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BackgroundPolygenic risk scores (PRS) are widely used to estimate disease risks and predict clinical outcomes. However, differences exist among PRS derived from genome-wide association study (GWAS) of ethnicities across the globe.ObjectivesWe aimed to build up PRS for predicting the development of rheumatoid arthritis (RA) in a Taiwanese population and investigate whether PRS of RA may be associated with bone erosion.MethodsWe constructed PRS using GWAS data from a hospital-based cohort of 2044 RA cases and 7950 non-RA controls participating in the Taiwan Precision Medicine Initiative. LDpred2, PLINK and PRsice2 models were used to evaluate the area under curve (AUC) of RA susceptibility in both training and testing datasets (1022 RA cases and 3975 controls). Demographic data, seropositivity of rheumatoid factor (RF), anti-citrullinated protein antibody (ACPA), treatment with biological and targeted synthetic disease modifying anti-rheumatic drugs (bDMARDs and tsDMARDs) and bone erosions by either plain x ray or ultrasonography were compared among quantiles of PRS.ResultsPRS of 97,396 single nucleotide polymorphisms derived from LDpred2 exhibited the highest AUC for predicting the development of RA in the overall dataset as compared with the remaining algorithms. Participants with the top RA-PRS quantile have the highest proportion of RF and ACPA positivity (74.8% & 65.0%, respectively), bone erosion (86.4%) and higher chance to receive bDMARDs or tsDMARDs (42.3%) as compared to the counterparts. In addition, RA-PRS quantile was a significant risk for bone erosion in the multivariate regression model with the adjustment of RF, ACPA positivity and therapeutic medication, specifically in the group of age < 60 years.ConclusionPRS is associated with seropositivity, erosive bone disease, need for advanced therapy in Taiwanese patients with RA.Reference[1]Honda S, Ikari K, Yano K, Terao C, Tanaka E, Harigai M, Kochi Y. Association of Polygenic Risk Scores With Radiographic Progression in Patients With Rheumatoid Arthritis. Arthritis Rheumatol. 2022 May;74(5):791-800.Table 1.Basic demographics of 2042 participants with RA by RA-PRS quantiles1st quantile(n=511)2nd quantile(n=510)3rd quantile(n=510)4th quantile(n=511)pvalueN%N%N%N%RA diagnosis age < 60 years36270.8438976.2738675.6940078.280.04Female gender40479.0641481.1840278.8239176.520.34BMI23.74.1024.34.4123.94.1423.64.060.04Smoking407.83407.84428.24428.220.99RF positivity24957.3727460.6230365.1634574.84<0.0001ACPA positivity15338.8320148.3225660.5228264.98<0.0001ESR (mm/hr)31.3826.1832.5629.2433.6127.8235.9329.050.07CRP (mg/L)0.771.800.891.900.792.210.972.210.39DAS284.291.444.271.444.121.354.421.470.10Periodontitis367.05326.27377.25305.870.79Boen erosion15877.0719378.7822785.3425586.440.01Glucocorticoid40278.6742182.5543284.7144687.280.002Methotrexate28054.7932062.7535369.2239076.32<0.0001Hydroxychloroquine41280.6343284.7144487.0645288.450.003Sulfasalazine15129.5519538.2418836.8622343.64<0.0001Target therapies13526.4216231.7619438.0421642.27<0.0001TNFi8817.221022013025.4915329.94<0.0001Non-TNFi5610.968115.889218.0410520.550.0003JAKi316.07418.04489.41418.020.26By ANOVA test.RA: rheumatoid arthritis; PRS: polygenic risk score; BMI: body mass index; RF: rheumatoid factor; ACPA: anti-citrullinated protein antibody; ESR: erythrocyte sedimentation rate; CRP: C reactive protein; DAS28: disease activity score by 28 joints; TNFi: tumor necrosis factor inhibitor; JAKi: Janus kinase inhibitorFigure 1.Risk of (A) bone erosion (B) RF positivity (C) ACPA positivity (D) targeted therapy in second, third and top quantiles as compared to the first quantile in participants aged < 60 years. RF: rheumatoid factor; ACPA: anti-citrullinated protein antibody. *p< 0.05Acknowledgements:NIL.Disclosure of InterestsNone Declared.

BackgroundSeveral studies have demonstrated immunogenicity after COVID-19 vaccination in patients with autoimmune rheumatic diseases (AIRD) [1], but the differences between mRNA-based and vector vaccines and the cellular responses to COVID-19 vaccines according to distinct immunogenicity in AIRD patients are still unclear.ObjectivesTo investigate the differences in efficacy and safety between the vector vaccine ChAdOx1 nCoV-19/AZD1222 (Oxford-AstraZeneca) and mRNA-based vaccine mRNA-1273 (Moderna) in patients with AIRD, and to explore the cell-cell interactions between high and low anti-SARS-CoV-2 IgG levels in patients with rheumatic arthritis (RA) by single-cell RNA sequencing (scRNA-seq).MethodsFrom September 16 to November 15, 2021, we consecutively enrolled 243 participants aged ≥20 years with AIRD who received COVID-19 vaccination, of whom 113 were immunized with AZD1222 and 130 with mRNA-1273. The level of serum IgG antibodies to the SARS-CoV-2 receptor-binding domain on the spike protein S1 subunit was quantified by electrochemiluminescence immunoassay at 4-6 weeks after vaccination. Moreover, peripheral blood mononuclear cells were isolated from two RA patient with high anti-SARS-CoV-2 IgG level and four RA patients with low level for scRNA-seq and cell-cell communication signal was analyzed by CellChat.ResultsThe anti-SARS-CoV-2 IgG seropositivity rate was 78.8% (89/113) for AZD1222 and 83.1% (108/130) for mRNA-1273. The level of anti-SARS-CoV-2 IgG was higher in patients who received mRNA-1273 than in those who received AZD1222 (β: 30.15, 95% CI: 11.67-48.63, p=0.002) (Table 1). Prednisolone-equivalent dose >5 mg/day and methotrexate (MTX) use in AIRD patients, and non-anti-tumor necrosis factor (TNF)-α biologics and Janus kinase (JAK) inhibitor use in RA patients were associated with inferior immunogenicity. ScRNA-seq revealed CD16-monocytes were predominant in RA patients with high anti-SARS-CoV2-IgG antibody level, and enriched pathways related to antigen presentation via major histocompatibility complex class II (MHC class II) were found (Figure 1). HLA-DRA and CD4 interaction was vigorous among all identified MHC-II pathway and was enhanced in high anti-SARS-CoV2-IgG antibody group.Table 1.Multivariate analysis of anti-SARS-CoV-2 IgG level in patients with rheumatic diseases following COVID-19 vaccinesMultivariate analysisβ95% CIp valueMedicationsGlucocorticoidsNot usedReference≤5 mg/day−22.48(−56.33,11.37)0.192>5 mg/day−23.45(−43.54,-3.36)0.022Methotrexate−24.89(−45.70,-4.08)0.019Targeted therapiesTargeted therapies group Not usedReference TNF inhibitor−15.78(−41.33,9.76)0.224 Non-TNF bDMARD−25.27(−55.47,4.93)0.100 JAK inhibitor−17.08(−47.23,13.07)0.265VaccineChAdOx1 nCoV-19/AZD1222ReferencemRNA-127330.15(11.67,48.63)0.002TNF: tumor necrosis factor, bDMARDs: biologic disease-modifying antirheumatic drugs, JAK: Janus kinase.Figure 1.The comprehensive cell atlas of PBMC of RA patients with high and low anti-SARS-CoV2-IgG antibodies. A) UMAP visualization of PBMC cells from RA patients. B) The proportion of cell types between high and low antibody groups. C) Volcano plot of CD16-monocyte showed differential expressed genes. D) Pathway analysis between high and low antibody groups; PRBC: peripheral blood mononuclear cell, RA: rheumatoid arthritis, NK cell: natural killer cell, pDC: plasmacytoid dendritic cell, CLP: common lymphoid progenitor.ConclusionmRNA-1273 and AZD1222 vaccines exhibited differential immunogenicity in patients with AIRD. Enriched pathways related to antigen presentation via MHC class II in CD16-monocytes might be associated with higher anti-SARS-CoV2-IgG level in RA patients and further study is warranted.References[1]Geisen UM, Berner DK, Tran F, et al. Immunogenicity and safety of anti-SARS-CoV-2 mRNA vaccines in patients with chronic inflammatory conditions and immunosuppressive therapy in a monocentric cohort. Ann Rheum Dis. 2021;80:1306-1311.AcknowledgementsThe authors thank the Biostatistics Task Force of Taichung Veterans General Hospital for their assistance with the statistical analysis in this study.Disclosure of InterestsNone declared