High Multi-biomarker Disease Activity Scores Research Articles

ACPA-negative RA consists of subgroups: patients with high likelihood of achieving sustained DMARD-free remission can be identified by serological markers at disease presentation

BackgroundDisease-modifying antirheumatic drug (DMARD)-free remission, the sustained absence of synovitis after DMARD cessation, is increasingly achievable, especially in autoantibody-negative rheumatoid arthritis (RA). However, underlying mechanisms are unknown and patient subgroups that achieve this outcome are insufficiently characterized. We evaluated whether serological biomarkers at disease onset, as measured within the multi-biomarker disease activity (MBDA) score, are differently expressed in RA patients who achieve sustained DMARD-free remission.MethodsTwo hundred ninety-nine RA patients were evaluated for achievement of sustained DMARD-free remission during a median follow-up of 4.3 years. Twelve biomarkers, as included in the MBDA score, were determined from the serum obtained at disease onset. Patients were categorized as having a low (< 30), moderate (30–44) or high (> 44) score. Analyses were stratified for anti-citrullinated protein antibodies (ACPA) based under the assumption that ACPA-positive and ACPA-negative RA are different disease entities.ResultsTwenty percent achieved sustained DMARD-free remission. Overall, high MBDA scores were associated with achieving DMARD-free remission (high vs. low HR 3.8, 95% CI 1.2–12.2). Among ACPA-negative RA patients, moderate or high scores associated strongly with DMARD-free remission (moderate vs. low HR 9.4, 95% CI 1.2–72.9; high vs. low HR 9.7, 95% CI 1.3–71.1). This association was independent of age and other clinical factors (high vs. low HR 8.2, 95% CI 1.1–61.8). For ACPA-negative RA patients, the biomarkers C-reactive protein, serum amyloid A and matrix metalloproteinase-3 were individually associated with sustained DMARD-free remission. Among ACPA-positive RA patients, scores were not associated with DMARD-free remission.ConclusionsACPA-negative RA patients who achieved sustained DMARD-free remission after treatment withdrawal were characterized by moderate to high MBDA scores at diagnosis. This is the first evidence that ACPA-negative RA can be subdivided in clinically relevant subsets at disease onset using a protein profile.

Predicting risk for radiographic damage in rheumatoid arthritis: comparative analysis of the multi-biomarker disease activity score and conventional measures of disease activity in multiple studies

Objective: To compare the multi-biomarker disease activity (MBDA) score with the DAS28-CRP and CRP for predicting risk of radiographic progression in patients with rheumatoid arthritis.Methods: Published studies of the MBDA score and radiographic progression with ≥100 patients per cohort were evaluated. Rates of radiographic progression over 1 year were determined across the low/moderate/high categories for MBDA score (low/moderate/high: <30, 30–44, >44), DAS28-CRP (low/moderate/high: ≤2.67, >2.67–4.09, >4.09) and CRP (low/moderate/high: ≤10, >10–30, >30 mg/L), with positive and negative predictive value (PPV, NPV) and relative risk (RR) determined for high vs. not-high (i.e. low and moderate combined) categories. Patient-level data from studies having all three measures was pooled to: (1) determine a combined RR for radiographic progression in the high vs. not-high categories for each measure; and (2) compare the predictive ability of MBDA score vs. DAS28-CRP by comparing the rates of radiographic progression observed in subgroups created by cross-classifying the high and not-high categories of each measure.Results: Five cohorts were identified for inclusion (total N=929). In each, radiographic progression was more frequent with increasing MBDA scores. Among the three cohorts with requisite data, PPVs were generally similar using categories of MBDA score, DAS28-CRP or CRP but NPVs were greater for MBDA score (93–97%) than DAS28-CRP or CRP (77–87%). RRs for radiographic progression were greater when based on categories of MBDA score than DAS28-CRP or CRP and the combined RR was greater for MBDA score (4.6, p < .0001) than DAS28-CRP (1.7, p = .02) or CRP (1.7, p = .002). For patients cross-classified by MBDA score and DAS28-CRP, high vs. not-high MBDA score significantly predicted radiographic progression independently of DAS28-CRP.Conclusions: High and not-high MBDA scores were associated with increased and low risk, respectively, for radiographic progression over one year. MBDA score was a better predictor of radiographic progression than DAS28-CRP or CRP.

Uptake and Clinical Utility of Multibiomarker Disease Activity Testing in the United States.

The clinical utility of the multibiomarker disease activity (MBDA) test for rheumatoid arthritis (RA) management in routine care in the United States has not been thoroughly studied. Using 2011-2015 Medicare data, we linked each patient with RA to their MBDA test result. Initiation of a biologic or Janus kinase (JAK) inhibitor in the 6 months following MBDA testing was described. Multivariable adjustment evaluated the likelihood of adding or switching biologic/JAK inhibitor, controlling for potential confounders. For patients with high MBDA scores who added a new RA therapy and were subsequently retested, lack of improvement in the MBDA score was evaluated as a predictor of future RA medication failure, defined by the necessity to change RA medications again. Among 60,596 RA patients with MBDA testing, the proportion adding or switching biologics/JAK inhibitor among those not already taking a biologic/JAK inhibitor was 9.0% (low MBDA), 11.8% (moderate MBDA), and 19.7% (high MBDA, p < 0.0001). Similarly, among those already taking biologics/JAK inhibitor, the proportions were 5.2%, 8.3%, and 13.5% (p < 0.0001). After multivariable adjustment, referent to those with low disease MBDA scores, the likelihood of switching was 1.51-fold greater (95% CI 1.35-1.69) for patients with moderate MBDA scores, and 2.62 (2.26-3.05) for patients with high MBDA scores. Among those with high MBDA scores who subsequently added a biologic/JAK inhibitor and were retested, lack of improvement in the MBDA score category was associated with likelihood of future RA treatment failure (OR 1.61, 95% CI 1.27-2.03). The MBDA score was associated with both biologic and JAK inhibitor medication addition/switching and subsequent treatment outcomes.

Determination of the minimally important difference (MID) in multi-biomarker disease activity (MBDA) test scores: impact of diurnal and daily biomarker variation patterns on MBDA scores

The Multi-Biomarker Disease Activity (MBDA) score is a validated rheumatoid arthritis (RA) disease activity measure based on 12 serum biomarkers. Here, we evaluate short-term biological variability of MBDA scores to determine the magnitude of change that might be considered clinically meaningful. Twenty-eight adult seropositive RA patients with clinically stable disease and no changes in RA medications for 4 weeks prior to study were enrolled. Nine serum samples were obtained over four consecutive days (non-fasting). MBDA score variation was assessed day-to-day (daily) and within 24 h (diurnal). The standard deviation (SD) of MBDA scores was calculated by a linear mixed model including random effects for patient, day, and time of day. The minimally important difference (MID) was calculated as {z}_{0.95}sqrt{2times mathrm{total} mathrm{variance} mathrm{of} mathrm{MBDAs}} . A subgroup analysis was performed for patients with active RA (moderate or high MBDA score). The SD of MBDA score change in the full cohort was 4.7 in a combined daily-diurnal variation analysis, which corresponds with an MID of 11. The SD of MBDA score change in the subset of patients with active RA (moderate/high MBDA scores) was 3.6. This corresponds with an MID of 8 units in patients with active RA for whom clinicians are most likely to need guidance with respect to therapeutic decisions. Changes in MBDA score ≥ 8 represent a change in RA disease activity that clinicians can use as a benchmark for therapeutic drug efficacy and can be incorporated into a treat-to-target strategy.

Predictive value of a multi-biomarker disease activity score for clinical remission and radiographic progression in patients with early rheumatoid arthritis: a post-hoc study of the OPERA trial

Objectives: Measurement of serum biomarkers at disease onset may improve prediction of disease course in patients with early rheumatoid arthritis (RA). We evaluated the multi-biomarker disease activity (MBDA) score and early changes in MBDA score for prediction of 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) remission and radiographic progression in the double-blinded OPERA trial.Method: Treatment-naïve RA patients (N = 180) with moderate or high DAS28 were randomized to methotrexate (MTX) + adalimumab (n = 89) or MTX + placebo (n = 91) in combination with glucocorticoid injection into swollen joints. X-rays of hands and feet were evaluated at months 0 and 12 (n = 164) by the total Sharp van der Heijde score (TSS). The smallest detectable change (1.8 TSS units) defined radiographic progression (∆TSS ≥ 2). Clinical remission (DAS28-CRP < 2.6) was assessed at baseline and 6 months. MBDA score was determined at 0 and 3 months and tested in a multivariable logistic regression model for predicting DAS28 remission at 6 months and radiographic progression at 1 year.Results: Baseline MBDA score was independently associated with radiographic progression at 1 year [odds ratio (OR) = 1.03/unit, 95% confidence interval (CI) = 1.01–1.06], and changes in MBDA score from baseline to 3 months with clinical remission at 6 months [OR = 0.98/unit, 95% CI 0.96–1.00). In anti-cyclic citrullinated peptide antibody (anti-CCP)-positive patients, 35 of 89 with high MBDA score (> 44) showed radiographic progression (PPV = 39%), compared with 0 of 15 patients (NPV = 100%) with low/moderate MBDA score (≤ 44) (p = 0.003).Conclusion: Early changes in MBDA score were associated with clinical remission based on DAS28-CRP at 6 months. In anti-CCP-positive patients, a non-high baseline MBDA score (≤ 44) had a clinical value by predicting very low risk of radiographic progression at 12 months.

Influence of obesity, age, and comorbidities on the multi-biomarker disease activity test in rheumatoid arthritis.

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 (<10mg/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.

A Multi-Biomarker Disease Activity Score and the Choice of Second-Line Therapy in Early Rheumatoid Arthritis After Methotrexate Failure.

ObjectiveTo investigate whether the Multi‐Biomarker Disease Activity (MBDA) score predicts optimal add‐on treatment in patients with early rheumatoid arthritis (RA) who were inadequate responders to MTX (MTX‐IRs).MethodsWe analyzed data from 157 MTX‐IRs (with a Disease Activity Score using the erythrocyte sedimentation rate [DAS28‐ESR] >3.2) from the Swedish Pharmacotherapy (SWEFOT) trial who were randomized to receive triple therapy (MTX plus sulfasalazine plus hydroxychloroquine) versus MTX plus infliximab. The MBDA score as a predictor of the subsequent DAS28‐based response to each second‐line treatment was analyzed at randomization with the Breslow‐Day test for 2 × 2 groups, using both validated categories (low [<30], moderate [30–44], and high [>44]) and dichotomized categories (lower [≤38] versus higher [>38]).ResultsAmong the 157 patients, 12% had a low MBDA score, 32% moderate, and 56% high. Of those with a low MBDA score, 88% responded to subsequent triple therapy, and 18% responded to MTX plus infliximab (P = 0.006); for those with a high MBDA score, the response rates were 35% and 58%, respectively (P = 0.040). When using 38 as a cutoff for the MBDA score (29% patients with lower scores versus 71% with higher scores), the differential associations with response to triple therapy versus MTX plus infliximab were 79% versus 44% and 36% versus 58%, respectively (P = 0.001). Clinical and inflammatory markers had poorer predictive capacity for response to triple therapy or MTX plus infliximab.ConclusionIn patients with RA who had an inadequate response to MTX, the MBDA score categories were differentially associated with response to subsequent therapies. Thus, patients with post‐MTX biochemical improvements (lower MBDA scores) were more likely to respond to triple therapy than to MTX plus infliximab. If confirmed, these results may help to improve treatment in RA.

Investigation of a multi-biomarker disease activity score in rheumatoid arthritis by comparison with magnetic resonance imaging, computed tomography, ultrasonography, and radiography parameters of inflammation and damage

Objectives: To investigate the multi-biomarker disease activity (MBDA) score by comparison with imaging findings in an investigator-initiated rheumatoid arthritis (RA) trial (HURRAH trial, NCT00696059).Method: Fifty-two patients with established RA initiated adalimumab treatment and had magnetic resonance imaging (MRI), ultrasonography (US), computed tomography (CT), and radiography performed at weeks 0, 26, and 52. Serum samples were analysed using MBDA score assays and associations between clinical measures, MBDA score, and imaging findings were investigated.Results: The MBDA score correlated significantly with MRI synovitis (rho = 0.65, p < 0.001), MRI bone marrow oedema (rho = 0.36, p = 0.044), and US power Doppler (PD) score at week 26 (rho = 0.35, p = 0.039) but not at week 0 or week 52. In the 15 patients who had achieved a Disease Activity Score based on C-reactive protein (DAS28-CRP) < 2.6 at week 26, MRI and/or US detected subclinical inflammation and 13 (87%) had a moderate/high MBDA score. For the cohort with available data, none of the four patients in MBDA remission (score ≤ 25) at week 26 had progression of imaging damage from baseline to week 52 whereas progression was observed in three out of nine (33%) and seven out of 21 (33%) patients with moderate (30–44) and high (> 44) MBDA scores, respectively.Conclusions: In this cohort, the MBDA score correlated poorly with MRI/US inflammation. However, the MBDA score and MRI/US were generally concordant in showing signs of inflammation in most patients in clinical remission during anti-tumour necrosis factor (anti-TNF) therapy. MBDA scores were elevated in all patients with structural damage progression.

Association of a multibiomarker disease activity score at multiple time-points with radiographic progression in rheumatoid arthritis: results from the SWEFOT trial

ObjectivesIn rheumatoid arthritis (RA), predictive biomarkers for subsequent radiographic progression (RP) could improve therapeutic choices for individual patients. We previously showed that the multibiomarker disease activity (MBDA) score in patients...

SAT0045 In Early RA, the Multi-Biomarker Disease Activity Score at Different Time-Points is Predictive of Subsequent Radiographic Progression

BackgroundThe prediction of radiographic progression in early rheumatoid arthritis (eRA) patients is important for optimal treatment. We previously demonstrated that a multi-biomarker disease activity (MBDA) score at baseline (BL) was...

FRI0042 Validation of A Multi-Biomarker Disease Activity Score in Rheumatoid Arthritis in Relation to Imaging Inflammation and Damage

BackgroundA multi-biomarker disease activity (MBDA) score has been validated as a measure of disease activity in rheumatoid arthritis (RA).ObjectivesThis study aimed to further validate the MBDA score in relation to...

Pretreatment multi-biomarker disease activity score and radiographic progression in early RA: results from the SWEFOT trial.

ObjectivesPrediction of radiographic progression (RP) in early rheumatoid arthritis (eRA) would be very useful for optimal choice among available therapies. We evaluated a multi-biomarker disease activity (MBDA) score, based on 12 serum biomarkers as a baseline predictor for 1-year RP in eRA.MethodsBaseline disease activity score based on erythrocyte sedimentation rate (DAS28-ESR), disease activity score based on C-reactive protein (DAS28-CRP), CRP, MBDA scores and DAS28-ESR at 3 months were analysed for 235 patients with eRA from the Swedish Farmacotherapy (SWEFOT) clinical trial. RP was defined as an increase in the Van der Heijde-modified Sharp score by more than five points over 1 year. Associations between baseline disease activity measures, the MBDA score, and 1-year RP were evaluated using univariate and multivariate logistic regression, adjusted for potential confounders.ResultsAmong 235 patients with eRA, 5 had low and 29 moderate MBDA scores at baseline. None of the former and only one of the latter group (3.4%) had RP during 1 year, while the proportion of patients with RP among those with high MBDA score was 20.9% (p=0.021). Among patients with low/moderate CRP, moderate DAS28-CRP or moderate DAS28-ESR at baseline, progression occurred in 14%, 15%, 14% and 15%, respectively. MBDA score was an independent predictor of RP as a continuous (OR=1.05, 95% CI 1.02 to 1.08) and dichotomised variable (high versus low/moderate, OR=3.86, 95% CI 1.04 to 14.26).ConclusionsIn patients with eRA, the MBDA score at baseline was a strong independent predictor of 1-year RP. These results suggest that when choosing initial treatment in eRA the MBDA test may be clinically useful to identify a subgroup of patients at low risk of RP.Trial registration numberWHO database at the Karolinska Institute: CT20080004; and clinicaltrials.gov: NCT00764725.

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...

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.

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.