DAS28 best reflects the physician's clinical judgment of response to infliximab therapy in rheumatoid arthritis patients: validation of the DAS28 score in patients under infliximab treatment

Rheumatoid arthritis (RA) is a complex disease with a broad spectrum of manifestations that requires an early intensive therapy in order to avoid joint destruction and physical disability. In order to measure the effect of therapy in daily practice and in clinical trials, many variables are recorded and different composite indices have been proposed to measure the remaining disease activity or the response to treatment. Those variables may cover items such as patient self-reported questionnaires, physician's scores including different joint scores, and serum markers of systemic inflammation.

Infliximab, in combination with methotrexate (MTX), is a highly effective therapy for a majority of RA patients. After an induction scheme at weeks 0, 2 and 6, the indicated dose of this therapy is 3 mg/kg every 8 weeks, although the ATTRACT trial suggested that a higher dose of 10 mg/kg every 8 weeks or a shorter perfusion interval may add benefit [1–3].

The present study is based on an expanded-access program in which patients suffering from active refractory RA were treated with intravenous infusions of infliximab (3 mg/kg + MTX) at weeks 0, 2, 6 and every 8 weeks thereafter. At week 22, patients not optimally responding to treatment could receive a dose increase of 100 mg (1 vial) per infusion from week 30 onwards [4]. The effect of dose escalation for the patients of this cohort has been discussed previously [4]. The decision to increase the dose was based on the treating rheumatologist's clinical judgment and can be considered as a measure of insufficient response to infliximab. It might be questioned which variables can be measured to best evaluate the effect of therapy and remaining disease activity in daily practice (and in clinical trials). The aim of the present analyses was to evaluate whether the decision to increase the dose could be reflected by using single variables or composite indices, alone or together in a model. We also wanted to evaluate whether this decision was mainly based on differences over time or on momentary disease activity.

The aim of the present analyses was to evaluate which single or composite variables, combined in a model, could discriminate the treating rheumatologist's decision to give a dose increase of infliximab to RA patients not optimally responding to an indicated dose of 3 mg infliximab every 8 weeks. Since different variables on different time points were available, we started to rank the continuous variables based on the AUC of ROC curves and sensitivities at the 95% specificity level. This strategy has previously been proposed for microarray data [17]. The calculation of sensitivities at the 95% specificity level is important in order not to overlook some variables with a relative small AUC but with a high specificity [16]. So, both methods ranked the DAS28 at week 22 as the variable which best discriminates the decision to give a dose increase. In a second and third analysis, we looked at whether response scores and differences in disease activity over time could give additional information to discriminate the rheumatologist's decision. Those analyses indicated that variables, including differences over time, seem to be less important than the momentary remaining disease activity at week 22, to discriminate the rheumatologist's decision.

After the prior selection of variables, based on the findings of the previous steps, we built the final model to discriminate the rheumatologist's decision, which was only slightly better than the DAS28. We think that the small gain in discriminative properties in comparison with the DAS28 is not enough to accept the increased complexity of this model. Moreover, in contrast to the DAS28, this model included the physician's global assessment of disease activity (VAS), which is investigator-dependent and has the draw-back that it cannot be calculated by a study nurse. All four analyses together indicated that the DAS28 is an important variable for evaluating insufficient response to infliximab therapy (especially in daily practice) and that this variable can only slightly be improved by adding supplemental variables.

DAS was developed in the early 1990s [19, 20] and later on, it was transformed into the DAS28 [7] in an era when therapy with biologicals was not yet available. In those initial studies, patients were scored by the same two independent nurses and the decision to change disease-modifying antirheumatic drug (DMARD) therapy during a follow-up period of up to 3 years was considered as a measure of insufficient response [20]. The present study is a multi-center study where patients were scored by the treating physician and the decision to give a dose increase of infliximab could happen only at one time point. This difference in study design and therapy may explain why in the present study the AUC of DAS28 is smaller than in other studies (AUC = 0.840 versus 0.933) [21]. Therefore, it is remarkable that despite those differences in study design, we could calculate a discriminant function (in the fifth analysis) that correlated so well with the DAS28 by using the 28SJC, 28TJC, ESR and patient disease activity VAS as independent variables and the physician's decision as a grouping variable. Not only the discriminant scores, but also the coefficients of this discriminant function were quite similar to the coefficients of the DAS28, indicating the robustness of the scores and coefficients of the DAS28 score.

In another, final analysis, we evaluated the alternative DAS scores and the squared root transformed SDAI and CDAI. All those alternative scores have a slightly worse AUC than the original DAS28, but seem good enough to be useful when some other variables are not available. We think the use of the DAS28 is feasible and time-effective using a preprogrammed calculator, spreadsheet or web-based calculator [11]. The unique characteristics of the DAS score make it a useful measure in a lot of applications. DAS28 as a continuous variable is a sensitive tool for measuring response to treatment in randomized controlled trials and facilitates the use of more complex statistical methods that can handle repeated measures over different time points [22–24].

Other studies demonstrated that a low DAS is an important prognostic factor of persistent remission and that DAS correlates with radiological progression [25, 26]. DAS may also be a useful parameter in daily clinical practice as a treatment goal and to evaluate the actual disease activity (which cannot be assessed by the categorical response scores) [27–31]. Our findings that the physician's decision to give a dose increase can best be modeled by a combination of measurements of remaining/momentary disease activity, represented by the DAS28 does not reduce the value of the response scores such as ACR response or DAS response scores. Indeed, those scores are important for measuring differences over time as a measure of global treatment effects in clinical trials [12, 13] but, as demonstrated by the present study, are not useful for evaluating the momentary disease activity in a single patient, which is important in daily practice. The continuous properties of the DAS28 score provide the additional opportunity for a cut-off, which can be chosen as a function of the purpose. Interestingly, we found a high predictive value for continuing the current dose as a measure of good response below a cut-off of 3.2. It is noteworthy that a DAS score of 3.2 is an important threshold for a good DAS response according to the EULAR criteria [12]. In contrast, for classification purpose, a higher cut-off (5.5) is more appropriate since this level displayed the highest accuracy. One should be aware that the displayed predictive values and accuracies may be highly influenced by the prevalence of insufficient response, reflected by the need for a dose increase, which was 21.5% in the present study. A lower a priori chance of the need for a dose increase may increase the accuracy of DAS (given the fixed cut-off of 5.5) and vice versa. Indeed, at a cut-off with a high specificity, the accuracy will increase when the a priori chance decreases (applying formula c given in the legend to Table 4).

The results of the present analyses indicate that the momentary DAS28 as a continuous composite index correlates best with the decision to give a dose increase of infliximab, which is a measure of insufficient response. The discriminative characteristics of the DAS could be slightly improved by the use of supplemental variables, although this results in the disadvantage of a more complex model and calculations. This study also demonstrates the robustness of the scores and coefficients of the DAS28 in a cohort of RA patients under infliximab therapy and therefore validates the DAS28 as a measure of disease activity in patients under treatment with biologicals.