We investigated 620 paired observations of DAS and DAS28 in 155 different patients. Table 1 shows the concordance and discordance rates of these observations.
Table 1DAS28 remission in case of DAS remission in 620 observations in 156 patients who participated in the COBRA trial
In 168 of 620 observations (27%), the remission criterion was met according to at least one of both remission definitions. In only 77 observations (13%) in 35 patients was the remission criterion met by both definitions, and in 91 observations (15%) in 53 patients paired observations were discordant with respect to remission. In 87 of 91 discordant observations in 49 patients (96%) DAS28 remission but not DAS remission was met. DAS remission but not DAS28 remission was met in only four of 91 observations in four patients (4%). Subsequently, comprehensive swollen and tender joint counts, ESR, and patient global assessments were investigated in the discordant pairs of observations with remission. Because DAS28 remission in the absence of DAS remission was extremely rare (n
4), we omitted this type of discordance from further analysis.
If the more conservative DAS remission was considered the gold standard, the sensitivity of DAS28 remission was 95%, the specificity 84%, the positive predictive value (PPV) only 47%, and the negative predictive value (NPV) 99%. Attempts to improve the statistical performance of DAS28 by changing the cut off level for remission using receiver operating characteristics (ROC) analysis resulted in an optimal (highest agreement) cut off level for DAS28 of 2.73 (sensitivity 99%, specificity 81%, PPV 43%, NPV 100%). Forcing a cut off level towards increased specificity increases PPV, but at the cost of sensitivity: a cut off level for DAS28 remission of 2.0 resulted in a PPV of 66% and a sensitivity of 70%.
The probability plots in fig 1 represent individual observations with DAS28 remission, stratified by the presence of DAS remission. It is obvious that discordant observations of remission (fulfilling DAS28 remission but not DAS remission) include far higher swollen or tender joint counts as well as patient global assessments that are worse than concordant observations (both DAS28 remission and DAS remission), pointing to a higher level of disease activity, with many active joints. The median (50th centile) number of swollen joints of 44 possibly swollen joints was 0 in the concordant observations, as compared with 3 in the discordant observations. The median number of tender joints was 0 in concordant observations, as compared with 6 in the discordant observations.
Figure 1Probability plots of swollen joint count, tender joint count, erythrocyte sedimentation rate (ESR), and patient global assessment of wellbeing in observations with DAS28 remission, with (concordant) or without (discordant) DAS remission. (more ...)
The probability plot shows that a swollen joint count >0 was found in 75% of discordant pairs v 48% of concordant pairs. Similarly, a tender joint count >0 was found in 90% of discordant v 40% of concordant observations.
The discrepancy with regard to ESR was only minimal: concordant and discordant observations of remissions had similar ESR values, and high ESRs (>30 mm) were only seen in the discordant pairs.
The entire plot for the patient global assessment is shifted to the left for the discordant v
concordant pairs, indicating a higher overall assessment (worse status). In line with this, we found in the discordant observations that patient global assessment correlated better with the 44 joint SJC (r
0.33) than with the 28 joint SJC (r
0.03), and with the 68 joint TJC (r
0.48) than with the 28 joint TJC (r
0.23), suggesting significant disease activity in the joints omitted by the 28 joint count.
Subsequently, we addressed the hypothesis that DAS28 remission could occur in the absence of swelling in the 28 joint count but in the presence of swelling in the joints not belonging to the 28 joint count. Table 2 shows that in observations with DAS28 remission based on an SJC of zero joints, important and clinically relevant swelling could occur in residual joints. The same was found with respect to tenderness. Table 2 also provides the mean SJC and TJC for the different types of joint count (comprehensive, condensed, and residual) for different scenarios. Importantly, in the scenario with discordant remission, the residual SJC accounted for 59% of the total SJC, where it was much lower in the other scenarios (and should be 16 of 44 (36%) assuming a proportional distribution). The residual TJC even accounted for 78% of the total TJC, where it was much lower in the other scenarios (and should be 40 of 68 (59%) assuming a proportional distribution). These results suggest that in a scenario defined by the presence of DAS28 remission but the absence of DAS remission, substantial disease activity (swelling and tenderness) is present preferentially in those joints that are not captured by the condensed 28 joint counts. Note that the mean joint count—but not the ESR—in the discordant remission scenario outweighs the mean joint count in the concordant remission scenario, in agreement with the probability plots in fig 1. Note also that this discordant remission scenario is the only one in which mean DAS is numerically higher than mean DAS28—another argument for an underestimation of disease activity by DAS28 in this particular scenario.
Table 2Swelling and tenderness as derived from different joint counts for different scenarios of disease activity, based on DAS28 and DAS remission criteria
We subsequently analysed whether the discrepancies between DAS remission and DAS28 remission could be specifically attributed to involvement of ankles and feet. Seventy one of 77 concordant observations and 83 of 87 discordant observations could be evaluated for swelling of lower extremity joints using the source data. Thirteen of 71 concordant observations (18%) v
42 of 83 discordant observations (51%) (χ2
16; p<0.0005) had swelling in at least one joint of the lower extremities (range 1 to 4).