Multi-biomarker Disease Activity Research Articles

FRI0066 Behavior of the multi-biomarker disease activity (vectra da algorithm) score and components in patients with rheumatoid arthritis treated with tocilizumab

BackgroundThe multi-biomarker disease activity (MBDA) score is a novel test that measures 12 biomarkers in serum to assess disease activity in patients with rheumatoid arthritis (RA). We previously reported the...

FRI0075 A multi-biomarker disease activity (vectra™ da algorithm) score and components are associated with sustained clinical remission in rheumatoid arthrits: the remira study.

BackgroundTherapeutic advances have made low disease-activity states (LDAS) and remission increasingly common for patients with rheumatoid arthritis (RA) [1]. In order to achieve and maintain tight-control of disease activity, it...

SAT0012 A Multi-Biomarker Disease Activity (VECTRA™ DA Algorithm) Score is Associated with Radiographic Outcomes in RA Patients Treated with TNF Inhibitors

BackgroundA novel multi-biomarker disease activity (MBDA) score that is based on the concentrations of 12 serum biomarkers has been shown to correlate with clinical disease activity in patients with rheumatoid...

AB1264 Pilot study of the impact of a multi-biomarker disease activity test for rheumatoid arthritis (vectra™ da) on treatment decisions in community practice

BackgroundGuidelines recommend routine measurement of disease activity. However, measurement does not improve outcomes unless it impacts treatment decisions. Recently, a multi-biomarker disease activity (MBDA) test for rheumatoid arthritis (RA) was...

FRI0174 A multibiomarker disease activity score (vectra™ da score) reflects clinical disease activity and tracks response in rheumatoid arthritis patients treated with anti-TNF therapy

BackgroundAnti-TNF therapy has been grown to a standard therapeutic strategy for rheumatoid arthritis (RA). To date, we have developed a multi-biomarker disease activity algorithm (MBDA) as a potential index to...

AB1343 Impact of a rheumatoid arthritis multi-biomarker disease activity test on clinical practice

BackgroundAssessment of disease activity in patients with RA includes patient and physician reported measures and differs by rheumatologist and practice, resulting in variability in treatment decisions and quality of care....

FRI0062 Evaluation of a multi-biomarker disease activity (vectra ™ da algorithm) in early rheumatoid arthritis and unclassified arthritis patients

BackgroundAccurate and frequent assessment of rheumatoid arthritis (RA) is critical for optimal treatment planning and would benefit from the availability of an objective, sensitive and robust way to measure disease...

Impact of Rheumatoid Arthritis Disease Activity Test on Clinical Practice

BackgroundVariability exists in the assessment of disease activity in rheumatoid arthritis (RA) patients that may affect quality of care.ObjectivesTo measure the impact on quality of care of a Multi-Biomarker Disease Activity (MBDA) test that quantitatively assesses RA disease activity.MethodsBoard-certified rheumatologists without prior experience with the MBDA test (N = 81) were randomized into an intervention or control group as part of a longitudinal randomized-control study. All physicians were asked to care for three simulated RA patients, using Clinical Performance and Value (CPV™) vignettes, in a before and after design. CPV™ vignettes have been validated to assess the quality of clinical practice and identify variation in care. The vignettes covered all domains of a regular patient visit; scores were determined as a percentage of explicit predefined criteria completed. Three vignettes, representing typical RA cases, were administered each round. In the first round, no physician received information about the MBDA test. In the second round, only physicians in the intervention group were given educational materials about the test and hypothetical test results for each of the simulated patients. The outcome measures were the overall quality of care, disease assessment and treatment.ResultsThe overall quality scores in the intervention group improved by 3 percent (p = 0.02) post-intervention compared with baseline, versus no change in the control group. The greatest benefit in the intervention group was to the quality of disease activity assessment and treatment decisions, which improved by 12 percent (p<0.01) compared with no significant change in the control group. The intervention was associated with more appropriate use of biologic and/or combination DMARDs in the co-morbidity case type (p<0.01).ConclusionsBased on these results, use of the MBDA test improved the assessment and treatment decisions for simulated cases of RA and may prove useful for rheumatologists in clinical practice.

A multi-biomarker score measures rheumatoid arthritis disease activity in the BeSt study

Objective. To evaluate a multi-biomarker disease activity (MBDA) score, a novel index based on 12 serum proteins, as a tool to guide management of RA patients.Methods. A total of 125 patients with RA from the Behandel Strategieën study were studied. Clinical data and serum samples were available from 179 visits, 91 at baseline and 88 at year 1. In each serum sample, 12 biomarkers were measured by quantitative multiplex immunoassays and the concentrations were used as input to a pre-specified algorithm to calculate MBDA scores.Results. MBDA scores had significant correlation with DAS28-ESR (Spearman’s ρ = 0.66, P < 0.0001) and also correlated with simplified disease activity index, clinical disease activity index and HAQ Disability Index (all P < 0.0001). Changes in MBDA between baseline and year 1 were also correlated with changes in DAS28-ESR (ρ = 0.55, P < 0.0001). Groups stratified by European League Against Rheumatism disease activity (DAS28-ESR ≤ 3.2, 3.2–5.1 and > 5.1) had significantly different MBDA scores (P < 0.0001) and MBDA score could discriminate ACR/EULAR Boolean remission with an area under the receiver operating characteristic curve of 0.83 (P < 0.0001).Conclusion: The MBDA score reflects current clinical disease activity and can track changes in disease activity over time.

Development of a Multi-Biomarker Disease Activity Test for Rheumatoid Arthritis

BackgroundDisease activity measurement is a key component of rheumatoid arthritis (RA) management. Biomarkers that capture the complex and heterogeneous biology of RA have the potential to complement clinical disease activity assessment.ObjectivesTo develop a multi-biomarker disease activity (MBDA) test for rheumatoid arthritis.MethodsCandidate serum protein biomarkers were selected from extensive literature screens, bioinformatics databases, mRNA expression and protein microarray data. Quantitative assays were identified and optimized for measuring candidate biomarkers in RA patient sera. Biomarkers with qualifying assays were prioritized in a series of studies based on their correlations to RA clinical disease activity (e.g. the Disease Activity Score 28-C-Reactive Protein [DAS28-CRP], a validated metric commonly used in clinical trials) and their contributions to multivariate models. Prioritized biomarkers were used to train an algorithm to measure disease activity, assessed by correlation to DAS and area under the receiver operating characteristic curve for classification of low vs. moderate/high disease activity. The effect of comorbidities on the MBDA score was evaluated using linear models with adjustment for multiple hypothesis testing.Results130 candidate biomarkers were tested in feasibility studies and 25 were selected for algorithm training. Multi-biomarker statistical models outperformed individual biomarkers at estimating disease activity. Biomarker-based scores were significantly correlated with DAS28-CRP and could discriminate patients with low vs. moderate/high clinical disease activity. Such scores were also able to track changes in DAS28-CRP and were significantly associated with both joint inflammation measured by ultrasound and damage progression measured by radiography. The final MBDA algorithm uses 12 biomarkers to generate an MBDA score between 1 and 100. No significant effects on the MBDA score were found for common comorbidities.ConclusionWe followed a stepwise approach to develop a quantitative serum-based measure of RA disease activity, based on 12-biomarkers, which was consistently associated with clinical disease activity levels.

An evaluation of molecular and clinical remission in rheumatoid arthritis by assessing radiographic progression

Objectives. To determine whether molecular remission defined by a multi-biomarker disease activity (MBDA) score predicts a reduced risk of joint damage progression, and whether the MBDA score can augment existing classifications of remission.Methods. The study examined 271 visits for 163 RA patients in the Leiden Early Arthritis Cohort. The MBDA score and other variables from each visit were evaluated for prediction of progression [change in Sharp–van der Heijde Score (ΔSHS) >3] over the ensuing 12 months. Positive likelihood ratios (PLRs) for non-progression were calculated for remission based upon DAS based on 28-joint counts and CRP (DAS28-CRP <2.32), EULAR/ACR Boolean criteria and MBDA score (≤25).Results. Ninety-three per cent of patients in MBDA-defined remission did not experience progression, compared with 70% of patients not in MBDA remission (P = 0.001). There were no significant differences in the fraction of non-progressers between patients in remission and those not in remission using either DAS28-CRP or EULAR/ACR criteria. The PLR for non-progression over 12 months for MBDA remission was 4.73 (95% CI 1.67, 15.0). Among patients in DAS28-CRP remission, those with a high MBDA score were 2.3 times as likely (95% CI 1.1, 3.7) to have joint damage progression during the next year.Conclusion. MBDA-defined remission was an indicator of limited radiographic progression over the following 12 months. For patients in DAS28-CRP remission, high MBDA scores were a significant indicator of elevated risk of progression. MBDA results may provide a useful adjunct to clinical assessment to identify progression-free remission and assess subclinical disease.

Impact of a multi-biomarker disease activity test on rheumatoid arthritis treatment decisions and therapy use

Objective:To assess how use of a multi-biomarker disease activity (MBDA) blood test for rheumatoid arthritis (RA) affects treatment decisions made by health care providers (HCPs) in clinical practice.Research design and methods:At routine office visits, 101 patients with RA were assessed by their HCPs (N = 6), and they provided blood samples for MBDA testing. HCPs completed surveys before and after viewing the MBDA test result, recording dosage and frequency for all planned RA medications and physician global assessment of disease activity. Frequency and types of change in treatment plan that resulted from viewing the MBDA test result were determined.Main outcome measure:Percentage of cases in which the HCP changed the planned treatment after viewing the MBDA test result.Results:Prior to HCP review of the MBDA test, disease modifying anti-rheumatic drug (DMARD) use by the 101 patients included methotrexate in 62% of patients; hydroxychloroquine 29%; TNF inhibitor 42%; non-TNF inhibitor biologic agent 19%; and other drugs at lower frequencies. Review of MBDA test results changed HCP treatment decisions in 38 cases (38%), of which 18 involved starting, discontinuing or switching a biologic or non-biologic DMARD. Other changes involved drug dosage, frequency or route of administration. The total frequency of use of the major classes of drug therapy changed by <5%. Treatment plans changed 63% of the time when the MBDA test result was perceived as being not consistent or somewhat consistent with the HCP assessment of disease activity.Study limitations:Limited sample size; lack of control group; no longitudinal follow-up.Conclusions:The addition of the MBDA test to clinical assessment led to meaningful changes in the treatment plans of 38% of RA patients being cared for by HCPs in office practice. Even though treatment was potentially improved, the overall quantity of drug use was minimally affected.

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

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.

Characterization of a multiplex, 12-biomarker test for rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disorder that primarily involves the joints. Accurate and frequent assessment of RA disease activity is critical to optimal treatment planning. A novel algorithm has been developed to determine a multi-biomarker disease activity (MBDA) score based upon measurement of the concentrations of 12 serum biomarkers in multiplex format. Biomarker assays from several different platforms were used in feasibility studies to identify biomarkers of potential significance. These assays were adapted to a multiplex platform for training and validation of the algorithm. In this study, the analytical performance of the underlying biomarker assays and the MBDA score was evaluated. Quantification of 12 biomarkers was performed with multiplexed sandwich immunoassays in three panels. Biomarker-specific capture antibodies were bound to specific locations in each well; detection antibodies were labeled with electrochemiluminescent tags. Data were acquired with a Sector Imager 6000, and analyte concentrations were determined. Parallelism, dynamic range, cross-reactivity, and precision were established for each biomarker as well as for the MBDA score. Interference by serum proteins, heterophilic antibodies, and common RA therapies was also assessed. The individual biomarker assays had 3-4 orders of magnitude dynamic ranges, with good reproducibility across time, operators, and reagent lots; the MBDA score had a median coefficient of variation of <2% across the score range. Cross-reactivity as well as interference by serum rheumatoid factor (RF), human anti-mouse antibodies (HAMA), or common RA therapies, including disease-modifying antirheumatic drugs and biologics, was minimal. The same MBDA score was observed in different subjects despite having different biomarker profiles, supporting prior literature reports that multiple pathways contribute to RA.

Performance of a multi-biomarker score measuring rheumatoid arthritis disease activity in the CAMERA tight control study

ObjectivesTo evaluate the performance of individual biomarkers and a multi-biomarker disease activity (MBDA) score in the early rheumatoid arthritis (RA) patient population from the computer assisted management in early rheumatoid...

Pre-analytical effects of blood sampling and handling in quantitative immunoassays for rheumatoid arthritis

Variability in pre-analytical blood sampling and handling can significantly impact results obtained in quantitative immunoassays. Understanding the impact of these variables is critical for accurate quantification and validation of biomarker measurements. Particularly, in the design and execution of large clinical trials, even small differences in sample processing and handling can have dramatic effects in analytical reliability, results interpretation, trial management and outcome. The effects of two common blood sampling methods (serum vs. plasma) and two widely-used serum handling methods (on the clot with ambient temperature shipping, “traditional”, vs. centrifuged with cold chain shipping, “protocol”) on protein and autoantibody concentrations were examined. Matched serum and plasma samples were collected from 32 rheumatoid arthritis (RA) patients representing a wide range of disease activity status. Additionally, a set of matched serum samples with two sample handling methods was collected. One tube was processed per manufacturer's instructions and shipped overnight on cold packs (protocol). The matched tube, without prior centrifugation, was simultaneously shipped overnight at ambient temperatures (traditional). Upon delivery, the traditional tube was centrifuged. All samples were subsequently aliquoted and frozen prior to analysis of protein and autoantibody biomarkers. Median correlation between paired serum and plasma across all autoantibody assays was 0.99 (0.98–1.00) with a median % difference of −3.3 (−7.5 to 6.0). In contrast, observed protein biomarker concentrations were significantly affected by sample types, with median correlation of 0.99 (0.33–1.00) and a median % difference of −10 (−55 to 23). When the two serum collection/handling methods were compared, the median correlation between paired samples for autoantibodies was 0.99 (0.91–1.00) with a median difference of 4%. In contrast, significant increases were observed in protein biomarker concentrations among certain biomarkers in samples processed with the ‘traditional’ method. Autoantibody quantification appears robust to both sample type (plasma vs. serum) and pre-analytical sample collection/handling methods (protocol vs. traditional). In contrast, for non-antibody protein biomarker concentrations, sample type had a significant impact; plasma samples generally exhibit decreased protein biomarker concentrations relative to serum. Similarly, sample handling significantly impacted the variability of protein biomarker concentrations. When biomarker concentrations are combined algorithmically into a single test score such as a multi-biomarker disease activity test for rheumatoid arthritis (MBDA), changes in protein biomarker concentrations may result in a bias of the score. These results illustrate the importance of characterizing pre-analytical methodology, sample type, sample processing and handling procedures for clinical testing in order to ensure test accuracy.

S.05.04 The social brain: social disability, cognitive deficits and event-related potentials in PRS

Traditional markers of inflammation are often required for inclusion in rheumatoid arthritis trials, yet patients with active disease may have normal lab tests. The potential use of the multi-biomarker disease activity (MBDA) test in this setting is unclear, as is understanding of whether it is influenced by patient characteristics (e.g., age, BMI, and comorbidities).Using data from the Corrona registry, we conducted a cross-sectional analysis of RA patients with MBDA tests. Patients were classified as low (<30), moderate (30–44, and high (>44) and by clinical and RA-related factors. Regression was used to evaluate the association between MBDA score and age, body mass index, comorbidities, and RA-related factors.Of 357 eligible patients, 76% (n = 273) had normal CRP (<10 mg/L) with high (33%), moderate (45%), and low (22%) disease activity by MBDA. The MBDA score was significantly associated with BMI, age, CDAI, and SJC. There was no association between MBDA score and fibromyalgia, diabetes, smoking, or COPD; none were confounders between MBDA score and either SJC or CDAI. For patients in CDAI remission, older age (2.6 units per decade; p = 0.03) and obesity (β = 10.5 for BMI > 30, referent to <25; p = 0.02) were independently associated with MBDA score. An adjusted MBDA score was proposed that was highly correlated with the original MBDA (r = 0.91).In this real-world analysis, the MBDA score was associated with RA disease activity, obesity, and age, and was negligibly affected by common comorbidities. Almost one-third of patients with normal CRP had high MBDA scores. An adjustment to the MBDA score to account for body mass index and age is proposed.

Quantitative characteristics of the Feyrter (APUD) cells of the neonatal rabbit lung in normoxia and chronic hypoxia.

Our studies show that the apparent number of Feyrter cells in the lung declines during the neonatal period in normoxic rabbits, and that in hypoxic animals a uniformly and significantly lower number of cells occurs as compared with the normoxic rabbits. There is some indication of degranulation of cells in the hypoxic groups. It is suggested that environmental and/or physiological factors associated with the start of extrauterine life, or lung development, may affect the apparent number and probable level of activity of these cells. These changes seem to be enhanced by hypoxia. Mast cells are scarce, and Feyrter cells are relatively more numerous along the airways. These cell types could possibly represent storage sites for 5-hydroxytryptamine, as suggested also by other investigators. Intraepithelial nerve fibres in bronchi and bronchioles were found but they were not limited to innervations of Feyrter cells or related cell bodies.