Introduction
As the number and diversity of therapeutic options for patients with rheumatoid arthritis (RA) increase, the need has grown for easily applicable clinical outcome measures that represent valid, stable improvements, are relevant to individual patients, and accurately discriminate between different active therapies in clinical trials and real-world settings. Ideally, these measures could also help guide therapeutic modifications in treat-to-target strategies during routine clinical care. A European League Against Rheumatism (EULAR) good response, which requires a decrease in Disease Activity Score-28 joints (DAS28) of 1.2 and a current DAS28 ≤ 3.2 [
1], is one possible option for comparing active agents and guiding treatment. However, a study of test–retest reliability over 7 days found that a DAS28 change of 1.2 was lower than the smallest detectable difference [
2], suggesting that some EULAR responses are due to inherent variability in DAS28 values rather than to stable therapy-associated changes.
Assessment of individual therapeutic responses based on the critical difference for improvement in DAS28, referred to as the DAS28-d
crit, provides an alternative to EULAR responses
. The DAS28-d
crit is a validated, statistically derived criterion defined as the minimum DAS28 change exceeding random fluctuation during stable therapy, and is a robust indicator of clinical response to RA treatment [
3]. In RA patients receiving stable therapy with conventional or biologic DMARDs during routine clinical care, the DAS28-d
crit corresponded to a DAS28 decrease (improvement) ≥ 1.8 [
3]; this value was confirmed in patients on tocilizumab monotherapy [
4] in the non-interventional ICHIBAN study [
5]. DAS28-d
crit responses are more closely correlated with patient-reported improvements in functional capacity than EULAR responses [
3] and are associated with significant improvements in patient-reported outcomes (PROs) [
6], thereby demonstrating the clinical relevance of this response criterion. The validation study focused on change from baseline in an observational cohort initiating treatment with a biologic therapy [
3]. To date, no studies have explored the potential utility of DAS28-d
crit in evaluating the comparative effectiveness of two active treatment arms in clinical studies.
Tocilizumab is an interleukin-6 inhibitor with efficacy in treating RA in placebo-controlled randomized trials as monotherapy [
7] and in combination with conventional disease-modifying antirheumatic drugs (DMARDs) [
8,
9]. This agent is effective and well tolerated during routine clinical care as intravenous (IV) or subcutaneous formulations [
10,
11]. Tocilizumab therapy results in superior improvements in disease activity compared with anti-tumor necrosis factor (TNF) agents [
12,
13]. In addition to improving objective clinical outcomes, tocilizumab results in significant improvements in PROs, including pain, fatigue, and function, compared with anti-TNF drugs [
14].
The goals of this study were (1) to evaluate the ability of DAS28-dcrit responses to differentiate between the effectiveness of active RA therapies in randomized and observational clinical studies through retrospective analysis of data from clinical trials of tocilizumab and comparator active agents and (2) to further explore the suitability of DAS28-dcrit as a statistical tool for evaluating individual responses to RA therapy across different agents and settings.
Discussion
In this study, we evaluated the ability of the DAS28-d
crit criterion to differentiate between the effectiveness of distinct active RA therapies and to provide a robust and stable assessment of individual responses to RA therapy across different agents and settings. DAS28 is the continuous variable most closely linked to the rheumatologist’s decision to modify treatment [
16]. However, a DAS28 change of 1.2, the criterion for a EULAR good response, is too low to be a reliable assessment of therapeutic response [
2]. We therefore evaluated the statistically determined DAS28-d
crit to assess individual therapeutic responses during tocilizumab clinical studies.
The DAS28-d
crit, which is based on DAS28 changes that exceed random fluctuation, is more stable and more closely linked to functional improvement than EULAR responses [
3]. In addition, it only involves one calculation and is therefore less cumbersome to apply in routine daily practice. Both DAS28-d
crit and EULAR response criteria require calculation of DAS28, but the DAS28-d
crit simplifies assessments of therapeutic response by requiring only two pieces of information: the baseline DAS28 and the current DAS28. In contrast, for a EULAR good or moderate response, the category of the current DAS28 (≤ 3.2, > 3.2 to ≤ 5.1, or > 5.1) and the extent of improvement (> 1.2 or 0.6 to ≤ 1.2) need to be taken into account [
1]. In a recent US study, the most common reason for not collecting RA metrics routinely was “takes too much of my time” [
17], suggesting that more easily applied assessments may help improve disease tracking and patient care. The DAS28-d
crit criterion has been used to evaluate patient responses in observational studies [
3], but had not previously been applied to randomized trial data or to studies comparing different active agents.
In this study, we used the previously published value for DAS28-d
crit (DAS28 improvement from baseline ≥ 1.8) [
3], which was confirmed in patients on tocilizumab monotherapy [
4], to retrospectively evaluate therapeutic responses in observational and randomized trials of tocilizumab versus comparator agents. We found that DAS28-d
crit response rates effectively discriminated between active treatments: DAS28-d
crit response rates were significantly higher in patients treated with tocilizumab than in those treated with anti-TNF comparators, thereby supporting the previously reported improved effectiveness of tocilizumab compared with anti-TNF drugs [
12,
13]. In addition to using DAS28-based outcome measures, previous reports from the ADACTA and ACT-iON studies found that the significantly improved activity of tocilizumab compared with anti-TNF agents was retained in assessments of the Clinical Disease Activity Index (CDAI), which does not contain an inflammatory marker [
12,
13], thereby suggesting that the variances observed between therapeutic agents represent true clinical differences and not simply an effect of tocilizumab on acute-phase reactants.
As in the DAS28-dcrit validation study, therapeutic responses as determined by the DAS28-dcrit were more stable over time than EULAR responses during continuing, consistent active therapy. In ADACTA, stable responses (at least 5 of the 6 visits) in patients with a response at any time point occurred approximately twice as often in patients who achieved a DAS28-dcrit response compared with a EULAR good response. We acknowledge the possibility that these data reflect a greater sensitivity to change with EULAR good responses compared with DAS28-dcrit responses. However, we consider it unlikely that 30% of patients on stable treatment had clinically significant differences in disease activity over a period of 24 weeks. Accordingly, we believe the more likely interpretation to be that DAS28-dcrit responses have greater stability over time versus EULAR good responses because these responses represent change that exceeds random fluctuations.
For both response measures, tocilizumab responses showed greater stability over time than responses to TNF inhibitors, suggesting that therapeutic responses to tocilizumab may be better maintained than therapeutic responses to anti-TNF agents. These findings are consistent with other reports of the long-term effectiveness of tocilizumab [
10,
11,
13,
18].
Previous studies have found that DAS28-d
crit responses are associated with improvements in function as assessed by the Funktionsfragebogen Hannover patient questionnaire [
3] and that patients with DAS28-d
crit responses are more likely to achieve individual responses in PROs than patients who do not achieve a DAS28-d
crit response [
6]. In this study, we extend these observations by showing that DAS28-d
crit responses were closely associated with improvements in mean values for PROs, regardless of the drug involved. Patient global health is one of the parameters used to derive the DAS28, so the association between a DAS28-d
crit response and global health is perhaps expected. However, the strong association with pain is more surprising and supports the clinical relevance of a DAS28-d
crit response as a surrogate for outcomes important to patients. The mean change in pain during tocilizumab and anti-TNF treatment exceeded the individual pain-d
crit response value of 30 mm (corresponding to 3 points on a scale of 0 to 10 as calculated by Scharbatke et al. [
6]) in the DAS28-d
crit responder group, but not in the group that did not achieve a DAS28-d
crit response, suggesting that changes in pain associated with a DAS28-d
crit response were clinically meaningful to patients. Patients with a DAS28-d
crit response also showed strong improvements in patient-reported function as assessed by the HAQ-DI. As has been reported previously [
6], fatigue was the PRO most refractory to improvement in patients achieving a therapeutic response.
Limitations of this study include the use of ad hoc analyses conducted retrospectively. In addition, although statistical assessments were adjusted for potential confounding factors, there were no adjustments for multiplicity, which may have had a slight impact on the reported data. The analyses reported here are specific to tocilizumab and TNF inhibitors and may not apply to conventional DMARDs or other biologic agents. The DAS28 assessments used in this study utilized ESR as the acute phase reactant; DAS28 values based on C-reactive protein may have varied slightly.
Because of the strong effect of tocilizumab on acute phase reactants, DAS28 evaluations may somewhat overestimate the therapeutic effects of this drug [
19]. However, compared with other included variables, ESR has been shown to make the smallest independent contribution to DAS28 [
20]. A retrospective analysis of data from the SATORI study, a double-blind comparative study of tocilizumab versus methotrexate, found that the coefficient of correlation between DAS28-ESR and the CDAI, which does not contain an inflammatory marker, was high (> 0.8) at baseline and throughout the study; the correlation did not decrease following improvements in ESR after tocilizumab initiation [
21]. As mentioned previously, CDAI assessments have shown improved disease activity with tocilizumab compared with anti-TNF comparators in previous reports [
12,
13]. However, CDAI-d
crit evaluations are not possible because, unlike the DAS28, the CDAI does not have a normal distribution over the span of disease activity [
22]. Because the CDAI is a nonlinear measure, it is not appropriate for a statistical tool such as dcrit which requires equidistance between score intervals to provide a valid outcome.
In conclusion, our study demonstrates that the DAS28-dcrit provides a robust statistical tool for evaluating individual responses to RA therapy with wide applicability across different active agents and clinical settings. In analyses of clinical trial data, the DAS28-dcrit criterion effectively discriminates between active agents, while its close association with PROs makes it a suitable and easy-to-use tool for treat-to-target treatment decisions. We believe a more stable response metric has the potential to improve outcome assessments, and we encourage the prospective use of the DAS28-dcrit response criterion in future RA studies to further examine its utility in both clinical trials and routine clinical care.
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