Using CRP for calculation of the DAS28 is an attractive alternative to ESR for a number of reasons. Firstly, CRP measurements are routinely used in clinical practice, and are often available in circumstances when ESR measurements are not. CRP levels are more sensitive to short-term changes in disease activity,22
whereas ESR can be influenced by a number of unrelated factors, such as age, gender or plasma proteins. Laboratory tests used to calculate CRP are faster than those used to measure ESR, and measurements can be standardised in a central laboratory for multicentre clinical trials.7
There is currently less clinical experience using DAS28 (CRP), and a formal validation study with respect to radiographic progression and functional assessment is needed.
Using data from two trials of abatacept, we have compared the DAS28 (CRP) with the DAS28 (ESR), and validated the DAS28 (CRP) against assessments of radiographic progression and physical function. Most patients were classified as having the same EULAR state regardless of which DAS28 definition is used. Despite this, several discrepancies were observed. Firstly, some patients (154/752; 20.5%) were classified as having a lower present DAS28 category when using the DAS28 (CRP) vs the DAS28 (ESR). In 76 out of these 154 cases, this resulted in patients being classified as being in a better EULAR state when measured with DAS28 (CRP). Secondly, certain patients were classified as having either large or moderate improvement, depending on which DAS28 definition was used; this type of discrepancy occurred at a similar frequency with both definitions, and would not be expected to result in more favourable results with one definition vs the other. Although the current analysis detected discrepancies in 17.6% of patients, these were moderate in magnitude; overall, there is general agreement between the two measures. The 2 DAS28 definitions also demonstrated agreement in classifying DAS28-defined remission, with the majority of discrepancies (33 cases) resulting in patients being classified as in remission with DAS28 (CRP) but not DAS28 (ESR). Considering the DAS28 (ESR) definition as the external comparison, there is support for the criterion validity of the DAS28 (CRP).
When a discrepancy occurs, the tendency is for the DAS28 (CRP) definition to yield a better response state. This has also been found in the work by Inoue et al23
and Matsui et al.24
To overcome this discrepancy, transforming the DAS28 (CRP) to more closely conform to the DAS28 (ESR) is an enticing idea. However, the concern is the generalisability of the transformation across different patient groups. Inoue et al23
derived an adjustment factor based on regressing DAS28 (ESR) on DAS28 (CRP) (ie, DAS28 (ESR)
1.01 DAS28 (CRP)+0.590). Applying this adjustment factor to the current dataset led to a larger percentage being classified with a worse response state using DAS28 (CRP) (2.9% classified as better and 12.9% classified worse, compared with the unadjusted results of 12.7% and 4.9%, respectively). Other approaches can be considered, for example, an adjustment factor could be based on regressing ln(ESR) on ln(CRP+1), which is the essential difference between the two DAS28 definitions, and using this adjustment in the DAS28 (ESR) formula. Applying this adjustment, a more equitable division resulted, with 4.5% in a better and 8.6% in a worse state; again, the generalisability of the transformation may be an issue.
The construct validity of the DAS28 (CRP) was evaluated by examining the trends in radiographic and functional progression across the EULAR responder states based on the DAS28 (CRP). For both definitions of the DAS28 there was generally good agreement between reduced radiographic progression and EULAR responses, and classification as a good EULAR responder was predictive of a lower rate of radiographic progression in patients treated with abatacept. However, some deviations from this trend were observed. For the DAS28 (ESR) definition, radiographic scores were generally higher for the moderate responders than for non-responders in the placebo group. This was also true for the DAS28 (CRP) definition, in the abatacept and placebo groups. Changes in HAQ-DI scores showed very similar linear trends for both definitions, with improvements in HAQ-DI across the EULAR responder states from none to moderate to good. These trends held for patients treated with abatacept and placebo, and demonstrate that improvements in the DAS28 (CRP) and DAS28 (ESR) are associated with improvements in physical function.
The level of sensitivity of the DAS28 (CRP) and DAS28 (ESR) is an important issue to consider, and differences could potentially contribute to discrepancies observed between the two measures. However, as the SRMs were identical for the two measures, and the relative efficiencies were comparable, suggesting the sensitivity to change of the DAS28 (CRP) and DAS28 (ESR) are very similar.
The analyses described here were performed only on patients for whom ESR and CRP measurements were available. The majority of patients who did not have both measurements had missing ESR data. This was due to technical issues associated with the fact that ESR assessments were performed locally on standard kits, whereas CRP was measured by a central laboratory, allowing electronic data transfer to the main database. Although only a subset of patients from each trial had CRP and ESR measurements, baseline demographics and clinical characteristics for this subset were comparable with those that did not have both measurements, suggesting that they were likely to be representative of the full patient population.
Two key findings have emerged from the current investigation. Firstly, the DAS28 (CRP) has been validated with respect to functional and radiographic progression, and the validation profile was similar to that based on ESR. Secondly, there was a tendency for the DAS28 (CRP) to yield a lower score and in some instances a better EULAR response (12.7% vs 4.9% for the CRP and ESR, respectively). Often the two definitions were generally comparable, and formulating a conclusion on the EULAR response state or remission status based on the DAS28 (CRP) definition provides a reasonable basis for assessing a patient, provided the user is aware of the tendency of the DAS28 (CRP) to yield a better response than the DAS28 (ESR). Currently, the same cut-off points for EULAR response states originally derived for the DAS28 (ESR) are also applied for the DAS28 (CRP). To increase the level of agreement between the two DAS28 formulations, one solution would be to derive a new set of cut-off points tailored for use with DAS28 (CRP). The development of a robust approach leading to set of cut-off points that can be generally applied across populations may prove difficult, as illustrated when the translation derived by Inoue et al23
and Matsui et al24
is applied to the current dataset. Exploration of a robust method that will translate DAS28 (CRP) to DAS28 (ESR) and the derivation of a corresponding set of cut-off points for the disease activity state for the CRP formulation are needed before a transformation of the DAS28 (CRP) definition is advocated. An appropriate research agenda encompassing the assembly of large and diverse datasets, and an analysis plan involving regression based models will help to provide further insight into the potential for achieving a better alignment of the DAS28 (CRP)-defined and the DAS28 (ESR)-defined EULAR response states.
In conclusion, we have provided a validation of the DAS28 (CRP) assessment and corresponding EULAR response states against radiographic progression and physical function. While the DAS28 (CRP) yielded a better EULAR response more often than the DAS28 (ESR), the validation profile was similar to that of the DAS28 (ESR), indicating that both definitions of the DAS28 criteria can be used as benchmarks to assess patient improvement and treatment effect, and can aid in the description and interpretation of changes in disease activity in patients with RA.