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Figure 1.
Schematic representation of the effects of tumor necrosis factor (TNF) in rheumatoid arthritis. IL indicates interleukin.

Schematic representation of the effects of tumor necrosis factor (TNF) in rheumatoid arthritis. IL indicates interleukin.

Figure 2.
Etanercept and cA2 (infliximab): schematic representation of 2 tumor necrosis factor (TNF) binding agents effective in the treatment of rheumatoid arthritis.

Etanercept and cA2 (infliximab): schematic representation of 2 tumor necrosis factor (TNF) binding agents effective in the treatment of rheumatoid arthritis.

Table 1. 
Cellular Composition of Rheumatoid Arthritis Synovium
Cellular Composition of Rheumatoid Arthritis Synovium
Table 2. 
Cytokines Detected in Rheumatoid Arthritis Synovial Tissue or Fluid*
Cytokines Detected in Rheumatoid Arthritis Synovial Tissue or Fluid*
1.
Pincus  TCallahan  LFSale  WGBrooks  ALPayne  LEVaughn  WK Severe functional declines, work disability, and increased mortality in seventy-five rheumatoid arthritis patients studied over nine years. Arthritis Rheum. 1984;27864- 872Article
2.
Callahan  LF The burden of rheumatoid arthritis: facts and figures. J Rheumatol Suppl. 1998;538- 12
3.
Fox  DA The role of T cells in the immunopathogenesis of rheumatoid arthritis: new perspectives. Arthritis Rheum. 1997;40598- 609Article
4.
Breedveld  FC New insights in the pathogenesis of rheumatoid arthritis. J Rheumatol Suppl. 1998;533- 7
5.
Arend  WPDayer  J-M Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum. 1990;33305- 315Article
6.
Brennan  FMMaini  RNFeldmann  M Cytokine expression in chronic inflammatory disease. Br Med Bull. 1995;51368- 384
7.
Badolato  ROppenheim  JJ Role of cytokines, acute-phase proteins, and chemokines in the progression of rheumatoid arthritis. Semin Arthritis Rheum. 1996;26526- 538Article
8.
Deleuran  BW Cytokines in rheumatoid arthritis: localization in arthritic joint tissue and regulation in vitro. Scand J Rheumatol. 1996;25 ((suppl 104)) 1- 34Article
9.
Starkebaum  G Role of cytokines in rheumatoid arthritis. Sci Med. March/April1998;6- 15
10.
Miossec  P The Th1/Th2 cytokine balance in arthritis. Miossec  Pvan den  Berg WBFirestein  GSeds.T Cells in Arthritis Basel, Switzerland Birkhäuser Publisher1998;93- 109
11.
Old  LJ Tumor necrosis factor (TNF). Science. 1985;230630- 632Article
12.
Vassalli  P The pathophysiology of tumor necrosis factors. Annu Rev Immunol. 1992;10411- 452Article
13.
Bazzoni  FBeutler  B The tumor necrosis factor ligand and receptor families. N Engl J Med. 1996;3341717- 1725Article
14.
Beutler  BMahoney  JLe Trang  NPekala  PCerami  A Purification of cachectin, a lipoprotein lipase-suppressing hormone secreted by endotoxin-induced RAW 264.7 cells. J Exp Med. 1985;161984- 995Article
15.
Oliff  ADefeo-Jones  DBoyer  M  et al.  Tumors secreting human TNF/cachectin induce cachexia in mice. Cell. 1987;50555- 563Article
16.
Tracey  KJVlassara  HCerami  A Cachectin/tumour necrosis factor. Lancet. 1989;11122- 1126Article
17.
Kriegler  MPerez  CDeFay  KAlbert  ILu  SD A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF. Cell. 1988;5345- 53Article
18.
Müller  UJongeneel  CVNedospasov  SALindahl  KFSteinmetz  M Tumour necrosis factor and lymphotoxin genes map close to H-2D in the mouse major histocompatibility complex. Nature. 1987;325265- 267Article
19.
Tracey  KJBeutler  BLowry  SF  et al.  Shock and tissue injury induced by recombinant human cachectin. Science. 1986;234470- 474Article
20.
Tracey  KJWei  HManogue  KR  et al.  Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation. J Exp Med. 1988;1671211- 1227Article
21.
Starnes  HF  JrWarren  RSJeevanandam  M  et al.  Tumor necrosis factor and the acute metabolic response to tissue injury to man. J Clin Invest. 1988;821321- 1325Article
22.
Perlmutter  DHDinarello  CAPunsal  PIColten  HR Cachectin/tumor necrosis factor regulates hepatic acute-phase gene expression. J Clin Invest. 1986;781349- 1354Article
23.
Dinarello  CACannon  JGWolff  SM  et al.  Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J Exp Med. 1986;1631433- 1450Article
24.
Nawroth  PPBank  IHandley  DCassimeris  JChess  LStern  D Tumor necrosis factor/cachectin interacts with endothelial cell receptors to induce release of interleukin 1. J Exp Med. 1986;1631363- 1375Article
25.
Pober  JSGimbrone  MA  JrLapierre  LA  et al.  Overlapping patterns of activation of human endothelial cells by interleukin 1, tumor necrosis factor, and immune interferon. J Immunol. 1986;1371893- 1896
26.
Leibovich  SJPoverini  PJShepard  HMWiseman  DMShively  VNuseir  N Macrophage-induced angiogenesis is mediated by tumour necrosis factor-α. Nature. 1987;329630- 632Article
27.
Strieter  RMKunkel  SLShowell  HJ  et al.  Endothelial cell gene expression of a neutrophil chemotactic factor by TNF-α, LPS, and IL-1β. Science. 1989;2431467- 1469Article
28.
Kehrl  JHMiller  AFauci  AS Effect of tumor necrosis factor α on mitogen-activated human B cells. J Exp Med. 1987;166786- 791Article
29.
Ranges  GEZlotnik  AExpevik  TDinarello  CACerami  APalladino  MA  Jr Tumor necrosis factor α/cachectin is a growth factor for thymocytes. J Exp Med. 1988;167937- 953Article
30.
Sung  SSBjorndahl  JMWang  CYKao  HTFu  SM Production of tumor necrosis factor/cachectin by human T cell lines and peripheral blood T lymphocytes stimulated by phorbol myristate acetate and anti-CD3 antibody. J Exp Med. 1988;167937- 953Article
31.
Husby  GWilliams  RC  Jr Synovial localization of tumor necrosis factor in patients with rheumatoid arthritis. J Autoimmun. 1988;1363- 371Article
32.
Brennan  FMMaini  RNFeldmann  M TNFα—pivotal role in rheumatoid arthritis? Br J Rheumatol. 1992;31293- 298Article
33.
Neidel  JSchulze  MLindschau  J Association between degree of bone erosion and synovial fluid levels of tumor necrosis factor α in the knee-joints of patients with rheumatoid arthritis. Inflamm Res. 1995;44217- 221Article
34.
Lupia  EMontrucchio  GBattaglia  EModena  VCamussi  G Role of tumor necrosis factor-α and platelet-activating factor in neoangiogenesis induced by synovial fluids of patients with rheumatoid arthritis. Eur J Immunol. 1996;261690- 1694Article
35.
Dayer  J-MBeutler  BCerami  A Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med. 1985;1622163- 2168Article
36.
Bertolini  DRNedwin  GEBringman  TSSmith  DDMundy  GR Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors. Nature. 1986;319516- 518Article
37.
Saklatvala  J Tumour necrosis factor α stimulates resorption and inhibits synthesis of proteoglycan in cartilage [letter]. Nature. 1986;322547- 549Article
38.
Paleolog  EMYoung  SStark  ACMcCloskey  RVFeldmann  MMaini  RN Modulation of angiogenic vascular endothelial growth factor by tumor necrosis factor α and interleukin-1 in rheumatoid arthritis. Arthritis Rheum. 1998;411258- 1265Article
39.
Leirisalo-Repo  MPaimela  LJäättelä  MKoskimies  SRepo  H Production of TNF by monocytes of patients with early rheumatoid arthritis is increased. Scand J Rheumatol. 1995;24366- 371Article
40.
Rubin  BYAnderson  SLSullivan  SAWilliamson  BDCarswell  EAOld  LJ High affinity binding of 125I-labeled human tumor necrosis factor (LuKII) to specific cell surface receptors. J Exp Med. 1985;1621099- 1104Article
41.
Tsujimoto  MYip  YKVilcek  J Tumor necrosis factor: specific binding and internalization in sensitive and resistant cells. Proc Natl Acad Sci U S A. 1985;827626- 7630Article
42.
Aggarwal  BBEessalu  TEHass  PE Characterization of receptors for human tumour necrosis factor and their regulation by γ-interferon. Nature. 1985;318665- 667Article
43.
Smith  CADavis  TAnderson  D  et al.  A receptor for tumor necrosis factor defines an unusual family of cellular and viral proteins. Science. 1990;2481019- 1023Article
44.
Brockhaus  MSchoenfeld  H-JSchlaeger  E-JHunziker  WLesslauer  WLoetscher  H Identification of two types of tumor necrosis factor receptors on human cell lines by monoclonal antibodies. Proc Natl Acad Sci U S A. 1990;873127- 3131Article
45.
Thoma  BGrell  MPfizenmaier  KScheurich  P Identification of a 60-kD tumor necrosis factor (TNF) receptor as the major signal transducing component in TNF responses. J Exp Med. 1990;1721019- 1023Article
46.
Butler  DMFeldmann  MDi Padova  FBrennan  FM p55 and p75 tumor necrosis factor receptors are expressed and mediate common functions in synovial fibroblasts and other fibroblasts. Eur Cytokine Netw. 1994;5441- 448
47.
Seckinger  PIsaaz  SDayer  J-M A human inhibitor of tumor necrosis factor α. J Exp Med. 1988;1671511- 1516Article
48.
Van Zee  KJKohno  TFischer  ERock  CSMoldawer  LLLowry  SF Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor α in vitro and in vivo. Proc Natl Acad Sci U S A. 1992;894845- 4849Article
49.
Cope  APAderka  DDoherty  M  et al.  Increased levels of soluble tumor necrosis factor receptors in the sera and synovial fluid of patients with rheumatic diseases. Arthritis Rheum. 1992;351160- 1169Article
50.
Brennan  FMGibbons  DLCope  APKatsikis  PMaini  RNFeldmann  M TNF inhibitors are produced spontaneously by rheumatoid and osteoarthritic synovial joint cell cultures: evidence of feedback control of TNF action. Scand J Immunol. 1995;42158- 165Article
51.
Steiner  GStudnicka-Benke  AWitzmann  GHöfler  ESmolen  J Soluble receptors for tumor necrosis factor and interleukin-2 in serum and synovial fluid of patients with rheumatoid arthritis, reactive arthritis and osteoarthritis. J Rheumatol. 1995;22406- 412
52.
Roux-Lombard  PPunzi  LHasler  F  et al.  Soluble tumor necrosis factor receptors in human inflammatory synovial fluids. Arthritis Rheum. 1993;36485- 489Article
53.
Feldmann  MBrennan  FMWilliams  ROElliott  MJMaini  RN Cytokine expression and networks in rheumatoid arthritis: rationale for anti-TNFα antibody therapy and its mechanism of action. J Inflamm. 1995-96;4790- 96
54.
Tracey  KJFong  YHesse  DG  et al.  Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 1987;330662- 664Article
55.
Mohler  KMTorrance  DSSmith  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;1511548- 1561
56.
Abraham  EGlauser  MPButler  T  et al.  p55 tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock: a randomized controlled multicenter trial. JAMA. 1997;2771531- 1538Article
57.
Williams  ROFeldmann  MMaini  RN Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc Natl Acad Sci U S A. 1992;899784- 9788Article
58.
Wooley  PHDutcher  JWidmer  MBGillis  S Influence of a recombinant human soluble tumor necrosis factor receptor Fc fusion protein on type II collagen-induced arthritis in mice. J Immunol. 1993;1516602- 6607
59.
Brennan  FMChantry  DJackson  AMaini  RFeldmann  M Inhibitory effect of TNFα antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet. 1989;2244- 247Article
60.
Kettelhut  ICFiers  WGoldberg  AL The toxic effects of tumor necrosis factor in vivo and their prevention by cyclooxygenase inhibitors. Proc Natl Acad Sci U S A. 1987;844273- 4277Article
61.
Barrera  PBoerbooms  AMThvan de Putte  LBAvan der Meer  JWM Effects of antirheumatic agents on cytokines. Semin Arthritis Rheum. 1996;25234- 253Article
62.
Barrera  PBoerbooms  AMTJanssen  EM  et al.  Circulating soluble tumor necrosis factor receptors, interleukin-2 receptors, tumor necrosis factor α, and interleukin-6 levels in rheumatoid arthritis: longitudinal evaluation during methotrexate and azathioprine therapy. Arthritis Rheum. 1993;361070- 1079Article
63.
Brennan  FMCope  APKatsikis  PGibbons  DLMaini  RNFeldmann  M Selective immunosuppression of tumour necrosis factor-alpha in rheumatoid arthritis. Andorini  Led.Selective Immunosuppression Basic Concepts and Clinical Applications Basel, Switzerland S Karger AG1995;48- 60
64.
Hart  PHHunt  EKBonder  CSWatson  CJFinlay-Jones  JJ Regulation of surface and soluble TNF receptor expression on human monocytes and synovial fluid macrophages by IL-4 and IL-10. J Immunol. 1996;1573672- 3680
65.
Kavanaugh  AF Anti-tumor necrosis factor-α monoclonal antibody therapy for rheumatoid arthritis. Kremer  JMed.Rheumatic Disease Clinics of North America 3rd ed. Philadelphia, Pa WB Saunders Co1998;593- 614
66.
Elliott  MJMaini  RNFeldmann  M  et al.  Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor α. Arthritis Rheum. 1993;361681- 1690Article
67.
Elliott  MJMaini  RNFeldmann  M  et al.  Repeated therapy with monoclonal antibody to tumour necrosis factor α (cA2) in patients with rheumatoid arthritis. Lancet. 1994;3441125- 1127Article
68.
Elliott  MJMaini  RNFeldmann  M  et al.  Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor α (cA2) versus placebo in rheumatoid arthritis. Lancet. 1994;3441105- 1110Article
69.
Kavanaugh  AFCush  JJSt Clair  EW  et al.  Anti-TNF-α monoclonal antibody (mAb) treatment of rheumatoid arthritis (RA) patients with active disease on methotrexate (MTX): results of a double-blind, placebo-controlled multicenter trial [abstract]. Arthritis Rheum. 1996;39 ((suppl)) S123Article
70.
Maini  RNBreedveld  FCKalden  JR  et al.  Low dose methotrexate (MTX) suppresses anti-globulin responses and potentiates efficacy of a chimeric monoclonal anti-TNFα antibody (cA2) given repeatedly in rheumatoid arthritis (RA) [abstract]. Arthritis Rheum. 1997;9 ((suppl)) S126
71.
Rankin  ECCChoy  EHSKassimos  D  et al.  The therapeutic effects of an engineered human anti-tumour necrosis factor alpha antibody (CDP571) in rheumatoid arthritis. Br J Rheumatol. 1995;34334- 342Article
72.
Rankin  ECCChoy  EHSSopwith  AMVetterlein  OPanayi  GSIsenberg  DA Repeated doses of 10 mg/kg of an engineered human anti-TNF-α antibody CDP571 in RA patients are safe and effective [abstract]. Arthritis Rheum. 1995;38 ((suppl)) 185
73.
Jacob  COMcDevitt  HO Tumour necrosis factor-α in murine autoimmune "lupus" nephritis. Nature. 1988;331356- 358Article
74.
Keffer  JProbert  LCazlaris  H  et al.  Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 1991;104025- 4031
75.
Camussi  GLupia  E The future role of anti-tumour necrosis factor (TNF) products in the treatment of rheumatoid arthritis. Drugs. 1998;55613- 620Article
76.
Scallon  BJMoore  MATrinh  HKnight  DMGhrayeb  J Chimeric anti-TNF-α monoclonal antibody cA2 binds recombinant transmembrane TNF-α and activates immune effector functions. Cytokine. 1995;7251- 259Article
77.
Moreland  LW Soluble tumor necrosis factor receptor (p75) fusion protein (Enbrel) as a therapy for rheumatoid arthritis. Kremer  JMed.Rheumatic Disease Clinics of North America 3rd ed. Philadelphia, Pa WB Saunders Co1998;579- 591
78.
Moreland  LWMargolies  GHeck  LW  Jr  et al.  Recombinant soluble tumor necrosis factor receptor (p80) fusion protein: toxicity and dose finding trial in refractory rheumatoid arthritis. J Rheumatol. 1996;231849- 1855
79.
Moreland  LWBaumgartner  SWSchiff  MH  et al.  Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med. 1997;337141- 147Article
80.
Moreland  LWSchiff  MHBaumgartner  SW  et al.  Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial. Ann Intern Med. 1999;130478- 486Article
81.
Weinblatt  MEKremer  JMBankhurst  AD  et al.  Phase II/III trial of the TNF receptor p75 Fc fusion protein (TNFR:Fc), Enbrel in combination with methotrexate (MTX) in RA patients. Arthritis Rheum. 1998;41 ((suppl)) S189Article
82.
Weinblatt  MEKremer  JMBankhurst  AD  et al.  A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med. 1999;340253- 259Article
83.
Sander  Oden Broeder  Avan der Hoogen  FLaan  Rvan de Putte  LRau  R 30 Months of treatment with a TNFα receptor-fusion protein (TNFR55-IgG1, RO 45-2081) in patients with severe refractory RA [abstract]. Arthritis Rheum. 1987;40 ((suppl)) S81
84.
Urs  CGhuerkauf  RStevens  RLesslauer  WRA and MS study groups, Immunogenicity of a human TNFR55-IgG1 fusion protein (Lenercept) in rheumatoid arthritis (RA) and multiple sclerosis (MS) patients [abstract]. Arthritis Rheum. 1998;41 ((suppl)) S58Article
85.
Martin  SFrazier  JSeely  J  et al.  A genetically modified tumor necrosis factor receptor I (sTNF-RI) that does not elicit antibody response in primates [abstract]. Arthritis Rheum. 1998;41 ((suppl)) S58Article
86.
Nicod  LPIsler  PChicheportiche  RSongeon  FDayer  J-M Production of prostaglandin E2 and collagenase is inhibited by the recombinant soluble tumour necrosis factor receptor p55-human γ3 fusion protein at concentrations a hundred-fold lower than those decreasing T cell activation. Eur Cytokine Netw. 1996;7757- 763
87.
Koopman  WJMoreland  LW Rheumatoid arthritis: anticytokine therapies on the horizon. Ann Intern Med. 1998;128231- 233Article
88.
Liu  JMarino  MWWong  G  et al.  TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination. Nat Med. 1998;478- 83Article
89.
McKall-Faienza  KJKawai  KKündig  TM  et al.  Absence of TNFRp55 influences virus-induced autoimmunity despite efficient lymphocytic infiltration. Int Immunol. 1998;10405- 412Article
90.
Kremer  JM Combination therapy with biological agents in rheumatoid arthritis: perils and promise. Arthritis Rheum. 1998;411548- 1551Article
91.
Chikanza  ICJawed  SNaughton  DBlake  DR Why do we need new treatments for rheumatoid arthritis? J Pharm Pharmacol. 1998;50357- 369Article
92.
Ettinger  RMebius  RBrowning  JL  et al.  Effects of tumor necrosis factor and lymphotoxin on peripheral lymphoid tissue development. Int Immunol. 1998;10727- 741Article
Review Article
February 28, 2000

Cytokine Blockade as a New Strategy to Treat Rheumatoid ArthritisInhibition of Tumor Necrosis Factor

Author Affiliations

From the Department of Internal Medicine/Rheumatology Division, University of Michigan Medical Center, Ann Arbor.

Arch Intern Med. 2000;160(4):437-444. doi:10.1001/archinte.160.4.437
Abstract

Rheumatoid arthritis (RA) is a common, frequently severe, chronic inflammatory disease. Although the cause of RA remains unknown, recent advances in understanding its pathogenesis have been substantial. Despite the use of a variety of medications, particularly methotrexate, treatment of RA is not fully effective in most patients. Until recently, insights into inflammatory mechanisms in RA had not been successfully translated into novel classes of therapeutic agents. This gap now will likely be bridged in the form of a new strategy for treating RA-cytokine blockade. Although a variety of cytokines are important in the pathogenesis of RA, tumor necrosis factor (TNF) seems to play a pivotal role. Neutralizing TNF in patients with RA, by means of soluble TNF receptors or anti-TNF monoclonal antibodies, has proven to be a powerful means of controlling disease activity. Studies are in progress to obtain additional information regarding long-term safety of TNF blockade and its effects on disease progression.

Rheumatoid arthritis (RA) affects 0.5% to 1.0% of the population and causes not only enormous morbidity but also substantial mortality.1 Most people with chronic RA experience work disability, and the total costs per year of this disease have been estimated at almost $9 billion in 1994 dollars (reviewed by Callahan2). Despite intensive study, the cause of RA remains unknown, and RA is defined using a set of empirically derived clinical criteria. In general, the treatment of RA has not been logically grounded on a sound understanding of pathogenesis. Instead, a heterogeneous array of anti-inflammatory and immunosuppressive agents has been used, many borrowed from other fields of medicine. Putative explanations for their effects on the biological mechanisms of RA have often followed, rather than preceded, demonstration of clinical efficacy. Despite such limitations, substantial strides have been made in the medical management of RA, including extensive use of methotrexate, aggressive treatment of RA earlier in its course, and development of effective treatment combinations with methotrexate and other traditional medications. Nevertheless, treatment of RA remains insufficiently effective and distressingly toxic for many patients. New strategies are clearly required.

RECENT CHANGES IN UNDERSTANDING RA: A FRAMEWORK FOR RETHINKING APPROACHES TO ITS MANAGEMENT

Although RA has typically been viewed as an autoimmune disease, this concept of its pathogenesis is still not supported by convincing demonstration of a unique autoantigen. Humoral and cellular immune responses to autoantigens, such as production of rheumatoid factors, occur in RA. However, none of the autoreactive phenomena observed in RA are specific to RA, present in all patients, or clearly linked to the destruction of cartilage and bone, the all-too-frequent consequence of long-term rheumatoid synovitis. The role of T cells in RA is currently a matter of considerable debate (reviewed by Fox3). Although T cells are abundant in the inflamed joint, critically involved in animal models of RA, and implicated in human RA by the association of class II major histocompatibility complex (MHC) alleles with RA, a T-cell–centered view of the disease has not yet led to clearer insight into the etiology of RA or breakthroughs in its treatment. Although the RA-MHC association seemed to suggest that T-cell recognition of an arthritogenic microbial antigen or autoantigen was an essential component of the pathogenesis of RA, this hypothesis remains unproved, and other explanations for the role of MHC in RA are receiving attention. T-cell–derived lymphokines are not the most abundant cytokines in synovial tissue or fluid, and attempts to treat RA using novel T-cell–depleting biological therapeutic agents, such as monoclonal antibodies, have been surprisingly ineffective.

Such disappointments do not exclude a role for T cells in this disease but might instead point to our incomplete appreciation of the complex nature of the synovial T-cell response in RA.3,4 Nevertheless, a balanced view of the pathogenesis of RA, and of appropriate molecular targets for novel therapeutic strategies, must also focus on the roles of other important cellular components of RA synovium and on their secreted mediators. An alternative model for understanding RA, distinct from traditional definitions of autoimmunity, is as a chronic tissue-specific inflammatory process to which a variety of immune responses can contribute. In such a model, unique elements of RA arise from the interactions between the variety of leukocytes that invade the joint and the native cellular components of joint tissue (Figure 1 and Table 1).

The synovium contains 2 principal cell populations, termed type A and type B synoviocytes. Type A synoviocytes belong to the monocyte-macrophage family, with potent phagocytic ability and the capacity to secrete large quantities of proinflammatory cytokines. Type B synoviocytes are specialized fibroblasts that produce hyaluronic acid and collagen. In an inflammatory milieu, type B synoviocytes can also secrete cytokines, proteases, and other inflammatory mediators. Type A and B synoviocytes are present in greatly increased numbers in RA synovium, along with other functionally important cell populations (Table 1). In addition, neutrophils in synovial fluid and chondrocytes in adjacent articular cartilage are important contributors to inflammatory pathways in the RA joint.

CYTOKINES IN RA: CRITICAL MEDIATORS OF ACUTE AND CHRONIC INFLAMMATION

Cytokines are proteins that function as intercellular messengers in inflammation, immune responses, and tissue repair or remodeling. During the past 2 decades, dozens of cytokines and their receptors have been discovered, cloned, and studied in human disease. Many have been classified as interleukins (ILs), whereas others carry designations associated with one of their biological activities, such as tumor necrosis factor (TNF), also termed TNF-α. Although cytokines are a dauntingly heterogeneous and complex group of molecules, some general principles regarding their biological features are worth summarizing:

  • Production of cytokines is generally not constitutive but is inducible as an activation response of cells to specific stimuli, such as microbial products or other cytokines.

  • Although individual cytokines might be characteristically produced by specific cell types, such as TNF by monocyte-macrophage lineage cells, most cytokines can be synthesized by a heterogeneity of cell types.

  • Cytokines produce biologic and pathologic effects by binding to specific cell surface receptors that contain 1 or more protein subunits and are linked to signal transduction systems that ultimately regulate transcription of specific, inducible genes.

  • Cytokines are pleiotropic (functionally heterogeneous) in their effects, depending on the cellular target on which they act and which concurrent activating or inhibitory factors, including other cytokines, are present. Existence of more than 1 receptor type for an individual cytokine explains only a small component of this pleiotropy.

  • Cytokines possess extensive redundance, or overlap, of their effects.

  • Cytokines act locally, in the tissue where they are synthesized, most of the time, unlike many conventional hormones. However, when produced in abundance, some cytokines, especially those with critical roles in inflammation and host defense such as IL-1 and TNF, have important and wide-ranging systemic effects.

  • Although generally functional as secreted molecules, some cytokines can also be biologically active in a membrane-bound form.

  • Physiological regulation of cytokine production and function is controlled at many levels, including secretion of cytokine receptor antagonists and production of soluble cytokine receptors. Examples include the IL-1 receptor antagonist and the soluble TNF receptor (sTNF-R).

In RA, cytokines are involved in almost all aspects of synovial inflammation and destruction of articular tissues.510Table 2 lists some of the many cytokines detected in RA synovial tissue or fluid. T-cell–derived cytokines are present at lower concentrations than are some of the monocyte-derived cytokines. This does not exclude an important role for such T-cell factors, which might exert potent local effects even when produced intermittently and in small quantities. Nevertheless, it is clear that TNF and IL-1 are 2 of the dominant cytokines in RA.

The total number of distinct cytokines in the RA joint is actually severalfold greater than that listed in Table 2.510 For example, IL-8 is only one of a large family of chemoattractant cytokines or chemokines that attract leukocytes of various types through activated and hyperplastic synovial endothelium into synovial tissue and fluid. Interleukin 10 and transforming growth factor β are examples of cytokines that could have anti-inflammatory potential in RA and other diseases. Others in this category include IL-4 and IL-13, of which the latter is found in RA synovium. An important point in this regard is that the presence of a cytokine in a lesion does not prove that it contributed to inflammation or tissue damage present in that lesion. Some cytokines might in fact be retarding these processes, albeit with limited success in RA.

Subsequent sections of this review focus on the role of TNF in RA. However, it is worth bearing in mind that IL-1 and TNF have overlapping and synergistic roles in RA. Nevertheless, some of the effects of these 2 cytokines and the mechanisms by which they are regulated are distinct. Therefore, interruption of IL-1 or TNF activity potentially represents 2 different novel approaches to the treatment of RA.

BIOLOGICAL FEATURES OF TNF

Tumor necrosis factor is a fascinating cytokine that illustrates each of the 8 points about the biological features of cytokines listed in the previous section.1113 Originally discovered as a factor induced by microbial lipopolysaccharide that can induce regression and cell death of some tumors,11 and shortly thereafter characterized as a mediator of cachexia induced by chronic infection14 or tumors,15 it is now known to mediate a vast spectrum of biologic effects. Tumor necrosis factor is a member of a large and growing family of secreted and cell membrane–bound proteins,13 including the closely related cytokines lymphotoxin α and β. Although macrophages are a primary source of TNF, a variety of cell types can synthesize this molecule, including lymphocytes, neutrophils, keratinocytes, mast cells, and some tumors.12 Tumor necrosis factor is translated as a membrane-associated 233–amino acid prohormone, following which a 76–amino acid signal peptide is proteolytically cleaved off to yield the mature 17-kd TNF molecule.16 The larger form can also be found as a transmembrane protein in some cell types.17 The genes for TNF and lymphotoxin α (formerly termed TNF-β) are closely linked to the MHC genes.18

In animals and humans, TNF induces a plethora of inflammatory and catabolic effects, including fever, shock, tissue injury, energy substrate mobilization, cachexia, anemia, and induction of hepatic acute-phase proteins.1922 The biologic effects of TNF are caused by direct actions on multiple target tissues and induction of other cytokines, such as IL-1, IL-6, and IL-8.12,23,24 Tumor necrosis factor–induced recruitment of leukocytes to localized inflammatory lesions is produced by multiple actions, including induction of adhesion molecules, chemokines, and even angiogenesis.2527 Tumor necrosis factor can potentiate lymphocyte activation,12,28,29 and it also is produced by activated lymphocytes.30 All these properties likely explain the importance of TNF in host defense against a variety of pathogens, especially intracellular bacteria and parasites, and possibly also some viruses (reviewed by Vassalli12).

ROLE OF TNF IN RA

Tumor necrosis factor is present at biologically significant levels in RA synovial tissue and fluid3134 but not in osteoarthritis synovium or systemic lupus erythematosus kidney tissue.31 Furthermore, the level of TNF in synovium seems to parallel the extent of both inflammation and bone erosion.31,33 As shown schematically in Figure 1, TNF triggers several of the most central and critical events in the acute and chronic synovial inflammation and ultimate tissue destruction characteristic of RA, including induction of multiple additional cytokines and chemokines, expression of adhesion molecules and increased levels of class I MHC determinants, synthesis and release of proteases and prostaglandin E2 by synovial fibroblasts (which is important in erosion of cartilage and bone),3537 and synovial neoangiogenesis.34,38 (Interleukin 1 shares some of these properties of TNF, including stimulation of the secretion of proteases, inflammatory cytokines, and prostaglandin E2.5,35) Some data suggest that monocytes from patients with early RA hyperproduce TNF when activated.39 Taking all the data into consideration, one can reasonably conclude that TNF is one of the most important cytokines in the pathogenesis of RA.

TNF RECEPTORS

Shortly after discovery of TNF, several laboratories established that this cytokine interacts with target cells by means of high-affinity, saturable receptors,4042 which also bind lymphotoxin α.42,43 Results of experiments using monoclonal antibodies suggested the existence of 2 distinct forms of the TNF receptor,44,45 which became known as p55 (or p60) and p75 (or p80). Tumor necrosis factor receptors are part of a family of cell-surface proteins that contain a cysteine-rich extracellular domain13,43 and a more variable cytoplasmic domain with complex signal-transduction properties (reviewed by Bazzoni and Beutler13). Biological responses mediated by the 2 types of TNF receptors on RA synovial fibroblasts overlap substantially,46 and this is likely to be true of other cell types that are targets of TNF. In RA but not osteoarthritis synovium, both the p55 and p75 receptors are strongly expressed.8 Most type A (macrophage-derived) and type B (fibroblastic) synoviocytes in the lining layers of RA synovium express p55 (more so than p75), and many of these cells also produce TNF.8 In RA synovial lymphoid aggregates and at the cartilage-pannus junction, p55 and p75 are abundant.8 Thus, all elements for local production and local utilization of TNF are present in the lesions of RA.

Tumor necrosis factor receptors are also produced naturally as soluble molecules, probably by proteolytic cleavage of the p55 and p75 extracellular domains at the cell membrane.4652 Such soluble receptors inhibit TNF action by competing with cell surface receptors for binding of TNF, thereby blocking the biologic effects of TNF.48,50 Patients with RA have circulating levels of sTNF-R that are higher (generally 2-6 ng/mL for each type of sTNF-R) than those in sera of healthy individuals, patients with osteoarthritis, or even patients with other forms of inflammatory arthritis49,51,52 and that are similar to circulating levels of sTNF-R in critically ill patients with hemorrhagic shock or sepsis.48 In synovial fluid, sTNF-R levels are severalfold higher than are those in serum, with levels in RA again higher than those in other forms of arthritis.49,51,52 In vitro50 and probably in vivo sTNF-R can regulate effects of TNF relevant to the pathogenesis of RA, but this is not sufficient to neutralize the high levels of bioactive TNF in patients with RA. Nevertheless, the available data provide a sound conceptual basis for strategies to treat RA by pharmacological elevation of sTNF-R levels.53

THERAPEUTIC INHIBITION OF TNF IN ANIMAL MODELS AND HUMAN DISEASE

In animal models of septic shock, either anti-TNF monoclonal antibody54 or sTNF-R55 is effective in reducing mortality, but the need for administration before exposure to bacterial products likely accounts for difficulty in demonstrating clinical benefit in human trials.56 Either approach to TNF neutralization is effective in murine collagen–induced arthritis not only in preventing disease but also in reducing ongoing joint inflammation.57,58 Moreover, anti-TNF antibody was demonstrated59 in 1989 to inhibit production of IL-1 by synovial cells in culture. The reciprocal regulation of TNF production by IL-1 was not observed in this system,59 although IL-1 seems to induce TNF during the development of fever.16,23

Some conventional and experimental pharmacological treatments for RA (that are not direct TNF antagonists) might work in part through some degree of reduction in TNF levels, although this was not known at the time that their clinical effects were discovered. For example, cyclooxygenase inhibitors can attenuate many of the acute effects of TNF.60 Corticosteroids, among their many anti-inflammatory actions, partially suppress production of several cytokines, including TNF (reviewed by Barrera et al61). Antimalarials, gold compounds, and sulfasalazine can suppress TNF production by monocytes in vitro, but D-penicillamine, methotrexate, and azathioprine do not seem to affect TNF production or function.61 Patients with RA treated with methotrexate or azathioprine showed no change in serum TNF levels during responses to treatment in 24 weeks, although IL-6 levels declined.62 Production of TNF was reported to be inhibited by several agents not yet fully evaluated for treatment of RA, including thalidomide, pentoxifylline, and tacrolimus (FK 506).61 The anti-inflammatory cytokine IL-10, which is under investigation as a possible treatment for RA, decreases TNF production by RA synoviocytes, and IL-4 has similar effects.63 However, IL-10, in contrast to IL-4, augments expression of the p75 TNF receptor on normal monocytes and on RA synovial fluid macrophages, with consequent increases in TNF-induced production of IL-1β by these cells.64 This result raises questions about the potential value of treating RA with IL-10. More data are needed regarding the effects of these and other agents on TNF production and function. Such information might be useful in developing combination treatments for RA that would include a TNF blocking agent and other drugs with different anti-inflammatory mechanisms.

TREATMENT OF RA WITH MONOCLONAL ANTI-TNF ANTIBODIES

The information described in the preceding sections has set the stage for studies to determine whether human RA can be treated by direct neutralization or blockade of TNF. Monoclonal antibodies to TNF were the first such approach to be evaluated clinically. The best-studied antibody is cA2 (infliximab), a chimeric mouse-human immunoglobulin (IgG1) molecule. Another humanized anti-TNF antibody tested in RA is CDP571 (reviewed by Kavanaugh65). The studies using cA2 have shown impressive and rapid clinical effects in established RA, in open trials66,67 and in double-blind, randomized, placebo-controlled trials.6870 cA2 is administered as an intravenous infusion, and doses of 1 to 20 mg/kg have been studied for up to 14 weeks. The response is dose dependent, with a single dose of 10 to 20 mg/kg able to generate clinically significant responses that persist for at least 1 month (median duration, 8 weeks) in 80% of patients. A striking degree of improvement is generally seen, with greater than 50% change in all clinical variables and in C-reactive protein and erythrocyte sedimentation rate. Retreatment is effective, although the duration of responses seems to decrease,67 possibly because of development of antibodies to the anti-TNF monoclonal antibody. cA2 is effective when added to methotrexate in patients with RA who are refractory to methotrexate, and methotrexate use might prolong the duration of responses to cA2, possibly retarding the human antichimeric antibody response.69,70 The CDP571 antibody is also effective in RA,71,72 although more limited data are available thus far than for cA2 (Figure 2).

Acute toxic effects of administration of cA2 in RA have generally been mild.65 With repeated treatment, antibodies to the cA2 (human antichimeric antibody) eventually develop.65 Although human antichimeric antibody is theoretically capable of producing toxic effects, the most frequent difficulty caused by human antichimeric antibody is likely to be diminished efficacy of cA2. Occasionally patients have developed infections (in rare cases, serious ones) during treatment, but it is not yet clear whether the incidence of infection will be greater than in other groups of patients with RA. Some patients with RA treated with cA2 have developed malignancies, including at least 3 cases of hematologic neoplasms,65 which probably occur at an increased frequency in RA. cA2 might accelerate clinical presentation of neoplasia by interfering with antitumor host-defense mechanisms. Of particular interest has been the appearance of antinuclear antibodies in a subset of patients and the less frequent occurrence of a transient systemic lupus erythematosus–like syndrome.65 The (NZBxNZW)F1 mouse, which develops murine lupus, tends to produce low levels of TNF, possibly on a genetic basis, and administration of TNF to such animals induces a significant delay in the development of glomerulonephritis.73 In contrast, transgenic mice that constitutively overexpress TNF develop inflammatory arthritis but no systemic lupus erythematosus–like lesions.74 These fascinating findings in animals and humans suggest that the ambient level of TNF might have a hitherto underappreciated capacity to control the form in which autoimmunity is expressed as a specific syndrome or disease.

The mechanisms of anti-TNF effects (and toxic effects) in RA need to be further explored. Findings to date (reviewed by Camussi and Lupia75) include decreases in serum acute-phase reactants, IL-1, IL-6, and soluble leukocyte-endothelial adhesion molecules. In synovium, lymphocyte infiltration and adhesion molecule expression are reduced. In addition to the multiple potential anti-inflammatory effects of TNF neutralization, it seems that cA2 could mediate complement-dependent lysis of cells that bear membrane-bound TNF.76 Whether cA2 can retard erosion of cartilage and bone in human RA by reducing secretion of tissue-destructive mediators is not yet established, although preliminary findings have been encouraging.

TREATMENT OF RA WITH sTNF-R

A second approach to TNF blockade in RA has been administration of a modified, genetically engineered form of the p75 TNF receptor, termed etanercept (reviewed by Moreland77). Etanercept is a dimeric molecule that contains two p75 sTNF-R extracellular domains attached to the Fc portion of human IgG1 (Figure 2). This dimeric molecule has greater TNF-binding affinity and a longer half-life (90 hours) than does the sTNF-R monomer. In a preliminary dose-finding study, etanercept was given to patients with RA at an initial intravenous dose of 4 to 32 mg/m2, followed by biweekly maintenance doses of 2 to 16 mg/m2 administered subcutaneously.78 A small placebo group allowed for sufficient comparison of clinical and laboratory variables to suggest efficacy of etanercept, especially at higher doses. Subsequently, 2 multicenter, placebo-controlled trials79,80 have demonstrated clinical benefit of this agent in refractory RA. In the first study, etanercept or placebo was administered to patients who previously had not responded to conventional disease-modifying agents and who received only nonsteroidal anti-inflammatory drugs, analgesics, and low-dose corticosteroids concurrently. At 16 mg/m2 (but not at ≤2 mg/m2) given subcutaneously twice weekly, substantial improvement was seen in multiple clinical and laboratory variables in 75% of treated patients compared with 14% of patients who received placebo.79 Etanercept was administered for 3 months, and after drug discontinuation the improvements observed were not maintained during subsequent 2-month follow-up. A subsequent study80 indicated that therapeutic benefit was maintained during a 6-month treatment interval. Ongoing studies are evaluating etanercept in early RA and when added to methotrexate in refractory RA.77 In patients with persistently active RA despite methotrexate treatment, the combination of methotrexate and etanercept treatment is safe and effective for at least 24 weeks.81,82 A p55 sTNF-R has also been tested in patients with RA, but only limited data suggesting efficacy and safety are available.8385 Unlike the p75 sTNF-R, the p55 sTNF-R (lenercept) is immunogenic,84 although molecular modifications of its conformation might mitigate this problem.85

Etanercept binds TNF, rendering it biologically inactive but still present in tissue fluids. In fact, the half-life of the TNF complexes is longer than that of free TNF.77 Much more information is required concerning the details of how etanercept treatment alters the pathophysiological mechanisms of RA and whether the therapeutic mechanisms differ from anti-TNF treatment. Studies using a p55 sTNF-R show that the concentration of this agent required to block release of collagenase and prostaglandin E2 by synovial fibroblasts is 100-fold lower than the concentration required to inhibit T-cell activation.86 This reflects response of T cells to membrane-bound TNF, which is more difficult to block with a soluble receptor. One intriguing difference between sTNF-R and anti-TNF monoclonal antibodies is the ability of sTNF-R to also bind, and undoubtedly neutralize, lymphotoxin α, which uses the same receptors as TNF.

To date, etanercept has been associated with only mild toxic effects, including injection-site reactions and mild upper respiratory tract symptoms,80,82 but no formation of neutralizing antibodies to TNF receptor. There have been a few cases of nonneutralizing antietanercept antibodies, which had no apparent clinical effect. With further experience, etanercept use might be found to induce immunologic changes such as anti-DNA antibodies, as has occurred with cA2 use.

FUTURE DIRECTIONS

Tumor necrosis factor blockade will likely become a major therapeutic advance in the treatment of RA and will probably be widely used in this disease.87 Extension of this approach to other conditions will require careful evaluation in each specific disease because animal models73,88,89 have proven that inhibition of TNF action can, in some instances, accelerate autoimmunity. Nevertheless, TNF blockade will probably be an important approach in the treatment of Crohn disease and, undoubtedly, for several other autoimmune or inflammatory diseases. In RA, issues of long-term efficacy, safety, and mechanisms of action of each approach to TNF blockade need to be addressed. Possibilities for synergistic efficacy with use of methotrexate, IL-1 blockade, or even antilymphocyte monoclonal antibodies88,90 must be investigated further. Additional pharmacological approaches to block TNF function are worth exploring91 given the generally high cost of biological agents.

The potential for a more problematic profile of toxic effects with long-term treatment needs to be considered. Problems with opportunistic infections, especially those caused by intracellular pathogens such as mycobacteria and Listeria, can be expected in view of the role of TNF in host defenses against such organisms. Given the combined role of TNF and lymphotoxin α in the development of peripheral lymphoid tissues,92 maintenance of the organizational integrity and host defense function of these tissues might be compromised by prolonged TNF blockade. Because TNF blockade does not cure RA but requires ongoing treatment to maintain efficacy, late-occurring toxic effects will pose new therapeutic challenges. Surprises and new insights, along with better control of chronic joint inflammation, await both the scientist and the clinician as potent blockade of one of nature's most powerful cytokines moves into clinical practice.

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Article Information

Accepted for publication May 3, 1999.

I thank the staff of Project House Inc, Hackensack, NJ, for their artistic assistance in development of the figures and Nancy Elslager, BA, for preparation of the manuscript.

Reprints: David A. Fox, MD, Department of Internal Medicine/Rheumatology Division, University of Michigan Medical Center, 3918 Taubman Center, Campus Box 0358, Ann Arbor, MI 48109-0358 (e-mail: dfox@umich.edu).

References
1.
Pincus  TCallahan  LFSale  WGBrooks  ALPayne  LEVaughn  WK Severe functional declines, work disability, and increased mortality in seventy-five rheumatoid arthritis patients studied over nine years. Arthritis Rheum. 1984;27864- 872Article
2.
Callahan  LF The burden of rheumatoid arthritis: facts and figures. J Rheumatol Suppl. 1998;538- 12
3.
Fox  DA The role of T cells in the immunopathogenesis of rheumatoid arthritis: new perspectives. Arthritis Rheum. 1997;40598- 609Article
4.
Breedveld  FC New insights in the pathogenesis of rheumatoid arthritis. J Rheumatol Suppl. 1998;533- 7
5.
Arend  WPDayer  J-M Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum. 1990;33305- 315Article
6.
Brennan  FMMaini  RNFeldmann  M Cytokine expression in chronic inflammatory disease. Br Med Bull. 1995;51368- 384
7.
Badolato  ROppenheim  JJ Role of cytokines, acute-phase proteins, and chemokines in the progression of rheumatoid arthritis. Semin Arthritis Rheum. 1996;26526- 538Article
8.
Deleuran  BW Cytokines in rheumatoid arthritis: localization in arthritic joint tissue and regulation in vitro. Scand J Rheumatol. 1996;25 ((suppl 104)) 1- 34Article
9.
Starkebaum  G Role of cytokines in rheumatoid arthritis. Sci Med. March/April1998;6- 15
10.
Miossec  P The Th1/Th2 cytokine balance in arthritis. Miossec  Pvan den  Berg WBFirestein  GSeds.T Cells in Arthritis Basel, Switzerland Birkhäuser Publisher1998;93- 109
11.
Old  LJ Tumor necrosis factor (TNF). Science. 1985;230630- 632Article
12.
Vassalli  P The pathophysiology of tumor necrosis factors. Annu Rev Immunol. 1992;10411- 452Article
13.
Bazzoni  FBeutler  B The tumor necrosis factor ligand and receptor families. N Engl J Med. 1996;3341717- 1725Article
14.
Beutler  BMahoney  JLe Trang  NPekala  PCerami  A Purification of cachectin, a lipoprotein lipase-suppressing hormone secreted by endotoxin-induced RAW 264.7 cells. J Exp Med. 1985;161984- 995Article
15.
Oliff  ADefeo-Jones  DBoyer  M  et al.  Tumors secreting human TNF/cachectin induce cachexia in mice. Cell. 1987;50555- 563Article
16.
Tracey  KJVlassara  HCerami  A Cachectin/tumour necrosis factor. Lancet. 1989;11122- 1126Article
17.
Kriegler  MPerez  CDeFay  KAlbert  ILu  SD A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF. Cell. 1988;5345- 53Article
18.
Müller  UJongeneel  CVNedospasov  SALindahl  KFSteinmetz  M Tumour necrosis factor and lymphotoxin genes map close to H-2D in the mouse major histocompatibility complex. Nature. 1987;325265- 267Article
19.
Tracey  KJBeutler  BLowry  SF  et al.  Shock and tissue injury induced by recombinant human cachectin. Science. 1986;234470- 474Article
20.
Tracey  KJWei  HManogue  KR  et al.  Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation. J Exp Med. 1988;1671211- 1227Article
21.
Starnes  HF  JrWarren  RSJeevanandam  M  et al.  Tumor necrosis factor and the acute metabolic response to tissue injury to man. J Clin Invest. 1988;821321- 1325Article
22.
Perlmutter  DHDinarello  CAPunsal  PIColten  HR Cachectin/tumor necrosis factor regulates hepatic acute-phase gene expression. J Clin Invest. 1986;781349- 1354Article
23.
Dinarello  CACannon  JGWolff  SM  et al.  Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J Exp Med. 1986;1631433- 1450Article
24.
Nawroth  PPBank  IHandley  DCassimeris  JChess  LStern  D Tumor necrosis factor/cachectin interacts with endothelial cell receptors to induce release of interleukin 1. J Exp Med. 1986;1631363- 1375Article
25.
Pober  JSGimbrone  MA  JrLapierre  LA  et al.  Overlapping patterns of activation of human endothelial cells by interleukin 1, tumor necrosis factor, and immune interferon. J Immunol. 1986;1371893- 1896
26.
Leibovich  SJPoverini  PJShepard  HMWiseman  DMShively  VNuseir  N Macrophage-induced angiogenesis is mediated by tumour necrosis factor-α. Nature. 1987;329630- 632Article
27.
Strieter  RMKunkel  SLShowell  HJ  et al.  Endothelial cell gene expression of a neutrophil chemotactic factor by TNF-α, LPS, and IL-1β. Science. 1989;2431467- 1469Article
28.
Kehrl  JHMiller  AFauci  AS Effect of tumor necrosis factor α on mitogen-activated human B cells. J Exp Med. 1987;166786- 791Article
29.
Ranges  GEZlotnik  AExpevik  TDinarello  CACerami  APalladino  MA  Jr Tumor necrosis factor α/cachectin is a growth factor for thymocytes. J Exp Med. 1988;167937- 953Article
30.
Sung  SSBjorndahl  JMWang  CYKao  HTFu  SM Production of tumor necrosis factor/cachectin by human T cell lines and peripheral blood T lymphocytes stimulated by phorbol myristate acetate and anti-CD3 antibody. J Exp Med. 1988;167937- 953Article
31.
Husby  GWilliams  RC  Jr Synovial localization of tumor necrosis factor in patients with rheumatoid arthritis. J Autoimmun. 1988;1363- 371Article
32.
Brennan  FMMaini  RNFeldmann  M TNFα—pivotal role in rheumatoid arthritis? Br J Rheumatol. 1992;31293- 298Article
33.
Neidel  JSchulze  MLindschau  J Association between degree of bone erosion and synovial fluid levels of tumor necrosis factor α in the knee-joints of patients with rheumatoid arthritis. Inflamm Res. 1995;44217- 221Article
34.
Lupia  EMontrucchio  GBattaglia  EModena  VCamussi  G Role of tumor necrosis factor-α and platelet-activating factor in neoangiogenesis induced by synovial fluids of patients with rheumatoid arthritis. Eur J Immunol. 1996;261690- 1694Article
35.
Dayer  J-MBeutler  BCerami  A Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med. 1985;1622163- 2168Article
36.
Bertolini  DRNedwin  GEBringman  TSSmith  DDMundy  GR Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors. Nature. 1986;319516- 518Article
37.
Saklatvala  J Tumour necrosis factor α stimulates resorption and inhibits synthesis of proteoglycan in cartilage [letter]. Nature. 1986;322547- 549Article
38.
Paleolog  EMYoung  SStark  ACMcCloskey  RVFeldmann  MMaini  RN Modulation of angiogenic vascular endothelial growth factor by tumor necrosis factor α and interleukin-1 in rheumatoid arthritis. Arthritis Rheum. 1998;411258- 1265Article
39.
Leirisalo-Repo  MPaimela  LJäättelä  MKoskimies  SRepo  H Production of TNF by monocytes of patients with early rheumatoid arthritis is increased. Scand J Rheumatol. 1995;24366- 371Article
40.
Rubin  BYAnderson  SLSullivan  SAWilliamson  BDCarswell  EAOld  LJ High affinity binding of 125I-labeled human tumor necrosis factor (LuKII) to specific cell surface receptors. J Exp Med. 1985;1621099- 1104Article
41.
Tsujimoto  MYip  YKVilcek  J Tumor necrosis factor: specific binding and internalization in sensitive and resistant cells. Proc Natl Acad Sci U S A. 1985;827626- 7630Article
42.
Aggarwal  BBEessalu  TEHass  PE Characterization of receptors for human tumour necrosis factor and their regulation by γ-interferon. Nature. 1985;318665- 667Article
43.
Smith  CADavis  TAnderson  D  et al.  A receptor for tumor necrosis factor defines an unusual family of cellular and viral proteins. Science. 1990;2481019- 1023Article
44.
Brockhaus  MSchoenfeld  H-JSchlaeger  E-JHunziker  WLesslauer  WLoetscher  H Identification of two types of tumor necrosis factor receptors on human cell lines by monoclonal antibodies. Proc Natl Acad Sci U S A. 1990;873127- 3131Article
45.
Thoma  BGrell  MPfizenmaier  KScheurich  P Identification of a 60-kD tumor necrosis factor (TNF) receptor as the major signal transducing component in TNF responses. J Exp Med. 1990;1721019- 1023Article
46.
Butler  DMFeldmann  MDi Padova  FBrennan  FM p55 and p75 tumor necrosis factor receptors are expressed and mediate common functions in synovial fibroblasts and other fibroblasts. Eur Cytokine Netw. 1994;5441- 448
47.
Seckinger  PIsaaz  SDayer  J-M A human inhibitor of tumor necrosis factor α. J Exp Med. 1988;1671511- 1516Article
48.
Van Zee  KJKohno  TFischer  ERock  CSMoldawer  LLLowry  SF Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor α in vitro and in vivo. Proc Natl Acad Sci U S A. 1992;894845- 4849Article
49.
Cope  APAderka  DDoherty  M  et al.  Increased levels of soluble tumor necrosis factor receptors in the sera and synovial fluid of patients with rheumatic diseases. Arthritis Rheum. 1992;351160- 1169Article
50.
Brennan  FMGibbons  DLCope  APKatsikis  PMaini  RNFeldmann  M TNF inhibitors are produced spontaneously by rheumatoid and osteoarthritic synovial joint cell cultures: evidence of feedback control of TNF action. Scand J Immunol. 1995;42158- 165Article
51.
Steiner  GStudnicka-Benke  AWitzmann  GHöfler  ESmolen  J Soluble receptors for tumor necrosis factor and interleukin-2 in serum and synovial fluid of patients with rheumatoid arthritis, reactive arthritis and osteoarthritis. J Rheumatol. 1995;22406- 412
52.
Roux-Lombard  PPunzi  LHasler  F  et al.  Soluble tumor necrosis factor receptors in human inflammatory synovial fluids. Arthritis Rheum. 1993;36485- 489Article
53.
Feldmann  MBrennan  FMWilliams  ROElliott  MJMaini  RN Cytokine expression and networks in rheumatoid arthritis: rationale for anti-TNFα antibody therapy and its mechanism of action. J Inflamm. 1995-96;4790- 96
54.
Tracey  KJFong  YHesse  DG  et al.  Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 1987;330662- 664Article
55.
Mohler  KMTorrance  DSSmith  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;1511548- 1561
56.
Abraham  EGlauser  MPButler  T  et al.  p55 tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock: a randomized controlled multicenter trial. JAMA. 1997;2771531- 1538Article
57.
Williams  ROFeldmann  MMaini  RN Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc Natl Acad Sci U S A. 1992;899784- 9788Article
58.
Wooley  PHDutcher  JWidmer  MBGillis  S Influence of a recombinant human soluble tumor necrosis factor receptor Fc fusion protein on type II collagen-induced arthritis in mice. J Immunol. 1993;1516602- 6607
59.
Brennan  FMChantry  DJackson  AMaini  RFeldmann  M Inhibitory effect of TNFα antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet. 1989;2244- 247Article
60.
Kettelhut  ICFiers  WGoldberg  AL The toxic effects of tumor necrosis factor in vivo and their prevention by cyclooxygenase inhibitors. Proc Natl Acad Sci U S A. 1987;844273- 4277Article
61.
Barrera  PBoerbooms  AMThvan de Putte  LBAvan der Meer  JWM Effects of antirheumatic agents on cytokines. Semin Arthritis Rheum. 1996;25234- 253Article
62.
Barrera  PBoerbooms  AMTJanssen  EM  et al.  Circulating soluble tumor necrosis factor receptors, interleukin-2 receptors, tumor necrosis factor α, and interleukin-6 levels in rheumatoid arthritis: longitudinal evaluation during methotrexate and azathioprine therapy. Arthritis Rheum. 1993;361070- 1079Article
63.
Brennan  FMCope  APKatsikis  PGibbons  DLMaini  RNFeldmann  M Selective immunosuppression of tumour necrosis factor-alpha in rheumatoid arthritis. Andorini  Led.Selective Immunosuppression Basic Concepts and Clinical Applications Basel, Switzerland S Karger AG1995;48- 60
64.
Hart  PHHunt  EKBonder  CSWatson  CJFinlay-Jones  JJ Regulation of surface and soluble TNF receptor expression on human monocytes and synovial fluid macrophages by IL-4 and IL-10. J Immunol. 1996;1573672- 3680
65.
Kavanaugh  AF Anti-tumor necrosis factor-α monoclonal antibody therapy for rheumatoid arthritis. Kremer  JMed.Rheumatic Disease Clinics of North America 3rd ed. Philadelphia, Pa WB Saunders Co1998;593- 614
66.
Elliott  MJMaini  RNFeldmann  M  et al.  Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor α. Arthritis Rheum. 1993;361681- 1690Article
67.
Elliott  MJMaini  RNFeldmann  M  et al.  Repeated therapy with monoclonal antibody to tumour necrosis factor α (cA2) in patients with rheumatoid arthritis. Lancet. 1994;3441125- 1127Article
68.
Elliott  MJMaini  RNFeldmann  M  et al.  Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor α (cA2) versus placebo in rheumatoid arthritis. Lancet. 1994;3441105- 1110Article
69.
Kavanaugh  AFCush  JJSt Clair  EW  et al.  Anti-TNF-α monoclonal antibody (mAb) treatment of rheumatoid arthritis (RA) patients with active disease on methotrexate (MTX): results of a double-blind, placebo-controlled multicenter trial [abstract]. Arthritis Rheum. 1996;39 ((suppl)) S123Article
70.
Maini  RNBreedveld  FCKalden  JR  et al.  Low dose methotrexate (MTX) suppresses anti-globulin responses and potentiates efficacy of a chimeric monoclonal anti-TNFα antibody (cA2) given repeatedly in rheumatoid arthritis (RA) [abstract]. Arthritis Rheum. 1997;9 ((suppl)) S126
71.
Rankin  ECCChoy  EHSKassimos  D  et al.  The therapeutic effects of an engineered human anti-tumour necrosis factor alpha antibody (CDP571) in rheumatoid arthritis. Br J Rheumatol. 1995;34334- 342Article
72.
Rankin  ECCChoy  EHSSopwith  AMVetterlein  OPanayi  GSIsenberg  DA Repeated doses of 10 mg/kg of an engineered human anti-TNF-α antibody CDP571 in RA patients are safe and effective [abstract]. Arthritis Rheum. 1995;38 ((suppl)) 185
73.
Jacob  COMcDevitt  HO Tumour necrosis factor-α in murine autoimmune "lupus" nephritis. Nature. 1988;331356- 358Article
74.
Keffer  JProbert  LCazlaris  H  et al.  Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 1991;104025- 4031
75.
Camussi  GLupia  E The future role of anti-tumour necrosis factor (TNF) products in the treatment of rheumatoid arthritis. Drugs. 1998;55613- 620Article
76.
Scallon  BJMoore  MATrinh  HKnight  DMGhrayeb  J Chimeric anti-TNF-α monoclonal antibody cA2 binds recombinant transmembrane TNF-α and activates immune effector functions. Cytokine. 1995;7251- 259Article
77.
Moreland  LW Soluble tumor necrosis factor receptor (p75) fusion protein (Enbrel) as a therapy for rheumatoid arthritis. Kremer  JMed.Rheumatic Disease Clinics of North America 3rd ed. Philadelphia, Pa WB Saunders Co1998;579- 591
78.
Moreland  LWMargolies  GHeck  LW  Jr  et al.  Recombinant soluble tumor necrosis factor receptor (p80) fusion protein: toxicity and dose finding trial in refractory rheumatoid arthritis. J Rheumatol. 1996;231849- 1855
79.
Moreland  LWBaumgartner  SWSchiff  MH  et al.  Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med. 1997;337141- 147Article
80.
Moreland  LWSchiff  MHBaumgartner  SW  et al.  Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial. Ann Intern Med. 1999;130478- 486Article
81.
Weinblatt  MEKremer  JMBankhurst  AD  et al.  Phase II/III trial of the TNF receptor p75 Fc fusion protein (TNFR:Fc), Enbrel in combination with methotrexate (MTX) in RA patients. Arthritis Rheum. 1998;41 ((suppl)) S189Article
82.
Weinblatt  MEKremer  JMBankhurst  AD  et al.  A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med. 1999;340253- 259Article
83.
Sander  Oden Broeder  Avan der Hoogen  FLaan  Rvan de Putte  LRau  R 30 Months of treatment with a TNFα receptor-fusion protein (TNFR55-IgG1, RO 45-2081) in patients with severe refractory RA [abstract]. Arthritis Rheum. 1987;40 ((suppl)) S81
84.
Urs  CGhuerkauf  RStevens  RLesslauer  WRA and MS study groups, Immunogenicity of a human TNFR55-IgG1 fusion protein (Lenercept) in rheumatoid arthritis (RA) and multiple sclerosis (MS) patients [abstract]. Arthritis Rheum. 1998;41 ((suppl)) S58Article
85.
Martin  SFrazier  JSeely  J  et al.  A genetically modified tumor necrosis factor receptor I (sTNF-RI) that does not elicit antibody response in primates [abstract]. Arthritis Rheum. 1998;41 ((suppl)) S58Article
86.
Nicod  LPIsler  PChicheportiche  RSongeon  FDayer  J-M Production of prostaglandin E2 and collagenase is inhibited by the recombinant soluble tumour necrosis factor receptor p55-human γ3 fusion protein at concentrations a hundred-fold lower than those decreasing T cell activation. Eur Cytokine Netw. 1996;7757- 763
87.
Koopman  WJMoreland  LW Rheumatoid arthritis: anticytokine therapies on the horizon. Ann Intern Med. 1998;128231- 233Article
88.
Liu  JMarino  MWWong  G  et al.  TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination. Nat Med. 1998;478- 83Article
89.
McKall-Faienza  KJKawai  KKündig  TM  et al.  Absence of TNFRp55 influences virus-induced autoimmunity despite efficient lymphocytic infiltration. Int Immunol. 1998;10405- 412Article
90.
Kremer  JM Combination therapy with biological agents in rheumatoid arthritis: perils and promise. Arthritis Rheum. 1998;411548- 1551Article
91.
Chikanza  ICJawed  SNaughton  DBlake  DR Why do we need new treatments for rheumatoid arthritis? J Pharm Pharmacol. 1998;50357- 369Article
92.
Ettinger  RMebius  RBrowning  JL  et al.  Effects of tumor necrosis factor and lymphotoxin on peripheral lymphoid tissue development. Int Immunol. 1998;10727- 741Article
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