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

Interstitial lung disease (ILD) is a progressive fibrotic disease associated with rheumatoid arthritis (RA); real-world data for evaluating RA–associated ILD (RA–ILD) are limited. We evaluated prevalence, time to onset, clinical characteristics and prognostic factors in patients diagnosed with RA (n = 8963) in the Discus Analytics JointMan database (2009–2019) with and without ILD. ILD prevalence was 4.1% (95% confidence interval 3.7–4.5); > 90% had an ILD diagnosis after RA diagnosis (mean time to onset 3.3 years). At baseline, a higher proportion of patients with RA–ILD were older (> 65 years), male, with history of chronic obstructive pulmonary disease (COPD) compared with patients in the RA cohort. Patients in the RA–ILD cohort were likely to have more severe RA characteristics and joint evaluation compared with patients without ILD, at baseline and before/after ILD diagnosis. In this large, real-world database patients with (vs without) ILD had a higher burden of RA characteristics. Previously established risk factors for RA–ILD were confirmed (age, baseline COPD, anti-cyclic citrullinated peptide positivity, C-reactive protein, Clinical Disease Activity Index score); thus, recognition of these factors and tracking routine disease activity metrics may help identify patients at higher risk of RA complications and lead to improved diagnosis and earlier treatment.

Background:Interstitial lung disease (ILD) is a known extraarticular manifestation of rheumatoid arthritis (RA). Previous studies have shown variability in the prevalence of RA-ILD, as well as clinical characteristics and risk factors of RA-ILD.Objectives:To evaluate the prevalence and time to onset of ILD and compare the clinical characteristics between RA patients (pts) with or without ILD using a large US electronic medical record (EMR)-based dataset.Methods:Pts with an initial RA diagnosis (ICD-9-CM code: 714.0; ICD-10-CM codes: M05 & M06) during the study period (01JAN2009-20SEP2019) were included from the Discus Analytics JointMan database. The initial RA diagnosis date was defined as the index date. Pts with ILD were identified by ICD diagnosis codes or by provider indication in the JointMan record. Pts who developed ILD before RA were excluded from this analysis. The prevalence and time to onset of ILD were reported. Pt demographics, comorbidities, RA characteristics and disease activity scores were compared for 6 months prior to or on the index date (baseline period) for selected adult RA pts with available information.Results:Among 8,963 identified RA pts, 337 (3.8%) were diagnosed with ILD on or after RA diagnosis. The median time to ILD onset post-RA was 2.3 years, and 47% had ILD within 2 years after RA diagnosis. RA-ILD pts were significantly older than those without ILD (65.8 years vs. 59.1 years; p<0.001; Table 1). At baseline, a higher percentage of RA-ILD pts had history of chronic obstructive pulmonary disease, positive rheumatoid factor, rheumatoid nodules, erosive joint disease, positive anti-cyclic citrullinated peptide antibody, and joint swelling compared to RA-only pts (Table 2). The mean ESR and RA disease activity scores were also significantly higher for RA-ILD pts.Table 1.Patient DemographicsPatient demographicsRA-ONLY COhort(N = 5,612)RA-ild coHORT(N = 205)P-valueAge, Mean ± SD, years59.1 ± 14.265.8 ± 11.8<.001Male, N (%)1,375 (24.5%)72 (35.1%)0.001Race, N (%) White4,014 (71.5%)165 (80.5%)0.005 African American365 (6.5%)9 (4.4%)0.226 Other/Missing1,233 (22.0%)31 (15.1%)0.020Table 2.Baseline Clinical CharacteristicsClinical CharacteristicsRA-ONLY COhort(N = 3,846)RA-ild coHORT(N = 115)P-valueHistory of Chronic Obstructive Pulmonary Disease, N (%)102 (2.7%)8 (7.0%)0.006Hypertension, N (%)900 (23.4%)23 (20.0%)0.395Serious Infection, N (%)38 (1.0%)3 (2.6%)0.091Rheumatoid Factor Positive, N (%)1,388 (36.1%)69 (60.0%)<.001Joint Stiffness, N (%)1,092 (28.4%)39 (33.9%)0.197Rheumatoid Nodules, N (%)153 (4.0%)17 (14.8%)<.001Erosive Joint Disease, N (%)459 (11.9%)23 (20.0%)0.009Anti-CCP Antibody Positive, N (%)858 (22.3%)45 (39.1%)<.001Joint Swelling*, N (%)2,861 (58.0%)123 (68.0%)0.008Joint Tenderness*, N (%)3,728 (75.6%)138 (76.2%)0.851ESR**, Mean ± SD, mm/hr22.0 ± 22.630.1 ± 25.5<.001CRP**, Mean ± SD, mg/L22.5 ± 13.060.6 ± 25.00.086CDAI, Mean ± SD16.4 ± 12.318.9 ± 15.70.044DAS28-CRP, Mean ± SD2.6 ± 1.23.1 ± 1.4<.001DAS28-ESR, Mean ± SD3.3 ± 1.43.9 ± 1.5<.001SDAI, Mean ± SD20.2 ± 29.328.6 ± 40.20.048* A total of 4,929 non-ILD and 181 ILD patients had joint swelling and tenderness data.** Variables were calculated among patients who had available information.Conclusion:This large real-world RA population provides insight into the burden of ILD in RA pts. Pts with ILD had a higher proportion of comorbidities and RA-related conditions and higher RA activity. Further analysis is warranted to assess the risk factors of ILD and its prognosis.Disclosure of Interests:Joe Zhuo Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Qisu Zhang Consultant of: I am a paid employee of STATinMED Research which is a paid consultant to Bristol-Myers Squibb Company., Keith Knapp Consultant of: In the last year, I was a paid consultant to Bristol Myers-Squibb Company., Employee of: I am a paid employee of Discus Analytics., Yuexi Wang Consultant of: I am a paid employee of STATinMED Research which is a paid consultant to Bristol-Myers Squibb Company., Cynthia Gutierrez Consultant of: I am a paid employee of STATinMED Research which is a paid consultant to Bristol-Myers Squibb Company., Ding He Consultant of: I am a paid employee of STATinMED Research which is a paid consultant to Bristol-Myers Squibb Company., Lin Xie Consultant of: I am a paid employee of STATinMED Research which is a paid consultant to Bristol-Myers Squibb Company., Sonie Lama Shareholder of: I own shares of Bristol-Myers Squibb Company., Employee of: I am a paid employee of Bristol-Myers Squibb Company., Gary Craig Consultant of: I have served as a consultant to Bristol-Myers Squibb Company., Employee of: I am a paid employee of Arthritis Northwest and VP of Discus Analytics., Speakers bureau: I am a member of the speakers bureau for Bristol-Myers Squibb Company.

Introduction: Shared epitope (SE) is present in high proportions of anti-citrullinated protein antibody (ACPA) ? patients with rheumatoid arthritis (RA) and is associated with poor prognosis. We assessed the role of SE in RA prognosis, in relation to ACPA positivity. Methods: Patients enrolled in the Brigham and Women's RA Sequential Study were included. Changes from baseline in disease activity (Disease Activity Score in 28 joints using C-reactive protein [DAS28 (CRP)], Clinical Disease Activity Index [CDAI], Simplified Disease Activity Index [SDAI]) to 1 year were assessed. Baseline characteristics were compared by SE and ACPA status (±; chi-squared, Kruskal-Wallis). Association between number of SE alleles and ACPA status (logistic regression models), relationships between baseline characteristics and changes in disease activity (adjusted linear regression model), and effect of ACPA on the association between SE and changes in disease activity (mediation analysis) were studied. Results: Nine hundred twenty-six patients were included. SE ? versus SEpatients had significantly longer disease duration and higher disease activity scores and were more likely to have erosive disease, have higher comorbidity burden, and be RF ? (all p \ 0.05). Among patients with one or two SE alleles (vs. 0), odds of being ACPA ? were 1.97 (p = 0.0003) and 3.82 (p \ 0.0001), respectively. SE ? versus SEpatients had worse disease activity scores as indicated by mean increases in DAS28 (CRP) of 0.22, CDAI of 2.07, and SDAI of 2.43 over 1 year (all p \ 0.05). Direct effect of SE ? accounted for 76.4-80.1% of total effect in disease activity increases. Conclusions: SE is strongly associated with ACPA positivity and higher disease activity in patients with RA. SE was associated with greater increases in disease activity over 1 year, which was partially mediated by the presence of ACPA.

Background:Rheumatoid arthritis (RA) has been shown a strong genetic association with particularHLA–DRB1alleles containing shared epitope (SE). However, whether SE is clinically useful in treatment choices is insufficiently investigated1and previous studies have presented mixed findings in the role of SE in the response of TNFi therapies2,3.Objectives:To assess the role of SE in response to TNFi treatment in real-world RA patients (pts).Methods:Pts enrolled in a large RA registry, Brigham and Women’s Hospital RA Sequential Study, with known SE and received TNFi therapies were included for the analysis. TNFi pts were identified by the first-time use of the drugs between March 2003 to June 2018. For this analysis, all pts were followed up to 1 year. Summary statistics are reported for demographics, serostatus and disease activity (DA) at baseline and follow-up, stratified by SE status. Given the strong association of SE and anti-citrullinated protein antibody (ACPA), the analysis was further stratified by ACPA status. The effect of SE on change in DA was assessed using linear regression model with age, gender, RA disease duration, baseline DA, smoking status, SE, ACPA and ACPA-SE interaction as covariates.Results:Of the 484 TNFi pts included in the study, 68.8% were SE+. SE+ pts (vs SE-) were more likely to be rheumatoid factor positive, have erosive disease and a higher disease duration, irrespective of ACPA status. No difference in the change of DA was observed by SE. In SE- pts, ACPA+ pts had a greater reduction of DA than ACPA- pts (Table 1). After accounting for baseline differences, there was no significant effect of SE status on the mean change from baseline in any of the 3 DA measures.(Figure 1) The change in DA was not associated with ACPA but was significantly affected by disease duration and baseline DA.Table 1.Disease Activity in TNFi Patients, Stratified by SE and ACPA StatusParameterSE+ (1 & 2 alleles, n=333)SE- (n=151)ACPA+ACPA–OverallACPA+ACPA-Overall(n=264)(n=69)(n=333)(n=90)(n=61)(n=151)Baseline, Mean (SD)DAS28 CRP3.94 (1.69)3.57 (1.61)3.86 (1.67)3.85 (1.49)3.45 (1.65)3.69 (1.57)CDAI23.06 (18.13)18.95 (15.96)22.25 (17.78)21.91 (15.96)17.72 (17.06)20.26 (16.48)SDAI24.08 (18.82)19.96 (16.59)23.27 (18.45)22.58 (16.34)18.55 (17.87)20.99 (17.01)Follow-up, Mean (SD)DAS28 CRP3.42 (1.55)2.69 (1.32)3.27 (1.53)3.19 (1.43)3.11 (1.53)3.16 (1.47)CDAI17.61 (15.53)12.11 (12.65)16.51 (15.14)15.15 (13.35)14.94 (14.73)15.07 (13.84)SDAI18.35 (15.73)12.45 (12.78)17.15 (15.34)15.31 (13.81)15.71 (15.45)15.46 (14.38)Change, Mean (SD)DAS28 CRP-0.48 (1.31)-0.65 (1.53)-0.52 (1.36)-0.52 (1.50)-0.24 (0.93)-0.42 (1.34)CDAI-4.29 (13.16)-4.79 (13.13)-4.39 (13.12)-6.45 (13.56)-2.63 (9.58)-4.99 (12.28)SDAI-4.74 (14.13)-5.07 (13.90)-4.80 (14.05)-6.87 (14.21)-2.97 (10.32)-5.41 (12.98)Figure 1.Linear Regression Model for Change in Disease Activity*Estimates, p-values are shown as data labels on the graphs; The above model is adjusted for age, gender, RA duration, smoking status, SE status, baseline DA, ACPA and ACPA*SE statusConclusion:This real-world study validates the finding from previous studies conducted in clinical settings that SE does not differentiate treatment response for TNFi therapies.References:[1]Saruhan-Direskeneli G, et al.Rheumatology (Oxford) 2007;46(12):1842-44[2]Skapenko A, et al.Clin Exp Rheumatol2019;37(5):783-790[3]Rigby W, et al.Annals of the Rheumatic Diseases2019;78(2):263-264Disclosure 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, Chidananda Samal Consultant of: I work as a consultant for Bristol-Myers Squibb Company, 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