Tumor necrosis factor antagonist mechanisms of action: A comprehensive review

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Abstract

During the past 30 years, elucidation of the pathogenesis of rheumatoid arthritis, Crohn's disease, psoriasis, psoriatic arthritis and ankylosing spondylitis at the cellular and molecular levels has revealed that these diseases share common mechanisms and are more closely related than was previously recognized. Research on the complex biology of tumor necrosis factor (TNF) has uncovered many mechanisms and pathways by which TNF may be involved in the pathogenesis of these diseases. There are 3 TNF antagonists currently available: adalimumab, a fully human monoclonal antibody; etanercept, a soluble receptor construct; and infliximab, a chimeric monoclonal antibody. Two other TNF antagonists, certolizumab and golimumab, are in clinical development.The remarkable efficacy of TNF antagonists in these diseases places TNF in the center of our understanding of the pathogenesis of many immune-mediated inflammatory diseases. The purpose of this review is to discuss the biology of TNF and related family members in the context of the potential mechanisms of action of TNF antagonists in a variety of immune-mediated inflammatory diseases. Possible mechanistic differences between TNF antagonists are addressed with regard to their efficacy and safety profiles.

Introduction

Rheumatoid arthritis (RA) has emerged as a prototypic immune-mediated inflammatory disease in our understanding of pathophysiologic mechanisms and is a common focus of clinical studies of tumor necrosis factor (TNF) antagonists. RA is a chronic disease in which inflammation of the synovial tissue results in articular cartilage and bone destruction. Parallel advances in research on the pathogenesis of RA and cytokine biology converged on TNF and interleukin-1 (IL-1) as key factors in inflammation and matrix destruction (Saxne et al., 1988, Arend and Dayer, 1990). The concept arose that elevated concentrations of TNF at the sites of inflammation were driving disease pathology, and the removal of excess TNF from sites of inflammation became a therapeutic goal (Brennan et al., 1989, Knight et al., 1993). In addition, transgenic mice expressing high concentrations of TNF spontaneously developed arthritis that was clinically and histopathologically similar to RA (Keffer et al., 1991). A collagen-induced arthritis model demonstrated that blockade of TNF was efficient in ameliorating the disease (Thorbecke et al., 1992, Williams et al., 1992). After the demonstration of the role of TNF and the efficacy of TNF blockade in experimental models, a pilot study was performed in patients with RA using a neutralizing, chimeric, monoclonal anti-TNF antibody, cA2, now called infliximab. The result of this pilot study was very positive (Elliott et al., 1993), and this study was followed by a larger multicenter study with the same antibody that unequivocally demonstrated the efficacy of the anti-TNF antibody in reducing disease activity and signs and symptoms of RA (Elliott et al., 1994). Today, there are 3 registered TNF antagonists in the United States and the European Union: infliximab, etanercept and adalimumab; each is indicated for several immune-mediated inflammatory diseases (Table 1). The current status of registered clinical trials for all 5 TNF antagonists can be accessed at http://clinicaltrials.gov/, http://www.who.int/, or http://www.actr.org.au/. Although different immune-mediated inflammatory diseases involve distinct target organs or tissues, they appear to share some common underlying mechanisms involving TNF. All 3 TNF antagonists are parenterally administered protein therapeutics (biologics); infliximab and adalimumab are monoclonal antibodies (mAbs) that specifically bind TNF; and etanercept is a TNF-receptor Fc-fusion protein that binds TNF and lymphotoxin (LT) family members. In addition, 2 other TNF antagonists in development — certolizumab pegol, refered to as certolizumab hereafter, and golimumab — also will be covered in this review, although relatively little information is publicly available on these agents.

The clinical efficacy profiles, dosage and routes of administration, pharmacokinetic parameters and immunogenicity profiles of the TNF antagonists are listed in Table 1. The clinical efficacy profiles of infliximab, etanercept and adalimumab have been reviewed in detail (Bang and Keating, 2004, Furst et al., 2007, Haraoui, 2005, Atzeni et al., 2005a). Infliximab and adalimumab have very similar efficacy profiles and are highly efficacious in RA, psoriasis, psoriatic arthritis, ankylosing spondylitis and Crohn's disease. The available clinical data suggest that LT blockade by etanercept offers no additional benefit over TNF blockade in the treatment of RA (Weinblatt et al., 1999, Weinblatt et al., 2003). Etanercept differs from infliximab and adalimumab primarily in the lack of efficacy of etanercept in granulomatous diseases, such as Crohn's disease, Wegener's granulomatosis and sarcoidosis (Sandborn et al., 2001, Utz et al., 2003, Wegener's Granulomatosis Etanercept Trial (WGET) Research Group, 2005). In addition, although etanercept has efficacy comparable to infliximab and adalimumab in RA, etanercept may be less efficacious than infliximab or adalimumab in psoriasis (Leonardi et al., 2003, Gottlieb et al., 2004, Gordon et al., 2006). In the treatment of RA, combinations of TNF antagonists with low-dosage methotrexate have generally been more efficacious than either drug alone (Maini et al., 1998, Klareskog et al., 2004, Breedveld et al., 2006). Treatment of patients with RA with methotrexate alone reduced the recruitment of synovial fluid neutrophils and synovial tissue macrophages, as well as the expression of adhesion molecules and metalloproteinases (Kraan et al., 2000a, Kraan et al., 2000b). Methotrexate also has immunosuppressive properties, including inhibition of activated T cells (Genestier et al., 1998) and selective inhibition of T cell–dependent animal models of RA (Lange et al., 2005). The mechanism of action of methotrexate is still under investigation, but its anti-inflammatory effects may be mediated by adenosine, folate antagonism, inhibition of spermine/spermidine production and/or alteration of cellular redox state (Montesinos et al., 2000, Cronstein, 2005). Thus, the enhanced efficacy of the combination of methotrexate with TNF antagonists may reflect true mechanistic synergism. The pharmacokinetic and immunogenicity profiles for infliximab, etanercept and adalimumab are dissimilar and will be discussed in detail later. Antibody concentrations against TNF antagonists were reduced by concomittant treatment with methotrexate, probably as a result of the immunosuppressive activity of methotrexate (Maini et al., 1998, Weinblatt et al., 2003, Anderson, 2005). Another interesting observation in the treatment of rheumatic diseases and Crohn's disease is that many patients who are nonresponsive, who have lost response or who are intolerant of one TNF antagonist responded when switched to a different TNF antagonist (van Vollenhoven et al., 2003, Barthel et al., 2005, Sandborn, 2005, Gomez-Reino and Group, 2006, Nikas et al., 2006, Bombardieri et al., 2007).

The overall safety profiles of infliximab, etanercept and adalimumab have been subject to more extensive scrutiny than most other drugs. TNF antagonists interfere with a key molecule in the immune defense system and their introduction came at a time when awareness of drug safety for new drugs had increased. Thus, apart from regular spontaneous adverse-event reportings, several extensive safety registries have been established in several countries. These safety registries have contributed to a more complete understanding of the risks and benefits of these drugs as compared with most other newly introduced pharmaceuticals. Some analyses of combined data from randomized, controlled trials or from safety registries indicated that TNF antagonists increased the overall risk of infections (Listing et al., 2005, Bongartz et al., 2006, Askling et al., 2007), but some studies have found there is no overall increased risk for infections after TNF blockade as compared with the frequency in patients with RA not treated with TNF antagonists (Dixon et al., 2006, Schiff et al., 2006a). However, the combined data from randomized controlled trials and safety registries have indicated that there is an increased risk for certain infections, particularly tuberculosis (TB) and other infections caused by intracellular microbes, after treatment with TNF antagonists (Askling et al., 2005, Carmona et al., 2005, Listing et al., 2005, Askling et al., 2006, Bongartz et al., 2006, Carmona et al., 2006, Schiff et al., 2006b). Cases of TB have been documented in patients treated with all TNF antagonists and the incidence has so far been shown to be greater and to occur earlier with infliximab and adalimumab than with etanercept (Keystone, 2005). Most of these cases were a result of reactivation of latent TB and occurred within the first few months of therapy (Bieber and Kavanaugh, 2004, Chen et al., 2006). Screening for latent TB prior to commencing therapy is advocated by the Centers for Disease Control and Prevention, the American Thoracic Society and others for all TNF antagonists. Screening with tuberculin skin tests and/or chest radiographs has markedly reduced the incidence of TB (Carmona et al., 2005, Lee and Kavanaugh, 2005, Chen et al., 2006). Further studies evaluating extended populations of patients and screening practices are warranted as part of the continued risk-management plans for these drugs.

The second major concern has been malignancies. An increased rate of lymphomas was initially detected in patients treated with TNF antagonists when compared with the risk for lymphomas in matched healthy controls from the population. However, there is strong evidence that disease activity is a driving force behind the increased risk for lymphomas in patients with RA irrespective of the treatment (Baecklund et al., 1998, Baecklund et al., 2004, Wolfe and Michaud, 2004, Baecklund et al., 2006). Data from safety registries indicate that the disease activity, rather than TNF antagonism, is likely to be responsible for the increased lymphoma risk that was initially reported in TNF antagonist–treated patients with RA (Wolfe and Michaud, 2004, Askling et al., 2006). There are, however, also reports that indicate that an increased frequency of lymphomas indeed may be associated with TNF blockade (Bongartz et al., 2006), and this issue merits close continued scrutiny in population-based surveillance registries. Currently, the risk for lymphomas after TNF blockade is considered limited enough not to exert a major influence over decisions to initiate or continue TNF-antagonist therapy in patients with RA with high disease activity or rapidly progressing joint destruction, but continued close scrutiny in registers is recommended by the United States Food and Drug Administration as well as the European Agency for the Evaluation of Medicinal Products. For solid cancers, no overall increased risk has been reported in registry studies, either in patients with RA treated with TNF antagonists or in other patients with RA (Gridley et al., 1993, Askling et al., 2006). However, Bongartz et al. (2006) reported an increased frequency of certain solid tumors, mainly from the skin, after TNF-antagonist treatment.

Other adverse events that have been associated with TNF-antagonist therapy include systemic lupus erythematosus-like syndromes and demyelinating diseases. This occurrence of other immune-mediated inflammatory diseases has been linked to the observation that removal of TNF may result in an increased activity of T and B cells that react with autoantigens and foreign antigens (Cope et al., 1994, Pasparakis et al., 1996, Berg et al., 2001, McDevitt et al., 2002). Increased frequencies of autoantibodies, in particular antinuclear antibodies and anti-dsDNA antibodies, has been reported after treatment with TNF antagonists, although less so with etanercept (de Rycke et al., 2005, Atzeni et al., 2005b). In clinical practice, the risk for development of systemic autoimmune diseases is low, and at present there is no recommendation for the monitoring of autoantibody titers during TNF-antagonist treatment. Interestingly, in a small open-label study, patients with systemic lupus erythematosus showed improvement of their inflammatory nephritis, despite elevation in autoantibody concentrations, after treatment with a TNF antagonist (Aringer et al., 2004).

Section snippets

Overview

The biology of TNF and LT in health and disease is complex and continues to be illuminated by ongoing preclinical and clinical studies. Several review articles have addressed the molecular, cellular and physiologic aspects of TNF and LT biology (Bazzoni and Beutler, 1996, Gommerman and Browning, 2003, Schottelius et al., 2004, Hehlgans and Pfeffer, 2005, Kollias, 2005, Ware, 2005, Aloisi and Pujol-Borrell, 2006). TNF and some forms of LT play a role in lymphoid tissue development and have a

Structures

The structures of the TNF antagonists infliximab, etanercept, adalimumab, certolizumab and golimumab are schematically represented in Fig. 4, which illustrates their similarities and differences. All agents except etanercept are anti-TNF mAbs or fragments thereof. Natural mAbs are derived from single B cells that clonally express copies of a unique heavy (H) chain and a unique light (L) chain that are covalently linked to form an antibody molecule of unique specificity. Engineered mAbs can be

Mechanisms of action

The mechanisms of action of TNF antagonists have been intensively studied, particularly for infliximab and etanercept, but many questions remain unresolved. Some of the observed clinical differences between the TNF antagonists, such as the lack of efficacy of etanercept in Crohn's disease, sarcoidosis and Wegener's granulomatosis, could conceivably be because of differences in mechanism, pharmacokinetics, tissue distribution and/or potency. Possible mechanisms of TNF–antagonist action in

Other inhibitors of tumor necrosis factor action

In addition to the TNF antagonists described in this review, pharmacologic agents that either suppress TNF production or block its action have also been examined. For example, the phosphodiesterase inhibitor pentoxifylline inhibits TNF transcription (Doherty et al., 1991), whereas CNI-1493, a tetravalent guanylhydrazone, inhibits TNF translation (Cohen et al., 1996). Thalidomide has been shown to inhibit TNF action by enhancing TNF mRNA degradation (Moreira et al., 1993). After promising

Summary and conclusions

The TNF antagonists infliximab, etanercept, adalimumab, certolizumab and golimumab are all effective therapeutic agents in RA that differ in their molecular structures and pharmacokinetic properties. Their strong clinical efficacy in RA and the potent neutralization of sTNF and tmTNF suggest that they achieve efficacy by preventing TNF from inducing TNFR-mediated cellular functions (Fig. 6). These functions include cell activation, cell proliferation, and cytokine and chemokine production, as

Acknowledgments

The authors are grateful for the helpful discussions with Zehra Kaymakcalan, Brad McRae, Philip Sugerman, Steven Rozzo, Oscar Segurado and Taro Fujimori; for critical review of the manuscript by Philip Sugerman and Susan Paulson; for preparation of Fig. 5 by Susan Paulson; and for the excellent editorial assistance by Lori Lush and colleagues at JK Associates, Inc.

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