This study evaluated composite measures of treatment response without acute-phase reactants with standard EULAR and ACR response criteria in a large, multi-centred observational RA cohort. Using CDAI-derived cut-offs for disease activity levels, there were moderate to substantial agreements between CDAI-derived and EULAR-defined responses. As might be expected, mACR20 and mACR50 responses were highly correlated with those defined by ACR20 and ACR50 response criteria. Taken together, these findings provide two alternative approaches for measuring treatment response in both observational research and clinical settings when acute-phase reactant measurements are not always available.
With respect to disease activity states, this work confirms that of others showing that CDAI correlates with DAS28 and the cut-off points derived in this study were similar as well [8
]. Aletaha and Smolen [8
] found substantial agreement between CDAI and DAS28 (weighted κ
0.70), which was slightly higher than the agreement in these analyses (using their methodology, the weighted κ in this population was 0.63). This suggests that CDAI cut-points for stratifying disease activity states in patients without acute-phase reactant results can indeed be applied in both clinical practice and observational research settings.
The actual numerical value for cut-off points for change in CDAI corresponding to DAS28 changes of 1.2 were somewhat lower than those from a recently published study; these findings are likely due to differences in the study populations and references used [11
]. Ranganath et al.
] developed cut-off points in a cohort of DMARD-naïve, RF-positive early RA patients. The patient population in this study differed as they had long-standing disease (mean disease duration of 11 years). While the cut-off points derived in this study were comparable with those previously published, validation of our derived cut-off points in an independent cohort would be of value and strengthen our results.
Goldman et al.
] similarly found that patterns of improvement defined by mACR20 scores without acute-phase reactants were consistent with accepted ACR20 scores. Comparing responses to therapy in both MTX-naïve early and DMARD-refractory late RA patients, they observed that both the mACR203of4
discriminated clinical improvement for etanercept vs
placebo. Various other modifications of the ACR response criteria have already begun to be implemented in observational registries missing individual components [20
]. The findings in the current study, coupled with the work of Goldman et al.
], provide convincing evidence that mACR responses can be applied to measure treatment responses in patients when acute-phase reactant measurements are not available.
In the current study, correlations between responses defined by mACR with accepted ACR response criteria were greater than those between CDAI- and EULAR-defined responses. In part, this may be due to fundamental differences between the instruments. Modified ACR criteria represent the same calculation as ACR responses, but with one or two measures removed, including ESR or CRP. In contrast, calculating CDAI is markedly different from DAS28, which is integral to defining EULAR responses. Although in these analyses mACR20 and mACR50 were superior to CDAI in assessing responses to treatment, there are circumstances when the CDAI-derived response criteria may be preferable to mACR, because it also incorporates an assessment of the final disease activity state. The importance of including the final disease activity state in a composite measure of response has been previously described [21
While acute-phase reactant measurements provide valuable clinical information in many patients, they are often not available at the time of the clinical evaluation. Moreover, excluding acute-phase reactant measurements from composite measures simplifies and streamlines the evaluation of disease activity and treatment responses, and may be what is required to convince rheumatologists to use such measures in daily practice. Goldman et al.
] have suggested that mACR20 could help physicians who do not conduct laboratory tests in their offices to guide treatment decisions, as well as facilitate group comparisons of changes in disease status. Based on the findings of the current study, utilization of CDAI-derived response criteria may be another alternative for clinical practice. In contrast, others have asserted that the ACR20, and by extension the mACR20, should be employed only for analysis of RCTs (for which the ACR response criteria were developed) or longitudinal databases and are not useful in the clinical management of individual patients [22
]. Indeed, further evaluation of the benefits and limitations of integrating CDAI and mACR in regular clinical practice in other populations may be needed, but the present evidence strongly suggests that alternative approaches without acute-phase reactants can be implemented. Moreover, these findings are also relevant for observational studies of DMARD and biological agent effectiveness.
The disease activity in this population, while consistent with other published US cohorts from clinical practice settings, was lower than those seen in patients participating in clinical trials [23
]. To address this potential limitation, we also examined the influence of disease activity on the agreement between the CDAI-derived response with the EULAR response, and the mACR and standard ACR response criteria based on disease activity. In addition, we compared those with acute-phase reactant results to those without in both the total population and initiators of DMARD therapy in our registry in terms of demographic and disease activity characteristics. The only significant difference was the proportion of patients with serological positivity among those who initiated a DMARD (80% in those with an ESR vs
58% in those without). Disease activity as measured by the CDAI was not statistically different in those with and without an ESR in both the populations.
In summary, we have demonstrated good to excellent agreements between both mACR and CDAI-derived responses with well-accepted ACR and EULAR composite measures, which include acute-phase reactant measurements. These findings have important implications. In clinical settings without access to results from acute-phase reactant testing, clinicians may choose to use the mACR- and CDAI-derived response to drive treatment decisions. Additionally, these tools may also be used for epidemiological and outcomes research using disease registry data where there may be missing laboratory results.