We read with great interest 2 recent articles (1, 2) on the American College of Rheumatology N (ACR-N) index (3). Using the early rheumatoid arthritis trial data, Drs. Siegel and Zhen claim that discriminative power between therapies is increased by the ACR-N and especially ACR-N area under the curve (AUC) (1). Dr. Boers argues that the ACR-N AUC reflects an AUC of relative improvement from baseline, crediting improvements achieved at earlier visits at each subsequent evaluation (2).
The multiplicative approach of the ACR-N AUC exaggerates response differences and, in fact, translates earlier efficacy into better efficacy. In contrast, in the context of absolute measures, AUC analyses are helpful, and not misleading. Continuous activity scales, such as the Disease Activity Score in 28 joints (DAS28) (4), allow cross-sectional assessment of individuals and patient populations at any point in time (5). More importantly, keeping the level of disease activity below a certain cutoff value has allowed for testing and confirming the benefits of tight control (6). This would hardly have been possible using the ACR or ACR-N criteria. Ideally, criteria should be easy to understand, transposable into clinical practice, and have validity and usefulness in a world of changing requirements and treatment approaches. For the ACR-N, all of these aspects do not apply. Moreover, the ACR-N does not help in addressing the most burning current question: what is the proportion of patients in whom low disease activity or remission is achieved?
We have recently introduced the Simplified Disease Activity Index (SDAI), the numerical sum of 5 core set variables (7). In developing novel criteria for low disease activity and remission, we found that the current DAS28 remission criteria allow for >10 swollen joints (8), as also seen by others (9, 10). In contrast, the remission cutoff for the SDAI is ≤3.3, which allows no patient to be considered to have disease remission if there are >2 tender or swollen joints. We have also recently validated the Clinical Disease Activity Index (CDAI), which is based on the SDAI but does not include measurement of acute-phase reactants (11). Based on the same data we used to derive the SDAI criteria (8), we have determined that a CDAI of ≤2.8 corresponded to remission, a CDAI of ≤10 to low disease activity, a CDAI of ≤22 to moderate disease activity, and a CDAI of >22 to high disease activity. It is this knowledge about the presence or absence of low disease activity or remission that is needed today; conceptually and practically, there is no way to define such criteria with the ACR-N.
Table 1 shows an example of 2 patients. Patient 1 has an ACR50 (12) response and an ACR-N of 65%, but considerable residual disease activity by virtue of the individual measures. The SDAI and the CDAI accordingly classify this patient as having moderate disease activity at the end point, while the DAS28 assigns the category of remission. Patient 2 achieves an ACR70 and an ACR-N of 83%, moderate disease activity (>3.2) by the DAS28, but remission by the SDAI and CDAI (0 swollen and 1 tender joint, normal C-reactive protein level). These examples not only show the importance of looking at absolute disease activity to make judgments about disease states, but also indicate that weighting of variables in an index can cause a problem.
|Patient 1||Patient 2|
|Baseline||End point||% improvement||Baseline||End point||% improvement|
|PGA, 10-cm VAS||6.9||2.2||68||5.7||0.5||91|
|EGA, 10-cm VAS||6.2||3.4||45||5.1||0.2||96|
|Pain, 10-cm VAS||9.5||3.6||62||5.5||0.6||86|
Rheumatologists today do not care about ACR20 or other minimal responses and do not wish to learn if a new drug or regimen allows a large proportion of patients to achieve minimal responses; they want to know the proportions of patients in whom low disease activity is achieved. Useful scoring systems should validly reflect this quest to achieve low disease activity and remission, regardless of the patient's level of disease activity at enrollment. Any other approach will lead us back into the darkness of the tunnel.