POS0344 RISK OF ACPA POSITIVITY BY MOTIF-BASED CLASSIFICATION OF HLA-DRB1 SHARED EPITOPE ALLELES IN RA
Authors: K. Wipfler, X. Han, S. S. H. Park, K. Wittstock, K. Michaud
Journal: Annals of the Rheumatic Diseases (2021)

Background: The shared epitope (SE) is the strongest known genetic risk factor for rheumatoid arthritis (RA) and is associated with an amino acid motif at positions 70-74 in HLA-DRB1. It is linked to anti-citrullinated protein antibody (ACPA) positivity, a specific serological marker for RA. In 2005, a new classification of HLA-DRB1 alleles was proposed, in which each allele is sorted into one of five classes (S1, S2, S3P, S3D, or X). 1 The method was subsequently validated for predicting risk of developing RA 2 and was described as “a major advance and a template for future studies.” 3 However, there have been relatively few studies utilizing this classification. Objectives: To characterize the prevalence of each SE genotype from the 2005 classification and their association with ACPA positivity in a cohort of individuals with RA. Methods: Participants in FORWARD, The National Databank for Rheumatic Diseases, with RA and donated serum (collected 2010-2019) were analyzed to obtain ACPA status and high-resolution HLA-DRB1 type. Alleles were classified based on the presence (S2, S3P) or absence (S1, S3D, X; collectively L) of the SE motif, and individuals were classified by allele pair. Logistic regression models (adjusted for age, sex, and race/ethnicity) to determine risk of ACPA positivity by class were generated using L/L as the reference. Results: Characteristics of the 855 participants at the time of sample collection are presented in Table 1. Overall, 67% of participants were SE positive and 51% were ACPA positive. Of the 1,710 total alleles, X was the most common (29%) followed by S3P (24%), S1 (18%), S2 (18%), and S3D (9%). Adjusted models showed that the risk of ACPA positivity was highest among those with the genotype S2/S3P, followed by S2/S2, S2/S3D, S2/X, S3P/S3D, S1/S2, S3P/S3P, S3P/X, and S1/S3P (Figure 1). Table 1. Characteristics of study population by SE status and allele count (mean [SD] or n [%]). Significance was assessed by Student’s t-test or Χ 2 test, as appropriate. SE negative SE positive P (SE- vs SE+) 0 alleles All 1 allele 2 alleles n=286 n=569 n=407 n=162 Age, years 57.4 (12.3) 58.1 (11.8) 58.0 (11.9) 58.5 (11.5) 0.42 RA duration, years 15.2 (12.8) 17.0 (13.9) 16.8 (14.1) 17.6 (13.4) 0.07 Female 259 (90.6) 500 (87.9) 359 (88.2) 141 (87.0) 0.24 White 260 (90.9) 525 (92.3) 372 (91.4) 153 (94.4) 0.49 History of smoking 117 (40.9) 223 (39.2) 166 (40.8) 57 (35.2) 0.63 RDCI, 0-9 2.4 (1.8) 2.0 (1.7) 2.1 (1.7) 1.9 (1.7) &lt;0.01 ACPA positive 74 (25.9) 365 (64.1) 241 (59.2) 124 (76.5) &lt;0.001 RF positive 84 (29.4) 333 (58.5) 219 (53.8) 114 (70.4) &lt;0.001 Pain VAS, 0-10 4.2 (2.7) 3.6 (2.7) 3.7 (2.6) 3.5 (2.9) &lt;0.01 Patient global severity, 0-10 4.0 (2.5) 3.3 (2.5) 3.4 (2.4) 3.1 (2.6) &lt;0.001 HAQ-II, 0-3 1.0 (0.7) 0.8 (0.6) 0.8 (0.6) 0.8 (0.6) &lt;0.001 csDMARD use 204 (71.3) 433 (76.1) 302 (74.2) 131 (80.9) 0.13 bDMARD use 165 (57.7) 351 (61.7) 244 (59.95) 107 (66.0) 0.26 Corticosteroid use 98 (34.3) 165 (29.0) 121 (29.7) 44 (27.2) 0.12 Figure 1. Risk of ACPA positivity by the motif-based classification and prevalence of SE by binary status, allele count, and class. The area within each circle is proportionate to the sample size of that group. Conclusion: The ranking by risk of ACPA positivity among this RA cohort is similar to the order of risk for developing RA, as determined in the 2006 validation paper for this classification method. A notable trend among the classes with one SE positive allele is the consistent ranking of S3D as higher risk, X in the middle, and S1 as the lowest, suggesting a potential protective effect from S1 alleles. Future work should examine clinical associations with these allele classes, including disease progression and treatment effects. References: [1]du Montcel, ST et al. New classification of HLA-DRB1 alleles supports the shared epitope hypothesis of rheumatoid arthritis susceptibility. Arthritis Rheum 52 , 1063–1068 (2005). [2]Michou, L et al. Validation of the reshaped shared epitope HLA-DRB1 classification in rheumatoid arthritis. Arthritis Res Ther 8 , R79 (2006). [3]Winchester, R. Reshaping Cinderella’s slipper: the shared epitope hypothesis. Arthritis Res Ther 8 , 109 (2006). Acknowledgements: This study was sponsored by Bristol Myers Squibb. Disclosure of Interests: Kristin Wipfler: None declared, Xue Han Employee of: Bristol Myers Squibb, Sarah (Sang Hee) Park Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Keith Wittstock Employee of: Bristol Myers Squibb, Kaleb Michaud: None declared