Editorial: The Multi‐Biomarker Disease Activity Test for Rheumatoid Arthritis: Is It a Valid Measure of Disease Activity?

One of the greatest unmet needs in rheumatology is a biomarker that enables highly sensitive and reliable measurement of disease activity in patients with rheumatoid arthritis (RA). Witness the enthusiasm of the rheumatology community for Vectra DA, the latest multibiomarker disease activity (MBDA) test, which was developed and marketed by Crescendo Biosciences and is available commercially in the US as a send-out laboratory test. This MBDA test measures 12 serum protein biomarkers using multiplex enzyme immunoassays and applies an algorithm to summarize the biologic information into a single score. The test is performed at the Crescendo Biosciences laboratory in South San Francisco, which is certified by the Clinical Laboratory Improvement Amendments and licensed in California. Vectra DA is described by Crescendo Biosciences as “Everything you need to know: the advanced blood test that helps you and your doctor better understand your RA disease activity with a single score” (1). In this issue of Arthritis & Rheumatology, Fleischmann and colleagues present data that appear to reveal substantial flaws in the validity of this test (2). The authors report the findings of a post hoc analysis of the AMPLE (Abatacept versus Adalimumab Comparison in Biologic-Naive RA Subjects with Background Methotrexate) 2-year phase IIIb randomized controlled trial (3). The AMPLE trial enrolled RA patients with a disease duration of ,5 years, who had moderate disease activity despite methotrexate therapy, and who were naive to biologic therapies. The results demonstrate that after baseline, MBDA-defined categories of low disease activity, moderate disease activity, or high disease activity were not consistent with the cutoffs for validated clinical measures of disease activity, including the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP), the Clinical Disease Activity Index (CDAI), and the Routine Assessment of Patient Index Data 3 (RAPID-3). There were no associations between the MBDA score and the DAS28-CRP, CDAI, or RAPID-3 in either treatment arm. At the end of the study, most patients had moderate or high disease activity based on the MBDA scores, whereas the majority of patients had low disease activity or remission based on the clinical measures. Perhaps the finding of moderate or high disease activity as determined by the MBDA test despite clinical indicators of minimal disease activity could yet be meaningful. Vectra DA is marketed as being a “deeper” or more “comprehensive” measure of disease activity, suggesting that the MBDA test can detect disease persistence even when clinical measures are insensitive to it (4). However, the foundation of this idea appears to crack further because of data showing not only that MBDA-classified disease activity failed to predict radiographic outcomes but also that the highest probability of radiographic nonprogression was evident in the groups with MBDA-defined moderate or high disease activity. Considering the extensive efforts to bring the MBDA test to the clinic, the results should be disappointing and quite humbling for proponents of biomarkers. Does this mean that the MBDA test is a failure as a disease activity test, or that something went wrong?