AB1243 TRAINING AND VALIDATION OF A MULTIVARIATE PREDICTOR OF RISK OF RADIOGRAPHIC PROGRESSION FOR PATIENTS WITH RHEUMATOID ARTHRITIS

Background:The multi-biomarker disease activity (MBDA) score, adjusted for age, sex and adiposity (MBDAadj), has been shown to be better than several conventional disease activity measures for predicting risk for radiographic progression (RP) in patients with rheumatoid arthritis (RA).1Serologic status and other non-disease activity measures are also predictive of RP risk. Combining them with the MBDAadjshould result in a stronger prognostic test for RP than any one measure alone.Objectives:Develop a multivariate model for predicting risk for RP that includes the adjusted MBDA score and other known predictors of RP.Methods:Four RA cohorts were used, two for training (OPERA and BRASS, n=555) and two for validation (SWEFOT and Leiden, n=397). Each pair of cohorts was heterogeneous in disease duration and treatment history. BMI data were not available for one validation cohort, so a BMI surrogate was modeled using forward selection with the two training cohorts and 3 others (CERTAIN, InFoRM, RACER) (N=1411). An RP risk score was then trained using forward selection in a linear mixed-effects regression, considering disease-related and demographic variables as predictors of change in modified total Sharp score over one year (ΔmTSS), with a random effect on cohort. The RP risk score was validated as a predictor of RP with two cutoffs (ΔmTSS >3 and >5) using logistic mixed-effects regression. Odds ratios (OR) and 95% profile likelihood-based confidence intervals (CI) were calculated from the models and significance was assessed by likelihood ratio tests. Risk curves were generated to show probability of RP as a function of the RP risk score.Results:The BMI surrogate included leptin, sex, age and age2and correlated well with BMI (ρ = 0.76). In training, the most significant independent predictors of RP were MBDAadj(p = 0.00020), seropositivity (p = 9.3 x 10-5), BMI surrogate score (p = 0.013) and use of targeted therapy (p = 0.0026). The final model was: RP risk score = 0.024 x MBDAadj+ 0.093 if seropositive – 0.063 x BMI surrogate score – 0.61 if using a targeted therapy. In validation, the OR (95% CI) of the RP risk score for predicting ΔTSS >3 or >5 were 2.2 (1.6, 3.2) (p = 2.6 × 10-6) and 3.1 (2.0, 5.0) (p = 5.7 × 10-8), respectively (Figure 1). The odds of a patient having RP increases by 50% for each 21-unit or 15-unit increase in MBDAadj, for RP defined as ΔTSS >3 or >5, respectively.Figure 1.Conclusion:A multivariate model containing adjusted MBDA score, seropositivity, a BMI surrogate and use of targeted therapy has been trained and validated as a prognostic test for radiographic progression in RA.References:[1]Curtis, et al.Rheumatology [Oxford].2018;58:874Disclosure of Interests:Thomas Huizinga Grant/research support from: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Consultant of: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Michael E. Weinblatt Grant/research support from: BMS, Amgen, Lilly, Crescendo and Sonofi-Regeneron, Consultant of: Horizon Therapeutics, Bristol-Myers Squibb, Amgen, Abbvie, Crescendo, Lilly, Pfizer, Roche, Gilead, Nancy Shadick Grant/research support from: Mallinckrodt, BMS, Lilly, Amgen, Crescendo Biosciences, and Sanofi-Regeneron, Consultant of: BMS, Cecilie Heegaard Brahe: None declared, Mikkel Ǿstergaard Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Merck, and Novartis, Consultant of: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Merete L. Hetland Grant/research support from: BMS, MSD, AbbVie, Roche, Novartis, Biogen and Pfizer, Consultant of: Eli Lilly, Speakers bureau: Orion Pharma, Biogen, Pfizer, CellTrion, Merck and Samsung Bioepis, Saedis Saevarsdottir Employee of: Part-time at deCODE Genetics/Amgen Inc, working on genetic research unrelated to this project, Megan Horton Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Brent Mabey Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Darl Flake Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Rotem Ben-Shachar Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Eric Sasso Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Alexander Gutin Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Elena Hitraya Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Jerry Lanchbury Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Jeffrey Curtis Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, UCB, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, UCB

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POS0454 COMPARISON OF MBDA SCORE, PATIENT GLOBAL ASSESSMENT AND EVALUATOR GLOBAL ASSESSMENT FOR PREDICTING RISK OF RADIOGRAPHIC PROGRESSION

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.1467 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 457-458

Author(s):

L. Calabrese ◽

M. E. Weinblatt ◽

N. Shadick ◽

C. Heegaard Brahe ◽

M. Østergaard ◽

...

Keyword(s):

Disease Activity ◽

Global Assessment ◽

Radiographic Progression ◽

Interaction Analysis ◽

Random Effect ◽

Patient Global Assessment ◽

Categorical Variables ◽

Continuous Variables ◽

Research Support ◽

Myriad Genetics

Background:Busy rheumatologists may assess disease activity and risk for radiographic progression (RP) in RA with informal, qualitative versions of evaluator and/or patient global assessments (EGA and PGA). RA patient care may be improved by having a convenient, objective disease activity measure that predicts risk for RP more accurately than EGA or PGA.Objectives:To compare the abilities of MBDA score, patient global assessment and evaluator global assessment to assess risk for radiographic progression (RP), and to assess the ability of MBDA score to predict RP among patients with concordant or discordant PGA and EGA.Methods:Patients were pooled from two RCTs of patients with recent onset RA treated with conventional and biologic DMARDs (OPERA and SWEFOT, N=386) and from a registry of patients with predominantly established RA and diverse treatments (BRASS, N=380). Pearson correlations were determined between MBDA scores (adjusted for the effects of age, sex and adiposity) (scale 1-100), PGA and EGA (each on a scale of 1-10) at baseline. PGA and EGA were considered discordant when they differed by >2.5. Univariable logistic regression assessed ability to predict RP (change in TSS >5 over 1 year) for MBDA score, PGA and EGA as continuous variables; and for discordance of PGA and EGA as 2-level (concordant vs. discordant) or 3-level (PGA>EGA, concordant, EGA>PGA) categorical variables. Multivariable regression considered the main effect and interaction terms of the MBDA score, as a continuous variable, paired with each other variable, to test the ability of each pair to assess risk of RP. All models included a random effect on cohort. Odds ratios were reported for every 10-unit increase in MBDA score. Frequency of RP was determined in subgroups with MBDA score low (<30), moderate (30-44) or high (>44) for patient groups based on PGA/EGA concordance or discordance.Results:The 766 patients studied were 76% female, 76% positive for RF and/or anti-CCP Ab, with mean age 55 years, DAS28-CRP 4.7, CRP 22 mg/L, CDAI 26, SJC 9.1, PGA 4.4, EGA 3.4, MBDA score 53. No interaction was seen between MBDA score and type of cohort (early vs established RA). PGA and EGA were discordant in 294 of 766 (38%) patients and were weakly to moderately correlated (r=0.38). Among discordant patients, PGA was >EGA in 227 cases and EGA was >PGA in 67 cases. Correlations between MBDA score and PGA or EGA were r=0.41 and r=0.34, respectively. In univariable analyses, MBDA score was a statistically significant predictor of radiographic progression (OR=1.53, p=6.3x10-8) whereas PGA, EGA, 2-level discordance and 3-level discordance were not (p=0.38, 0.47, 0.74, 0.83, respectively). In multivariable analyses, significant interactions were observed between MBDA score and discordance (2-level, p=0.0029; 3-level, p=0.0087). The interaction analysis demonstrated, in PGA/EGA-concordant patients, low risk of radiographic progression when MBDA score was low and elevated risk when it was high (OR=1.33 [1.1, 1.59]). A relationship between MBDA score and RP risk was also demonstrated, with heightened trend, among discordant patients with PGA >EGA (OR=2.04 [1.53, 2.81]) and EGA >PGA (OR=3.43 [1.37, 13.8]) (Figure 1).Conclusion:MBDA score was a significant predictor of radiographic progression, whereas PGA and EGA were not. MBDA score predicted progression whether PGA and EGA were concordant or discordant. These results suggest that MBDA score detects joint-damaging disease activity more accurately than PGA and EGA and it does so whether or not PGA and EGA are in agreement.Disclosure of Interests:Leonard Calabrese Grant/research support from: AbbVie, Bristol-Myers Squibb, Cresecendo, Genentech, Gilead, GlaxoSmithKline, Horizon, Janssen, Novartis, and Sanofi., Michael E. Weinblatt Shareholder of: Canfite, Inmedix, Scipher, and Vorso, Consultant of: AbbVie, Aclaris, Amgen, Bayer, Bristol-Myers Squibb, Crescendo Bioscience, Corrona, EqRX, GSK,Genosco, Gilead, Lilly, Novartis, Pfizer, Roche, Set Point, Grant/research support from: Bristol-Myers Squibb, Myriad Genetics, Inc.,Eli Lilly and Sanofi, Nancy Shadick Consultant of: BMS, Grant/research support from: Lilly, mallinckrodt, BMS, Amgen and Sanofi, Cecilie Heegaard Brahe: None declared, Mikkel Østergaard Consultant of: Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Centocor, GSK, Hospira, Janssen, Merck, Novartis, Orion, Pfizer, Regeneron, Roche, Takeda, and UCB, Grant/research support from: AbbVie, BMS, Celgene, Myriad Genetics, Inc., Janssen, and Merck, Merete L. Hetland Speakers bureau: Orion, Grant/research support from: AbbVie, Biogen, BMS, CelltrionRoche, Myriad Genetics, Inc., Eli Lily, MSD, Pfizer, and UCB, Megan Horton Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Darl Flake Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Eric Sasso Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Autoimmune

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THU0207 SUSTAINABILITY OF RESPONSE TO UPADACITINIB AS MONOTHERAPY OR IN COMBINATION AMONG PATIENTS WITH RHEUMATOID ARTHRITIS AND PRIOR INADEQUATE RESPONSE TO CONVENTIONAL SYNTHETIC DMARDS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.1233 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 327.1-328

Author(s):

A. Kavanaugh ◽

M. H. Buch ◽

B. Combe ◽

L. Bessette ◽

I. H. Song ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Inadequate Response ◽

Research Support ◽

Two Phase ◽

First Occurrence ◽

Activity Measures ◽

Disease Activity Measures

Background:The primary treatment goal for patients (pts) with rheumatoid arthritis (RA) is a state of sustained clinical remission (REM) or low disease activity (LDA).1,2Objectives:To assess the long-term sustainability of responses to upadacitinib (UPA), a JAK inhibitor, with or without background csDMARD(s) in pts with RA.Methods:Data are from two phase 3 randomized, controlled trials of UPA in RA pts with roughly similar baseline disease characteristics: SELECT-NEXT enrolled pts with an inadequate response (IR) to csDMARD(s) on background stable csDMARD(s) receiving UPA 15 mg or 30 mg once daily or placebo for 12 weeks (wks); SELECT-MONOTHERAPY enrolled methotrexate (MTX)-IR pts receiving UPA 15 mg or 30 mg monotherapy or blinded MTX for 14 wks. After 12/14 wks, pts could enter a blinded long-term extension and receive UPA 15 mg or 30 mg for up to 5 years. This post hoc analysis evaluated clinical REM (CDAI ≤2.8; SDAI ≤3.3), LDA (CDAI≤10; SDAI≤11), and DAS28(CRP) <2.6/≤3.2 at first occurrence before Wk 84; additionally, these measures were evaluated at 3, 6, and 12 months after the first occurrence for the total number of pts randomized to UPA 15 mg. Sustainability of response was evaluated by Kaplan-Meier only for those pts who achieved REM/LDA and was defined as time to the earliest date of losing response at two consecutive visits or discontinuation of study drug. The predictive ability of time to clinical REM/LDA was assessed using Harrell’s concordance (c)-index (for reference, an index ~ 0.5, indicates no ability to predict; an index of 1 or -1 would be a perfect prediction). The last follow up dates were 22 March, 2018 (SELECT-NEXT) and 25 May, 2019 (SELECT-MONOTHERAPY), when all pts had reached the Wk 84 visit.Results:Through Wk 84, the percent of treated pts achieving CDAI REM/LDA was 43%/79% for those receiving UPA 15 mg with background csDMARD(s) (SELECT-NEXT) and 37%/76% for those receiving UPA 15 mg without background csDMARD(s) (SELECT-MONOTHERAPY). 35%/25% of pts randomized to UPA 15 mg with background csDMARD(s) and 27%/23% of pts randomized to UPA 15 mg without background csDMARD(s) achieved sustained CDAI REM through 6/12 months after the first occurrence. 64%/56% of pts randomized to UPA 15 mg with background csDMARD(s) and 61%/56% of pts randomized to UPA 15 mg without background csDMARD(s) achieved sustained CDAI LDA through 6/12 months after the first occurrence (Figure 1). Time to initial clinical REM/LDA did not appear to be associated with sustained disease control. The c-indices (95%CI) for CDAI REM in the UPA 15 mg with background csDMARD(s) and UPA 15 mg without background csDMARD(s) groups were 0.541 (0.47, 0.62) and 0.568 (0.49, 0.65) and that of LDA were 0.521 (0.46, 0.58) and 0.498 (0.43, 0.56), respectively. Through last follow-up visit, 55% of pts receiving UPA 15 mg with background csDMARD(s) and 62% of pts receiving UPA 15 mg without background csDMARD(s) remained in CDAI REM while 72% and 70% of pts remained in CDAI LDA, respectively (Figure 2). Similar results were observed across other disease activity measures (SDAI REM/LDA and DAS28(CRP) <2.6/≤3.2).Conclusion:More than a quarter and more than a half of pts with RA and prior IR to csDMARD(s) receiving UPA with or without background csDMARD therapy achieved sustained clinical REM and LDA, respectively, across disease activity measures. Sustainability of responses appeared comparable among pts receiving UPA with or without background csDMARDs through up to 84 wks.References:[1]EULAR: Smolen JS, et al. Ann Rheum Dis 2017;76:960–977.[2]ACR: Singh et al. Arthritis & Rheumatology Vol. 68, No. 1, January 2016, pp 1–26.Disclosure of Interests: :Arthur Kavanaugh Grant/research support from: Abbott, Amgen, AstraZeneca, BMS, Celgene Corporation, Centocor-Janssen, Pfizer, Roche, UCB – grant/research support, Maya H Buch Grant/research support from: Pfizer, Roche, and UCB, Consultant of: Pfizer; AbbVie; Eli Lilly; Gilead Sciences, Inc.; Merck-Serono; Sandoz; and Sanofi, Bernard Combe Grant/research support from: Novartis, Pfizer, Roche-Chugai, Consultant of: AbbVie; Gilead Sciences, Inc.; Janssen; Eli Lilly and Company; Pfizer; Roche-Chugai; Sanofi, Speakers bureau: Bristol-Myers Squibb; Gilead Sciences, Inc.; Eli Lilly and Company; Merck Sharp & Dohme; Pfizer; Roche-Chugai; UCB, Louis Bessette Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, UCB Pharma, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, UCB Pharma, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Sanofi, In-Ho Song Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Yanna Song Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Jessica Suboticki Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Peter Nash Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB

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SAT0046 MODIFIED DISEASE ACTIVITY SCORE AT 3 MONTHS IS A SIGNIFICANT PREDICTOR FOR RAPID RADIOGRAPHIC PROGRESSION AT 12 MONTHS COMPARED WITH OTHER MEASURES

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.1762 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 954.1-954

Author(s):

M. Movahedi ◽

D. Weber ◽

P. Akhavan ◽

E. Keystone

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Disease Activity Score ◽

Radiographic Progression ◽

Activity Score ◽

Controlled Study ◽

Tender Joint Count ◽

Double Blind ◽

Activity Measures ◽

Disease Activity Measures

Background:Progressive rheumatoid arthritis (RA) is responsible for joint damage causing disabilities with no agreement on which disease measures best predict radiographic progressionObjectives:We aimed to determine which disease activity measures including disease activity score (DAS), modified (M) DAS28 (CRP), clinical disease activity index (CDAI), and health assessment questionnaire disability index (HAQ-DI) best predict rapid radiographic progression (RRP) in early RA patients at baseline (BL) and 3 months.Methods:PREMIER data, a 2-year, multicenter, double-blind active comparator–controlled study with methotrexate (MTX) naïve RA patients and active disease <3 years, were used. Only patients in the MTX arm were analyzed. RRP was defined as change in modified total Sharp (mTSS) > 3.5 at month 12. Logistic regression analysis assessed impact of measures at BL and 3 months on RRP at 12 months. Best cut-off points of M-DAS28(CRP) was also estimated using area under the receiver operating characteristic curve.Results:149 patients were included: female (n=113; 75.8%), positive RF (n=127; 85.2%), mean (SD) age 52.9 (13.3) years, disease duration 0.8 (0.9) year, DAS28(CRP) 6.3 (0.9). After adjusting for potential confounders, only M-DAS28(CRP) at BL (adjOR=3.29; 95% CI: 1.70-6.36) and 3 months (adjOR=2.56; 95% CI: 1.43-4.56) strongly predicted RRP at 12 months. M-DAS28(CRP) 4.5 and 2.6 at BL and 3 months maximized sensitivity and specificity for prediction of RRP.Conclusion:M-DAS28(CRP) was a stronger predictor at BL and 3 months for RRP compared with other disease activity measures. Removing tender joint count and patient global assessment from DAS28(CRP) improves prediction of RRP.References:[1] Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, et al. The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis and rheumatism. 2006;54(1):26-37.Acknowledgments :The authors wish to knowledge AbbVie Canada Inc. for providing patients data.Disclosure of Interests:Mohammad Movahedi Consultant of: Allergan, Deborah Weber: None declared, Pooneh Akhavan: None declared, Edward Keystone Grant/research support from: AbbVie; Amgen; Gilead Sciences, Inc; Lilly Pharmaceuticals; Merck; Pfizer Pharmaceuticals; PuraPharm; Sanofi, Consultant of: AbbVie; Amgen; AstraZeneca Pharma; Bristol-Myers Squibb Company; Celltrion; F. Hoffman-La Roche Ltd.; Genentech, Inc; Gilead Sciences, Inc.; Janssen, Inc; Lilly Pharmaceuticals; Merck; Myriad Autoimmune; Pfizer Pharmaceuticals, Sandoz, Sanofi-Genzyme, Samsung Bioepsis., Speakers bureau: AbbVie; Amgen; Bristol-Myers Squibb; Celltrion; F. Hoffman-La Roche Ltd, Janssen, Inc; Merck; Pfizer Pharmaceuticals; Sanofi-Genzyme; UCB

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AB1239 THE EFFECT OF INFLUENZA VACCINATION ON THE MULTI-BIOMARKER DISEASE ACTIVITY SCORE AND ITS COMPONENT BIOMARKERS IN HEALTHY SUBJECTS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.1188 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1910-1911

Author(s):

D. Furst ◽

L. Lenz ◽

M. Horton ◽

D. Flake ◽

E. Sasso ◽

...

Keyword(s):

Influenza Virus ◽

Influenza Vaccine ◽

Disease Activity ◽

Virus Vaccine ◽

Healthy Subjects ◽

Influenza Virus Vaccine ◽

National Institutes Of Health ◽

Research Support ◽

Myriad Genetics ◽

Over Time

Background:The multi-biomarker disease activity (MBDA) blood test measures 12 protein biomarkers (IL-6, CRP, SAA, EGF, VEGF, VCAM, MMP-1, MMP-3, leptin, resistin, TNF-RI and YKL40). It uses a validated algorithm to provide a score on a scale of 1-100 for assessing disease activity in patients with rheumatoid arthritis (RA). The MBDA score reflects several molecular aspects of inflammation, including cytokines, acute phase reactants, growth factors, molecular adhesion, metalloproteinases and hormones. Insights gained by understanding how vaccination affects these biomarkers in healthy subjects - in whom the level of inflammation prior to vaccination should be low and stable - may aid the understanding of how vaccination affects patients with RA.Objectives:The goal of this study was to understand how immunization of healthy subjects with the influenza vaccine affects the assessment of inflammation with the MBDA score and its 12 biomarkers.Methods:A 4-strain influenza virus vaccine (Fluarix Quadrivalent, GlaxoSmithKline) was administered intramuscularly to 22 healthy volunteer subjects on October 24, 2018. Serum samples were obtained immediately prior to vaccination (baseline) and 1, 2 and 3 weeks after vaccination. No restrictions were placed on subject activity. Samples were stored at -80oC until measurement of the 12 MBDA biomarkers for determination of the adjusted MBDA score, hereafter called the MBDA score. (Adjustment accounts for the effects of age, sex and adiposity1). MBDA scores (natural scale) and biomarker concentrations (log scale) were modeled using generalized estimating equations (GEE) that account for correlations between measurements from the same subject at multiple timepoints. Significance of MBDA score change or biomarker concentration change over time was determined by a likelihood ratio test of timepoints.Results:Of the 22 healthy subjects receiving the influenza virus vaccine, 14 (63.6%) were female, with mean (SD) age of 40.0 years (8.9). MBDA scores were low (<30), moderate (30-44) or high (>44) for 15 (68%), 6 (27%) and 1 (5%) subjects at baseline, and this distribution was stable over time (Figure 1). Overall, MBDA scores did not change significantly over time (p=0.48, Figure 2). Mean changes in MBDA score (95% CI) from baseline to weeks 1, 2 and 3 were 0.32 (-3.07, 3.71), 0.82 (-3.03, 4.67) and 2.86 (-1.10, 6.82), respectively (Figure 2); the week 3 value becomes 0.95 (-1.78, 3.68) if the week 3 outlier is removed. Among the 66 post-baseline measurements of change in MBDA score (Figure 2), 3 (5%) exceeded the 95% CI for change in MBDA score in this study (i.e., 14). When assessing the entire cohort across all timepoints, EGF was the only biomarker that demonstrated statistically significant change over time (p=5.6 x 10-7). At weeks 1, 2 and 3, the mean relative concentrations of EGF, compared with baseline, were 0.62 (0.52, 0.74), 0.86 (0.70, 1.06) and 0.62 (0.50, 0.76), respectively.Figure 1Figure 2Conclusion:Immunization of 22 healthy subjects with a quadrivalent influenza vaccine did not have a statistically significant effect on MBDA scores during a 3-week observation, and it had minimal effect on the component biomarkers.References:[1]Curtis et al.Rheumatology [Oxford]2018;58:874Disclosure of Interests:Daniel Furst Grant/research support from: AbbVie, Actelion, Amgen, BMS, Corbus Pharmaceuticals, the National Institutes of Health, Novartis, Pfizer, and Roche/Genentech, Consultant of: AbbVie, Actelion, Amgen, BMS, Cytori Therapeutics, Corbus Pharmaceuticals, the National Institutes of Health, Novartis, Pfizer, and Roche/Genentech, Speakers bureau: CMC Connect (McCann Health Company), Lauren Lenz Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Megan Horton Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Darl Flake Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Eric Sasso Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Michael E. Weinblatt Grant/research support from: BMS, Amgen, Lilly, Crescendo and Sonofi-Regeneron, Consultant of: Horizon Therapeutics, Bristol-Myers Squibb, Amgen, Abbvie, Crescendo, Lilly, Pfizer, Roche, Gilead

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FRI0057 A MODEL FOR QUANTIFYING THE EFFECT OF INFLAMMATION ON CARDIOVASCULAR DISEASE RISK PREDICTION IN RA PATIENTS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.2384 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 604.2-605

Author(s):

R. Ben-Shachar ◽

D. Flake ◽

R. Bamford ◽

B. Mabey ◽

E. Sasso ◽

...

Keyword(s):

Risk Factors ◽

Cardiovascular Disease ◽

Disease Activity ◽

Risk Score ◽

Cvd Risk ◽

Increased Risk ◽

Myriad Genetics ◽

The Difference ◽

Molecular Score ◽

Conventional Risk Factors

Background:Patients with rheumatoid arthritis (RA) are at increased risk for cardiovascular disease (CVD)[1]. Quantifying the effect of inflammation on CVD risk is important because rheumatologists can reduce inflammation with effective RA medications. A new score has been developed for predicting the risk for a CVD event (MI, stroke or CV death) in RA patients. It combines serological measures of inflammation (the multi-biomarker disease activity [MBDA] score, a measure of RA disease activity; and three individual biomarkers [TNF-RI, MMP-3 and leptin]), with age and four conventional CVD risk factors (smoking, hypertension, diabetes and history of a high- risk CVD condition)[2]. To gain insight into the potential effect that treating inflammation may have on the CVD risk score, it would be useful to know how the score is affected by the level of inflammation.Objectives:Explore the quantitative contribution of inflammation to CVD risk score in individual RA patients.Methods:To quantify the effect of inflammation on the CVD risk score across a range of MBDA scores, a commercial dataset of 177,486 RA patients with ≥2 MBDA tests between October 2010 and June 2019 was split 2:1 into training and validation datasets. Curves showing variation in the CVD risk score across the spectrum of all possible MBDA scores (1-100) were generated for canonical patient types differing in the number of conventional risk factors (0 to 4) and age (45, 55, 65, 75, 85 years). To generate these curves, the contributions of TNF-RI, MMP-3 and leptin to the CVD risk score were treated in aggregate (denoted the molecular score) and estimated using a linear regression model of the difference in molecular scores vs. the difference in MBDA scores. This model for the molecular score was fit in the training dataset, then in the full dataset, with dataset (training or validation) and the interaction between dataset and change in MBDA score included as additional predictor variables. The method was considered validated if the F-test for the interaction variable was not significant at the 0.05 level.Results:The model for estimating the molecular score from the MBDA scores was validated and shown to fit the data well (Figure 1). The estimated molecular score was applied to the CVD risk score algorithm to generate curves that show how CVD risk score varies with MBDA score for several distinct patient types. These curves demonstrate that the predicted 3-year CVD risk increases continuously and markedly with increasing level of inflammation, as represented by the MBDA score (Figure 2). Age and the number of conventional risk factors also affected the predicted CVD risk, with older patients (Figure 2a) and those with more conventional risk factors (Figure 2b) being at higher risk for a CVD event.Conclusion:The level of CVD risk predicted by a new prognostic test for RA patients depends not only on conventional risk factors, which are relatively time invariant, but also varies greatly due to inflammation, which can potentially be reduced with RA treatment.References:[1]Agca et al (2017).Ann Rheum Dis.76(1):17-28. doi: 10.1136/annrheumdis-2016-209775.[2]Curtis JR, Xie F, Crowson CS et al. (2019) ACR meeting abstract #446Disclosure of Interests:Rotem Ben-Shachar Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Darl Flake Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Richard Bamford Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Brent Mabey Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Eric Sasso Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Jeffrey Curtis Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, UCB, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, UCB

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Very early MRI responses to therapy as a predictor of later radiographic progression in early rheumatoid arthritis

Arthritis Research & Therapy ◽

10.1186/s13075-019-2000-1 ◽

2019 ◽

Vol 21 (1) ◽

Cited By ~ 5

Author(s):

Philip G. Conaghan ◽

Mikkel Østergaard ◽

Orrin Troum ◽

Michael A. Bowes ◽

Gwenael Guillard ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Early Rheumatoid Arthritis ◽

Radiographic Progression ◽

Multivariate Analyses ◽

Clinical Disease ◽

Clinical Disease Activity ◽

Activity Measures ◽

Univariate Analyses ◽

Disease Activity Measures

Abstract Background The objective of this study was to evaluate early changes in magnetic resonance imaging (MRI) and clinical disease activity measures as predictors of later structural progression in early rheumatoid arthritis (RA). Methods This was a post hoc analysis of data pooled across treatments from a three-arm (tofacitinib monotherapy, tofacitinib with methotrexate [MTX], or MTX monotherapy) trial of MTX-naïve patients with early, active RA. Synovitis, osteitis and erosions were assessed with the Outcome Measures in Rheumatology (OMERACT) RA MRI scoring system (RAMRIS) and RAMRIQ (automated quantitative RA MRI assessment system; automated RAMRIS) at months 0, 1, 3, 6 and 12. Radiographs were assessed at months 0, 6 and 12, and clinical endpoints were assessed at all timepoints. Univariate and multivariate analyses explored the predictive value of early changes in RAMRIS/RAMRIQ parameters and disease activity measures, with respect to subsequent radiographic progression. Results Data from 109 patients with a mean RA duration of 0.7 years were included. In univariate analyses, changes in RAMRIS erosions at months 1 and 3 significantly predicted radiographic progression at month 12 (both p < 0.01); changes in RAMRIQ synovitis and osteitis at months 1 and 3 were significant predictors of RAMRIS erosions and radiographic progression at month 12 (all p < 0.01). In subsequent multivariate analyses, RAMRIS erosion change at month 1 (p < 0.05) and RAMRIQ osteitis changes at months 1 and 3 (both p < 0.01) were significant independent predictors of radiographic progression at month 12. Univariate analyses demonstrated that changes in Clinical Disease Activity Index (CDAI) and Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28-4[ESR]) at months 1 and 3 were not predictive of month 12 radiographic progression. Conclusions MRI changes seen as early as 1 month after RA treatment initiation have the potential to better predict long-term radiographic progression than changes in disease activity measures. Trial registration ClinicalTrials.gov, NCT01164579.

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POS0086 ANALYSIS OF DISEASE ACTIVITY MEASURES IN THE CONTEXT OF A METHOTREXATE WITHDRAWAL STUDY AMONG PATIENTS WITH RHEUMATOID ARTHRITIS TREATED WITH TOFACITINIB 11 MG ONCE DAILY + METHOTREXATE: POST HOC ANALYSIS OF DATA FROM ORAL SHIFT

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.56 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 251.2-251

Author(s):

R. Fleischmann ◽

B. Haraoui ◽

M. H. Buch ◽

D. Gold ◽

G. Sawyerr ◽

...

Keyword(s):

Disease Activity ◽

Research Support ◽

Open Label ◽

Double Blind ◽

Once Daily ◽

Treatment Groups ◽

Post Hoc Analysis ◽

Activity Measures ◽

Post Hoc ◽

Disease Activity Measures

Background:The Phase 3b/4 study ORAL Shift demonstrated sustained efficacy and safety of tofacitinib modified-release (MR) 11 mg once daily (QD) following methotrexate (MTX) withdrawal that was non-inferior to continued tofacitinib + MTX use (per DAS28-4[ESR]), in patients (pts) with rheumatoid arthritis (RA) who achieved CDAI-defined low disease activity (LDA) with tofacitinib + MTX at Week (W)24.1Objectives:To assess the performance of alternative disease activity measures at W24 (randomisation) and W48 (study endpoint) in ORAL Shift.Methods:ORAL Shift (NCT02831855) enrolled pts aged ≥18 years with moderate to severe RA and an inadequate response to MTX. Pts received open-label tofacitinib MR 11 mg QD + MTX for 24 weeks. Achievement of CDAI LDA (≤10) at W24 was set as the criteria for entry to the 24-week double-blind MTX withdrawal phase, with pts randomised 1:1 to receive tofacitinib MR 11 mg QD + placebo (PBO) (ie blinded MTX withdrawal) or continue tofacitinib + MTX. In this post hoc analysis, efficacy analyses were performed in 8 subgroups defined by achievement of various disease activity criteria at W24: DAS28-4(ESR) remission (<2.6) or LDA (≤3.2); DAS28-4(CRP) <2.6 or ≤3.2; RAPID3 remission (≤3) or LDA (≤6); CDAI remission (≤2.8); and SDAI remission (≤3.3). For each subgroup, the proportion of pts who achieved the corresponding disease activity criterion at W48 was calculated, with a 95% confidence interval (CI) estimated using the normal approximation to the binomial distribution. The change (Δ) from W24 to W48 in least squares (LS) mean DAS28-4(ESR) and DAS28-4(CRP) was also calculated in each subgroup, with a 95% CI for the difference between treatment groups estimated using a mixed model with repeated measures. Nominal p values were calculated and are presented with no formal statistical hypothesis testing formulated.Results:Overall, 694 pts entered the open-label phase of ORAL Shift, and 530 were randomised and received treatment in the double-blind phase; 264 and 266 pts received tofacitinib + PBO and tofacitinib + MTX, respectively (Figure 1a). Considering those pts who were randomised and treated, the proportion of pts achieving each disease activity criterion at W24 varied, but was similar between treatments within each subgroup (Figure 1a). Among pts who met each disease activity criterion at W24, generally the majority of pts in both treatment groups also met the same criterion at W48 (Figure 1b). Numerically more pts receiving tofacitinib + MTX vs tofacitinib + PBO continued to meet the corresponding criterion at W48. Regardless of the disease activity criterion met at W24, differences between treatment groups in LS mean ΔDAS28-4(ESR) (Figure 1c) and ΔDAS28-4(CRP) (data not shown) from W24 to W48 favoured tofacitinib + MTX vs tofacitinib + PBO.Conclusion:This post hoc analysis of data from pts randomised and treated in ORAL Shift demonstrated that, regardless of the disease activity state criterion met at W24, generally a majority of pts receiving tofacitinib maintained achievement of the corresponding disease activity criterion at W48, with or without continued MTX. Differences between treatment groups in LS mean ΔDAS28-4(ESR) from W24 to W48, as defined by achievement of LDA or remission with a variety of disease activity measures, were less than a change of 1.2, which is considered to be the threshold for a minimal clinically important improvement.2References:[1]Cohen et al. Lancet Rheumatol 2019; 1: E23-34.[2]Ward et al. Ann Rheum Dis 2015; 74: 1691-1696.Acknowledgements:Study sponsored by Pfizer Inc. Medical writing support was provided by Gemma Turner, CMC Connect, and funded by Pfizer Inc.Disclosure of Interests:Roy Fleischmann Speakers bureau: Pfizer Inc, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celltrion, Eli Lilly, GlaxoSmithKline, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis, UCB, Grant/research support from: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celltrion, Eli Lilly, Genentech, GlaxoSmithKline, Janssen, Novartis, Pfizer Inc, Samumed, Sanofi-Aventis, UCB, VORSO, Boulos Haraoui Speakers bureau: Amgen, Pfizer Inc, UCB, Consultant of: AbbVie, Amgen, Eli Lilly, Merck, Pfizer Inc, UCB, Grant/research support from: AbbVie, Maya H Buch Speakers bureau: AbbVie, Consultant of: AbbVie, Eli Lilly, Gilead, MSD, Pfizer Inc, Roche, Sanofi, Grant/research support from: Pfizer Inc, Roche, UCB, David Gold Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Gosford Sawyerr Consultant of: Pfizer Inc, Employee of: Syneos Health Inc, Harry Shi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Annette Diehl Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Kristen Lee Shareholder of: Pfizer Inc, Employee of: Pfizer Inc.

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FRI0131 SUSTAINABILITY OF RESPONSE BETWEEN UPADACITINIB AND ADALIMUMAB AMONG PATIENTS WITH RHEUMATOID ARTHRITIS AND PRIOR INADEQUATE RESPONSE TO METHOTREXATE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.1230 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 647.1-648

Author(s):

P. Nash ◽

A. Kavanaugh ◽

M. H. Buch ◽

B. Combe ◽

L. Bessette ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Predictive Ability ◽

Study Drug ◽

Inadequate Response ◽

Research Support ◽

First Occurrence ◽

Activity Measures ◽

Disease Activity Measures

Background:The primary treatment goal for patients (pts) with rheumatoid arthritis (RA) is a state of sustained clinical remission (REM) or low disease activity (LDA).1,2Objectives:To assess the long-term sustainability of response to upadacitinib (UPA), a JAK inhibitor, and adalimumab (ADA), both with background methotrexate (MTX), among pts with RA and prior inadequate response to MTX.Methods:In the phase 3, randomized, placebo (PBO) and active-controlled SELECT-COMPARE trial, pts on stable background MTX received UPA 15 mg once daily, PBO, or ADA 40 mg every other week. Pts not achieving 20% improvements in tender/swollen joint counts (Weeks 14-22) or LDA (CDAI ≤10 at Week 26) were rescued from UPA to ADA or PBO/ADA to UPA; all non-rescued PBO pts were switched to UPA at Week 26. This post hoc analysis evaluated clinical REM (CDAI ≤2.8; SDAI ≤3.3), LDA (CDAI≤10; SDAI≤11), and DAS28(CRP) <2.6/≤3.2 at first occurrence before Week 72 or prior to treatment switch; additionally, these measures were evaluated at 3, 6, and 12 months after the first occurrence for the total number of pts randomized to UPA (n=651) or ADA (n=327). Sustainability of response was evaluated by Kaplan-Meier only for those pts who achieved REM/LDA and was defined as time to the earliest date of losing response at two consecutive visits, discontinuation of study drug, or losing response at the time of rescue. The predictive ability of time to clinical REM/LDA was assessed using Harrell’s concordance (c)-index (for reference, an index ~ 0.5, indicates no ability to predict; an index of 1 or -1 would be a perfect prediction). The date of the last follow up was 6 July, 2018, when all pts had reached the Week 72 visit.Results:Through Week 72, a significantly higher proportion of pts receiving UPA + MTX vs ADA + MTX achieved CDAI REM (41% vs 31%, p=.0035) as well as CDAI LDA (70% vs 59%, p=.0007). 26%/22% of pts randomized to UPA + MTX and 16%/14% of pts randomized to ADA + MTX achieved sustained CDAI REM at 6/12 months after the first occurrence. Additionally, 49%/46% of pts randomized to UPA + MTX and 36%/34% of pts randomized to ADA + MTX achieved sustained CDAI LDA at 6/12 months after the first occurrence (Figure 1). Time to initial clinical REM/LDA did not appear to be associated with sustained disease control. The c-indices (95% CI) for CDAI REM in the UPA +MTX and ADA + MTX groups were 0.528 (0.48, 0.58) and 0.510 (0.43, 0.59) and that of LDA were 0.601 (0.56, 0.64) and 0.555 (0.50, 0.61), respectively. Through last follow-up visit, 51% of UPA + MTX pts and 45% of ADA + MTX pts remained in CDAI REM while 65% of UPA + MTX pts and 58% of ADA + MTX pts remained in CDAI LDA, respectively (Figure 2). Similar results were observed across other disease activity measures (SDAI REM/LDA and DAS28(CRP) <2.6/≤3.2).Conclusion:A significantly greater proportion of pts with RA and prior inadequate response to MTX receiving UPA + MTX vs ADA + MTX achieved clinical REM or LDA across disease activity measures. REM and LDA were sustained through Week 72 in both treatment arms, with numerically higher proportions retaining response among UPA-treated pts.References:[1]EULAR: Smolen JS, et al. Ann Rheum Dis 2017;76:960–977.[2]ACR: Singh et al. Arthritis & Rheumatology Vol. 68, No. 1, January 2016, pp 1–26.Disclosure of Interests:Peter Nash Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Arthur Kavanaugh Grant/research support from: Abbott, Amgen, AstraZeneca, BMS, Celgene Corporation, Centocor-Janssen, Pfizer, Roche, UCB – grant/research support, Maya H Buch Grant/research support from: Pfizer, Roche, and UCB, Consultant of: Pfizer; AbbVie; Eli Lilly; Gilead Sciences, Inc.; Merck-Serono; Sandoz; and Sanofi, Bernard Combe Grant/research support from: Novartis, Pfizer, Roche-Chugai, Consultant of: AbbVie; Gilead Sciences, Inc.; Janssen; Eli Lilly and Company; Pfizer; Roche-Chugai; Sanofi, Speakers bureau: Bristol-Myers Squibb; Gilead Sciences, Inc.; Eli Lilly and Company; Merck Sharp & Dohme; Pfizer; Roche-Chugai; UCB, Louis Bessette Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, UCB Pharma, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, UCB Pharma, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Sanofi, In-Ho Song Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Yanna Song Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Jessica Suboticki Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Roy Fleischmann Grant/research support from: AbbVie, Akros, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer, IngelhCentrexion, Eli Lilly, EMD Serono, Genentech, Gilead, Janssen, Merck, Nektar, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, Samsung, Sandoz, Sanofi Genzyme, Selecta, Taiho, UCB, Consultant of: AbbVie, ACEA, Amgen, Bristol-Myers Squibb, Eli Lilly, Gilead, GlaxoSmithKline, Novartis, Pfizer, Sanofi Genzyme, UCB

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Uncoupling of Collagen II Metabolism in Newly Diagnosed, Untreated Rheumatoid Arthritis Is Linked to Inflammation and Antibodies Against Cyclic Citrullinated Peptides

The Journal of Rheumatology ◽

10.3899/jrheum.091265 ◽

2010 ◽

Vol 37 (6) ◽

pp. 1113-1120 ◽

Cited By ~ 12

Author(s):

ANNE FRIESGAARD CHRISTENSEN ◽

KIM HØRSLEV-PETERSEN ◽

STEPHAN CHRISTGAU ◽

HANNE MERETE LINDEGAARD ◽

TINE LOTTENBURGER ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Radiographic Progression ◽

Early Stage ◽

Cartilage Regeneration ◽

Newly Diagnosed ◽

Collagen Formation ◽

Radiographic Outcomes ◽

Activity Measures ◽

Collagen Ii

Objective.To investigate the relationship between markers of collagen II synthesis and degradation with disease activity measures, autoantibodies, and radiographic outcomes in a 4-year protocol on patients with early rheumatoid arthritis (RA) who are naïve to disease-modifying antirheumatic drugs.Methods.One hundred sixty patients with newly diagnosed, untreated RA entered the Cyclosporine, Methotrexate, Steroid in RA (CIMESTRA) trial. Disease activity and radiograph status were measured at baseline and 4 years. The N-terminal propeptide of collagen IIA (PIIANP) and the cross-linked C-telopeptide of collagen II (CTX-II) were quantified at baseline by ELISA. PIIANP was also assayed at 2 and 4 years. Anticyclic citrullinated peptide (anti-CCP) was recorded at baseline. An uncoupling index for cartilage collagen metabolism was calculated from PIIANP and CTX-II measurements.Results.PIIANP was low at diagnosis and 4 years on (p < 0.001), irrespective of treatment and disease activity. PIIANP was lowest in anti-CCP positive patients (p = 0.006), and there was a negative correlation between PIIANP and anti-CCP titers (ρ = −0.25, p 0.002). CTX-II was increased (p < 0.001) and correlated positively with disease activity and radiographic progression, but not with anti-CCP (p = 0.93). The uncoupling index was not superior to CTX-II in predicting radiographic changes.Conclusion.These results suggest that cartilage collagen formation and degradation are unbalanced when RA is diagnosed. The different associations of collagen II anabolism (PIIANP) and collagen II degradation (CTX-II) with anti-CCP, synovitis, and radiographic progression indicate that at this early stage of RA, cartilage collagen degradation is mainly driven by synovitis, while anti-CCP antibodies may interfere with cartilage regeneration by inhibiting collagen IIA formation. Trial registration j.nr NCT00209859.

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FRI0553 DEVELOPMENT AND VALIDATION OF A BIOMARKER-BASED CARDIOVASCULAR RISK PREDICTION SCORE IN RHEUMATOID ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.2350 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 878-879

Author(s):

J. Curtis ◽

F. Xie ◽

C. S. Crowson ◽

B. Mabey ◽

D. Flake ◽

...

Keyword(s):

High Risk ◽

Risk Prediction ◽

Risk Score ◽

Prediction Models ◽

Test Results ◽

Research Support ◽

Risk Prediction Models ◽

Myriad Genetics ◽

History Of ◽

Incremental Improvement

Background:Rheumatoid arthritis (RA) patients are at elevated risk for cardiovascular (CV) events, but risk stratification based on CV prediction models is not part of routine rheumatology practice.Objectives:To develop and validate a biomarker-based CV risk prediction model and compare it to alternative risk prediction models.Methods:We constructed a cohort of RA patients - age ≥40 with ≥1 RA diagnosis from a rheumatologist, excluding patients with malignancy, past myocardial infarction (MI) or stroke - by linking Medicare administrative data from 2006-2016 to multi-biomarker disease activity (MBDA) test results obtained as part of routine care. The cohort was split 2:1 to create training and internal validation datasets. The composite CV outcome was MI, stroke or CV death occurring within 3 years. Clinical predictors examined were: age, sex, race, traditional CV risk factors (e.g. diabetes, hypertension, hyperlipidemia, high-risk CV conditions [e.g. angina]), RA-related factors (e.g. glucocorticoid use, MTX, number of prior biologics), adjusted MBDA score1and its 12 biomarkers, log-transformed. Backward elimination was used to remove predictors with p ≥0.05. The resulting CV risk score was compared to four prediction models (age+sex; age+sex+CRP; age+sex+diabetes+hypertension+ smoking+high risk CV [±CRP]) in the validation dataset. We evaluated: 1) incremental improvement in the likelihood ratio test (LRT) statistic, 2) discrimination (AUROC), and 3) goodness-of-fit (predicted vs. observed, based on Kaplan-Meier estimates). Validation analyses were prespecified.Results:30,751 RA patients with 904 CV events were linked to MBDA test results and eligible for analysis. Patient characteristics were mean (SD) age 68.7 (9.5) years; 23.4% age <65; 82% women. Comorbidities included diabetes (39%), hypertension (78%), smoking (24%) and history of high-risk CV condition (37%). RA-related features included use of glucocorticoids (58%), MTX (60%), TNFi (33%) and other biologics (16%). Mean (SD) MBDA score was 41 (14). The final covariates included in the MBDA-based CV risk score were age, diabetes, hypertension, smoking, history of high-risk CV conditions, adjusted MBDA score, leptin, TNFRI and MMP-3. Median (IQR) of the predicted 3-year CV risk was 3.4% (2.1%, 5.6%). Based on extrapolation to 10-year risk, 9.4% of patients would be considered low, 10.2% borderline, 52.2% intermediate, and 28.2% high risk per 2019 ACC/AHA guidelines.Compared to four simpler CV prediction models, significant improvement in the LRT statistic was observed with the addition of the biomarker-based CV risk score (Figure 1). Model fit was good across deciles (Figure 2). The AUROC was 0.70. The MBDA-based model reclassified 28.5% of patients vs. the model based on age+sex+diabetes+hypertension +smoking+high risk CV+CRP.Figure 1.Incremental Improvement of MBDA-based CV Risk Score Compared to Other CV Risk Prediction ModelsFigure 2.MBDA-Based CV Risk Score Calibration for Composite CV Outcome at 3 YearsConclusion:A biomarker-based prediction score incorporating a few clinical risk factors appears to have good accuracy to predict CV risk in RA. Additional validation in independent cohorts will help verify its performance characteristics.References:[1] Curtis et al.,Rheumatology2018;58:874.Disclosure of Interests:Jeffrey Curtis Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, UCB, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, UCB, Fenglong Xie: None declared, Cynthia S. Crowson Grant/research support from: Pfizer research grant, Brent Mabey Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Darl Flake Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Richard Bamford Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Cheryl Chin Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Eric Sasso Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Elena Hitraya Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Rotem Ben-Shachar Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Alexander Gutin Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Jerry Lanchbury Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc.

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