Data from numerous clinical trials with the anti-TNF agents infliximab, etanercept, and adalimumab have confirmed the validity of TNF-a as a therapeutic target in rheumatoid arthritis. Proof of principle for TNF-a blockade was initially established in an open-label study in which infliximab was administered intravenously in divided doses over 2 weeks (either 10 mg per kilogram a fortnight apart, or four doses of 5 mg per kilogram every4 days). The results clearly demonstrated that these relatively large doses of antibody were tolerated without any immediate adverse reaction (Elliott et al. 1993). Although these early studies were not primarily designed to test efficacy, a remarkable reduction in pain, stiffness, swelling, and joint tenderness was observed within 24 h, with maximum benefit at around 2-4 weeks, and sustained for the entire 8-week duration of the study in the majority of patients. Relief of fatigue within hours of the infusion was consistently reported. Subsequent studies in both the early and established phases of disease confirm that long-term, repeated use of anti-TNF agents results in sustained improvement in symptoms and signs of disease in the majority of patients (Kremer et al. 2003; Maini et al. 2004; Lipsky et al. 2000; Klareskog et al. 2004; St Clair et al. 2004; Breedveld et al. 2004, 2006; Emery 2005; Bathon et al. 2000; Genovese et al. 2002).
In studies of rheumatoid populations having failed to respond adequately after exposure to multiple DMARD therapies, with active disease despite ongoing metho-trexate therapy, between 50 % and 70 % of patients are reported to achieve an ACR 20 response level at 6 months, as compared to between 20% and 30% of patients treated with methotrexate alone (Weinblatt et al. 1999; Maini et al. 1999; Keystone et al. 2004).
However, it is important to note that caution should be applied when comparing differences between proportions of responders or magnitude of response between studies, as the nature of the study populations is very different with respect to baseline disease activity and rate of structural damage to joints. At the more stringent 50% ACR response level, the difference between the proportion of patients with established disease responding on methotrexate alone and those responding on the combination of methotrexate and a TNF inhibitor is approximately 20-40% at 1 year and, similarly, at the ACR 70 % response level, approximately 15% of the study population (Weinblatt et al. 1999; Maini et al. 1999; Keystone et al. 2004).
Most TNF inhibitors have been evaluated using a step-up clinical trial design in patients with active disease despite methotrexate therapy, who then received either the TNF inhibitor or placebo. In many of these trials, however, a biologic monotherapy arm was absent. Nonetheless, in a study of patients with an inadequate response to methotrexate, infliximab was administered at a dose of 1, 3, or 10 mg per kilogram, with or without a fixed low dose of methotrexate, while control groups were treated with placebo infusions and methotrexate (Maini et al. 1998). In this trial, the duration of response to repeated biologic administration was inversely related to the production of human anti-chimeric antibodies to the infliximab. Higher doses of infliximab were found to be less immunogenic than a low dose of 1 mg per kilogram, and concomitant meth-otrexate administration further reduced the occurrence of human anti-chimeric antibody responses. Although reduced immunogenicity of the biologic agent administered may be one mechanism whereby methotrexate has an additive or synergistic benefit when used in combination with TNF inhibitors, it is likely that there are other effects beyond this mediated through complementary mechanism of action, although these have yet to be fully elucidated.
In the TEMPO study (Trial of Etanercept and Methotrexate with radiographic Patient Outcomes), the combination of methotrexate with etanercept was clearly superior to that of either methotrexate or etanercept alone (Klareskog et al. 2004). Similarly, in the PREMIER study (prospective, multi-centre, randomized, double-blind, active comparator-controlled, parallel groups study comparing the fully human monoclonal anti-TNF-a antibody D2E7 given every 2nd week with methotrexate given weekly, and the combination of
D2E7 and methotrexate administered over 2 years in patients with early rheumatoid arthritis), the combination of adalimumab and methotrexate consistently demonstrated superior efficacy in every area over either methotrexate or adalimumab as monotherapies (Breedveld et al. 2006). In this study, at week 52,43 % of patients on combination therapy achieved remission by DAS 28 criteria of less than 2.6 as compared with 23 % of patients receiving adalimumab alone and 21 % of patients receiving methotrexate alone. In the ASPIRE study of infliximab in early rheumatoid arthritis, 17% of patients receiving 6 mg per kilogram of infliximab together with methotrexate achieved an ACR 70 response for six or more consecutive months and 12% of patients receiving infliximab at 3 mg per kilogram together with methotrexate. This contrasted with under 8 % of patients on methotrexate alone (St Clair et al. 2004). Fifteen percent of patients on methotrexate alone achieved remission criteria by DAS 28 at week 54, whereas the addition of infliximab at 3 mg per kilogram enhanced this figure to 21 %, and further to 31 % at a dose of 6 mg per kilogram.
One of the early studies to look at biomarkers after anti-TNF therapy demonstrated dose-dependent reductions in serum concentrations of pro-matrix metalloproteinase 1 and pro-matrix metalloproteinase 3 (Brennan et al. 1997). These reductions in mediators of cartilage degradation predicted that TNF blockade might have the benefit of significant inhibition of radiographic damage to joints. That this was indeed the case was confirmed in the 54-week analyses from the ATTRACT study (Lipsky et al. 2000). In this trial, infliximab, at doses of 3 mg per kilogram or 10 mg per kilogram, given every 4 or 8 weeks, when added to therapeutic doses of methotrexate was found to give sustained reduction in symptoms and signs of disease that were significantly greater than the reduction associated with methotrexate alone. In patients treated with meth-otrexate as a monotherapy, joint space narrowing and erosions progressed as anticipated. In contrast, therapy with infliximab plus methotrexate prevented the progressive joint damage characteristic of rheumatoid arthritis and even resulted in improvement in the radiographic score from baseline in a significant percentage of patients (Lipsky et al. 2000).
Combination therapy halted progression of joint damage not only with limited radiographic destruction at baseline, but also in those with extensive damage. Similar findings have been reported for etanercept.
When administered together with methotrexate, the combination was significantly better in inhibition of radiographic progression compared with methotrexate or etanercept alone, in a population of patients who were methotrexate-naive at study entry (Klareskog et al. 2004). Very similar findings have been reported for adalimumab given in combination with methotrexate in the established phase of disease (Keystone et al. 2004).
There is also good evidence that antibodies targeting TNF significantly inhibit progression of structural damage in the early phase of disease (St Clair et al. 2004; Breedveld et al. 2006). These observations confirm the pathogenic role of TNF-a in the early phase of rheumatoid arthritis and suggest that in the proportion of patients with high likelihood of radiographic progression, early intervention with a TNF inhibitor together with methotrexate may provide long-term benefits in terms offunctional capabilitybypreservingjointinteg-rity (Breedveld et al. 2004). Surprisingly, significant inhibition of radiographic damage has even been reported in those patients failing to achieve a clinical response at the ACR 20 level (Smolen et al. 2005). This fascinating observation in effect defines a subpopulation in whom there is a dissociation between inflammatory and destructive pathways.
Changes in functional status are assessed by means of the HAQ score. It has been determined that an improvement from baseline of 0.3 in HAQ score represents a clinically meaningful change. There is data for all three currently available anti-TNF inhibitors to show that repeated therapy over time, in particular when an anti-TNF agent is combined with methotrexate, leads to significant improvement in physical function and quality of life (Klareskog et al. 2004; Keystone et al. 2004; Maini et al. 2004).
Preservation or improvement of function is a particularly important goal of therapy in the early phases of disease. In the ASPIRE study, 60% of patients treated with methotrexate as a monotherapy achieved an improvement in HAQ exceeding 0.3, whereas 71 % of all patients receiving infliximab together with methotrex-ate achieved an improvement of this magnitude (St Clair et al. 2004). Similarly, in the PREMIER study, patients receiving adalimumab and methotrexate achieved a 1.1 improvement from baseline in HAQ score at the end of 1 year, as compared with a 0.8 improvement in patients treated with methotrexate alone. With adalimumab alone, the improvement was
0.9 (Breedveld et al. 2006). In the light of these findings, it is not a surprise, but nonetheless very welcome, to see emerging data indicating that in early disease, treatment with infliximab and methotrexate gives a higher probability of maintaining employment than treatment with methotrexate alone (Smolen et al. 2006). These data would predict a lowering of the indirect costs associated with rheumatoid arthritis, such as disability benefits, as well as reduced direct costs of patient care over time, such as those associated with joint arthro-plasty; but as yet, there are few long-term data that can reliably offset the expense of anti-TNF therapies themselves against the anticipated long-term savings.
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