Academic Rheumatology Unit, University of Liverpool, Clinical Sciences Centre, University Hospital Aintree, Longmoor Lane, Liverpool L9 7AL, UK.
Correspondence to: R. J. Moots. E-mail: rjmoots{at}liv.ac.uk
The development of anti-tumour necrosis factor (TNF-
) therapy has been a milestone in the treatment of rheumatoid arthritis (RA) and is proving equally important in other inflammatory-mediated conditions [13]. The three currently licensed biological anti-TNF-
drugs, etanercept, infliximab and adalimumab, have all been clearly shown to suppress disease activity in RA. They all target the same moleculebut are they really just more of the same and, indeed, are all three needed? As uptake of anti-TNF-
therapy increases around the world, these questions are becoming increasingly posed. However, it is also becoming clear that these drugs possess significant differences, both in vitro and clinically. Understanding these differences is of course important for the clinic, but equally important is the appreciation that these drugs provide new tools to investigate the pathogenesis of RA and other inflammatory disorders and inform the development of newer generations of anti-inflammatory drugs.
The two main strategies employed to neutralize TNF- in current biologicals involve monoclonal IgG antibody or soluble TNF-
receptor. Infliximab is a humanized mouse monoclonal antibody, adalimumab a fully human monoclonal antibody, and etanercept a construct comprising two human p75 TNF-
receptors coupled to the Fc portion of a monoclonal human antibody. These structural differences go a long way to explaining the many differences of these drugs in vitro and in vivo. Binding assays using radioactively labelled TNF-
have revealed that infliximab binds both monomeric (inactive) and trimeric (active) forms of soluble TNF [4], whilst etanercept is more likely to bind the active trimeric form [5]. Furthermore, infliximab forms stable complexes with soluble TNF-
, whereas etanercept tends to form relatively unstable complexes, allowing dissociation of TNF-
and the potential to form a reservoir for binding TNF-
[4, 6]. Etanercept alone is able to bind to and neutralize lymphotoxin (TNF-ß) [7].
Another important consequence of the structural differences between these drugs is the fact that infliximab and adalimumab (but not etanercept) fix complement, and therefore can lyse cells that express TNF- on their surface [8]. Since TNF-
is initially expressed on the cell surface before being cleaved off by TNF-
converting enzyme, a wide range of cells, including T cells, may be susceptible. Indeed, preliminary reports appear to confirm this in vivo, with a decrease in absolute numbers of peripheral blood CD4+ T cells (which express interferon
and TNF-
) in patients with ankylosing spondylitis treated with infliximab and a reciprocal increase with etanercept [9, 10]. Other immunological differences between these agents have also been observed. For example, the anergic phenotype of T cells in RA [11] normalizes when treated with anti-TNF-
drugs in vitro, but ex vivo this has only been reported in patients taking etanercept [12].
Anti-TNF- drugs are being used increasingly in other inflammatory diseases. This experience has revealed that not all of them are effective in every condition. Whilst in RA all three drugs are highly effective, in Crohn's disease [13, 14] and Behçet's disease [15] there is a clear clinical benefit with infliximab but not etanercept. Conversely, in clinical trials for severe heart failure, infliximab aggravated the condition whilst etanercept did not [16, 17].
The reasons underlying these differences are unknown. However, there are a number of possible explanations. The high drug concentrations arising only from the intravenous bolus of infliximab may be important in Crohn's disease. It is also possible that these agents possess different capacities to penetrate into the gut wall. However, there are no published data addressing this. Equally, the ability of infliximab and adalimumab (but not etanercept) to lyse cells expressing surface TNF- may be important in suppressing the inflammatory response underlying Crohn's disease. Either way, these fundamental differences in efficacy beg for further work, using these agents as tools to provide crucial insights into the basic pathological mechanisms.
The anti-TNF- therapies have subtly different side-effect profiles. All are associated, as expected, with an increase in infection, which may be serious [18]. However, patients taking infliximab appear to have a higher risk of infection from histoplasmosis, coccidiomycosis or reactivation of tuberculosis (TB) [19, 20], although this is contended [21]. Cases of TB were also reported in the early studies of adalimumab, particularly at doses higher than those that were subsequently licensed, suggesting a doseresponse effect. The reasons for this remain unclear, but it is possible that, by virtue of their ability to fix complement, the monoclonal anti-TNF-
antibodies interfere with granuloma formation in a manner that is beneficial in Crohn's disease but detrimental in the reactivation of TB, whereas etanercept has neither of these effects. The potential risk of reactivation of mycobacterial infections is a particular cause of concern in developing countries, where there is a much higher burden of chronic infection.
The choice of biological treatment for RA may depend pragmatically on a number of factors, including patient preference, the tolerability of methotrexate and day-case infusion facilities. Since a direct head-to-head comparison is not likely, it is difficult to determine if one biological drug works better than another in RA. Preliminary studies have attempted to address this. The Swedish Observational Study, for example, reported a lower drop-off rate and greater efficacy with regard to ACR 20 and 50 in patients taking etanercept compared with infliximab [22]. However, as with any observational study, there are many confounding variables and it is important not to over-interpret this. Similarly, meta-analyses have suggested either that the three anti-TNF- therapies are either equally effective in RA [23] or that there are modest benefits in favour of etanercept compared with infliximab [24] or adalimumab [25]. However, these studies have been published so far only in abstract form.
Anecdotal experience in many large centres, including ours [18, 26, 27], has shown that some patients with RA (and other inflammatory autoimmune disorders) may respond to one anti-TNF- agent but not another in what appears to be an idiosyncratic manner. These observations are both important and intriguing. They suggest that patients failing on one anti-TNF-
drug may still benefit from another (although increasing experience suggests that only a minority will benefit from such a switch). Amongst many potential factors, one with at least some supporting evidence is a recent report of a patient who responded to etanercept after failing on infliximab [28] and who had considerable expression of lymphotoxin on synovial biopsy. In this case, the ability of etanercept but not infliximab to neutralize lymphotoxin is a compelling explanation.
The advent of anti-TNF- drugs has certainly been a major advance in the treatment of inflammatory arthritis, heralding a new era for rheumatology. These drugs are effective, but there is also no doubt that they differ in many significant waysfrom structure, through pharmacokinetics to clinical properties. Understanding the differences between these drugs in the laboratory is an important challenge for the future, not just to explain their differences in clinical settings, but also to stimulate new programmes of drug discovery and development, which may lead to newer generations of even more effective therapies.
R.J.M. has received sponsorship to attend meetings and research funding from and/or acted in an advisory capacity to a number of pharmaceutical and biotechnology companies involved in the development or manufacture of anti-rheumatic therapies. The other authors have declared no conflicts of interest.
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