Influence of obesity, age, and comorbidities on the multi-biomarker disease activity test in rheumatoid arthritis
Introduction
Quantitative assessment of disease activity for patients with rheumatoid arthritis (RA) is recommended in multiple U.S. and international recommendations and quality of care guidelines [1], [2], [3]. Quantitative measurement is also a necessary feature of randomized controlled trials (RCTs) in RA to track response to therapy. Most measures to track RA disease activity are in part dependent on patients’ assessments, with various measures incorporating different facets of patient-reported pain, global health, and tenderness on a joint examination. It might be inferred that these measures are intended to reflect only the patient’s RA, but it is recognized that a variety of factors might impact a patient’s self-assessment of their own arthritis-related disease activity and overall health states. These issues complicate the use of composite clinical disease activity measures either for patient care or for eligibility for RA trials.
Among the factors that may influence the patient-reported aspects of the composite RA indices of disease activity are medical comorbidities. Health conditions (other than arthritis) associated with chronic pain, those that amplify pain (e.g., fibromyalgia), or otherwise contribute to patient’s self-perceptions of their health state may therefore confound accurate measurement and interpretation of standard composite indices of disease activity such as the DAS28, the Clinical Disease Activity Index (CDAI), and others. In part for this reason, physicians often turn to additional methods to obtain data to complement clinical assessment. Acute phase reactants such as C reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) are often helpful to provide additional data to gauge RA disease activity. Moreover, given the well-established role that CRP and ESR have in the realm of RA clinical trials, an elevated CRP and/or ESR is a common requirement for inclusion in RA RCTs. However, these lab tests have notable limitations, including the possibility that they are within the laboratory limit of normal despite clear and convincing evidence that the patient’s RA is active on the basis of other measures (e.g., multiple swollen joints on physical examination) [4]. Indeed, failure to meet this lab-based criterion is among the most common reasons for screen failure rates in RA trials that often exceed 50%.
A multi-biomarker disease activity (MBDA) test that might improve upon limitations of traditional lab measures might provide a valuable complement to address both limitations in clinical assessment with composite RA disease activity measures and that of traditional lab measures. Prior work has suggested that a 12 analyte MBDA test might prove useful to augment clinical assessment in patients with certain comorbidities such as fibromyalgia, where patients might have tender joint count and a higher patient global than those without fibromyalgia. In one study, 25 patients with RA and fibromyalgia were compared to patients with RA but without fibromyalgia [5]. The MBDA test in these RA patients was unaffected by the presence of concomitant fibromyalgia. Post-hoc results from an RCT setting re-evaluating potential inclusion criteria have shown that allowing an elevated MBDA test, in addition to or instead of an elevated CRP as one of the inclusion criteria, could allow 47% more patients to be classified as eligible for a trial [6] without meaningful diminution of the clinical effect size of the RA treatments being compared.
These studies have been limited by their small size (25 RA patients with fibromyalgia) and potentially limited generalizability of patients enrolled in an RCT compared to routine care. Given this evidence base, we conducted an analysis of the MBDA score in routine care settings, testing the hypothesis that the MBDA score is significantly affected by patient factors such as age and obesity, proxied by body mass index (BMI), as well as comorbidities common to RA patients. We also descriptively examined the MBDA in relation to common lab and clinical assessments used for RA management.
Section snippets
Methods
We evaluated cross-sectional data from Corrona, a large longitudinal registry of U.S. patients with RA that has been collected by more than 625 rheumatologists in 40 states. These data are derived from approximately 335,000 individual patient visits over a 14-year span. Patients are recruited from both private practice and university sites in the U.S. All patients provided explicit consent to participate, and the research was governed by both the New England IRB and institutional, and
Results
Of the 530 patients who had MBDA scores recorded within ±7 days of a CORRONA visit date, 364 also had a recorded CRP value measured at the same time. An additional 7 patients were omitted due to implausible or missing data (e.g., CRP > 500, missing gender information), yielding an eligible sample size of 357 patients. These individuals were cared for by 51 physicians, an average of 7 patients per physician. The mean MBDA score was 43. Patient characteristics of the eligible sample (Table 1)
Discussion
Rheumatologists sometimes want adjunct data to assess RA patients’ RA disease activity beyond clinical assessment for patients who are difficult to examine, have a large burden of psychologic distress and associated somatization complaints (e.g., concomitant fibromyalgia), or where there is longstanding disease with associated damage, making detecting the presence of synovitis difficult. While obtaining additional data to assess RA might come in form of information from musculoskeletal
Disclosures
Dr. Harrold is an employee of UMass Medical School and Corrona, LLC, a member of the Corrona Research Foundation, has a grant from Pfizer and received consulting fees from Roche. Dr. Greenberg is an employee and shareholder of Corrona, LLC and has received consulting fees or remuneration from AstraZeneca, Celgene, Genentech, Janssen, Novartis, and Pfizer. Dr. Curtis has received research grants and consulting fees from Abbvie, Amgen, BMS, Janssen, Myriad Genetics, Roche, Pfizer, and UCB. Dr.
Acknowledgments
This work was supported by the CORRONA Research Foundation. Publication of the manuscript was not conditional on any external approval.
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