Adjustment of the multi-biomarker disease activity score to account for age, sex and adiposity in patients with rheumatoid arthritis.

OBJECTIVE: To develop and evaluate an adjusted score for the multi-biomarker disease activity (MBDA) test to account for the effects of age, sex and adiposity in patients with RA. METHODS: Two models were developed to adjust MBDA score for age, sex and adiposity, using either serum leptin concentration or BMI as proxies for adiposity. Two cohorts were studied. A cohort of 325 781 RA patients who had undergone commercial MBDA testing and had data for age, sex and serum leptin concentration was used for both models. A cohort of 1411 patients from five studies/registries with BMI data was used only for the BMI-adjusted MBDA score. Univariate and multivariate linear regression analyses evaluated the adjusted MBDA scores and conventional clinical measures as predictors of radiographic progression, assessed in terms of modified total Sharp score (ΔmTSS). RESULTS: Two models were developed, based on findings that MBDA score was higher in females than males and increased with age, leptin concentration and BMI. In pairwise regression analyses, the leptin-adjusted (P = 0.00066) and BMI-adjusted (P = 0.0027) MBDA scores were significant independent predictors of ΔmTSS after adjusting for DAS28-CRP, whereas DAS28-CRP was not, after adjusting for leptin-adjusted (P = 0.74) or BMI-adjusted (P = 0.87) MBDA score. Moreover, the leptin-adjusted MBDA score was a significant predictor of ΔmTSS after adjusting for the BMI-adjusted MBDA score (P = 0.025) or the original MBDA score (0.027), whereas the opposite was not true. CONCLUSION: Leptin-adjusted MBDA score significantly adds information to DAS28-CRP and the original MBDA score in predicting radiographic progression. It may offer improved clinical utility for personalized management of RA.

A multi-biomarker score measuring disease activity in rheumatoid arthritis patients tapering adalimumab or etanercept: predictive value for clinical and radiographic outcomes.

Objective: The aim was to evaluate the predictive value of the baseline multi-biomarker disease activity (MBDA) score in long-standing RA patients with low disease activity tapering TNF inhibitors (TNFi) for successful tapering or discontinuation, occurrence of flare and major flare, and radiographic progression. Methods: Dose REduction Strategies of Subcutaneous TNF inhibitors (Dutch Trial Register, NTR 3216) is an 18-month non-inferiority randomized controlled trial comparing tapering of TNFi until discontinuation or flaring with usual care (UC) in long-standing RA patients with stable low disease activity. Flare was defined as DAS28-CRP increase >1.2 or >0.6 if current DAS ⩾3.2; major flare was a flare lasting >3 months, despite treatment intervention. MBDA scores were measured at baseline. Radiographs were scored at baseline and 18 months using the Sharp-van der Heijde score. The area under the receiver operating characteristic (AUROC) curve was used to analyse the capability of baseline MBDA score to predict the above-mentioned outcomes. Results: Serum samples and outcomes were available for 171 of 180 patients from Dose REduction Strategies of Subcutaneous TNF inhibitors (115 tapering; 56 UC). AUROC analyses showed that baseline MBDA score was not predictive for the above-mentioned clinical outcomes in the taper group, but did predict major flare in the UC group (AUROC = 0.72, 95% CI: 0.56, 0.88). Radiographic progression was minimal and was not predicted by MDBA score. Conclusion: In this disease activity-guided strategy study of TNFi tapering in RA patients with low disease activity, baseline MBDA score was not predictive for successful tapering, discontinuation, flare, major flare or radiographic progression in patients who tapered TNFi.

Relationship of multi-biomarker disease activity score and other risk factors with radiographic progression in an observational study of patients with rheumatoid arthritis.

OBJECTIVES: To evaluate the multi-biomarker disease activity (MBDA) score as a predictor of radiographic progression and compare it with other risk factors among patients with established RA receiving non-biologic DMARDs. METHODS: For 163 patients with RA, we assessed 271 visits for MBDA score (scale of 1-100), clinical data and subsequent 1-year radiographic progression (change in Sharp-van der Heijde score [SHS]). Scatter plot and non-parametric quantile regression curves evaluated the relationship between the MBDA score and change in SHS. Changes in joint space narrowing and erosions were compared among MBDA categories with Wilcoxon rank-sum tests. The ability of the MBDA score to independently predict progression was determined by multivariate models and cross-classification of MBDA score with other risk factors. Generalized estimating equation methodology was used in model estimations to adjust for same-patient visits, always ≥1 year apart. RESULTS: Patient characteristics included 67% female, 66%/67% RF(+)/anti-CCP(+); mean age 55 years, MBDA score 43 (moderate = 30-44); median disease duration 4.6 years, SHS 23. Radiographic progression was infrequent for low MBDA scores. Relative risk for progression increased continuously as the MBDA score increased, reaching 17.4 for change in SHS >5 with MBDA scores ≥60. Joint space narrowing and erosion progression were associated with MBDA score. MBDA score was associated with radiographic progression after adjustments for other risk factors. MBDA score significantly differentiated risk for progression when swollen joint count, CRP or DAS28-CRP was low, and among seropositive patients. CONCLUSION: MBDA score enhanced the ability of conventional risk factors to predict radiographic progression in patients with established RA receiving non-biologic DMARDs.

Multibiomarker disease activity score and C-reactive protein in a cross-sectional observational study of patients with rheumatoid arthritis with and without concomitant fibromyalgia.

OBJECTIVES: To examine the association between a multibiomarker disease activity (MBDA) score, CRP and clinical disease activity measures among RA patients with and without concomitant FM. METHODS: In an observational cohort of patients with established RA, we performed a cross-sectional analysis comparing MBDA scores with CRP by rank correlation and cross-classification. MBDA scores, CRP and clinical measures of disease activity were compared between patients with RA alone and RA with concomitant FM (RA and FM) by univariate and multivariate analyses. RESULTS: CRP was ⩽1.0 mg/dl for 184 of 198 patients (93%). MBDA scores correlated with CRP (r = 0.755, P < 0.001), but were often discordant, being moderate or high for 19%, 55% and 87% of patients with CRP ⩽0.1, 0.1 to ⩽0.3, or 0.3 to ⩽1.0 mg/dl, respectively. Among patients with CRP ⩽1.0 mg/dl, swollen joint count (SJC) increased linearly across levels of MBDA score, both with (P = 0.021) and without (P = 0.004) adjustment for CRP, whereas CRP was not associated with SJC. The 28-joint-DAS-CRP, other composite measures, and their non-joint-count component measures were significantly greater for patients with RA and FM (n = 25) versus RA alone (n = 173) (all P ⩽ 0.005). MBDA scores and CRP were similar between groups. CONCLUSION: MBDA scores frequently indicated RA disease activity when CRP did not. Neither one was significantly greater among patients with RA and FM versus RA alone. Thus, MBDA score may be a useful objective measure for identifying RA patients with active inflammation when CRP is low (⩽1.0 mg/dl), including RA patients with concomitant FM.

Interpreting the multi-biomarker disease activity score in the context of tocilizumab treatment for patients with rheumatoid arthritis.

The multi-biomarker disease activity (MBDA) score measures 12 proteins involved in the pathophysiology of rheumatoid arthritis (RA) to assess disease activity (DA). Previous studies demonstrated correlations between MBDA and clinical DA scores with some RA therapies. In this analysis, the relationship between DA and MBDA scores and changes in MBDA component biomarkers were evaluated in tocilizumab (TCZ)-treated patients. Patients from the ACT-RAY study were included in this analysis if they had DA measures and serum collected at pre-specified time points with sufficient serum for MBDA testing at ≥1 visit. Descriptive statistics, associations between outcomes, and percentage agreement between DA categories were calculated. Seventy-eight patients were included and were similar to the ACT-RAY population. Correlations between MBDA score and DAS28-CRP were ρ = 0.50 at baseline and ρ = 0.26 at week 24. Agreement between low/moderate/high categories of MBDA score and DAS28-CRP was observed for 77.1 % of patients at baseline and 23.7 % at week 24. Mean changes from baseline to weeks 4, 12, and 24 were proportionately smaller for MBDA score than DAS28-CRP. Unlike some other MBDA biomarkers, interleukin-6 (IL-6) concentrations increased in most patients during TCZ treatment. Correlations and agreement between MBDA and DAS28-CRP or CDAI scores were lower at week 24 versus baseline. The proportionately smaller magnitude of response observed for MBDA score versus DAS28-CRP may be due to the influence of the increase in IL-6 concentrations on MBDA score. Thus, MBDA scores obtained during TCZ treatment should be interpreted cautiously and in the context of available clinical information.

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.

External validation of a multi-biomarker-based score for predicting risk of cardiovascular disease in patients with rheumatoid arthritis.

BACKGROUND: A multi-biomarker disease activity (MBDA)-based cardiovascular disease (CVD) risk score was developed and internally validated in a Medicare cohort to predict 3-year risk for myocardial infarction (MI), stroke or CVD death in patients with rheumatoid arthritis (RA). It combines the MBDA score, leptin, MMP-3, TNF-R1, age and four clinical variables. We are now externally validating it in a younger RA cohort. METHODS: Claims data from a private aggregator were linked to MBDA test data to create a cohort of RA patients ≥18 years old. A univariable Cox proportional hazards regression model was fit using the MBDA-based CVD risk score as sole predictor of time-to-a-CVD event (hospitalized MI or stroke). Hazard ratio (HR) estimate was determined for all patients and for clinically relevant subgroups. A multivariable Cox model evaluated whether the MBDA-based CVD risk score adds predictive information to clinical data. RESULTS: 49,028 RA patients (340 CVD events) were studied. Mean age was 52.3 years; 18.3% were male. HR for predicting 3-year risk of a CVD event by the MBDA-based CVD risk score in the full cohort was 3.99 (95% CI: 3.51-4.49, p = 5.0×10-95). HR were also significant for subgroups based on age, comorbidities, disease activity, and drug use. In a multivariable model, the MBDA-based CVD risk score added significant information to hypertension, diabetes, tobacco use, history of CVD, age, sex and CRP (HR = 2.27, p = 1.7×10-7). CONCLUSION: The MBDA-based CVD risk score has been externally validated in an RA cohort that is younger than and independent of the Medicare cohort that was used for development and internal validation.

Long-term efficacy and safety of adalimumab in patients with moderate to severe psoriasis treated continuously over 3 years: results from an open-label extension study for patients from REVEAL.

BACKGROUND: REVEAL was a 52-week phase III trial of adalimumab therapy for moderate to severe chronic plaque psoriasis. Patients from REVEAL could enter an open-label extension trial to receive adalimumab for approximately 3 years of total therapy. OBJECTIVE: We sought to determine long-term efficacy and safety of continuous adalimumab therapy for patients from REVEAL. METHODS: Efficacy and safety over greater than 3 years of treatment were analyzed for 4 groups of patients from REVEAL. Patients who received adalimumab continuously from baseline were grouped by their responses in REVEAL: (1) greater than or equal to 75% improvement in Psoriasis Area and Severity Index (PASI) score (PASI 75) at weeks 16 and 33 (sustained responders); (2) less than PASI 75 at week 16; and (3) greater than or equal to PASI 75 at week 16 with 50% to less than 75% improvement in PASI score at week 33. Results were also analyzed for patients who began adalimumab after 16 weeks of placebo therapy. RESULTS: For patients with sustained PASI 75 responses during REVEAL, efficacy was generally well maintained over 3 years, with 75%/90%/100% improvement in PASI score response rates (last observation carried forward) of 83%/59%/33% after 100 weeks and 76%/50%/31% after 160 weeks of continuous therapy. Some patients with less than PASI 75 responses in REVEAL also achieved long-term PASI 75 responses. Efficacy in the placebo/adalimumab group was consistent with the ensemble of results from the other 3 groups. Adverse event rates were consistent with those during REVEAL. LIMITATIONS: The REVEAL study design prevented analyzing all patients from the adalimumab arm as one long-term cohort. CONCLUSION: Adalimumab efficacy was well maintained over more than 3 years of continuous therapy for patients with sustained initial PASI 75 responses. Maintenance was best at the PASI 100 level.

Evaluation of the impact of age and adiposity on a multi-biomarker disease activity score before and after adjustment.

PURPOSE: We assessed the impact of adjustment of the multi-biomarker disease activity score (MBDA) for age, sex, and leptin, over the range of age and adiposity, and assessed relationships with clinical disease activity. METHODS: Patients with RA, ages 18-75 years, were recruited from clinical practices and completed whole-body DXA to quantify fat mass indices (FMI, kg/m2). FMI Z-scores were calculated based on distributions in a reference population. Descriptive statistics described relationships between age, FMI Z-score, and the original MBDA and adjusted MBDA (aMBDA). Swollen joint counts (SJC) and the clinical disease activity index (CDAI) were assessed over MBDA categories. RESULTS: There were 104 participants (50% female) with mean (SD) age of 56.1 (12.5) and body mass index (BMI) of 28.8 (6.9). Older age was associated with higher MBDA scores in men. The aMBDA was not associated with age. The original MBDA score was associated with FMI Z-score among women (Rho = 0.42, p = 0.002) but not men. The aMBDA was not associated with FMI Z-score in either women or men. The aMBDA score was lower than the original MBDA in the highest quartile of FMI in women and was higher in the lowest FMI quartiles in women and men. CDAI, SJC, and radiographic scores were similar across activity categories for the original MBDA score and aMBDA. CONCLUSIONS: The aMBDA demonstrated reduced associations with adiposity, particularly among women. The aMBDA may be less likely to overestimate disease activity in women with greater adiposity and to underestimate disease activity in men and women with lesser adiposity. Key Points • Leptin adjustment of the MBDA score reduces the influence of adiposity, particularly among women. • Leptin adjustment results in significantly higher estimated disease activity in thin men and women. • The adjusted and unadjusted score correlate similarly with clinical disease activity measures.

Validation of the adjusted multi-biomarker disease activity score as a prognostic test for radiographic progression in rheumatoid arthritis: a combined analysis of multiple studies.

BACKGROUND: The multi-biomarker disease activity (MBDA) test measures 12 serum protein biomarkers to quantify disease activity in RA patients. A newer version of the MBDA score, adjusted for age, sex, and adiposity, has been validated in two cohorts (OPERA and BRASS) for predicting risk for radiographic progression. We now extend these findings with additional cohorts to further validate the adjusted MBDA score as a predictor of radiographic progression risk and compare its performance with that of other risk factors. METHODS: Four cohorts were analyzed: the BRASS and Leiden registries and the OPERA and SWEFOT studies (total N = 953). Treatments included conventional DMARDs and anti-TNFs. Associations of radiographic progression (ΔTSS) per year with the adjusted MBDA score, seropositivity, and clinical measures were evaluated using linear and logistic regression. The adjusted MBDA score was (1) validated in Leiden and SWEFOT, (2) compared with other measures in all four cohorts, and (3) used to generate curves for predicting risk of radiographic progression. RESULTS: Univariable and bivariable analyses validated the adjusted MBDA score and found it to be the strongest, independent predicator of radiographic progression (ΔTSS > 5) compared with seropositivity (rheumatoid factor and/or anti-CCP), baseline TSS, DAS28-CRP, CRP SJC, or CDAI. Neither DAS28-CRP, CDAI, SJC, nor CRP added significant information to the adjusted MBDA score as a predictor, and the frequency of radiographic progression agreed with the adjusted MBDA score when it was discordant with these measures. The rate of progression (ΔTSS > 5) increased from < 2% in the low (1-29) adjusted MBDA category to 16% in the high (45-100) category. A modeled risk curve indicated that risk increased continuously, exceeding 40% for the highest adjusted MBDA scores. CONCLUSION: The adjusted MBDA score was validated as an RA disease activity measure that is prognostic for radiographic progression. The adjusted MBDA score was a stronger predictor of radiographic progression than conventional risk factors, including seropositivity, and its prognostic ability was not significantly improved by the addition of DAS28-CRP, CRP, SJC, or CDAI.

Derivation and internal validation of a multi-biomarker-based cardiovascular disease risk prediction score for rheumatoid arthritis patients.

BACKGROUND: Rheumatoid arthritis (RA) patients have increased risk for cardiovascular disease (CVD). Accurate CVD risk prediction could improve care for RA patients. Our goal is to develop and validate a biomarker-based model for predicting CVD risk in RA patients. METHODS: Medicare claims data were linked to multi-biomarker disease activity (MBDA) test results to create an RA patient cohort with age ≥ 40 years that was split 2:1 for training and internal validation. Clinical and RA-related variables, MBDA score, and its 12 biomarkers were evaluated as predictors of a composite CVD outcome: myocardial infarction (MI), stroke, or fatal CVD within 3 years. Model building used Cox proportional hazard regression with backward elimination. The final MBDA-based CVD risk score was internally validated and compared to four clinical CVD risk prediction models. RESULTS: 30,751 RA patients (904 CVD events) were analyzed. Covariates in the final MBDA-based CVD risk score were age, diabetes, hypertension, tobacco use, history of CVD (excluding MI/stroke), MBDA score, leptin, MMP-3 and TNF-R1. In internal validation, the MBDA-based CVD risk score was a strong predictor of 3-year risk for a CVD event, with hazard ratio (95% CI) of 2.89 (2.46-3.41). The predicted 3-year CVD risk was low for 9.4% of patients, borderline for 10.2%, intermediate for 52.2%, and high for 28.2%. Model fit was good, with mean predicted versus observed 3-year CVD risks of 4.5% versus 4.4%. The MBDA-based CVD risk score significantly improved risk discrimination by the likelihood ratio test, compared to four clinical models. The risk score also improved prediction, reclassifying 42% of patients versus the simplest clinical model (age + sex), with a net reclassification index (NRI) (95% CI) of 0.19 (0.10-0.27); and 28% of patients versus the most comprehensive clinical model (age + sex + diabetes + hypertension + tobacco use + history of CVD + CRP), with an NRI of 0.07 (0.001-0.13). C-index was 0.715 versus 0.661 to 0.696 for the four clinical models. CONCLUSION: A prognostic score has been developed to predict 3-year CVD risk for RA patients by using clinical data, three serum biomarkers and the MBDA score. In internal validation, it had good accuracy and outperformed clinical models with and without CRP. The MBDA-based CVD risk prediction score may improve RA patient care by offering a risk stratification tool that incorporates the effect of RA inflammation.

Comparisons of affinities, avidities, and complement activation of adalimumab, infliximab, and etanercept in binding to soluble and membrane tumor necrosis factor.

The TNF antagonists adalimumab, infliximab, and etanercept are effective treatments for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and psoriasis, but only adalimumab and infliximab have been found to be efficacious in Crohn's disease. The present studies evaluated the TNF-binding and complement-activating properties of adalimumab, infliximab, and etanercept to determine whether these properties may explain differences in their clinical efficacy profiles. Association and dissociation rates of binding to soluble TNF were measured by surface plasmon resonance, and were found to be similar for adalimumab, infliximab, and etanercept, as were their calculated binding affinities. Avidity of binding to soluble TNF, measured by KinExA technology, was 10- to 20-fold greater for soluble etanercept (K(D)=0.4 picomolars [pM]) than for soluble adalimumab or infliximab (K(D)=8.6 and 4.2 pM, respectively). (125)I-adalimumab, -infliximab, and -etanercept bound to membrane TNF (mTNF) on mTNF-transfected cells with similar affinities (K(D)=483, 468, and 445 pM, respectively) that were each lower than for soluble TNF. Complement-dependent cytotoxicity (CDC) was induced in mTNF-transfected cells by adalimumab and infliximab, but was not induced in activated normal human PBMC by any of the 3 agents. In conclusion, the binding properties of adalimumab, infliximab, and etanercept were similar for soluble TNF, and very similar for mTNF, yet none of the 3 was able to induce CDC in activated PBMC. These results suggest that the different clinical efficacy profiles of these agents are not explained by differences in either TNF-intrinsic binding properties or complement lysis.

Tumor necrosis factor antagonist mechanisms of action: a comprehensive review.

During the past 30 years, elucidation of the pathogenesis of rheumatoid arthritis, Crohn's disease, psoriasis, psoriatic arthritis and ankylosing spondylitis at the cellular and molecular levels has revealed that these diseases share common mechanisms and are more closely related than was previously recognized. Research on the complex biology of tumor necrosis factor (TNF) has uncovered many mechanisms and pathways by which TNF may be involved in the pathogenesis of these diseases. There are 3 TNF antagonists currently available: adalimumab, a fully human monoclonal antibody; etanercept, a soluble receptor construct; and infliximab, a chimeric monoclonal antibody. Two other TNF antagonists, certolizumab and golimumab, are in clinical development. The remarkable efficacy of TNF antagonists in these diseases places TNF in the center of our understanding of the pathogenesis of many immune-mediated inflammatory diseases. The purpose of this review is to discuss the biology of TNF and related family members in the context of the potential mechanisms of action of TNF antagonists in a variety of immune-mediated inflammatory diseases. Possible mechanistic differences between TNF antagonists are addressed with regard to their efficacy and safety profiles.

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.

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.

BACKGROUND: Disease-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. METHODS: Two 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. RESULTS: Twenty 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. CONCLUSIONS: ACPA-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.

The multi-biomarker disease activity score tracks response to rituximab treatment in rheumatoid arthritis patients: a post hoc analysis of three cohort studies.

BACKGROUND: A multi-biomarker disease activity (MBDA) score has been validated as an objective measure of disease activity in rheumatoid arthritis (RA) and shown to track response to treatment with several disease-modifying anti-rheumatic drugs (DMARDs). The objective of this study was to evaluate the ability of the MBDA score to track response to treatment with rituximab. METHODS: Data were used from 57 RA patients from three cohorts treated with rituximab 1000 mg and methylprednisolone 100 mg at days 1 and 15. The MBDA score was assessed in serum samples obtained at baseline and 6 months. Spearman's rank correlation coefficients were calculated for baseline values, 6-month values, and change from baseline to 6 months (∆), between MBDA score and the following measures: disease activity score assessing 28 joints (DAS28) using erythrocyte sedimentation rate (ESR) or high-sensitivity C-reactive protein (hsCRP), ESR, (hs)CRP, swollen and tender joint counts assessing 28 joints (SJC28, TJC28), patient visual analogue scale for general health (VAS-GH), health assessment questionnaire (HAQ), and radiographic progression over 12 months using Sharp/van der Heijde score (SHS), as well as six bone turnover markers. Additionally, multivariable linear regression analyses were performed using these measures as dependent variable and the MBDA score as independent variable, with adjustment for relevant confounders. The association between ∆MBDA score and European League Against Rheumatism (EULAR) response at 6 months was assessed with adjustment for relevant confounders. RESULTS: At baseline, the median MBDA score and DAS28-ESR were 54.0 (IQR 44.3-70.0) and 6.3 (IQR 5.4-7.1), respectively. MBDA scores correlated significantly with DAS28-ESR, DAS28-hsCRP, ESR and (hs)CRP at baseline and 6 months. ∆MBDA score correlated significantly with changes in these measures. ∆MBDA score was associated with EULAR good or moderate response (adjusted OR = 0.89, 95% CI = 0.81-0.98, p = 0.02). Neither baseline MBDA score nor ΔMBDA score correlated statistically significantly with ∆SHS (n = 11) or change in bone turnover markers (n = 23), although ∆SHS ≥ 5 was observed in 5 (56%) of nine patients with high MBDA scores. CONCLUSIONS: We have shown, for the first time, that the MBDA score tracked disease activity in RA patients treated with rituximab and that change in MBDA score reflected the degree of treatment response.

Multi-biomarker disease activity score as a predictor of disease relapse in patients with rheumatoid arthritis stopping TNF inhibitor treatment.

OBJECTIVE: Successfully stopping or reducing treatment for patients with rheumatoid arthritis (RA) in low disease activity (LDA) may improve cost-effectiveness of care. We evaluated the multi-biomarker disease activity (MBDA) score as a predictor of disease relapse after discontinuation of TNF inhibitor (TNFi) treatment. METHODS: 439 RA patients who were randomized to stop TNFi treatment in the POET study were analyzed post-hoc. Three indicators of disease relapse were assessed over 12 months: 1) restarting TNFi treatment, 2) escalation of any DMARD therapy and 3) physician-reported flare. MBDA score was assessed at baseline. Associations between MBDA score and disease relapse were examined using univariate analysis and multivariate logistic regression. RESULTS: At baseline, 50.1%, 35.3% and 14.6% of patients had low (<30), moderate (30-44) or high (>44) MBDA scores. Within 12 months, 49.9% of patients had restarted TNFi medication, 59.0% had escalation of any DMARD and 57.2% had ≥1 physician-reported flare. MBDA score was associated with each indicator of relapse. At least one indicator of relapse was observed in 59.5%, 68.4% and 81.3% of patients with low, moderate or high MBDA scores, respectively (P = 0.004). Adjusted for baseline DAS28-ESR, disease duration, BMI and erosions, high MBDA scores were associated with increased risk for restarting TNFi treatment (OR = 1.85, 95% CI 1.00-3.40), DMARD escalation (OR = 1.99, 95% CI 1.01-3.94) and physician-reported flare (OR = 2.00, 95% 1.06-3.77). CONCLUSION: For RA patients with stable LDA who stopped TNFi, a high baseline MBDA score was independently predictive of disease relapse within 12 months. The MBDA score may be useful for identifying patients at risk of relapse after TNFi discontinuation.

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.

Brief report: enhancement of patient recruitment in rheumatoid arthritis clinical trials using a multi-biomarker disease activity score as an inclusion criterion.

OBJECTIVE: 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. METHODS: We evaluated patients from the Swedish Pharmacotherapy (SWEFOT) trial, which did not include any selection criteria for CRP levels. Clinical outcomes were assessed after 3 months of methotrexate (MTX) monotherapy in MTX-naive RA patients (n = 220) and after 3-10 months of add-on therapy in patients who were incomplete responders to MTX alone (MTX-IR) (n = 127). Radiographic outcomes were assessed at 1 year in all patients. Within each cohort, the outcomes were compared between patients with a CRP level of ≤10 mg/liter and an MBDA score of >44 at the start of the respective treatment interval versus those with a CRP level of >10 mg/liter. RESULTS: Patients with both a CRP level of ≤10 mg/liter and an MBDA score of >44 at baseline had clinical and radiographic outcomes that were comparable to those in patients with a CRP level of >10 mg/liter at baseline. This broadened definition of the inclusion criteria identified an additional 24% of patients in the MTX-naive cohort and 47% in the MTX-IR cohort. CONCLUSION: Patient recruitment into RA clinical trials may be substantially enhanced, without any decrease in clinical and radiographic outcomes, by using as an inclusion criterion "a CRP level of >10 mg/liter and/or an MBDA score of >44."