Rheumatology Advance Access originally published online on March 3, 2008
Rheumatology 2008 47(4):495-499; doi:10.1093/rheumatology/ken002
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Predictors of response to anti-TNF therapy according to ACR and EULAR criteria in patients with established RA: results from the South Swedish Arthritis Treatment Group Register
1Department of Rheumatology, Lund University Hospital, SE-221 85 Lund and 2Department of Rheumatology, Spenshult, SE-313 92 Oskarström, Sweden.
Correspondence to: L. E. Kristensen, Department of Rheumatology, Lund University Hospital, SE-221 85 Lund, Sweden. E-mail: larserik_kristensen{at}yahoo.com
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Abstract |
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Objective. To identify factors predicting response to first TNF blocking treatment course in patients with established RA with a special focus on gender differences.
Methods. Patients with active RA initiating their first treatment course of TNF-blocking therapy were enrolled. The study period was March 1999 through September 2006. The prospective protocol included information on demographics, clinical characteristics of patients and response measures. Fulfilment of ACR 50–70% improvement and European League Against Rheumatism (EULAR) good response or remission [28-joint disease activity score (DAS28) <2.6] at 3 months were chosen as primary outcome measures. Potential predictors of responses were identified using multivariate binary logistic regression models.
Results. In total, 1565 patients were included in the study. Gender did not influence treatment response. Consistently, concomitant methotrexate (MTX) was significantly associated with EULAR remission, EULAR good response, ACR50 response and ACR70 response with odds ratios (ORs) 1.97, 2.13, 2.10 and 1.75, respectively. Concurrent treatment with other DMARDs was also significantly associated with EULAR remission, EULAR good response and ACR50 response (OR: 1.96, 2.24 and 1.94, respectively). Likewise, low HAQ at baseline consistently predicted good clinical outcome. Disease activity at baseline was directly associated with favourable response when measured by ACR50 and ACR70 (OR: 1.59 and 1.60, respectively), whereas DAS28 score at baseline was inversely associated with EULAR remission (OR: 0.78).
Conclusions. In this observational study of patients with established RA, gender did not predict response to anti-TNF therapy, whereas treatment with concomitant DMARDs, especially MTX and low disability were associated with good response. Choice of outcome measures may influence the predictive value of baseline features.
KEY WORDS: Response, Anti-TNF-
therapy, Biologics register, Predictors, Rheumatoid arthritis
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Introduction |
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Since the introduction of TNF blocking agents the efficacy and tolerability have been studied in randomized controlled clinical trials [1–8] as well as in observational studies [9–11] of patients with RA. However, data regarding predictors of good clinical response to anti-TNF therapy are still sparse [12]. Recently, Hyrich et al. [12] reported that concomitant methotrexate (MTX), high functional level and male sex were associated with good clinical response in RA patients included in the British Biologics Register.
Also, a meta-analysis of clinical trials before the era of biologicals has shown association of female gender and disability with poor response to conventional DMARDs [13]. Moreover, male sex has recently been shown to be a major predictor of remission in patients with early RA primarily receiving traditional DMARD therapy [14]. Finally, it has been speculated that male patients should have greater benefit of anti-TNF blockers due to influence of these remedies on the neuroendocrine axis including increased levels of anti-inflammatory androgens in the synovial tissue in males as compared with females [15].
We have previously reported on the frequency of response according to different criteria in an observational cohort where we used the structured clinical protocol developed by the South Swedish Arthritis Treatment Group (SSATG) [10]. We found that more rigorous response criteria, such as ACR50 and European League Against Rheumatism (EULAR) good response, identified a similar proportion of responders, but agreement at the individual level was poor [16]. The results indicate that the predictive value of certain baseline features might depend on the response criteria chosen.
In this study, we have investigated whether sex or other features of the patients present at treatment initiation were associated with clinical response to TNF blocking therapy in patients with RA in an observational patient cohort at 3 months. We also wanted to study if the application of different response criteria influenced the results of the predictor analysis. In order to confirm the consistency of 3 months’ data, patients at 6 months of follow-up were studied as a secondary end point.
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Patients and methods |
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Patients
Data were collected using a structured clinical protocol designed for drug monitoring [10, 11]. No formal approval from the ethical committee was necessary, as the protocol was designed to meet the legal documentation required in Sweden.
The patients were treated with anti-TNF therapy at centres in southern Sweden reporting data to the SSATG register during the period March 1999 through September 2006.
Patients, eligible for the study had a diagnosis of RA according to clinical judgement of the treating physician. A previous review of patients included in this cohort showed that 98% of the patients fulfilled the ACR 1987 classification criteria for RA [10]. Subjects were selected by physicians based on disease activity and/or unacceptable steroid use. No formal level of disease activity was required; however, the patients should have received at least two DMARDs including MTX previously without acceptable response. Patients with <3 month of follow-up or having received previous courses of biologic therapy were excluded from this study. The patients were separated according to gender. Three months of follow-up was chosen in this open-label study as primary outcome to ensure low number of dropouts due to incomplete data. Also clinical evaluation at 3 months represents a pivotal assessment point regarding treatment continuation according to the local guidelines.
Dosages followed the recommendations by the manufacturers. Etanercept was administered as a 25 mg subcutaneous dose twice a week. Infliximab was infused at 3 mg/kg at 0, 2, 6 and then every 8th week. Depending on primary or secondary failure the dosage of infliximab could be increased in steps of 100 mg to a maximum of 500 mg administered at 4- to 8-week intervals. Adalimumab was administered as a 40 mg subcutaneous dose every other week.
Method
Clinical data were prospectively collected at 0, 3 and 6 months. At inclusion, the following data were recorded: year of disease onset, previous and concomitant DMARD treatment and systemic prednisolone dosage. At inclusion and at each follow-up visit, clinical data were registered: HAQ score, patient-scored visual analogue scale for pain (VASpain) and general health (VASglobal), physician's global assessment of disease activity on a five-grade Likert scale (Evalglobal), 28 tender and swollen joint count, ESR and CRP. Fulfilment of the ACR response criteria 50%, 70% (ACR50, ACR70) [13] and the EULAR responses using 28-joint Disease Activity Score (DAS28) were calculated at 3 months of follow-up [17]. Patients with DAS28 scores <2.6 at follow-up were considered to be in remission (EULAR remission). The rational for using ACR50 and ACR70 together with EULAR good and remission criteria is to investigate whether certain predictors depend on the type of response criteria chosen [16].
Recordings of clinical data for the response criteria were performed immediately prior to each infliximab administration, while patients receiving etanercept and adalimumab were scored independently of drug administration. Thus, patients receiving infliximab always had the lowest possible level of anti-TNF blocking capacity when evaluated for efficacy biasing this group of patients. The current study therefore pools the different TNF blocking preparations. In addition, during the inclusion time from March 1999 through September 2006, the access of different TNF blocking drugs varied markedly making comparisons of adalimumab, etanercept and infliximab even more difficult [11].
Statistical analysis
Baseline clinical characteristics were analysed by Mann–Whitney U-test for comparison of groups for continuous variables, whereas chi-square test was used for categorical variables. Independent predictors of treatment response were identified using a logistic regression model and association models. Subsequently, the predictors of EULAR and ACR response at 3 and 6 months were modelled using multivariate binary logistic regression models. The following variables were included in the analysis: age at inclusion, gender, disease duration at inclusion, baseline HAQ, baseline DAS28, baseline CRP-level, prednisolone usage and concomitant DMARD or NSAID therapy. The DMARDs were grouped according to concurrent MTX usage alone or in combination with other DMARDs, other concurrent DMARD usage and finally anti-TNF administered as monotherapy. Level of significance was chosen to be P < 0.05.
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Results |
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Baseline data
During the observational period a total of 1565 patients were enrolled in the study. Of those, 59 patients (3.7%) were excluded from the regression models due to lack of follow-up data. There were no statistical differences in age, sex, disease duration and concomitant DMARD usage between the dropouts and the patients included in the regression models (data not shown).
Demographic data and clinical characteristics of patients studied are summarized in Table 1. Clear differences are seen between males and females at baseline. Generally, men were older and had better functional status as measured by HAQ (P < 0.01), lower disease activity as measured by DAS28 (P < 0.01) and fewer previous DMARDs (P < 0.01). However, when looking at the components of the DAS28 score only subjective variables were lower for males than for females. Thus, patient global evaluation and number of tender joints as measured by 28-joint index were higher for females than for males (P < 0.01). Also VASpain was significantly higher for females compared with males (P < 0.01). On the other hand, no differences were found in number of swollen joints, physician's global evaluation and ESR. In fact, the CRP level was significantly higher in males than in females (P < 0.01). Finally, MTX-treated males received higher weekly dosage than females (P < 0.01), and fewer males received anti-TNF treatment without concomitant DMARDs (P = 0.01).
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Responders
The proportion of patients fulfilling ACR50, ACR70, EULAR good responses and DAS28 remission based on a non-responder analysis is shown in Table 2. No significant differences between males and females were found at 3 and 6 months of follow-up. Figure 1 shows DAS28 scores at baseline and 3 months of follow-up according to gender. The absolute changes in DAS28 scores are evident for both males and females after 3 months of follow-up. Moreover, DAS28 scores are consistently lower for males both at baseline but also at 3 months of follow-up (P < 0.01), thus placing the average male closer to the 2.6 cut-point for remission.
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Regression analysis
In order to search for predictors of positive treatment response, a multivariate binary logistic regression model was created. Figure 2 shows odds ratios (ORs) and 95% CIs for the predictors studied. Values for age, disease duration, CRP-level and prednisolone usage were omitted from the figures because of limited impact on clinical response, and these variables are described in the text only.
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At 3 months, when adjusting for differences in baseline data, we did not find any significance when studying the predictive value of gender for either of the four response criteria. On the other hand, MTX use was associated with EULAR remission (OR: 1.97, P < 0.01), EULAR good response (OR: 2.13, P < 0.01), ACR50 response (OR: 2.10, P < 0.01) and ACR70 response (OR: 1.75, P = 0.04) at 3 months. Also, concurrently other DMARD treatment showed a trend for predicting good treatment responses with significant responses at 3 months for EULAR good (OR: 2.24, P < 0.01), DAS remission (OR: 1.96, P = 0.01) and ACR50 response (OR: 1.84, P = 0.01). Regular NSAID usage was a significant positive predictor of DAS28 remission (OR: 1.48, P = 0.04).
HAQ score was inversely associated with response to TNF blocking therapy (P < 0.01). High HAQ score reflects low functional level in RA patients, thus better functional capacity predicts good treatment response.
Disease activity at treatment initiation showed a dichotomized association with treatment response depending on response criteria chosen. Thus, DAS28 scores were directly associated with favourable response when measured by ACR50 (OR: 1.59, P < 0.01) and ACR70 (OR: 1.60, P < 0.01), whereas disease activity was inversely associated with DAS28 remission (OR: 0.78, P < 0.01) and EULAR good response (OR: 0.89, P = 0.09), although the latter association was not significant. Disease duration did not predict treatment response.
Results from the regression analysis at 6 months of follow-up showed consistency with the 3 months’ primary end point data with regard to concomitant MTX, gender, disease duration, baseline DAS28 level and HAQ scores (Fig. 2). On the other hand, other DMARDs only showed a non-significant trend for predicting good treatment response, while regular NSAID usage was a significant positive predictor of EULAR good response (OR: 1.40, P = 0.04) instead of DAS28 remission.
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Discussion |
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In this study, concomitant MTX usage and low HAQ score at treatment initiation were identified as predictors of good treatment response at 3 months of follow-up, which is consistent with the study reported by Hyrich et al. [12]. Also, concurrent treatment with other DMARDs identified good responders. In addition, we found a dichotomized relationship between disease activity at baseline as measured by DAS28 score, and response to either ACR criteria or EULAR criteria including remission DAS28 < 2.6. Thus, depending on the response criteria chosen, DAS28 score was either directly associated with treatment response (ACR criteria) or inversely associated (EULAR criteria). The secondary end point predictors of response at 6 months of follow-up were on the whole consistent with the 3 months’ data. However, the positive effect of other DMARDs seemed less evident at 6 months of follow-up, possibly because of less power in the analysis at this time point. Thus, factors influencing response to anti-TNF therapy at 3 months of follow-up appears to consistently predict response during a longer treatment course.
The direct association found between ACR50 and ACR70 responses and baseline DAS28 might be explained by a greater potential for treatment response in patients with high disease activity. This was not reproduced for predictors of EULAR good response possibly because of the inherent dependency of EULAR good responders to reach absolute DAS28 scores of <3.2 [17], much in analogy with the requirement for fulfilling the EULAR remission criteria (Fig. 1). On the other hand, ACR response criteria do not measure absolute disease activity, thus, patients fulfilling the ACR50 criteria may still have rather high disease activity [17]. Furthermore, the actual response rates observed in our cohort (Table 2) were somewhat lower than results obtained in published randomized clinical trials [2, 7, 8]. This might be due to strict inclusion criteria used in clinical trials omitting patients with non-trivial comorbidities [18, 19]. Also patients enrolled in our cohort often were treated with different DMARD combinations other than MTX and sometimes receiving anti-TNF blocking agents as monotherapy (Table 1). Also patients receiving infliximab were evaluated just prior to the drug administration where the amount of anti-TNF is at the lowest concentration, thus potentially diminishing the overall response rates. More importantly, we presented response data based on a non-responder analysis. This notably deflates the actual number of responders in the observational setting, as all subjects still remaining in the study, but for some reason are lacking response data, are accounted for as not responding at all [20]. The response rates presented in Table 2 can therefore not uncritically be extrapolated. Previous publications present more adequate and nuanced response data from our cohort [10, 11].
A possible explanation for the apparent superiority of concomitant MTX to predict response may be that MTX is a potent drug in itself, which has been proven in randomized placebo controlled trials [7]. Another reason could be that patients tolerating MTX also possess yet undefined characteristics predisposing to good treatment responses, for which we were unable to adjust. The same explanations can be claimed for the positive effect of other DMARDs; however, interestingly, to our knowledge this combination has only been studied indirectly [21].
HAQ score is, especially in established RA, directly related to level of disability [22], thus making it plausible that patients already mutilated by their RA have less potential for good clinical responses to TNF blocking therapy. Thus, our data suggest that degree of disability rather than disease duration in itself is associated with treatment response, as disease duration did not predict response to therapy.
In contrast to previous reports [12–15] of the association between male sex and favourable response to treatment in RA, we did not find any association between gender and response to anti-TNF treatment.
In fact, the OR varied between 0.75 and 1.52 for different response criteria and times of follow-up (Fig. 2). However, according to Fig. 1, males generally had lower DAS28 scores both at baseline and at 3 months of follow-up. Remission is defined as DAS28 < 2.6, and the inverse association between DAS28 at baseline and chance of remission found in this study is therefore obvious. Thus, it can be speculated that the predictive value of male sex found by Hyrich et al. [12] is to some degree confounded by lower baseline scores of DAS28. Indeed, it should be noted that the positive effect of male sex reported in their study was only significant for patients achieving remission. Notably, DAS28 scores at baseline were also strongly associated with remission in the study by Hyrich et al. [12]. However, the differences found might also reflect genetic or environmental variations between RA patients in Sweden and the UK.
On the other hand, this study in agreement with other studies [14, 23] does find clear distinctions in characteristics of men and women with RA. Thus, we find higher baseline DAS28, HAQ and pain scores for the females, whereas the CRP level was higher in males. Apart from the CRP, perception of pain plays a central role in the differences mentioned above, and this finding is not unique for the rheumatic diseases. Sex differences in the perception of pain in general have been widely studied both in the clinical and experimental setting [24–26]. The reason for these distinctions is complex and should be attributed to various causes including biological, psychological and social differences between the two sexes [24–26]. Moreover, genetic differences between males and females play a role in RA joint inflammation i.e. when studying levels of anti-inflammatory androgens in the synovial tissue [15]. And males might have a milder RA disease course than women. Thus, when initiating and evaluating treatment with TNF blocking agents these underlying dissimilarities between men and women should be kept in mind.
The open non-randomized nature of observational studies generates methodological limitations [18, 19, 27]. Confounding by indication and observation bias cannot be excluded from this study. We therefore chose to group all anti-TNF remedies together, and not perform separate analyses. However, at present there is only little knowledge of predictors for good treatment response in the observational setting [12], thus giving no obvious reason for biasing recordings of patients with certain characteristics at 3 or 6 months of follow-up.
In conclusion, this study did not find an association between gender and treatment response. On the other hand, we identified concomitant MTX, other concurrent DMARDs and low HAQ values at inclusion as positive predictors of treatment response to TNF blocking therapy at 3 months of follow-up. The dichotomized association between disease activity as measured by DAS28 and response according to ACR criteria on one side and response according to EULAR criteria on the other, reflect the inherent differences of these criteria. This should be considered when evaluating the efficacy of anti-TNF-treated patients both individually and in observational cohorts.
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Acknowledgements |
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We are indebted to all colleagues and staff in the South Swedish Arthritis Treatment Group for cooperation and data supply.
Funding: This study was supported by grants from Österlund and Kock Foundations, King Gustav V 80 year fund, and Reumatikerförbundet.
Disclosure statement: L.E.K. and M.C.K. have received a fee for speaking from Wyeth. P.G. has received fees for speaking from Wyeth, Abbot and Schering-Plough. All other authors have declared no conflicts of interest.
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