R. Bolce

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

Objectives Prediction 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. Methods Baseline 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. Results Among 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). Conclusions In 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 number WHO database at the Karolinska Institute: CT20080004; and clinicaltrials.gov: NCT00764725.

A multibiomarker disease activity score for rheumatoid arthritis predicts radiographic joint damage in the BeSt study.

Objective. To determine whether a multibiomarker disease activity (MBDA) score predicts radiographic damage progression in the subsequent year in patients with early rheumatoid arthritis. Methods. There were 180 serum samples available in the BeSt study (trial numbers NTR262, NTR 265): 91 at baseline (84 with radiographs available) and 89 at 1-year followup (81 with radiographs available). Radiographs were assessed using the Sharp/van der Heijde Score (SvdH). Twelve serum biomarkers were measured to determine MBDA scores using a validated algorithm. Receiver-operating curves and Poisson regression analyses were performed, with Disease Activity Score (DAS) and MBDA score as independent variables, and radiographic progression as dependent variable. Results. At baseline, MBDA scores discriminated more between patients who developed radiographic progression (increase in SvdH ≥ 5 points) and patients who did not [area under the curve (AUC) 0.767, 95% CI 0.639–0.896] than did DAS (AUC 0.521, 95% CI 0.358–0.684). At 1 year, MBDA score had an AUC of 0.691 (95% CI 0.453–0.929) and DAS had an AUC of 0.649 (95% CI 0.417–0.880). Adjusted for anticitrullinated protein antibody status and DAS, higher MBDA scores were associated with an increased risk for SvdH progression [relative risk (RR) 1.039, 95% CI 1.018–1.059 for baseline MBDA score; 1.037, 95% CI 1.009–1.065 for Year 1 MBDA score]. Categorized high MBDA scores were also correlated with SvdH progression (RR for high MBDA score at baseline 3.7; low or moderate MBDA score as reference). At 1 year, high MBDA score gave a RR of 4.6 compared to low MBDA score. Conclusion. MBDA scores predict radiographic damage progression at baseline and during disease course.

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

Objectives In 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 with newly diagnosed RA identified patients at risk for RP. We evaluated the MBDA score at multiple time-points as a predictor of RP during 2 years of follow-up. Methods A subset of patients with RA (N=220) from the Swedish Farmacotherapy (SWEFOT) trial were analysed for MBDA score, disease activity score of 28 joints (DAS28), C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) at baseline (BL), month 3 and year 1, for predicting RP based on modified Sharp/van der Heijde scores at BL, year 1 and year 2. Results Patients with persistently low MBDA (<30) scores or those with a decrease from moderate (30–44) to low MBDA scores, did not develop RP during 2 years of follow-up. The highest risk for RP during 2 years of follow-up (42%) was observed among patients with persistently high (>44) MBDA scores. Among methotrexate non-responders with a high MBDA score at BL or month 3, significantly more of those who received triple therapy had RP at year 2 compared with those who received antitumour necrosis factor therapy. Conclusions Measuring the MBDA score both before and during treatment in RA was useful for the assessment of individual patient risk for RP during 2 years of follow-up. In comparison with low CRP, ESR or DAS28, a low MBDA score at any time-point was associated with numerically lower proportions of RP. Trial registration number NCT00764725.

A multi-biomarker disease activity score tracks clinical response consistently in patients with rheumatoid arthritis treated with different anti-tumor necrosis factor therapies: A retrospective observational study

Abstract Objectives. To assess the ability of a multi-biomarker disease activity (MBDA) score to track clinical response in patients with rheumatoid arthritis (RA) treated with different TNF inhibitors. Methods. The study included 147 patients who had received adalimumab, etanercept, or infliximab for a year or more, during routine clinical care at the University Hospital of Occupational and Environmental Health, Japan. MBDA scores and clinical measures of disease activity were evaluated at baseline and, after 24 weeks (N = 84) and 52 weeks of treatment. Relationships between the changes (∆) in MBDA score and changes in clinical measures or EULAR response categories were evaluated. Results. The median disease activity was 5.7 by DAS28-ESR and 64 by MBDA score at baseline, and decreased significantly with treatment. ∆MBDA scores over 1 year correlated with ∆DAS28-ESR (r = 0.48) and ∆DAS28-CRP (r = 0.46). Linear relationships between ∆MBDA scores and ∆DAS28-ESR or ∆DAS28-CRP were not significantly different between TNF inhibitors. The MBDA scores declined significantly more in good responders (median change: –29) than moderate (–21), and more in moderate than in non-responders (+ 2), by the EULAR criteria. Conclusions. MBDA scores tracked disease activity and treatment response in patients with RA treated with three TNF inhibitors. The relationships between ∆MBDA scores and ∆DAS28-ESR or ∆DAS28-CRP were consistent across the three TNF inhibitor groups.

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

To 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).

Response to: ‘MBDA: what is it good for?’ by Yazici et al

We appreciate Drs Yazici and Swearingens1 interest in our paper.2 The multi-biomarker disease activity (MBDA) blood test has been validated as a quantitative measurement of rheumatoid arthritis (RA) disease activity.3 The research question addressed in our paper …

Brief Report: Enhancement of Patient Recruitment in Rheumatoid Arthritis Clinical Trials Using a Multi‐Biomarker Disease Activity Score as an Inclusion Criterion

Rheumatoid arthritis (RA) clinical trials often exclude patients who have low C‐reactive protein (CRP) levels, which slows enrollment into the trial. The purpose of this study was to determine whether high Multi‐Biomarker Disease Activity (MBDA) scores (>44) in RA patients with low CRP levels (≤10 mg/liter) could be used as a complement to CRP levels >10 mg/liter to enhance patient recruitment without affecting clinical trial outcomes.

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

Background The 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 predictive for radiographic progression over the first year of treatment. Objectives To evaluate the MBDA score at different time-points and its change during treatment as a predictor of radiographic progression over the first two years of treatment in eRA. Methods The analyses were performed on radiographic progression of patients from the SWEFOT trial, assessed by van der Heijde modified Sharp scores (SHS) from BL to years 1 and 2 (n=220) and from year 1 to year 2 (n=133); and on the MBDA & disease activity scores (DAS28) and C-reactive protein (CRP) at BL (n=220), month 3 (n=220 & n=205) and year 1 (n=133). Radiographic progression was defined as ΔSHS>5. Mann-Whitney U and Chi-square tests were used for comparisons of disease activity measures between progressors and non-progressors, and for determining significance of proportion of radiographic progressors. Results The median values of MBDA score, CRP (mg/L) and DAS28 at BL for progressors (n=41) and non-progressors (n=179) were 70 and 58 (p=0.001), 28 and 18 (p=0.049), and 6.1 and 5.7 (p=0.136), respectively. After 3 months of MTX therapy the corresponding values were 48 and 40 (p=0.001), 9 and 9 (p=0.213), and 4.8 and 4.0 (p=0.009), respectively. At each time-point patients with low MBDA score had a lower mean ΔSHS and a smaller proportion of subsequent radiographic progressors than those with low CRP or low DAS28 (table). The highest risk for progression from BL to year 1 or 2 (25% and 42% respectively), or from year 1 to year 2 (36%), was observed among patients with high MBDA score at BL which remained high at 3 or 12 months. In contrast, patients with high MBDA score at BL and low MBDA score at months 3 or 12 had much lower risk for progression (6%, 18% and 4% respectively). All patients with persistent low MBDA score throughout 1 year did not progress radiographically over 2 years. Those who had a moderate MBDA score at BL and achieved low MBDA at months 3 or 12 did not progress either. Conclusions MBDA scores at BL and at 3 & 12 months of treatment, as well as change in MBDA category were predictive of subsequent radiographic progression during up to 2 years. At all measured time points a low MBDA score or achievement of the latter was associated with low risk for subsequent x-ray progression. Disclosure of Interest K. Hambardzumyan: None declared, R. Bolce Shareholder of: Crescendo Bioscience, Employee of: Crescendo Bioscience, S. Saevarsdottir: None declared, K. Forslind: None declared, I. Petersson Speakers bureau: UCB Pharma, Pfizer, AbbVie, P. Geborek: None declared, S. Ernestam: None declared, E. Sasso Shareholder of: Crescendo Bioscience, Employee of: Crescendo Bioscience, D. Chernoff Shareholder of: Crescendo Bioscience, Consultant for: Crescendo Bioscience, S. Cruickshank Consultant for: Crescendo Bioscience, R. Van Vollenhoven Grant/research support: Abb Vie, BMS, GSK, Pfizer, Roche, UCB, Consultant for: AbbVie, Biotest, BMS, Crescendo Bioscience, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB, Vertex DOI 10.1136/annrheumdis-2014-eular.3719

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.

FRI0100 Determining minimum clinically important change in multi biomarker disease activity score associated with clinical improvement in methotrexate naÏve patients with early rheumatoid arthritis

Background The Multi-Biomarker Disease Activity (MBDA) score is a validated tool that quantifies 12 biomarkers to assess disease activity in rheumatoid arthritis (RA) patients. Many studies have demonstrated usefulness of the score for assessing RA disease activity. Objectives To determine minimum clinically important change in MBDA score (ΔMBDA) from baseline (BL) to Month 3 (M3) associated with clinical improvement (decrease in DAS-ESR >1.2) in early RA patients after initiating methotrexate (MTX). Methods We evaluated the MBDA test in patients from one of the sites participating in the Solna Epidemiological Investigation of RA (EIRA) cohort. EIRA patients were eligible if they were ≥18 years; RA diagnosis within 12 months of symptom duration; had serum and clinical assessments at BL and M3; and clinical follow-up data in the Swedish Rheumatology Quality Register. Patients naïve to disease modifying anti-rheumatic drugs who received MTX were included. Kruskal-Wallis was used to test the null hypothesis that medians of ΔMBDA scores of 3 EULAR response groups are equal. Receiver operating characteristic (ROC) analysis was performed. The optimal threshold of ΔMBDA associated with DAS28-ESR improvement (decrease in DAS-ESR >1.2 at M3) was determined by Youden criterion maximizing sum of sensitivity and specificity. Results 176 patients were included: 72% women, mean age 51 (SD: 11.7) years, mean DAS28-ESR score 5.6 (SD: 0.99); 51% had ESR <28 mm/hr, 66% were anti-CCP2+, and 22% received prednisone. Mean BL MBDA score was 56.8 (SD: 14.7) with 8 (5%) patients in low (<30), 29 (16%) patients in moderate (30–44) and 139 (79%) patients in high MBDA disease activity categories. Median MBDA scores for patients with no EULAR response worsened by 2 points and for patients with moderate and good response improved by 12 and 16 points, respectively (p<0.0001 across groups, Fig 1A). Median MBDA scores improved by 10 points for all patients and 15 points in patients with a DAS28-ESR decrease >1.2. The best combination of sensitivity and specificity to achieve a DAS28-ESR decrease >1.2 was provided by a ≥8 point MBDA score improvement (Fig 1B). A similar result was obtained using the bootstrap method. AUROC was 0.77 (95% CI: 0.71, 0.84). 125 patients (71%) had concordance between DAS28-ESR improvement and ΔMBDA improvement at the optimal threshold (Table 1).Table 1. Performance Measures (95% CI) Based on Optimal Threshold of ΔMBDA Score from BL to M3 Associated with DAS28-ESR Improvement Improvement DAS28-ESR (decrease >1.2) Yes No Total MBDA (optimal threshold: improvement ≥8 points) Yes 75 27 102 No 24 50 74 Total 99 77 176 Sensitivity: 0.76 (0.66, 0.83); Positive predictive value: 0.74 (0.64, 0.81); Specificity: 0.65 (0.54, 0.75); Negative predictive value: 0.68 (0.56, 0.77).r Concordance rate: 71%. Conclusions The optimal threshold of ΔMBDA score associated with a clinically relevant decrease of DAS28 was 8 points. Using this threshold, the MBDA test is informative to detect clinical improvement. Thus, based on these results improvement in MBDA score ≥8 points at M3 after initiating MTX is indicative of meaningful clinical improvement. Disclosure of Interest K. Chatzidionysiou Consultant for: AbbVie, Pfizer, Eli Lilly, UCB, Roche, A. Hensvold: None declared, S. Saevarsdottir: None declared, R. Bolce Shareholder of: Myriad Genetics, Inc., Employee of: Crescendo Bioscience Inc., D. Chernoff Shareholder of: Myriad Genetics, Inc., Employee of: Crescendo Bioscience Inc., C. Hwang Shareholder of: Myriad Genetics, Inc., Employee of: Crescendo Bioscience Inc., X. Wang Shareholder of: Myriad Genetics, Inc., Employee of: Crescendo Bioscience Inc., A. Catrina Grant/research support from: Roche, Abbvie, Consultant for: BMS, GSK, Pfizer, Roche, Lilly, Abbvie