenic mice. J Immunol 172:577–584
Horai R, Saijo S, Tanioka H, Nakae S, Sudo K, Okahara A, Ikuse T, Asano M, Iwakura Y (2000) Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice. J Exp Med 191:313–320
Saijo S, Asano M, Horai R, Yamamoto H, Iwakura Y (2002) Suppression of autoimmune arthritis in interleukin-1-deficient mice in which T cell activation is impaired due to low levels of CD40 ligand and OX40 expression on T cells. Arthritis Rheum 46:533–544
Ma Y, Thornton S, Boivin GP, Hirsh D, Hirsch R, Hirsch E (1998) Altered susceptibility to collagen-induced arthritis in transgenic mice with aberrant expression of interleukin-1 receptor antagonist. Arthritis Rheum 41:1798–1805
Palmer G, Talabot-Ayer D, Szalay-Quinodoz I, Maret M, Arend WP, Gabay C (2003) Mice transgenic for intracellular interleukin-1 receptor antagonist type 1 are protected from collagen-induced arthritis. Eur J Immunol 33:434–440
Ji H, Pettit A, Ohmura K, Ortiz-Lopez A, Duchatelle V, Degott C, Gravallese E, Mathis D, Benoist C (2002) Critical roles for interleukin 1 and tumor necrosis factor alpha in antibody-induced arthritis. J Exp Med 196:77–85
Kagari T, Doi H, Shimozato T (2002) The importance of IL-1 beta and TNF-alpha, and the noninvolvement of IL-6, in the development of monoclonal antibody-induced arthritis. J Immunol 169:1459–1466
Choe JY, Crain B, Wu SR, Corr M (2003) Interleukin 1 receptor dependence of serum transferred arthritis can be circumvented by toll-like receptor 4 signaling. J Exp Med 197:537–542
Haase I, Hobbs RM, Romero MR, Broad S, Watt FM (2001) A role for mitogen-activated protein kinase activation by integrins in the pathogenesis of psoriasis. J Clin Invest 108:527–536
Zenz R, Eferl R, Kenner L, Florin L, Hummerich L, Mehic D, Scheuch H, Angel P, Tschachler PE, Wagner EF (2005) Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins. Nature 437:369–375
Suematsu S, Matsuda T, Aozasa K, Akira S, Nakano N, Ohno S, Miyazaki J, Yamamura K, Hirano T, Kishimoto T (1989) IgG1 plasmacytosis in interleukin 6 transgenic mice. Proc Natl Acad Sci USA 86:7547–7551
Hirano T (1991) Interleukin 6 (IL-6) and its receptor: their role in plasma cell neoplasias. Int J Cell Cloning 9:166–184
Ishihara K, Sawa S, Ikushima H, Hirota S, Atsumi T, Kamimura D, Park SJ, Murakami M, Kitamura Y, Iwakura Y, Hirano T (2004) The point mutation of tyrosine 759 of the IL-6 family cytokine receptor gp130 synergizes with HTLV-1 pX in promoting rheumatoid arthritis-like arthritis. Int Immunol 16:455–465
De Benedetti F, Alonzi T, Moretta A, Lazzaro D, Costa P, Poli V, Martini A, Ciliberto G, Fattori E (1997) Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-I. A model for stunted growth in children with chronic inflammation. J Clin Invest 99:643–650
Alonzi T, Fattori E, Lazzaro D, Costa P, Probert L, Kollias G, De Benedetti F, Poli V, Ciliberto G (1998) Interleukin 6 is required for the development of collagen-induced arthritis. J Exp Med 187:461–468
Ohshima S, Saeki Y, Mima T, Sasai M, Nishioka K, Nomura S, Kopf M, Katada Y, Tanaka T, Suemura M, Kishimoto T (1998) Interleukin 6 plays a key role in the development of antigen-induced arthritis. Proc Natl Acad Sci USA 95:8222–8226
Samoilova EB, Horton JL, Hilliard B, Liu TS, Chen Y (1998) IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis: roles of IL-6 in the activation and differentiation of autoreactive T cells. J Immunol 161:6480–6486
Sawczenko A, Azooz O, Paraszczuk J, Idestrom M, Croft NM, Savage MO, Ballinger AB, Sanderson IR (2005) Intestinal inflammation-induced growth retardation acts through IL-6 in rats and depends on the −174 IL-6 G/C polymorphism in children. Proc Natl Acad Sci USA 102:13260–13265
Suzuki A, Hanada T, Mitsuyama K, Yoshida T, Kamizono S, Hoshino T, Kubo M, Yamashita A, Okabe M, Takeda K, Akira S, Matsumoto S, Toyonaga A, Sata M, Yoshimura A (2001) CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation. J Exp Med 193:471–481
Keffer J, Probert L, Cazlaris H, Georgopoulos S, Kaslaris E, Kioussis D, Kollias G (1991) Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J 10:4025–4031
Alexopoulou L, Pasparakis M, Kollias G (1997) A murine transmembrane tumor necrosis factor (TNF) transgene induces arthritis by cooperative p55/p75 TNF receptor signaling. Eur J Immunol 27:2588–2592
Kontoyiannis D, Pasparakis M, Pizarro TT, Cominelli F, Kollias G (1999) Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 10:387–398
Li P, Schwarz EM (2003) The TNF-α transgenic mouse model of inflammatory arthritis. Springer Semin Immunopathol 25:19–33
Probert L, Plows D, Kontogeorgos G, Kollias G (1995) The type I interleukin-1 receptor acts in series with tumor necrosis factor (TNF) to induce arthritis in TNF-transgenic mice. Eur J Immunol 25:1794–1797
Kollias G, Douni E, Kassiotis G, Kontoyiannis D (1999) On the role of tumor necrosis factor and receptors in models of multiorgan failure, rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. Immunol Rev 169:175–194
Butler DM, Malfait AM, Mason LJ, Warden PJ, Kollias G, Maini RN, Feldmann M, Brennan FM (1997) DBA/1 mice expressing the human TNF-alpha transgene develop a severe, erosive arthritis: characterization of the cytokine cascade and cellular composition. J Immunol 159:2867–2876
Batten M, Fletcher C, Ng LG, Groom J, Wheway J, Laabi Y, Xin X, Schneider P, Tschopp J, Mackay CR, Mackay F (2004) TNF deficiency fails to protect BAFF transgenic mice against autoimmunity and reveals a predisposition to B cell lymphoma. J Immunol 172:812–822
Mori L, Iselin S, De Libero G, Lesslauer W (1996) Attenuation of collagen-induced arthritis in 55-kDa TNF receptor type 1 (TNFR1)-IgG1-treated and TNFR1-deficient mice. J Immunol 157:3178–3182
Cope AP, Patel SD, Hall F, Congia M, Hubers HA, Verheijden GF, Boots AM, Menon R, Trucco M, Rijnders AW, Sonderstrup G (1999) T cell responses to a human cartilage autoantigen in the context of rheumatoid arthritis associated and non-associated HLA-DR4 alleles. Arthritis Rheum 42:1497–1507
Cope AP, Liblau RS, Yang XD, Congia M, Laudanna C, Schreiber RD, Probert L, Kollias G, McDevitt HO (1997) Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling. J Exp Med 185:1573–1584
Fisher CJ Jr, Opal SM, Lowry SF, Sadoff JC, LaBrecque JF, Donovan HC, Lookabaugh JL, Lemke J, Pribble JP, Stromatt SC et al (1994) Role of interleukin-1 and the therapeutic potential of interleukin-1 receptor antagonist in sepsis. Circ Shock 44:1–8
Fisher CJ Jr, Slotman GJ, Opal SM, Pribble JP, Bone RC, Emmanuel G, Ng D, Bloedow DC, Catalano MA; IL-1RA Sepsis Syndrome Study Group (1994) Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial. Crit Care Med 22:12–21
Vincent JL, Slotman G, Van Leeuwen PA, Shelly M, Nasraway S, Tenaillon A, Bander J, Friedman G (1999) IL-1ra administration does not improve cardiac function in patients with severe sepsis. J Crit Care 14:69–72
Campion GV, Lebsack ME, Lookabaugh J, Gordon G, Catalano M, The IL-1Ra Arthritis Study Group (1996) Dose-range and dose-frequency study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. Arthritis Rheum 39:1092–1101
Bresnihan B, Alvaro-Gracia JM, Cobby M, Doherty M, Domljan Z, Emery P, Nuki G, Pavelka K, Rau R, Rozman B, Watt I, Williams B, Aitchison R, McCabe D, Musikic P (1998) Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum 41:2196–2204
Jiang Y, Genant HK, Watt I, Cobby M, Bresnihan B, Aitchison R, McCabe D (2000) A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: radiologic progression and correlation of Genant and Larsen scores. Arthritis Rheum 43:1001–1009
Antin JH, Weisdorf D, Neuberg D, Nicklow R, Clouthier S, Lee SJ, Alyea E, McGarigle C, Blazar BR, Sonis S, Soiffer RJ, Ferrara JL (2002) Interleukin-1 blockade does not prevent acute graft-vs-host disease: results of a randomized, double-blind, placebo-controlled trial of interleukin-1 receptor antagonist in allogeneic bone marrow transplantation. Blood 100:3479–3482
Chevalier X, Giraudeau B, Conrozier T, Marliere J, Kiefer P, Goupille P (2005) Safety study of intraarticular injection of interleukin 1 receptor antagonist in patients with painful knee osteoarthritis: a multicenter study. J Rheumatol 32:1317–1323
Emsley HC, Smith CJ, Georgiou RF, Vail A, Hopkins SJ, Rothwell NJ, Tyrrell PJ; Acute Stroke Investigators (2005) Acute Stroke Investigators. A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. J Neurol Neurosurg Psychiatry 76:1366–1372
Tan AL, Marzo-Ortega H, O’Connor P, Fraser A, Emery P, McGonagle D (2004) Efficacy of anakinra in active ankylosing spondylitis: a clinical and magnetic resonance imaging study. Ann Rheum Dis 63:1015–1041
Haibel H, Rudwaleit M, Listing J, Sieper J (2004) Open label trial of anakinra in active ankylosing spondylitis over 24 weeks. Ann Rheum Dis 64:296–298
Genovese MC, Cohen S, Moreland L, Lium D, Robbins S, Newmark R, Bekker P; 20000223 Study Group (2004) Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 50:1412–1419
Seitz M, Kamgang RK, Simon HU, Villiger PM (2005) Therapeutic interleukin (IL) 1 blockade normalises increased IL1 beta and decreased tumour necrosis factor alpha and IL10 production in blood mononuclear cells of a patient with CINCA syndrome. Ann Rheum Dis 64:1802–1803
Choy EH, Isenberg DA, Garrood T, Farrow S, Ioannou Y, Bird H, Cheung N, Williams B, Hazleman B, Price R, Yoshizaki K, Nishimoto N, Kishimoto T, Panayi GS (2002) Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: a randomized, double-blind, placebo-controlled, dose-escalation trial. Arthritis Rheum 46:3143–3150
Nishimoto N, Yoshizaki K, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Hashimoto J, Azuma J, Kishimoto T (2004) Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum 50:1761–1769
Ito H, Takazoe M, Fukuda Y, Hibi T, Kusugami K, Andoh A, Matsumoto T, Yamamura T, Azuma J, Nishimoto N, Yoshizaki K, Shimoyama T, Kishimoto T (2004) A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn’s disease. Gastroenterology 126:989–996
Woo P, Wilkinson N, Prieur AM, Southwood T, Leone V, Livermore P, Wythe H, Thomson D, Kishimoto T (2005) Open label phase II trial of single, ascending doses of MRA in Caucasian children with severe systemic juvenile idiopathic arthritis: proof of principle of the efficacy of IL-6 receptor blockade in this type of arthritis and demonstration of prolonged clinical improvement. Arthritis Res Ther 7:R1281–1288
Yokota S, Miyamae T, Imagawa T, Iwata N, Katakura S, Mori M, Woo P, Nishimoto N, Yoshizaki K, Kishimoto T (2005) Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 52:818–825
Ogilvie EM, Fife MS, Thompson SD, Twine N, Tsoras M, Moroldo M, Fisher SA, Lewis CM, Prieur AM, Glass DN, Woo P (2003) The −174G allele of the interleukin-6 gene confers susceptibility to systemic arthritis in children: a multicenter study using simplex and multiplex juvenile idiopathic arthritis families. Arthritis Rheum 48:3202–3206
Mandler RN, Kerrigan DP, Smart J, Kuis W, Villiger P, Lotz M (1992) Castleman’s disease in POEMS syndrome with elevated interleukin-6. Cancer 69:2697–2703
Nishimoto N, Kanakura Y, Aozasa K, Johkoh T, Nakamura M, Nakano S, Nakano N, Ikeda Y, Sasaki T, Nishioka K, Hara M, Taguchi H, Kimura Y, Kato Y, Asaoku H, Kumagai S, Kodama F, Nakahara H, Hagihara K, Yoshizaki K, Kishimoto T (2005) Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood 106:2627–2632
Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, Smolen J, Emery P, Harriman G, Feldmann M, Lipsky P; ATTRACT Study Group (1999) Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet 354:1932–1939
Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, Jackson CG, Lange M, Burge DJ (1999) A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 340:253–259
Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, Teoh LA, Fischkoff SA, Chartash EK (2003) Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 48:35–45
Braun J, Brandt J, Listing J, Zink A, Alten R, Golder W, Gromnica-Ihle E, Kellner H, Krause A, Schneider M, Sorensen H, Zeidler H, Thriene W, Sieper J (2002) Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 359:1187–1193
Gorman JD, Sack KE, Davis JC Jr (2002) Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha. N Engl J Med 346:1349–1356
Brandt J, Khariouzov A, Listing J, Haibel H, Sorensen H, Grassnickel L, Rudwaleit M, Sieper J, Braun J (2003) Six-month results of a double-blind, placebo-controlled trial of etanercept treatment in patients with active ankylosing spondylitis. Arthritis Rheum 48:1667–1675
Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, Burge DJ (2000) Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 356:385–390
Reich K, Nestle FO, Papp K, Ortonne JP, Evans R, Guzzo C, Li S, Dooley LT, Griffiths CE; EXPRESS study investigators (2005) Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial. Lancet 366:1367–1374
Antoni CE, Kavanaugh A, Kirkham B, Tutuncu Z, Burmester GR, Schneider U, Furst DE, Molitor J, Keystone E, Gladman D, Manger B, Wassenberg S, Weier R, Wallace DJ, Weisman MH, Kalden JR, Smolen J (2005) Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT). Arthritis Rheum 52:1227–1236
Mease PJ, Gladman DD, Ritchlin CT, Ruderman EM, Steinfeld SD, Choy EH, Sharp JT, Ory PA, Perdok RJ, Weinberg MA; Adalimumab Effectiveness in Psoriatic Arthritis Trial Study Group (2005) Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial. Arthritis Rheum 52:3279–3289
Lovell DJ, Giannini EH, Reiff A, Cawkwell GD, Silverman ED, Nocton JJ, Stein LD, Gedalia A, Ilowite NT, Wallace CA, Whitmore J, Finck BK (2000) Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N Engl J Med 342:763–769
Quartier P, Taupin P, Bourdeaut F, Lemelle I, Pillet P, Bost M, Sibilia J, Kone-Paut I, Gandon-Laloum S, LeBideau M, Bader-Meunier B, Mouy R, Debre M, Landais P, Prieur AM (2003) Efficacy of etanercept for the treatment of juvenile idiopathic arthritis according to the onset type. Arthritis Rheum 48:1093–1101
Schmeling H, Horneff G (2005) Etanercept and uveitis in patients with juvenile idiopathic arthritis. Rheumatology 44:1008–1011
Bozkurt B, Torre-Amione G, Warren MS, Whitmore J, Soran OZ, Feldman AM, Mann DL (2001) Results of targeted anti-tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure. Circulation 103:1044–1047
Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT; Anti-TNF Therapy Against Congestive Heart Failure Investigators (2003) 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 107:3133–3140
St Clair EW, van der Heijde DM, Smolen JS, Maini RN, Bathon JM, Emery P, Keystone E, Schiff M, Kalden JR, Wang B, Dewoody K, Weiss R, Baker D; Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset Study Group (2004) Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum 50:3432–3443
De Rycke L, Baeten D, Kruithof E, Van den Bosch F, Veys EM, De Keyser F (2005) Infliximab, but not etanercept, induces IgM anti-double-stranded DNA autoantibodies as main antinuclear reactivity: biologic and clinical implications in autoimmune arthritis. Arthritis Rheum 52:2192–2201
Aringer M, Graninger WB, Steiner G, Smolen JS (2004) Safety and efficacy of tumor necrosis factor alpha blockade in systemic lupus erythematosus: an open-label study. Arthritis Rheum 50:3161–3169
Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, Genovese MC, Wasko MC, Moreland LW, Weaver AL, Markenson J, Finck BK (2000) A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 343:1586–1593
Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, Zwinderman AH, Ronday HK, Han KH, Westedt ML, Gerards AH, van Groenendael JH, Lems WF, van Krugten MV, Breedveld FC, Dijkmans BA (2005) Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum 52:3381–3390
Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, Martin Mola E, Pavelka K, Sany J, Settas L, Wajdula J, Pedersen R, Fatenejad S, Sanda M; TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) Study Investigators (2004) Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 363:675–681
D’haens G, Van Deventer S, Van Hogezand R, Chalmers D, Kothe C, Baert F, Braakman T, Schaible T, Geboes K, Rutgeerts P (1999) Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn’s disease: a European multicenter trial. Gastroenterology 116:1029–1034
Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, Podolsky DK, Sands BE, Braakman T, DeWoody KL, Schaible TF, van Deventer SJ (1999) Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 340:1398–1405
Van den Brande JM, Braat H, van den Brink GR, Versteeg HH, Bauer CA, Hoedemaeker I, van Montfrans C, Hommes DW, Peppelenbosch MP, van Deventer SJ (2003) Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease. Gastroenterology 124:1774–1785
Mitoma H, Horiuchi T, Hatta N, Tsukamoto H, Harashima S, Kikuchi Y, Otsuka J, Okamura S, Fujita S, Harada M (2005) Infliximab induces potent anti-inflammatory responses by outside-to-inside signals through transmembrane TNF-alpha. Gastroenterology 128:376–392
Shen C, Assche GV, Colpaert S, Maerten P, Geboes K, Rutgeerts P, Ceuppens JL. Adalimumab induces apoptosis of human monocytes: a comparative study with infliximab and etanercept. Aliment Pharmacol Ther 21:251–258
Catrina AI, Trollmo C, af Klint E, Engstrom M, Lampa J, Hermansson Y, Klareskog L, Ulfgren AK (2005) Evidence that anti-tumor necrosis factor therapy with both etanercept and infliximab induces apoptosis in macrophages, but not lymphocytes, in rheumatoid arthritis joints: extended report. Arthritis Rheum 52:61–72
Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, Travers S, Rachmilewitz D, Hanauer SB, Lichtenstein GR, de Villiers WJ, Present D, Sands BE, Colombel JF (2005) Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 353:2462–2476
Melikoglu M, Fresko I, Mat C, Ozyazgan Y, Gogus F, Yurdakul S, Hamuryudan V, Yazici H (2005) Short-term trial of etanercept in Behcet’s disease: a double blind, placebo controlled study. J Rheumatol 32:98–105
Aeberli D, Oertle S, Mauron H, Reichenbach S, Jordi B, Villiger PM (2002) Inhibition of the TNF-pathway: use of infliximab and etanercept as remission-inducing agents in cases of therapy-resistant chronic inflammatory disorders. Swiss Med Wkly 132:414–422
Mariette X, Ravaud P, Steinfeld S, Baron G, Goetz J, Hachulla E, Combe B, Puechal X, Pennec Y, Sauvezie B, Perdriger A, Hayem G, Janin A, Sibilia J (2004) Inefficacy of infliximab in primary Sjogren’s syndrome: results of the randomized, controlled Trial of Remicade in Primary Sjogren’s Syndrome (TRIPSS). Arthritis Rheum 50:1270–1276
Sankar V, Brennan MT, Kok MR, Leakan RA, Smith JA, Manny J, Baum BJ, Pillemer SR (2004) Etanercept in Sjogren’s syndrome: a twelve-week randomized, double-blind, placebo-controlled pilot clinical trial. Arthritis Rheum 50:2240–2245
Wegener’s Granulomatosis Etanercept Trial (WGET) Research Group (2005) Etanercept plus standard therapy for Wegener’s granulomatosis. N Engl J Med 352:351–361
Kobelt G, Andlin-Sobocki P, Brophy S, Jonsson L, Calin A, Braun J (2004) The burden of ankylosing spondylitis and the cost-effectiveness of treatment with infliximab (Remicade). Rheumatology 43:1158–1166
Kobelt G, Lindgren P, Singh A, Klareskog L (2005) Cost effectiveness of etanercept (Enbrel) in combination with methotrexate in the treatment of active rheumatoid arthritis based on the TEMPO trial. Ann Rheum Dis 64:1174–1179
Mugnier B, Balandraud N, Darque A, Roudier C, Roudier J, Reviron D (2003) Polymorphism at position −308 of the tumor necrosis factor alpha gene influences outcome of infliximab therapy in rheumatoid arthritis. Arthritis Rheum 48:1849–1852
Choy EH, Hazleman B, Smith M, Moss K, Lisi L, Scott DG, Patel J, Sopwith M, Isenberg DA (2002) Efficacy of a novel PEGylated humanized anti-TNF fragment (CDP870) in patients with rheumatoid arthritis: a phase II double-blinded, randomized, dose-escalating trial. Rheumatology 41:1133–1137
Schreiber S, Rutgeerts P, Fedorak RN, Khaliq-Kareemi M, Kamm MA, Boivin M, Bernstein CN, Staun M, Thomsen OO, Innes A; CDP870 Crohn’s Disease Study Group (2005) A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn’s disease. Gastroenterology 129:807–818
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Möller, B., Villiger, P.M. Inhibition of IL-1, IL-6, and TNF-α in immune-mediated inflammatory diseases. Springer Semin Immun 27, 391–408 (2006). https://doi.org/10.1007/s00281-006-0012-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00281-006-0012-9