Original articleEarly non-response to certolizumab pegol in rheumatoid arthritis predicts treatment failure at one year. Data from a randomised phase III clinical trial
Introduction
Rheumatoid arthritis (RA) is a progressive destructive autoimmune disease of the joints with a prevalence of around 0.5% in the general population [1], [2], [3]. The disease course is typically characterised by episodic acute exacerbations separated by periods of relative disease stability. Recovery from exacerbations is rarely complete, resulting in progressive irreversible structural damage to the affected joints [4].
The goals of treatment are to relieve symptoms, to prevent exacerbations and to slow structural joint damage. Long-term maintenance therapy is based on the use of disease-modifying antirheumatic drugs (DMARDs), a class that includes both synthetic drugs and biological agents. Considerable between-patient heterogeneity in response to DMARDs appears to exist, with ACR50 response rates in randomised clinical trials being generally less than fifty percent [5] and even lower in everyday clinical practice [6]. The recommended treatment strategy is to initiate treatment with DMARDs as early as possible after diagnosis, to monitor patients regularly using composite measures of disease activity and, in case of inadequate response, to switch to another DMARD in order to achieve or maintain tight control of disease activity [7], [8]. Such strategies have been shown to be highly effective [9], [10], [11], [12], [13]. Current practice guidelines recommend initiating treatment, typically with methotrexate, and re-evaluating the treatment at three-monthly intervals, and in case of non-response, switching to another synthetic DMARD or to a biological agent [7], [14] or moving to combination therapy [15] in order to achieve tight disease control.
In order to follow such a strategy, rheumatologists need to know the most appropriate clinical information to assess treatment response or failure. Although the American College of Rheumatology (ACR) [14] and the European League Against Rheumatism (EULAR) [7] both emphasise in their practice guidelines the importance of timely adaptation of treatment in case of inadequate response, neither provide any explicit guidance on the most appropriate criteria for defining treatment failure. In everyday practice, large improvements in disease status are unambiguous and the physician is reassured about maintaining the current treatment. However, if clinical evolution following treatment initiation is modest, physicians may adopt a strategy of ‘watchful waiting’ which may be detrimental to long-term prognosis rather than taking a more proactive approach [16].
A number of studies have investigated the association between early measures of clinical outcome and long-term treatment response [17], [18], [19], [20], [21], [22]. However, from the therapeutic perspective of clinical practice, the issue is not so much to predict treatment response but to predict treatment failure as accurately and as early as possible so that therapy can be adjusted accordingly and the overall long-term therapeutic outcome optimised. The sensitivity and specificity of a given predictive markers will not be the same with respect to treatment failure as with respect to treatment response. In particular, a marker that will predict treatment response with high sensitivity but with low specificity will predict failure with low sensitivity and high specificity. For this reason, it is important to identify reliable and practical markers of treatment failure.
To our knowledge, there is little information available on the comparative performance of potential early measures of treatment failure. A recent study of infliximab has suggested that the combination of disease activity after six weeks and infliximab serum trough levels may be a useful as a predictor of treatment failure after six months of therapy [23]. A post-hoc analysis of a study of certolizumab pegol [24] has also demonstrated that a change in DAS-28 score of < 1.2 during the first three months of the study was predictive of failure to achieve low disease activity at one year. It remains to be demonstrated what is the most appropriate early clinical measure to determine treatment failure. The objective of the present study was to quantify and compare the positive predictive values (PPV) of different validated clinical criteria of non-response determined at three months with respect to clinical failure at one year in patients with RA starting biological anti-TNFα therapy with certolizumab pegol.
Section snippets
Design
This study corresponds to a post-hoc analysis of data from the RAPID 1 [25] prospective, randomised, placebo-controlled, double-blind Phase III clinical trial, conducted between February 2005 and October 2006, which evaluated the efficacy and safety of certolizumab pegol in adult patients with RA. The methodology of this trial has been described in detail elsewhere [25] and is briefly summarised below.
The RAPID 1 trial included 982 adult patients fulfilling the 1987 ACR criteria for RA [26] who
Study population
Of the 393 patients who were originally randomised to the 200 mg maintenance dose of certolizumab pegol, 11 were excluded since they had been previously exposed to a TNFα inhibitor. The study sample thus consisted of 382 patients randomised into the certolizumab pegol 200 mg maintenance dose group and with no prior exposure to TNFα inhibitor. Of these 382 patients, 96 (25.1%) were withdrawn from the study due to inadequate efficacy. These included 72 patients who failed to meet the ACR20
Discussion
In this study, we demonstrate that the values of different early disease activity measures can be used to predict treatment failure in RA patients starting treatment with an anti-TNFα. Although all the measures performed acceptably in correctly predicting treatment failure, some differences were observed, notably with the HAQ-DI performing least well.
As has been observed previously by Curtis et al. [19], several of the early measures tested are not entirely suitable for use in everyday clinical
Funding
This publication was funded by UCB Pharma.
Disclosure of interest
FB is a consultant for UCB Pharma. TP is a consultant for UCB Pharma. PC received consulting fees, speaking fees and/or honoraria from Abbott, Wyeth-Pfizer, Roche, Chugai, Bristol-Myers Squibb, Schering-Plough, UCB Pharma, and was investigator for Roche Chugai, Sanofi Aventis, Abbott, Wyeth-Pfizer and BMS. TDC was an employee of UCB Pharma at the time of the study. JMJ is an employee of UCB Pharma, and holds UCB Pharma stock options. CS is an employee of UCB Pharma. LRF is a consultant for UCB
Acknowledgments
The authors would like to thank Foxymed (Paris, France) and Costello Medical Consulting for editorial support.
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