Sat0061 role of Shared Epitope in the Prognosis of Rheumatoid Arthritis in Relation to Acpa Positivity

Abstract

Background:The mechanistic association ofHLA-DRB1alleles that code a “shared epitope” (SE) with rheumatoid arthritis (RA) is not yet clear. Previous data has suggested the carriage of SE is associated with the production of cyclic citrullinated peptide antibodies (anti-CCP)1and severe RA2-4. The interrelationship among SE, anti-citrullinated protein antibody (ACPA) positivity and disease outcomes is not fully understood.Objectives:To assess the RA prognosis associated with the carriage of SE, in relation to ACPA positivity.Methods:Pts enrolled in a large RA registry, Brigham and Women’s Hospital RA Sequential Study between March 2003 to June 2018, with known SE and ACPA status were included in the analysis. HLA-DRB1 SE status was determined by allele-specific polymerase chain reaction and DNA sequencing for most of the subjects and by GWAS-based imputation for the rest. Disease activity (DA) was measured at baseline (BL) and 1-year follow-up by DAS28(CRP), CDAI and SDAI. Pts were stratified by SE+ (1 or 2 SE alleles) and SE- (0 alleles) and ACPA status. We analyzed the relationship of SE with ACPA positivity and change in DA by a linear regression model separately. A mediation analysis was used to examine the mediating effect of ACPA on association between SE and change in DA.Results:Out of 926 pts included in the analysis, 65.1% were SE+, of whom 75.6% were ACPA+. In comparison, 51.7% were ACPA+ in SE- pts. SE+ pts were similar with SE- pts in age, gender, BMI and smoking status, but had longer disease duration, were more likely to be rheumatoid factor positive, have erosive disease and higher comorbidity burden irrespective of ACPA status. The differences were more pronounced if the pts were also ACPA+. Adjusting for BL differences, pts with SE 1 and 2 alleles (vs 0) had an odd ratio of 1.97 (95% CI:1.36-2.84; p=0.0003) and 3.82 (95% CI: 2.44-5.98; p<.0001) to be ACPA +, respectively. The regression analysis suggests that SE+ (vs SE-) pts had an average increase in DAS28 (CRP) of 0.22 (p=0.033), CDAI of 2.07 (p=0.045) and SDAI of 2.43 (p=0.029) over a year (Fig 1). Using a mediation analysis, the direct effect of SE+ account for 78.8% to 81.0% of total effect in the increase in DAS28 (CRP), CDAI and SDAI, and the indirect effect mediated by ACPA account for 19.0% to 21.2% (Table 1).Table 1.Mediation Analysis for SE and ACPA Association with Change in DAParameterChange in DAS28 CRP (N=666)Change in CDAI (N=653)Change in SDAI (N=629)EstimateP-valueEstimateP-valueEstimateP-valueTotal Effect of SE on DA change0.220.0342.050.0472.400.030Direct effect of SE on DA change excluding mediation of ACPA0.170.1011.570.1401.890.098Indirect effect of SE on DA change due to ACPA mediation and interaction0.040.1830.480.1330.510.143The model is adjusted with other covariates: Age, Gender, Charlson comorbidity score; baseline biologic use, Smoking status, baseline DA, Interaction term (ACPA*SE)Figure 1.Linear Regression Model for SE Association with Change in Disease Activity *Estimates, p-values are shown as data labels on the graphs; Change in disease activity (DA) = (follow-up DA- baseline DA); The above model is adjusted for age, gender, CCI, baseline DA, baseline biologic use, SE status and smoking statusConclusion:SE is strongly related to ACPA and a greater burden of disease in RA pts. In pts receiving standard treatments including biologics, SE is predictive of a greater increase in DA, which is partially mediated by the presence of ACPA.References:[1] Dayan I, et al.,Arch of Rheumatology, 2010;25:012-018.[2] Gregerson PK, et al,Arthritis Rheum. 1987;30:1205-1213.[3] Turesson C, et al.Arthritis Res Ther. 2005;7:R1386-1393.[4] Moreno I, et al.J Rheumatol. 1996;23:6-9.Disclosure of Interests:Joe Zhuo Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Joshua Bryson Shareholder of: I own shares of Bristol-Myers Squibb Company, Employee of: I am a paid employee of Bristol-Myers Squibb Company, Qian Xia Shareholder of: I own shares of Bristol-Myers Squibb Company, Employee of: I am a paid employee of Bristol-Myers Squibb Company, Niyati Sharma Consultant of: I work as a consultant for Bristol-Myers Squibb Company, Sheng Gao Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Sonie Lama Shareholder of: I own shares of Bristol-Myers Squibb Company., Employee of: I am a paid employee of Bristol-Myers Squibb Company., 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

The Role of Shared Epitope in Rheumatoid Arthritis Prognosis in Relation to Anti-Citrullinated Protein Antibody Positivity

“…Among both SE + and SE − patients, 87% of ACPA + patients were also RF + . SE + versus SE − patients were similar in terms of age, sex, BMI, and smoking status (Table 1 ) [ 26 ]. However, SE + versus SE − patients had a significantly longer disease duration and were more likely to have erosive disease and a higher comorbidity burden (as measured by CCI) and be RF + (all p < 0.05).…”

“…Patients who were SE + versus SE − had significantly greater (mean [95% CI]) increases in DAS28 (CRP) (0.22 [0.02, 0.42]; p = 0.034), CDAI (2.07 [0.04, 4.09]; p = 0.046), and SDAI (2.43 [0.25, 4.61]; p = 0.029) scores over 1 year (Fig. 1 ) [ 26 ]. Disease activity scores at baseline were also significantly ( p < 0.0001 for all outcomes) associated with mean (95% CI) changes in DAS28 (CRP) (− 0.40 [− 0.47 − 0.34]), CDAI (− 0.42 [− 0.47, − 0.36]), and SDAI (− 0.43 [− 0.49, − 0.37]) scores at 1 year.…”

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Fig. 1 Linear regression model of the association between baseline characteristics and change in disease activity [ 26 ]. a Change in DAS28 (CRP), b change in CDAI, and c change in SDAI.

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“…Using a mediation analysis, the direct effect of SE + accounted for 76.4–80.1% of the total effect in the increases in DAS28 (CRP), CDAI, and SDAI scores, and the indirect effect of SE + mediated by ACPA accounted for 19.9–23.6% (Table 2 ) [ 26 ]; neither the direct nor the indirect effects were significant. Mediation analysis of the effect of ACPA on the change in disease activity was not performed for SE − patients.…”

“…SE ? versus SEpatients were similar in terms of age, sex, BMI, and smoking status (Table 1) [26]. However, SE ?…”