Karen Hambardzumyan

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.

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 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 …

Obesity is a strong predictor of worse clinical outcomes and treatment responses in early rheumatoid arthritis: results from the SWEFOT trial

Objectives The aim of this paper was to analyse the impact of obesity, in addition to known predictors, on disease outcome in early rheumatoid arthritis (RA). Methods Body mass index (BMI) was available in 260 patients from the Swedish pharmacotherapy trial (SWEFOT). Differences in disease activity (DAS28), functional impairment (HAQ), pain (Visual Analogue Scale, VAS-pain) and radiographic damage were evaluated over 24 months between BMI categories (obese BMI >30, n=43; overweight BMI=25–29.9, n=74; normal BMI <25, n=143) using non-parametric testing. Predictors of European League Against Rheumatism non-remission (DAS28 ≥2.6) at 24 months of follow-up were evaluated using binary univariate and multivariate logistic regression. Results Obesity at baseline was associated with worse continuous-scale clinical outcomes over 24 months (DAS28, HAQ and VAS-pain at last visit: obese vs normal: p<0.001; obese vs overweight: p<0.05). Furthermore, obese patients compared with non-obese patients had significantly greater odds of non-remission at 24 months (adjusted OR (aOR) 5.2; 95% CI 1.8 to 15.2). Other independent predictors were female sex (aOR 2.6; 95% CI 1.1 to 5.8), current smoking (aOR 2.6; 95% CI 1.1 to 6.3) and HAQ (per-unit increase, aOR 1.9; 95% CI 1.1 to 3.4). The pattern was similar among seropositive and seronegative patients; and in the subgroups of methotrexate responders and patients randomised at 3 months to add-on of sulfasalazine+hydroxychloroquine, although not significant with add-on of infliximab. Obesity had no independent association to radiographic progression. Conclusions In this early RA trial reflecting today’s standard treatment, obesity, in addition to sex, smoking and functional impairment strongly lowered the chance of attaining good clinical outcomes, including remission, today’s treatment goal. This highlights the importance of considering lifestyle modification as one of the cornerstones of RA care. Trial registration number NCT00764725; Post-results. WHO database at the Karolinska University Hospital: CT20080004.

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

THU0091 High multi-biomarker disease activity score is associated with high risk of radiographic progression in six studies

Background The multi-biomarker disease activity (MBDA) test uses a validated algorithm with 12 serum protein biomarkers to assess disease activity in patients with RA. The MBDA score has previously been found to be a predictor of risk for radiographic progression (RP). Objectives To evaluate data from six cohorts to collectively establish the relationship between the MBDA score and risk for RP. Methods Clinical, MBDA score and radiographic data were analyzed for 6 cohorts with N>100: Leiden, SWEFOT Year 1, SWEFOT Year 2, OPERA Year 1, and AMPLE Year 1 (abatacept and adalimumab arms) (see Figure). Analyses used published results when available or patient-level data when not (i.e., for Leiden; and for OPERA CRP analyses). Frequency of RP over one year was determined by category of MBDA score (low, moderate [30–44], high on a scale of 1–100) at the start of the year for four cohorts and by category of MBDA score at the end of the year for AMPLE cohorts (as published). RP was defined using the threshold for change in total modified Sharp score (ΔmTSS) specific to each study (2 to >5 TSS units). Positive and negative predictive values (PPV and NPV) were determined for each study by comparing patients with high MBDA score (>44), DAS28-(ESR/CRP) (>5.1 or >4.09) or CRP (>3 mg/dL) vs. those in a not-high category. Relative risk (RR) for RP was determined for each study, and in a meta-analysis of the non-overlapping patient groups with MBDA scores available at the start of the year (Leiden, SWEFOT Year 1 and OPERA Year 1). Results of multivariate analyses and analyses that combined MBDA score with other risk factors for RP were summarized. Results The 6 study cohorts included patients receiving csDMARDs alone or with adalimumab, infliximab or abatacept. Overall rates of RP were 10–26%. In each study, RP was most frequent among patients with a high vs. not-high MBDA score (>44 vs. ≤44). For high MBDA scores, NPVs were 93–97% and PPVs were 18–32%, with RR values of 3.6–9.5 (P=0.002 to <0.0001) (Figure). In a meta-analysis of the Leiden, SWEFOT Year 1 and OPERA Year 1 cohorts, RR was 5.1 (P<0.0001) for MBDA categories, and 1.4 (P=0.23) and 1.6 (P=0.01) for categories of DAS28-CRP or CRP, respectively. Previously published multivariate analyses in the Leiden and SWEFOT Year 1 cohorts showed that MBDA score was an independent predictor of RP compared with other predictors. In the Leiden cohort, MBDA score was the strongest predictor and high MBDA score discriminated between high and low risk for RP among patients with high SJC (>5) or high DAS28-CRP, with PPV as high as 57%. Conclusions High MBDA scores were associated with increased risk for RP in 6 study cohorts, including patients treated with csDMARDs, TNFi and abatacept. Based on high NPVs (≥93%), the MBDA score used alone had clinical value for identifying patients with little or no risk of RP. Combining the MBDA score with clinical measures yielded PPVs approaching 60%, suggesting that biomarkers can help stratify patients by their risk for RP. Disclosure of Interest J. Curtis Grant/research support from: Crescendo Bioscience Inc., Consultant for: Crescendo Bioscience Inc., C. Brahe: None declared, M. Ostergaard Grant/research support from: AbbVie, BMS, Boehringer-Ingelheim, Eli Lilly, Janssen, Merck, Pfizer, Roche, UCB, Celgene, Sanofi, Regeneron, Novartis, T Jensen, M. Hetland Grant/research support from: AbbVie, BMS, MSD, Pfizer, Crescendo Bioscience Inc., UCB, Eli Lilly, Speakers bureau: Orion, K. Hambardzumyan: None declared, S. Saevarsdottir: None declared, X. Wang Shareholder of: Myriad Genetics, Inc., Employee of: Crescendo Bioscience Inc., E. Sasso Shareholder of: Myriad Genetics, Inc., Employee of: Crescendo Bioscience Inc., T. Huizinga Consultant for: Merck, UCB, Bristol Myers Squibb, Biotest AG, Pfizer, GSK, Novartis, Roche, Sanofi-Aventis, Abbott, Crescendo Bioscience Inc., Nycomed, Boeringher, Takeda, Zydus, Epirus, Eli Lilly

FRI0062 Obesity Is Associated with Worse Clinical Outcomes Yet Limited Radiographic Progression in Early Rheumatoid Arthritis: Table 1.

Background In RA, being overweight or obese has previously been shown to be associated with worse clinical outcomes (1, 2), yet also less radiographic damage (2, 3). Objectives To confirm if body mass index (BMI) is associated with worse clinical disease activity or inversely associated with radiographic outcomes in early RA. Methods BMI, categorized as normal (<25, n=141), overweight (25–29.9, n=74), and obese (≥30, n=43), was available in 258 patients who were enrolled in the Swedish pharmacotherapy (SWEFOT) trial. After initial methotrexate for 3 months, non-responders were randomized to triple therapy or anti-TNF therapy, while responders continued on methotrexate. Disease activity (DAS28), functional impairment (HAQ), VAS-pain, and radiographic damage (Sharp van der Heijde score, SHS) were evaluated regularly. Here, results are shown at 24 months of follow-up. Results Treatment allocation and baseline outcome measures did not differ across the BMI categories. In a dose-response manner, higher BMI at baseline was associated with worse clinical outcomes over 24 months (DAS28, HAQ, and VAS-pain) (Table). Patients with normal (58%) or overweight (50%) BMI had a proportionally greater chance of attaining 24-month clinical remission (DAS28<2.6) than obese patients (23.1%) (OR 3.2 [95% CI 1.6–6.3], p<0.001; OR 2.2 [95% CI 1.2–4.1], p=0.007, respectively). Among absolute radiographic scores, no significant differences were observed, yet radiographic progression (ΔSHS≥1, baseline-24 months) was halted more frequently (56.3%) among obese patients than normal/overweight patients combined (37.6%) (OR 1.9 [95% CI 1.0–3.6], p=0.049) (obese vs. normal (40%), OR 1.7 [95% CI 0.9–3.1], p=0.101; obese vs. overweight (32.7%), OR 1.8 [95% CI 1.1–3.2], p=0.032).Table 1. Outcome measures after 24 months of disease-modifying antirheumatic agents Outcomes [Medians (IQR)] Normal (n=141) Overweight (n=74) Obese (n=43) P valuea DAS28 2.4 (1.7, 3.4)* 2.6 (2.2, 3.8)† 3.2 (2.8, 4.8)†* p<0.001 HAQ 0.3 (0.0, 0.8)* 0.5 (0.0, 1.0)† 0.8 (0.4, 1.3)†* p<0.001 VAS-pain 18.5 (6.0, 35.0)* 25.0 (8.0, 47.0)† 39.0 (22.0, 61.0)†* p<0.001 ESR 10.0 (6.0, 18.0)* 13.5 (8.0, 23.0) 18.0 (11.0, 26.0)* p=0.008 SHS 7.0 (2.0, 16.3) 6.5 (2.0, 14.0) 5.0 (0.8, 13.0) p=0.519 aKruskal-Wallis test (individual comparisons: Mann-Whitney U test; post-hoc comparisons: Dunn-Bonferroni (DB) correction). †Overweight vs. Obese: DAS28, p=0.012 (DB, p=0.020; adjusted, p=0.060); HAQ, p=0.030 (DB, p=0.021; adjusted. p=0.062); VAS Pain, p=0.025 (DB, p=0.023, adjusted: p=0.069). *Normal vs. Obese: Mann-Whitney or DB + adjustment, p<0.001 (erythrocyte sedimentation rate (ESR): p=0.003 (DB, p=0.003, adjusted: p=0.009)). Conclusions Obesity at diagnosis was found to be a strong predictor of worse long-term clinical outcomes in early RA – including disease activity, functional impairment, and pain; thus confirming previous findings. Nonetheless – as has also been previously shown – obesity was associated with a better chance of halting radiographic progression. References Sandberg ME, et al. Ann Rheum Dis. 2014 Nov;73(11):2029–33; Vidal C, et al. J Rheumatol. 2015 Dec;42(12):2261–9; Baker JF, et al. Ann Rheum Dis. 2014 Nov;73(11):1923–8 Disclosure of Interest A. Levitsky: None declared, S. Saevarsdottir: None declared, K. Brismar: None declared, K. Hambardzumyan: None declared, C. Lourdudoss: None declared, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, Pfizer, Roche, and UCB, Consultant for: AbbVie, Biotest, BMS, Crescendo, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB, and Vertex

The use of a multi-biomarker disease activity score as an inclusion criterion in rheumatoid arthritis clinical trials may enhance patient recruitment.

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.