In this study we showed that the CDAI, a simple composite index obtained by numerical summation of four solely clinical variables, is a valid instrument with which to follow patients with RA. Our hypothesis was originally based on feasibility arguments, namely the frequent lack of immediate access to laboratory results in the clinic, but was further strengthened by statistical arguments related to the low contribution made by the acute phase response to the composite scores. In fact, all data obtained support our clinically derived hypothesis that APRs provide little information on actual disease activity on top of that provided by the combination of several clinical components. This was the case for all analyzed RA activity scores, despite the differences in their construction and component weighing.
For many rheumatologists, this lack of additional information provided by APR may be intriguing because CRP and ESR are among the most commonly used laboratory tests in the evaluation of RA disease activity [39
], and their importance as surrogates of the disease process, as well as predictors of disease outcome, are well recognized and irrefutable [36
]. However, APRs did not seem to contribute information to composite scores that was sufficiently important to change judgement of disease activity, in addition to merely using clinical measures. In fact, when we divided all patients into 10 groups based on their disease activity ranks within the cohort, as measured using the different scores, we found statistical agreement that was indicative of high clinical conformity of classifications by different scores. All of these findings indicate that content validity of the CDAI is well maintained despite the absence of CRP as a component.
In accordance with these notions is the observation that as much as 85% of the variance in the DAS28 was explained without ESR; 95% of the variances in the SDAI and the DAS28-CRP were explained by their composing clinical variables (i.e. without CRP). The similarity in these results between the DAS28-CRP and the SDAI further supports previous indications that transformation and/or weighing of the clinical variables does not confer an advantage compared with their simple numerical summation [21
]. However, it should be borne in mind that the DAS28-CRP has only recently been made public and must be regarded with caution until it has been more widely studied; in fact, the present investigation may represent the first validation of the DAS28-CRP. Interestingly, our analyses reveal a high degree of colinearity between the two global assessments employed in the SDAI and CDAI. Because both patient and physician global assessment are parts of the widely applied and validated ACR/EULAR/WHO-ILAR core set variables of RA disease activity assessment, it would not be intuitive to eliminate any one of them, especially as, in contrast to the APRs, they do not correlate with structural damage independently. In addition, because these two variables are usually assessed jointly, the elimination of any one of them would not increase the feasibility of calculating the score.
In a cross-sectional analysis of a large number of patients, the CDAI not only had correlational validity compared with the SDAI, from which it was derived, but also compared with the DAS28 and the DAS28-CRP. Also, there was no difference beyond chance in the correlation of CDAI with the HAQ as compared with the respective correlations of SDAI and DAS28 with the HAQ. This finding is especially noteworthy because the HAQ is a functional measure, which is not based on or constructed with core set elements used in the DAS28 or SDAI. Moreover, when related to different degrees of ACR response, the results obtained using CDAI were graded with statistically significant and clinically meaningful differences between all group means, and were very similar to those seen for the respective DAS28 and SDAI groups. Also, for the CDAI, effect sizes appeared to be even more graded between the different ACR responder groups.
Thus, although none of the comparators in this study represents a 'gold standard' for disease activity measurement, the validity of the new score was proven not only with respect to other composite scores but also with respect to the HAQ, which is a completely distinct construct. In addition, the CDAI was shown to have very good agreement with other composite indices on the categorization of individual patients, which is an important aspect in the clinical use of this score. Furthermore, all mentioned correlation analyses were successfully validated in a second, completely independent cohort of newly diagnosed patients with RA who overall had a higher level of disease activity and were untreated at baseline. The different characteristics of the two cohorts, and the similar correlation coefficients for the three indices obtained within each cohort indicate that the application of our findings might not be confined to patient cohorts with particular characteristics, such as disease duration or disease activity.
A limitation of the CDAI is that many physicians do not perform detailed joint counts in the assessment of RA disease activity [38
]. On the other hand, joint counts are also required for other composite disease activity scores, and the CDAI allows elimination of at least one variable that is frequently missed at patient visits – the APR. Although a considerable number of measurements was missing in the overall source dataset, these missing data were random. This was also evident from the similar clinical characteristics of patients with and without available APR measurements. Therefore, and given the large number of complete patient observations, an unbiased analysis was assured. Like for the DAS28 [41
], a possible criticism of the CDAI is that it does not include assessment of joints in the feet; however, in the course of proving the reliability of the 28 joint count [42
], it was found that this reduced joint count reflects overall joint involvement very well and that, in the presence of low joint counts, the joints of the feet rarely add a significant number of additionally involved joints – a finding that we have also observed in our database (data not shown). It might also be regarded as a further limitation that the CDAI was not developed by factor and/or discriminant analysis of individual variables. However, the value of all core set variables has been shown repeatedly [10
] and their responsiveness has likewise been demonstrated [26
]. In addition, there are several conceptual and methodological advantages of composite scores compared with individual items [29
]. Moreover, the SDAI, from which the CDAI was derived, has also been validated and shown to have practicability, discriminant capacity and sensitivity to change in several studies [21
]. Likewise, as a composite score, the test–retest reliability of the CDAI is based on the reliability of its individual components, which, although not assessed here, has proven to be good.
Despite omission of the APR from the formula, the CDAI maintained a clinically important ability to predict outcome, measured as radiological progression over 3 years. This stability of construct validity across the scores is therefore also in accord with our initial hypothesis. Interestingly, the deletion of the APR from the SDAI did not change the correlation of the score with radiographic progression; there was a similar degree of correlation with radiographic changes whether DAS28 (using ESR), SDAI (using CRP), or CDAI (using no APR) were employed. Furthermore, the observation that the APR alone also was associated with radiographic progression is not only in accordance with previous reports [36
] but also suggests an independent relationship with structural damage of both clinical variables (as reflected by the composite CDAI score) and APR. We did not use HAQ scores as an outcome measure because in this early cohort the links between damage and function are expected to be small [31
]. HAQ scores in this cohort would therefore be a surrogate of disease activity, rather than an independent measure of irreversible loss of function [30
Our introduction of the CDAI was not intended to suggest that the acute phase response does not represent an important measure in the follow up of RA, or that it should be deleted from existing indices such as the DAS28 and the SDAI. In particular, the ESR contributes 15% to the DAS28 composition, which is not an irrelevant amount of information. However, the validity of the CDAI, as revealed here by multiple statistical analyses in two different cohorts, shows that the APR is not an absolute requirement in the context of disease activity scores. In fact, we would urge physicians to continue to obtain an APR measure regularly during follow up because, like the CDAI, it reflects disease activity and correlates with long-term outcome. However, as stated above, the APR can be employed as an independent measure as well as being a part of a composite index.
Because calculation of the SDAI (and of the DAS28) is frequently limited at the time of the patient's visit either by a wait for laboratory results or their unavailability, omitting the APR from the score allows unlimited and immediate assessment of disease activity by including only variables that are available by physical examination and patient questioning at the time of interaction with the patient. Therapeutic decisions will then be possible without further delay. Of course, clinic settings can be revised to have laboratory results delivered at the time of patient visits, although this may not be easy in all situations, and in reality is often not the case. Thus, using a purely clinical score facilitates consistent patient assessment, which might be more attractive for routine application to many physicians, who currently base their treatment decisions on more general and subjective impressions rather than on standardized assessments. The fact that joint counts are frequently not assessed routinely does not diminish these notions; deletion of joint counts from composite scores cannot be justified for a disease of the joints, and joint counts can always be performed at the time of patient visit to the clinic by the physician or another assessor. Moreover, in this age of expensive therapies, consistent assessment of disease activity might soon become compulsory from the payer's perspective. Thus, the ability to adopt a simple but valid score will potentially have great implications with respect to implementation of new therapeutic concepts. At the same time, less frequent laboratory investigations do not appear to impair the physician's ability to detect adverse treatment effects, but can reduce the overall costs of care considerably [45
Of course, further validation of the CDAI will be required to fully confirm its value. Such additional investigations should include analyses of construct validity with regard to radiographic damage and predictive value with regard to long-term functional outcome in larger cohorts of patients. In addition, cutoffs for disease activity categories, including remission, as well as changes that reflect important responses must be determined. Such analyses are currently underway.