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Rheumatology Advance Access published online on May 25, 2008
Rheumatology, doi:10.1093/rheumatology/ken204
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Assessment of anti-TNF-{alpha} efficacy in rheumatoid arthritis: is 3 months sufficient?

J. M. Pocock1, J. C. Vasconcelos2 and A. J. K. Östör1

1Department of Rheumatology, Addenbrooke's Hospital and 2Department of Public Health and Primary Care, Centre for Applied Medical Statistics, University of Cambridge, Cambridge, UK.

Correspondence to: A. J. K. Östör, Rheumatology Clinical Research Unit, Box 194, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. E-mail: andrew.ostor{at}addenbrookes.nhs.uk


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Summary
 Supplementary data
 Acknowledgements
 References
 
Objectives. The optimal therapeutic trial duration of anti-TNF-{alpha} therapy is currently unknown. The British Society for Rheumatology (BSR) guidance states that non-response at 3 months warrants re-evaluation of treatment and recommends not to persist beyond 6 months. The National Institute for Health and Clinical Excellence (NICE) specifies treatment continuation if response is achieved by 6 months, yet the European League against Rheumatism (EULAR) and the American College of Rheumatology (ACR) maintain a 3 month cut-off. No evidence exists to support a 6 month therapeutic trial over 3 months. Thus, we undertook a study to evaluate the proportion of patients who failed to meet NICE response criteria at 3 months but obtained this by 6 months, and to identify predictive factors for this.

Methods. Patients who commenced anti-TNF-{alpha} therapy for RA were studied, counting those who switched to a second or third agent separately for each instigation of therapy (n = 244). Response at 3 and 6 months was defined according to NICE criteria as a ≥1.2 reduction in Disease Activity Score (DAS28).

Results. Of the 189 patients with available 3 month DAS28 responses, 149 fulfilled response criteria. Of the 40 who failed, 27 continued treatment, of whom 21 were available for follow-up at 6 months. Out of the 21 patients, 12 (57%; 95% CI 36, 78) achieved a response at this time. This data set was too small to investigate predictors of response at 6 months.

Conclusions. A substantial proportion of patients who fail NICE response criteria at 3 months and continue on treatment to 6 months achieve a response. These results support a 6 month therapeutic trial over 3 months.

KEY WORDS: Rheumatoid arthritis, Anti-tumour necrosis factor, Therapeutic trial duration, The British Society for Rheumatology, National Institute for Health and Clinical Excellence, European League Against Rheumatism, Disease Activity Score, Response criteria, Biological therapies


   Introduction
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Methods
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Patients with moderate to severe RA may be treated with antagonists of TNF-{alpha}, an inflammatory cytokine overproduced in the synovium in inflammatory arthritis. Three such anti-TNF-{alpha} agents are currently licensed in the UK: Infliximab, Adalimumab and Etanercept. These drugs can be effective in patients who have failed to respond to conventional first-line DMARD therapy; however, some fail to show an improvement, partially respond or develop side-effects necessitating discontinuation of therapy. In the UK, response to treatment is measured using the European League against Rheumatism (EULAR) 28-joint Disease Activity Score (DAS28) response criteria (supplementary figure 1, available as supplementary data at Rheumatology online). Under current National Institute for Health and Clinical Excellence (NICE) guidelines, patients are required to have a DAS28 of ≥5.2 to be eligible for anti-TNF-{alpha} therapy, a level considered to be indicative of high disease activity [1]. An adequate response to anti-TNF-{alpha} (one justifying continuation of treatment) is defined by NICE as a DAS28 improvement of ≥1.2 [1]. This is a simplification of EULAR response criteria, encompassing all those who achieve a good EULAR response and some who achieve a moderate EULAR response (supplementary figure 1, available as supplementary data at Rheumatology online).

A question exists, however, regarding the length of time patients should remain on anti-TNF-{alpha} agents before they are deemed inefficacious. 2007 NICE guidelines on the use of all three TNF-{alpha} antagonists specify that treatment should be continued only if there is a response at 6 months [1]. This recommendation replaced the earlier 2002 NICE guidelines on the use of Etanercept and Infliximab, which recommended withdrawal of therapy in the event of non-response at 3 months [2]. The change eventuated as a result of consultation with expert clinicians who felt 3 months was insufficient to fully evaluate the response in instances where patients’ response might be influenced by other factors such as infections or changes in concurrent medications such as corticosteroids [1].

Similarly, current British Society for Rheumatology (BSR) guidance states that non-response at 3 months warrants re-evaluation of the use of treatment, recommending not waiting beyond 6 months [3]. This was an update of earlier 2001 guidance specifying treatment discontinuation in the event of non-response after 3 months [4]. The newer guidelines were introduced with the intention that anti-TNF-{alpha} should only be continued in the absence of response at 3 months if other changes in therapy had been implemented during the trial time, such as a reduction in steroids [5]. This recommendation was based on opinion rather than evidence [5]. Paradoxically, an audit of steroid use during anti-TNF-{alpha} therapy initiation in 99 patients found that steroid reduction during the 3 month trial was actually associated with a greater DAS28 response to anti-TNF-{alpha} (P = 0.06) [5].

The ACR states that the maximum time in which benefit from anti-TNF-{alpha} is to be expected is 12 weeks for Etanercept and 4 months for Infliximab [6]. In addition, a 2007 international consensus statement maintained that improvement should be shown within 12 weeks of commencing anti-TNF-{alpha} therapy; otherwise continued use of treatment should be re-evaluated [7].

Investigation of UK patients using data from the British Society for Rheumatology Biologics Register (BSRBR) has shown that a response in patients on Etanercept and Infliximab may be seen in up to 6 months [8]. However, no assessment was carried out at 3 months; hence, initial non-responders were not identified.

With the lack of an evidence base to support the use of a 6 month therapeutic trial over 3 months, a retrospective study of the comparative efficacy of anti-TNF-{alpha} therapy at 3 and 6 months was carried out in our institution. The aim was to evaluate the proportion of patients on anti-TNF-{alpha} medication who failed to achieve a response at 3 months but nevertheless continued on therapy and went on to achieve a response at 6 months, to indicate if there was a role for the longer trial duration. Additionally, predictive factors for a late response were investigated including the association of a full response at 6 months with a partial response at 3 months.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 Summary
 Supplementary data
 Acknowledgements
 References
 
All patients commencing anti-TNF-{alpha} therapy for RA at our institution from June 2002 to March 2007 (n = 196) were reviewed retrospectively, with data collected on DAS28 values at 0 (baseline), 3 and 6 months. Patients who switched to a second or third anti-TNF-{alpha} agent following failure of the first were counted separately for each anti-TNF-{alpha} therapy initiation (n = 244). Response at 3 and 6 months was defined according to 2007 NICE guidelines specifying a DAS28 improvement of ≥1.2.

For the purposes of this analysis we identified two groups of patients, those who did and who did not achieve a response at 6 months despite not responding at 3 months. For these patients we further subdivided the response at 3 months into two categories: partial response (DAS28 improvement 0.6–1.2) or poor response (DAS28 improvement <0.6). Other potential predictive factors of response at 6 months were recorded, including the anti-TNF-{alpha} agent, whether the patient was on first-line therapy or had switched from a previous anti-TNF-{alpha} agent, disease severity at outset represented by the baseline DAS28 and any dose escalation of anti-TNF-{alpha} between 3 and 6 months.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 Summary
 Supplementary data
 Acknowledgements
 References
 
Of the 244 instances in which anti-TNF-{alpha} therapy was instigated, DAS28 responses at 3 months were available for 189 patients. Thirteen patients had discontinued therapy by this time for reasons of primary inefficacy (n = 3), drug toxicity (n = 8), death (n = 1) or had moved away (n = 1). Of the other 42 patients with unavailable 3 month DAS28 values, eight discontinued therapy at this point due to inefficacy, and the remaining 34 progressed to 6 months; however, only six had DAS28 values available at that stage.

Of those patients for whom DAS28 values at 3 months were available, 149 (78.8%) fulfilled response criteria and 40 patients (21.2%) failed. Of these 40 patients, 13 were taken off treatment due to inefficacy at that time leaving 27 patients on therapy, 21 of whom were available for follow-up at 6 months. At that stage, 12 of the 21 (57%; 95% CI 36, 78) achieved a NICE response. The remaining six patients had either stopped due to poor tolerability (n = 1) or did not have an available 6 month DAS28 due to patient non-attendance (n = 1), assessment moved to 9 months (n = 1) or unknown reasons (n = 3) (supplementary figure 2, available as supplementary data at Rheumatology online).

Of the 21 patients, 20 in the final analysis were females and none had had any changes to their anti-TNF-{alpha} dose regimen, either in frequency or quantity, between the 3 and 6 month assessments. Both 6 month responders and non-responders included patients who had achieved a partial response at 3 months, patients who were switchers and non-switchers, and patients on the anti-TNF-{alpha} agents Adalimumab and Etanercept (Table 1). However, the group sizes were too small to allow statistical analysis to identify whether any of these were predictive factors that could be used to aid clinical decision making at the 3 month assessment.


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  		TABLE 1. Comparison of 6 month responders and non-responders

 

   Discussion
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 Methods
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Summary
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The evidence for anti-TNF-{alpha} efficacy at 3 months is convincing, but that for a first response between 3 and 6 months is virtually non-existent. To date there have been 14 randomized controlled trials (RCTs) investigating the efficacy of specific anti-TNF-{alpha} agents with a minimum of 6 months’ follow-up (see supplementary table 1, available as supplementary data at Rheumatology online) [9–22]. Of these, 11 reported outcomes at times approximately equivalent to both 3 and 6 months [9, 11–15, 17–19, 21, 22], but only three used the DAS28 as an outcome measure [11, 21, 22]. Taylor et al. [21] found only one patient responding by DAS28 criteria in the 3- to 6-month window period, Quinn et al. [22] reported a small decrease in the median DAS28 between 3 and 6 months and van de Putte et al. [11] stated that moderate to good EULAR responses peaked at approximately week 12 and remained stable thereafter. This latter study also differentiated between moderate and good EULAR responses, showing a slight decrease in moderate responses between 3 and 6 months whilst good EULAR response rates continued to rise [11].

This difference between moderate and good responses was reflected in many studies using ACR response criteria, representing improvements in several parameters of 20, 50 or 70% [23]. They were reported in 13 RCTs, of which seven showed a plateau in ACR20 responses after 3 months [9, 11–13, 15, 17, 21] and four demonstrated an increase in the number of ACR50 and ACR70 responses between 3 and 6 months [9, 11, 12, 17]. It was not stated whether these improvements occurred in the same patients or were new responses in different patients.

In all but one of these studies, cumulative responses at 3 and 6 months were given. As loss of efficacy may be seen over time with anti-TNF-{alpha} therapy [24], overall response rate at 6 months may underrepresent the number of late responders. The only study that quantified the number of first responses after 3 months stated that 2 out of 67 patients first achieved an ACR20 response after 12 weeks [9].

In our study, a substantial proportion of patients (57%) who failed at 3 months but continued on therapy achieved a response at 6 months. This supports the implementation of a longer trial period and provides evidence supporting the changes in BSR and NICE guidelines. Use of TNF-{alpha} blockers carries the potential for serious toxicity, so continuation in the face of inefficacy should be avoided; however, our results indicate that a 3-month therapeutic trial may be inadequate in some patients.

The decision to continue therapy in only 27 of the 40 non-responders at 3 months was due to a variety of factors. Most patients who continued had responded (albeit marginally) at 3 months; therefore, a holistic view was taken rather than strictly adhering to DAS28 criteria with its limitations. Of the 21 patients, 16 who continued were on adalimumab, about which there were no NICE guidelines. Furthermore, this recalcitrant group had no further therapeutic options and it was felt appropriate to continue them on therapy. It could be argued that the 13 who ceased treatment at 3 months were a group who responded particularly poorly and so would not benefit from an increased therapeutic trial duration. However, whilst the mean DAS28 improvement for this group at 3 months was lower than that for continuers, there was a comparable proportion of ‘partial responders’, indicating variability within this group and that not all had a poor initial response (Table 2). This group also had fewer switchers and so there were greater therapeutic options open to these patients, which may have led to a more ready decision to discontinue at 3 months.


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  		TABLE 2. Sample characteristics of 3-month continuers and discontinuers

 
There is a possibility that DAS28 changes could have improved whether anti-TNF-{alpha} was continued or not. This phenomenon of regression to the mean has been described previously [25]. Both patients who receive an increased frequency of anti-TNF-{alpha} to combat a reduction in response, and those who do not, show similar subsequent improvements and ‘recapture’ their initial response. Because of this, caution is needed when interpreting apparent improvements following dose escalation in practice, including increasing the frequency or quantity of the drug, or both [26]. None of the patients in our study had any dose escalation between 3 and 6 months. The only way to truly evaluate regression to the mean would be to evaluate 6 month DAS28 levels in patients who discontinued at 3 months, seeing if they displayed a similar level of improvement to the patients continued on anti-TNF-{alpha}. However, no such values were available for our group.

Due to the sample size (21 patients), no meaningful statistical analysis could be carried out to identify significant predictive factors for the late response. We were particularly interested in any association with partial response at 3 months, as this could have aided clinical decision making at the crucial 3 month assessment. Thus, it is not currently possible to determine which patients who fail this assessment are most likely to subsequently respond at 6 months. This makes the extension of the therapeutic trial period more crucial to allow all patients an equal chance of a late response. Alternatively, rather than a strict DAS28 response criteria, a more holistic approach to assessing response could be implemented. Since response to anti-TNF-{alpha} is in reality found to be a continuum rather than bimodal, there is in practice no clear distinction in response between responders and non-responders, hence the use of a cut-off DAS28 value is somewhat arbitrary [27]. Additionally, concern has been raised over the discrepancy between NICE and EULAR definitions of response, which may unfairly penalize patients who obtain a EULAR moderate response but fail to reach the NICE criteria justifying continuation of therapy [28]. However, in order to allow clinical decisions to be made distinction is required between responders and non-responders. It has been suggested that other measures of response could be utilized in addition to the DAS28, such as HAQ and SF-36 scores, to give a fuller indication of clinical improvement [29].


   Summary
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Summary
Supplementary data
 Acknowledgements
 References
 
Little evidence exists as to whether anti-TNF-{alpha} should be continued for 6 months despite current BSR and NICE recommendations. This is the first study to specifically investigate response between 3 and 6 months. In this retrospective cohort study, 57% of patients who remained on therapy despite failing the 3 month assessment attained a response by 6 months, supporting a longer trial period. Further investigation is required to determine predictors for this later response that could be identified at 3 months to aid clinicians’ judgement as to whether anti-TNF-{alpha} should be continued for a full 6 months.

Formula


   Supplementary data
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 Methods
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 Supplementary data
Acknowledgements
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Supplementary data are available at Rheumatology Online.


   Acknowledgements
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The authors would like to thank Maria Mouyis and specialist nurses Els Owen and Tracey Nash for their assistance with data collection, and Toby Prevost for his input on statistical aspects of the manuscript.

Disclosure statement: A.O. has received honoraria and travel support for conferences from and acts as a consultant for Abbott, Schering-Plough, Wyeth, Roche and Bristol-Myers-Squibb. All other authors have declared no conflicts of interest.


   References
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Submitted 25 January 2008; revised version accepted 17 April 2008.
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