Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score

Abstract

Introduction: Frequent assessments of rheumatoid arthritis (RA) disease activity allow timely adaptation of therapy, which is essential in preventing disease progression. However, values of acute phase reactants (APRs) are needed to calculate current composite activity indices, such as the Disease Activity Score (DAS)28, the DAS28-CRP (i.e. the DAS28 using C-reactive protein instead of erythrocyte sedimentation rate) and the Simplified Disease Activity Index (SDAI). We hypothesized that APRs make limited contribution to the SDAI, and that an SDAI-modification eliminating APRs - termed the Clinical Disease Activity Index (CDAI; i.e. the sum of tender and swollen joint counts [28 joints] and patient and physician global assessments [in cm]) - would have comparable validity in clinical cohorts.

Method: Data sources comprised an observational cohort of 767 RA patients (average disease duration 8.1 +/- 10.6 years), and an independent inception cohort of 106 patients (disease duration 11.5 +/- 12.5 weeks) who were followed prospectively.

Results: Our clinically based hypothesis was statistically supported: APRs accounted only for 15% of the DAS28, and for 5% of the SDAI and the DAS28-CRP. In both cohorts the CDAI correlated strongly with DAS28 (R = 0.89-0.90) and comparably to the correlation of SDAI with DAS28 (R = 0.90-0.91). In additional analyses, the CDAI when compared to the SDAI and the DAS28 agreed with a weighted kappa of 0.70 and 0.79, respectively, and comparably to the agreement between DAS28 and DAS28-CRP. All three scores correlated similarly with Health Assessment Questionnaire (HAQ) scores (R = 0.45-0.47). The average changes in all scores were greater in patients with better American College of Rheumatology response (P < 0.0001, analysis of variance; discriminant validity). All scores exhibited similar correlations with radiological progression (construct validity) over 3 years (R = 0.54-0.58; P < 0.0001).

Conclusion: APRs add little information on top (and independent) of the combination of clinical variables included in the SDAI. A purely clinical score is a valid measure of disease activity and will have its greatest merits in clinical practice rather than research, where APRs are usually always available. The CDAI may facilitate immediate and consistent treatment decisions and help to improve patient outcomes in the longer term.

Figure 1

Contribution of individual variables to composite scores. Explanation of score variability for (a) the Simplified Disease Activity Index (SDAI), (b) the Disease Activity Score (DAS)28, and (c) the DAS28-CRP for the respective clinical and acute phase reactant (APR) variables, at zero-order (i.e. R² if the variable was introduced as the first one; black bars) or finally (i.e. R² if variable was introduced in the model as the last one; grey bars), and item colinearity within the respective composite index (1 - tolerance, expressed as percentage; white bars; n = 767). CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; PGA/EGA, patient/evaluator global assessment of disease activity (100 mm visual analogue scale); TJC/SJC, tender/swollen joint count (28 joints).

Figure 2

Cross-sectional correlation of composite scores and correlation with HAQ scores. Matrix displaying Spearman rank coefficients (95% confidence intervals) for cross-sectional correlations of Disease Activity Score (DAS)28, Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), and Health Assessment Questionnaire (HAQ) in the routine cohort (upper diagonal half; n = 720 for correlations with HAQ, otherwise n = 767) and the inception cohort (lower diagonal half; n = 104 for correlation with HAQ, otherwise n = 105).

Figure 3

Changes in composite scores in relation to ACR response. Changes in (a) Disease Activity Score (DAS)28, (b) Simplified Disease Activity Index (SDAI) and (c) Clinical Disease Activity Index (CDAI) in relation to the achieved American College of Rheumatology (ACR) response of 91 patients in the inception cohort. ACR ranges were defined as ACR <20 (n = 28, 30.8%), ACR 20–69 (n = 20, 22.0%) and ACR ≥ 70 (n = 43, 47.2%), allowing analysis of independent observations. Error bars span the 95% confidence interval of the mean. Differences in group changes were statistically significant for all three scores (P < 0.0001, one-way analysis of variance). Presented P values for post hoc pairwise group comparisons are subjected to Bonferroni adjustment. *P < 0.0001 for ≥ ACR70 group compared with other groups.

Figure 4

Association of composite scores with radiological outcome. Correlation with changes in Larsen scores within 3 years from entering the inception cohort (n = 56) of time-averaged (a) Disease Activity Score (DAS)28 (R = 0.58, 95% confidence interval [CI] 0.37–0.73), (b) Simplified Disease Activity Index (SDAI; R = 0.59, 95% CI 0.39–0.74), and (c) Clinical Disease Activity Index (CDAI; R = 0.54, 95% CI 0.32–0.70). All correlations are significant (P < 0.0001). (d) C-rectaive protein (CRP; R = 0.28, 95% CI 0.02 to 0.51; P = 0.025).