These results demonstrate a significant association between the MBDA score and the DAS28-CRP in heterogeneous groups of RA patients with diversity in autoantibody status, disease activity, and RA therapy receiving care in multiple clinical centers. The MBDA score was able to consistently distinguish patients in different categories of clinical disease activity. Our results provide evidence of criterion validity for the MBDA test by demonstrating a significant association with the DAS28-CRP and other validated disease activity measures.
As a continuous score, the MBDA score was correlated with the DAS28-CRP with coefficients of 0.56 and 0.43 in seropositive and seronegative patients, respectively. In comparison, correlations to the DAS28-ESR and DAS28-CRP reported for other clinical measures range from 0.43–0.70 for the RAPID3 and from 0.51–0.54 for the multidimensional and modified Health Assessment Questionnaires (39–41
). Correlations of the SDAI and CDAI with the DAS28-CRP tend to be greater (range 0.80–0.93) (10
), since these 3 measures have many components in common. The MBDA score emphasizes the activity of underlying biologic pathways rather than external signs and symptoms and should therefore provide information that is different from, and complementary to, clinical assessment. Studies are underway to assess the utility of the MBDA score when used in conjunction with clinical assessment and to compare cross-sectional and longitudinal relationships of different disease activity measures (including the MBDA score) to various RA outcomes, including imaging-based (e.g., magnetic resonance imaging [MRI], ultrasound, radiographs) assessments of joint inflammation and damage progression.
In addition to criterion validity, results from the Nested-1 analysis provide evidence of the discriminant validity of the MBDA score by demonstrating that changes in the score were associated with both the DAS28-CRP and ACR50 treatment response for patients receiving MTX or anti-TNF therapy. MBDA scores declined more in clinical responders than in nonresponders, with significant changes detectable as early as 2 weeks after therapy initiation. Our finding that an early drop in MBDA score was indicative of subsequent DAS28-CRP response is intriguing and should be evaluated in larger studies to determine whether the MBDA score might allow earlier evaluation of treatment efficacy. Taken together, these findings suggest that biomarkers may help assess treatment response, even shortly after treatment initiation, in both clinical trials and clinical practice.
The face validity of the MBDA test is supported by the relationship of the component biomarkers to biologic mechanisms relevant to RA disease activity. Despite the fact that biomarker selection for the test was based on statistical contribution to estimation of disease activity, the MBDA biomarkers represent critical cytokine signaling pathways in RA (IL-6, TNFRI) as well as hallmark RA disease processes, including angiogenesis and tissue remodeling (VEGF-A, EGF), cell recruitment and invasion (VCAM-1), cartilage remodeling (MMPs), and elevated acute-phase response (CRP, SAA). Associations between many of these biomarkers and disease activity have previously been reported (42–48
Content validity requires comprehensive evaluation of all relevant facets of disease activity (24
). Since the MBDA score does not include physical evaluation and is intended to complement rather than replace clinical assessment, content validity is both limited and less relevant. While the MBDA score does not reflect signs and symptoms, the 12 biomarkers are functionally diverse and more biologically comprehensive than current laboratory tests and clinical tools.
The diverse biology underlying the MBDA biomarkers is also consistent with the hypothesis that integration of information from multiple pathways can enhance disease activity assessment. To explore this hypothesis, we evaluated the contribution of non-CRP biomarkers to the MBDA score and prediction of the DAS28-CRP. Our results verified that the MBDA score without CRP was an independent predictor of the DAS28-CRP in seropositive patients, indicating that the non-CRP biomarkers provide additional information on disease activity in these patients. Characterization of the relationship between MBDA score and outcomes not themselves based on CRP, such as joint damage progression and disability, is currently underway and will offer a more meaningful way to assess the value of the MBDA score above and beyond CRP.
The patients examined in the validation studies were diverse in terms of geographic origin and disease characteristics, and they were not selected except for their clinical disease activity levels. Consequently, the study results indicate that the MBDA score is a valid measure of disease activity in representative current RA patients, including a variety of therapies and comorbidities. However, since emerging therapies for RA may have novel effects on biomarkers, it will be important to study the performance of the score in patients treated with drugs with new mechanisms of action. In addition, since some comorbidities can affect biomarker levels, it is also important to investigate whether they affect the relationship between the MBDA score and clinical disease activity. No significant effects on the MBDA score have been found for several comorbidities commonly found in patients with RA (49
), but further studies are warranted.
Demonstration of the criterion, discriminant, and face validity of the MBDA score is an important step in the full qualification of this novel disease activity measure. These findings support the use of the MBDA score as an objective measure of disease activity that reflects the diverse underlying biology of RA. Ongoing and future research on the MBDA score will include evaluating its relationship to imaging-based assessment of inflammation (ultrasound and MRI) and its construct validity by assessing its ability to predict long-term outcomes such as RA flare, joint damage progression, and disability. Ultimately, the clinical utility of the MBDA test may be best determined by prospective studies that evaluate whether patient outcomes are improved by the use of the test as an adjunct to clinical assessment.