Potential Sequence of TNF Inhibitors in Rheumatoid Arthritis and Evidence for Staying in Class Before Switching Mechanisms

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - Annual European Congress of Rheumatology (EULAR)

Berlin, Germany / June 6-9, 2012

Berlin - Approximately 30% of patients with rheumatoid arthritis (RA) treated with a tumour necrosis factor (TNF) inhibitor will not have an adequate response. However, inadequate response on one of these agents does not predict failure on another from this class. Rather, according to expert commentary heard at the 2012 EULAR, patients not responding to one TNF inhibitor should undergo trials with others before moving to another strategy, including another type of biologic. There is no established order of first- or second-line TNF inhibitors, although first employing those agents with the least immunogenicity is a reasonable approach based on a potential for cross-resistant antidrug antibodies. The growing consensus for initiating these agents in patients with moderate disease who are not attaining remission on non-biologics is drawing attention to initial drug selection.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec                                                                                                      

Tumour necrosis factor (TNF) inhibitors are identified in the EULAR guidelines as the first-line strategy in patients not adequately managed on non-biologic disease-modifying antirheumatic drugs (DMARDs). While inhibition of TNF, one of the key components of the inflammatory response, can provide unprecedented levels of disease control in rheumatoid arthritis (RA), phase III studies with these agents consistently demonstrate that about 30% of patients fail to achieve ACR20 response. Based on subsequent studies in which patients not responding to the initial biologic did respond to a second, the non-responders are not necessarily the same 30%.

“The likelihood of a response on a second TNF inhibitor after failure of an initial biologic is lower than that observed for patients naive to this therapy, but the benefit is meaningful,” reported Dr. Peter Nash, University of Queensland, Brisbane, Australia. He indicated that in patients with a potential need for indefinite treatment to control disease, the TNF inhibitor class of therapy should not be discarded after an initial failure. Importantly, the ability of one TNF inhibitor to control disease after another fails is not surprising, given disparities in their exact mechanisms and chemical structures. For example, etanercept, the first licensed TNF inhibitor, achieves binding as a fusion protein. The other available TNF inhibitors are monoclonal antibodies (MAbs) but these also differ in the recombinant techniques with which they are produced.

Effect of Neutralizing Antibodies

One of the major issues is the substantial proportion of patients who develop neutralizing antibodies while taking a MAb. There is a variety of evidence that neutralizing antibodies diminish response, including a new study of 407 patients previously exposed to TNF inhibitors who were then treated with adalimumab or the fusion inhibitor etanercept. Both agents were effective but the presence of MAb antibodies adversely affected the efficacy of adalimumab but was not a factor for the efficacy of etanercept.

“Adalimumab-treated patients without antibodies had the best outcomes and those who were positive for antibodies had the worse,” reported Dr. Charlotte Krieckaert, VU Medical Centre, Amsterdam, The Netherlands. She suggested, “Treatment response rates to adalimumab might be increased by strategies that counteract the development of antibodies.”

Data from the STURE (Stockholm TNF Follow-Up Registry), presented at the 2011 EULAR meeting, also suggested different rates of efficacy, possibly due to differences in risk of generating neutralizing antibodies, between TNF inhibitors after a switch (Chatzidionysiou et al. EULAR 2011, abstract FRI0208). In that study, presented by investigators at Stockholm’s Karolinska Institute, 850 patients who had failed their first TNF inhibitor were switched to a second. At 6 months, the improvement in Disease Activity Score 28 (DAS 28) was 1.24 points among those switched to another MAb and 1.57 points (P=0.01) among those switched to etanercept. A difference favouring etanercept was also observed after second and third switches.

Importance of Methotrexate

The potential adverse impact of neutralizing antibodies on MAbs was also made by a meta-analysis here at the 2012 EULAR that attempted to quantify the impact of the presence of antibodies for the efficacy of TNF inhibitors. In data that appeared in the abstract book (although the poster was never mounted during the assigned presentation), co-treatment with methotrexate (MTX) appeared to attenuate the loss of potency from neutralizing antibodies.

“In studies where the proportion of patients co-treated with MTX was <79%, the presence of antibodies reduced therapeutic response by 80% (RR 0.20; 95% CI, 0.12-0.36), while in studies where that proportion on MTX was ≥79%, the effect size of a reduced drug response was attenuated to 50% (RR 0.50; 95% CI, 0.36-0.69),” reported investigators led by Dr. Sandra Garcês, Hospital Garcia de Orta, Almada, Portugal. A previously published study suggested no difference in efficacy of etanercept in patients receiving a TNF inhibitor for the first time or who had neutralizing antibodies from previous exposure to a MAb (Jamnitski et al. Ann Rheum Dis 2011;70:284-8).

The current EULAR guidelines call for adding a TNF inhibitor when non-biologic DMARDs are inadequate for disease control. While there are no controlled trials to determine whether it is better to start with etanercept to avoid neutralizing antibodies or switch to etanercept when efficacy is lost due for any reason (including the development of neutralizing antibodies), new clinical data encourage adding the TNF inhibitor to the DMARD rather than switching from a DMARD to a TNF inhibitor. For example, one study presented here at the 2012 EULAR compared etanercept remission rates in the TEMPO clinical trial to those achieved in the routine clinical practice setting as captured in the prospective RADIUS II observational study. The study found that patients who received simultaneous etanercept and MTX achieved remission sooner and in higher proportions than those receiving etanercept monotherapy, according to Dr. Edward C. Keystone, University of Toronto, Ontario.

Early Remission = Longer Remission

This is important because “patients achieving sustained remission early [<6 months] had a longer duration of remission,” Dr. Keystone confirmed. While he suggested that “continued remission may be more likely in patients who achieved remission earlier,” he also noted that “patients with lower RA disease activity were more likely to reach remission.” This is a key and emerging issue because health care funding in many parts of the world, including those in some provinces in Canada, require a threshold of disease progression before biologics are permitted.

Commenting on practices in the UK, where a DAS of 5.1 in patients already on maximally tolerated doses of MTX are required before the health service will fund a biologic, Dr. Nash remarked that such restrictions are like denying a change in the therapy for diabetes until patients have an HbA1c of 18. He suggested these restrictions are blind to the emerging evidence that earlier, more aggressive therapy prevents irreversible bone damage and increases the likelihood of achieving complete and durable remission.

Treating to Target: An International Consensus

While Dr. Nash acknowledged that much of the evidence supporting the initiation of biologics in patients with moderate disease who cannot attain remission on DMARDs alone is derived from observational studies, he noted that several prospective studies are underway. This includes the PRESERVE trial with etanercept and the CERTAIN trial with certolizumab.

“Although ACR and EULAR now recommend that patients with moderately active disease be considered for biologic therapy with the goal of remission to improve outcomes, these patients do not necessarily have access to this therapy, whether through lack of reimbursement or willingness of physicians to prescribe,” Dr. Nash observed. He suggested that it is necessary to change this orientation in order to fulfill the principles of treating to target, which is the EULAR-endorsed principle of disease control, rather than disease improvement.

“Treating to target now has an international consensus that the goal is to get patients to remission or at least to a very low level of disease activity,” affirmed Prof. Josef Smolen, Medical University of Vienna, Austria. As senior author of the EULAR guidelines, Prof. Smolen insisted that the paradigm has changed because of the evidence that tight disease control can now be achieved in the majority of patients.


RA is a chronic disease that poses a risk of significant disability if poorly controlled. Although many patients do achieve remission with non-biologic DMARDs, there is a consensus that therapy should be stepped up even in patients with moderate disease who do not achieve remission on non-biologic DMARDs. TNF inhibitors, the first-line biologics, should not be withheld until advanced disease stages because of the diminished likelihood of achieving remission and the potential for irreversible joint destruction. Although there are alternative biologics, TNF inhibitors are not interchangeable and patients should be given a trial with more than one agent in this class if an initial drug fails before moving to other types of biologics. The sequence of TNF inhibitors has not been established, but selecting a front-line agent with a low risk of immunogenicity may better preserve this class.   


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