How does infliximab work in rheumatoid arthritis?
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Since the initial characterization of tumor necrosis factor alpha (TNFα), it has become clear that TNFα has diverse biologic activity. The realization that TNFα plays a role in rheumatoid arthritis (RA) has led to the development of anti-TNF agents for the treatment of RA. Infliximab, a chimeric monoclonal antibody that specifically, and with high affinity, binds to TNFα and neutralizes the cytokine, is currently approved for the treatment of RA and Crohn's disease, another immune-inflammatory disorder. In addition to establishing the safety and efficacy of infliximab, clinical research has also provided insights into the complex cellular and cytokine-dependent pathways involved in the pathophysiology of RA, including evidence that supports TNFα involvement in cytokine regulation, cell recruitment, angiogenesis, and tissue destruction.
Keywordsinfliximab rheumatoid arthritis signaling pathways tumor necrosis factor
Anti-Tumor necrosis factor Trial in Rheumatoid Arthritis with Concomitant Therapy
tumor necrosis factor alpha
vascular endothelial growth factor.
Tumor necrosis factor alpha (TNFα) is the name given to a serum factor that was derived in 1975 from endotoxin-treated mice and found to be capable of inducing necrosis of a methylcholanthrene-induced murine sarcoma . The molecular characterization of TNFα in the 1980s revealed that it is identical to cachectin, a previously described serum factor that was found to be responsible for weight loss and fever in experimental animal models [2, 3]. The diverse biologic activities of TNFα soon became apparent. Aside from its tumoricidal property, it was recognized that, following injection into animals or humans, TNFα causes signs and symptoms of shock, including multi-organ damage via pro-inflammatory effects on vascular endothelium. The realization that TNFα may play a role in rheumatoid arthritis (RA) followed four demonstrations: firstly, its ability to degrade cartilage and bone in vitro; secondly, its arthritogenic properties in animal models; thirdly, its co-localization with TNF receptors in RA synovium and the pannus-cartilage junction; and fourthly, its pivotal role in regulating the production of interleukin (IL)-1 in cultured RA-derived synovial cells (a mixture of lymphoid cells, macrophages, dendritic cells, B cells, endothelial cells, and fibroblasts) [4, 5].
Support for the role of TNFα in RA, and hence its promise as a therapeutic target candidate, came from the observation that the clinical signs and tissue damage of collagen-induced arthritis in mice were ameliorated by administration of a monoclonal anti-TNFα antibody . In 1992, 20 patients with active RA despite treatment with disease-modifying antirheumatic drugs were the first to be treated with an anti-TNFα agent, infliximab (Remicade®, Centocor, Inc, Malvern, Pa). In this open-label clinical trial by our group at the Kennedy Institute of Rheumatology Division, the safety and marked anti-inflammatory effect of intravenously administered infliximab was associated with a dramatic reduction in C-reactive protein (CRP) and erythrocyte sedimentation rate . A multicenter, randomized, placebo-controlled trial in Europe quickly followed and confirmed the anti-inflammatory effect of a single intravenous infusion of infliximab . However, most patients relapsed within 3 to 8 weeks demonstrating the requirement for repeat therapy . The duration of benefit before relapse was related to the size of the drug dose (1 or 10 mg/kg).
The efficacy and optimal dose of infliximab, as well as an enhanced therapeutic efficacy when coadministered with methotrexate (MTX), was subsequently established in a follow-up, randomized, controlled clinical trial [10, 11]. The consistency of a sustained therapeutic clinical response in long-term treatment (2 years) with infliximab plus MTX under double-blinded, placebo-controlled conditions has now been demonstrated in the international, multicenter Anti-Tumor necrosis factor Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) [12, 13, 14]. Patients were randomized to receive either four dose schedules of infliximab plus weekly doses of MTX (median dose 15 mg/wk) or MTX alone. Serial radiographs performed at 24, 54, and 102 weeks of this trial have revealed retardation or arrest (and even improvement in 39% to 54% of patients) of both joint space narrowing (which equates with cartilage loss) and bone erosion. These results are in contrast to the progressive damage in the control group of patients who were treated with MTX alone [12, 14]. These data are consistent with the hypothesis that TNFα plays a key role in the perpetuation of inflammation and destruction of cartilage and bone in RA.
Infliximab, a chimeric (mouse Fv1, human IgG1) monoclonal antibody, specifically binds to both soluble and membrane-bound TNFα with high affinity (Ka = 1010 M-1), forming stable nondisassociating immune complexes . The binding of infliximab to TNFα prevents the binding of TNFα to its receptors and blocks the initiation of the intracellular signaling that leads to gene transcription and subsequent biologic activity. The binding of infliximab to membrane-bound TNFα in vitro results in lysis of cell lines via a complement- or antibody-dependent cell cytotoxicity mechanism [16, 17]. Whether this in vitro action has an in vivo correlate has not been confirmed. The similarity of clinical results observed for infliximab and etanercept, another anti-TNF agent, suggests that cell lysis may not be a necessary prerequisite, as etanercept does not exhibit similar cell lytic properties in vitro.
Treatment of RA patients with infliximab has provided an opportunity for clinical investigations that have illuminated aspects of its cellular and molecular bases of action and have provided insights into the pathogenesis of RA.
Pharmacokinetics and clinical response
Infliximab regulates the cytokine network
Infliximab regulates cell recruitment
Infliximab regulates a major angiogenic factor and angiogenesis
From the early stages of disease, rheumatoid synovial inflammation is accompanied by a marked increase in angiogenesis. The increase in blood vessel density provides a conduit for the increased trafficking of blood-borne immune and inflammatory cells into joints. This increase in trafficking leads to the formation of vascular pannus tissue that invades and destroys cartilage and bone in the "bare area" of the attachment of synovium to subchondral bone.
Infliximab prevents cartilage catabolism and bone erosion
The most compelling evidence for the ability of anti-TNFα therapy to prevent cartilage loss and bone erosions following the onset of disease was obtained by histologic examination of joints in the collagen-induced arthritis mouse model of RA . In this model, preservation of chondrocytes and cartilage matrix and the lack of pannus invasion of bone were notable features in response to treatment with infliximab. In RA patients in the ATTRACT trial, protection of cartilage and bone was observed – possibly with healing – as judged by comparison of baseline and 54-week radiographs of hands and feet in patients treated with infliximab [12, 25]. This finding supports the conclusion that mechanisms of tissue destruction in RA are TNFα-dependent. Whether the coadministration of MTX with infliximab plays a part in the mechanism of action needs to be clarified. Because etanercept as monotherapy significantly slowed progression of bone erosions in early RA patients over one year compared with MTX monotherapy, the bone-protective action of anti-TNFα therapy is not in doubt . A reduction in matrix metalloproteinase-1 and matrix metalloproteinase-3 following infliximab treatment has been documented, and although the cellular and molecular basis of anti-TNFα in this regard is not yet understood, this implies that a downregulation of matrix-degrading enzymes may be involved .
In animal models, IL-1 appears to play a critical role in cartilage destruction; it has been proposed that IL-1 may be a better therapeutic target in RA and that the joint protective effect of anti-TNFα therapy involves regulation of IL-1 production [33, 34]. The activation and function of osteoclasts appear to involve not only IL-1 and TNFα, but also the receptor activator of NFκB ligand (RANKL), also known as TNF-related activation-induced cytokine (TRANCE), and the interaction of RANKL with RANK [35, 36]. Further work is necessary to delineate the relative importance of these mechanisms.
Infliximab therapy for RA has illuminated the multiple pathways regulated by TNFα and its mechanism of action. These studies have begun to unravel the complex cellular and cytokine-dependent pathways that are involved and have provided a new therapeutic benchmark. The lessons we have learned will help to identify future research in developing the next generation of antirheumatic drugs with an improved efficacy and safety profile.
We wish to thank the Arthritis Research Council, which has supported our work through its grants to The Kennedy Institute of Rheumatology. We also thank Centocor, Inc. for providing additional support for the infliximab clinical studies.
- 5.Maini RN, Feldmann M: Pocket Reference to TNFα Antagonism and Rheumatoid Arthritis. 2000, London: Science Press, LtdGoogle Scholar
- 8.Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, Leeb B, Breedveld FC, Macfarlane JD, Bijl H, Woody JN: Randomised double-blind comparison of chimeric mono-clonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet. 1994, 344: 1105-1110. 10.1016/S0140-6736(94)90628-9.PubMedCrossRefGoogle Scholar
- 10.Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfar-lane JD, Antoni C, Leeb B, Elliott MJ, Woody JN, Schaible TF, Feldmann M: Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 1998, 41: 1552-1563. 10.1002/1529-0131(199803)41:3<565::AID-ART28>3.3.CO;2-#.PubMedCrossRefGoogle Scholar
- 11.Maini RN, Elliott MJ, Long-Fox A, Feldmann M, Kalden JR, Antomio C, Smolen JS, Leeb B, Breedveld FC, Macfarlane JD, Bijl H, Woody JN: Clinical response of rheumatoid arthritis to anti-TNFα (cA2) monoclonal antibody is related to administered dose and persistence of circulating antibody [abstract]. Arthritis Rheum. 1995, 38 (suppl 9): S186-Google Scholar
- 12.Lipsky P, van der Heijde D, St. Clair W, Smolen J, Furst D, Kalden J, Weisman M, Breedveld F, Emery P, Keystone E, Harriman G, Maini R: 102-wk clinical & radiologic results from the ATTRACT trial: a 2 year, randomized, controlled, phase 3 trial of infliximab (Remicade®) in pts with active RA despite MTX [abstract]. Arthritis Rheum. 2000, 43: S269-Google Scholar
- 13.Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, Smolen J, Emery P, Harriman G, Feldmann M, Lipsky P: Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet. 1999, 354: 1932-1939. 10.1016/S0140-6736(99)05246-0.PubMedCrossRefGoogle Scholar
- 14.Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, Smolen JS, Weisman M, Emery P, Feldmann M, Harriman GR, Maini RN: Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med. 2000, 343: 1594-1602. 10.1056/NEJM200011303432202.PubMedCrossRefGoogle Scholar
- 16.Siegel SA, Shealy DJ, Nakada MT, Le J, Woulfe DS, Probert L, Kollias G, Ghrayeb J, Vilcek J, Daddona PE: The mouse/human chimeric monoclonal antibody cA2 neutralizes TNF in vitro and protects transgenic mice from cachexia and TNF lethality in vivo. Cytokine. 1995, 7: 15-25. 10.1006/cyto.1995.1003.PubMedCrossRefGoogle Scholar
- 17.Barone D, Krantz C, Lambert D, Maggiora K, Mohler K: Comparative analysis of the ability of etanercept and infliximab to lyse TNF-expressing cells in a complement dependent fashion [abstract]. Arthritis Rheum. 1999, 42 (suppl): S90-Google Scholar
- 18.Ulfgren AK, Andersson U, Engstrom M, Klareskog L, Maini RN, Taylor PC: Systemic anti-tumor necrosis factor alpha therapy in rheumatoid arthritis down-regulates synovial tumor necrosis factor alpha synthesis. Arthritis Rheum. 2000, 43: 2391-2396. 10.1002/1529-0131(200011)43:11<2391::AID-ANR3>3.0.CO;2-F.PubMedCrossRefGoogle Scholar
- 19.Charles P, Elliott MJ, Davis D, Potter A, Kalden JR, Antoni C, Breedveld FC, Smolen JS, Eberl G, deWoody K, Feldmann M, Maini RN: Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis. J Immunol. 1999, 163: 1521-1528.PubMedGoogle Scholar
- 22.Lorenz HM, Antoni C, Valerius T, Repp R, Grunke M, Schwerdtner N, Nusslein H, Woody J, Kalden JR, Manger B: In vivo blockade of TNF-alpha by intravenous infusion of a chimeric mono-clonal TNF-alpha antibody in patients with rheumatoid arthritis. Short term cellular and molecular effects. J Immunol. 1996, 156: 1646-1653.PubMedGoogle Scholar
- 24.Tak PP, Taylor PC, Breedveld FC, Smeets TJM, Daha MR, Kluin PM, Meinders AE, Maini RN: Decrease in cellularity and expression of adhesion molecules by anti-tumor necrosis factor alpha monoclonal antibody treatment in patients with rheumatoid arthritis. Arthritis Rheum. 1996, 39: 1077-1081.PubMedCrossRefGoogle Scholar
- 25.Paleolog EM, Young S, Stark AC, McCloskey RV, Feldmann M, Maini RN: Modulation of angiogenic vascular endothelial growth factor by tumor necrosis factor alpha and interleukin-1 in rheumatoid arthritis. Arthritis Rheum. 1998, 41: 1258-1265. 10.1002/1529-0131(199807)41:7<1258::AID-ART17>3.0.CO;2-1.PubMedCrossRefGoogle Scholar
- 26.Taylor PC, Peters AM, Paleolog E, Chapman PT, Elliott MJ, McCloskey R, Feldmann M, Maini RN: Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis factor α blockade in patients with rheumatoid arthritis. Arthritis Rheum. 2000, 43: 38-47. 10.1002/1529-0131(200001)43:1<38::AID-ANR6>3.0.CO;2-L.PubMedCrossRefGoogle Scholar
- 28.Fava RA, Olsen NJ, Spencer-Green G, Yeo KT, Yeo TK, Berse B, Jackman RW, Senger DR, Dvorak HF, Brown LF: Vascular permeability factor/endothelial growth factor (VPF/VEGF): accumulation and expression in human synovial fluids and rheumatoid synovial tissue. J Exp Med. 1994, 180: 341-346. 10.1084/jem.180.1.341.PubMedCrossRefGoogle Scholar
- 30.Taylor P, Patel S, Paleolog E, McCloskey R, Feldmann M, Maini RN: Reduced synovial vascularity following TNFα blockade in RA. [abstract]. Arthritis Rheum. 1998, 41 (suppl 1): S295-Google Scholar
- 31.Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, Genovese MC, Wasko MC, Moreland LW, Weaver AL, Markenson J, Finck BK: A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000, 343: 1586-1593. 10.1056/NEJM200011303432201.PubMedCrossRefGoogle Scholar
- 32.Brennan FM, Browne KA, Green PA, Jaspar JM, Maini RN, Feld-mann M: Reduction of serum matrix metalloproteinase 1 and matrix metalloproteinase 3 in rheumatoid arthritis patients following anti-tumour necrosis factor-alpha (cA2) therapy. Br J Rheumatol. 1997, 36: 643-650. 10.1093/rheumatology/36.6.643.PubMedCrossRefGoogle Scholar
- 36.Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T: Osteoclast differentiation factor is a ligand for osteoprote-gerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA. 1998, 95: 3597-3602. 10.1073/pnas.95.7.3597.PubMedPubMedCentralCrossRefGoogle Scholar