Switching Tumor Necrosis Factor Inhibitors: an Opinion

Edward C Keystone


Nat Clin Pract Rheumatol. 2006;2(11):576-577. 

Tumour necrosis factor (TNF) inhibitors have changed the therapeutic standard of treatment for patients with rheumatoid arthritis (RA), providing substantial benefits in terms of clinical and radiographic outcomes. Three selective TNF inhibitors have been approved by the FDA for the treatment of RA: infliximab (Remicade®, Centocor, Malvern, PA); etanercept (Enbrel®, Immunex, Thousand Oaks, CA); and adalimumab (Humira®, Abbott Laboratories, Abbott Park, IL). Despite the proven efficacy of these TNF inhibitors, a significant proportion of patients demonstrate an inadequate response to one or more of these agents. Consequently, switching to a second or third TNF inhibitor has become standard practice. The question arises of whether there is a scientific or clinical rationale for switching TNF inhibitors.

At first glance, a TNF inhibitor would not be expected to show efficacy after failure of another inhibitor with the same mechanism of action. Evidence has accumulated, however, demonstrating that TNF inhibitors are similar—but not identical—in their mechanism of action. The various TNF inhibitors seem to differ in several aspects: mechanism of action, efficacy in diseases other than RA, and safety profile. Monoclonal antibodies, such as infliximab and adalimumab, differ from the fusion protein etanercept in their pharmacokinetics, avidity and affinity to TNF, their ability to bind membrane-bound TNF, and their ability to induce apoptosis.[1] Unlike infliximab and adalimumab, etanercept is capable of binding lymphotoxin β and has not been shown to induce neutralizing antibodies. Infliximab also differs from adalimumab in terms of pharmacokinetics and dosing regimen.

Although the available TNF inhibitors have similar efficacy in RA, they differ in their effectiveness in other rheumatologic diseases. Etanercept, in contrast to the monoclonal antibodies, is not effective in the treatment of granulomatosis disorders such as Crohn's disease, Wegener's granulomatosis, and sarcoidosis. Infliximab and adalimumab are associated with an increased risk of granulomatous infections such as mycobacterium tuberculosis and histoplasmosis, compared with etanercept. Taken together, the data provide a strong rationale for switching TNF inhibitors in the event of failure.

There are more than 19 published reports about switching TNF inhibitors for the treatment of RA.[2,3] A number of issues make interpretation of the results problematic, not the least of which is the lack of randomized, controlled trials. In the majority of studies, the patient sample size is small, the study duration is short, and baseline demographics are often inadequately described. Issues such as confounding by indication and tendency toward the mean are not adequately considered. Significantly, little information is provided regarding the dose, dosing regimen, or duration of prior treatment with TNF inhibitors when considering the response to subsequent TNF inhibitors. At least some of the effect of switching TNF inhibitors might relate to regression toward the mean: the tendency of patients with very active disease to improve without additional therapeutic intervention.

A number of issues need to be addressed in order to determine the optimal therapeutic strategies for switching TNF inhibitors. A key question is whether or not failure of one TNF inhibitor precludes response to another. Data from an open-label trial have shown that the response to subsequent TNF inhibitors is reduced in proportion to the number of prior TNF inhibitors taken. A further reduced, but still significant, response is observed even to the third TNF inhibitor.[4] By contrast, in a controlled trial, patients demonstrated almost identical clinical responses to adalimumab, regardless of whether infliximab had been used previously.[5] The data from the latter trial emphasize the critical importance of controlled studies in this area. Data has accumulated suggesting that the response to a second TNF inhibitor seems to depend on the reason for the failure of the prior agent.

Several studies have demonstrated that patients are more likely to respond to a subsequent agent if prior treatment with a TNF inhibitor was discontinued because of adverse reactions to treatment, rather than lack of efficacy. With few exceptions, patients experiencing loss of effect of a TNF inhibitor after an initial response are more likely to respond to another agent, than patients failing a TNF inhibitor initially. For example, Van der Bijl and colleagues showed that patients who switched to adalimumab after no initial response to infliximab had little response compared to those who lost their initial response to infliximab.[6]

Whether TNF inhibitors differ in efficacy after failure of the same TNF inhibitor was addressed in a retrospective analysis of a large, open-label trial.[7] Although responses to adalimumab after secondary failure with etanercept or infliximab were comparable, a marked reduction in response to adalimumab was observed in patients exhibiting a primary failure to etanercept, compared with patients with a primary failure to infliximab.[7] Whether the difference reflects optimization of the infliximab dose (maximum dose was 3.0 mg/kg for 8 weeks) remains unclear. The fact that failure to optimize the dose of infliximab might influence responses of a subsequent TNF inhibitor was suggested by Bingham et al.;[8] they demonstrated only a modest response to etanercept (47% ACR20 and 19% ACR50) after escalating the infliximab dose and defining an inadequate response as a Disease Activity Score 28 greater than 4.5. Their results underline the need for further data on the influence of optimizing infliximab dosing and having a prespecified definition of TNF inhibitor 'failure'.

Although TNF inhibitors seem effective regardless of which agent precedes them, there is little data as to the relative merits of using any one agent preferentially, in terms of the order in which they are used. Preliminary data from a large, open-label study suggest that etanercept was more effective after infliximab than infliximab was after etanercept. This result, however, could have been due to other treatment failures in the infliximab-second group as a consequence of human-antichimeric-antibody responses; no information was available in this regard.

The need for randomized, controlled trials to more accurately assess response to TNF inhibitors after failure of a prior TNF inhibitor was emphasized by recent reports on the efficacy of new biologic agents used before and after the failure of TNF inhibitors. Placebo-controlled studies of abatacept and rituximab demonstrated that ACR responses substantially decreased in patients who had failed treatment with a TNF inhibitor, compared with those who were TNF-inhibitor naive. The marked reduction in placebo responses in patients who had prior TNF inhibitor exposure, however, was significant. Some differences in the effect size were seen between abatacept[9] and infliximab,[10] before and after previous TNF treatment. The results of uncontrolled studies of responses to TNF inhibitors could be quite misleading because of this.

A number of tentative conclusions can be drawn from the data generated in the studies of switching TNF inhibitors: firstly, failure of one TNF inhibitor does not preclude the use of another. Whether the magnitude of the response to a second or third TNF inhibitor is significantly altered, however, is yet to be definitively determined. Secondly, the patient's response to a subsequent TNF inhibitor seems to be influenced significantly by the reason for discontinuing treatment with the previous TNF inhibitor. And finally, the influence of the order in which agents are used remains unclear.

Available data suggest that switching TNF inhibitors is effective for the treatment of patients with RA. More rigorous, randomized, placebo-controlled studies are needed to address unresolved issues.

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