Validation of a novel multibiomarker test to assess rheumatoid arthritis disease activity

Abstract

Objective: Quantitative assessment of disease activity in rheumatoid arthritis (RA) is important for patient management, and additional objective information may aid rheumatologists in clinical decision making. We validated a recently developed multibiomarker disease activity (MBDA) test relative to clinical disease activity in diverse RA cohorts.

Methods: Serum samples were obtained from the Index for Rheumatoid Arthritis Measurement, Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study, and Leiden Early Arthritis Clinic cohorts. Levels of 12 biomarkers were measured and combined according to a prespecified algorithm to generate the composite MBDA score. The relationship of the MBDA score to clinical disease activity was characterized separately in seropositive and seronegative patients using Pearson's correlations and the area under the receiver operating characteristic curve (AUROC) to discriminate between patients with low and moderate/high disease activity. Associations between changes in MBDA score and clinical responses 6-12 weeks after initiation of anti-tumor necrosis factor or methotrexate treatment were evaluated by the AUROC.

Results: The MBDA score was significantly associated with the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) in both seropositive (AUROC 0.77, P < 0.001) and seronegative (AUROC 0.70, P < 0.001) patients. In subgroups based on age, sex, body mass index, and treatment, the MBDA score was associated with the DAS28-CRP (P < 0.05) in all seropositive and most seronegative subgroups. Changes in the MBDA score at 6-12 weeks could discriminate both American College of Rheumatology criteria for 50% improvement responses (P = 0.03) and DAS28-CRP improvement (P = 0.002). Changes in the MBDA score at 2 weeks were also associated with subsequent DAS28-CRP response (P = 0.02).

Conclusion: Our findings establish the criterion and discriminant validity of a novel multibiomarker test as an objective measure of RA disease activity to aid in the management of RA in patients with this condition.

Figure 1

Biomarkers used to estimate each component of the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) in the multibiomarker disease activity (MBDA) algorithm. The algorithm uses different subsets of biomarkers and/or different weightings to predict each component of the DAS28-CRP, including the tender joint count (TJC), swollen joint count (SJC), patient global assessment (PG), and CRP level. The resulting mathematical relationship between the DAS28-CRP and MBDA score is: MBDA = (DAS28-CRP) × 10.53 + 1. PTJC = predicted TJC; PSJC = predicted SJC; PPG = predicted PG; TJC28 = 28-joint TJC; SJC28 = 28-joint SJC; VEGF-A = vascular endothelial growth factor A; VCAM-1 = vascular cell adhesion molecule 1; IL-6 = interleukin-6; SAA1 = serum amyloid A1; EGF = epidermal growth factor; TNFRI = tumor necrosis factor receptor type I; MMP-1 = matrix metalloproteinase 1.

Figure 2

Mean changes from baseline in the multibiomarker disease activity (MBDA) score. A, Change in the MBDA score in all patients. B, Change in the MBDA score in Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) responders vs. nonresponders after treatment initiation in the Nested-1 study. Error bars show the 95% confidence interval (95% CI) of mean changes in the MBDA score. P values in A are for the t-test of change from baseline. At the final visit (6 or 12 weeks), mean changes from baseline in the MBDA score were −8.4 (95% CI −4.6, −12.2) for all patients (n = 45), −13.9 (95% CI −19.7, −8.1) for DAS28-CRP responders (n = 24), and −2.1 (95% CI −5.7, 1.4) for nonresponders (n = 21). Similar results were observed for patients with complete sample data, i.e., those with MBDA scores available at 0, 2, 6, and 12 weeks (n = 27). A DAS28-CRP response was defined as a decrease in the DAS28-CRP of ≥1.2 units and an ending DAS28-CRP score of <3.2 at the last study visit.