Background/Purpose: Rheumatoid arthritis (RA) is characterized by the presence of auto-antibodies to post translationally modified proteins (anti-modified protein antibodies (AMPA)): anti-citrullinated protein antibodies (ACPA), anti-carbamylated protein antibodies (anti-CarP) and anti-acetylated protein antibodies (AAPA). ACPA is unique since an association with the risk factors smoking and the human leukocyte antigen (HLA) – shared epitope (SE) is found only in the ACPA positive patients. However the association of SE and smoking with all three AMPA has remained unstudied. Nonetheless, this association is of great interest, since it would increase our understanding if the pathological mechanisms underlying the development of these auto-antibodies are unique of shared.

Objective: To investigate the association of SE and smoking with the different kinds of AMPA.

Methods: 648 RA patients fulfilling the 1987 RA criteria from the Leiden Early Arthritis Cohort, of whom data were available on the presence of ACPA, AAPA and anti-CarP, smoking and SE status were included. SE positivity was defined as having ≥1 of the following HLA alleles: DRB1*01:01, *01:02, *04:01, *04:04, *04:05, *04:08 and*10:01. Healthy controls (n=1211) for SE analysis were randomly selected from the collection of the section of Immunogenetics and Transplantation Immunology from the Leiden University Medical Center. The association between auto-antibodies and SE and smoking was assessed by logistic regression analysis.

Results: When investigating the association of smoking with the presence of the various combinations of AMPA, a significant association was only found in the triple positive patients (OR 1.67 (1.08 – 2.60), p0.02), table 1. There was no association with smoking for patients positive for one or two auto-antibodies.

SE was solely associated with ACPA positive patients, whereas the association with SE was similar among patients who were single-positive for ACPA compared to patients harboring 1 or 2 additional auto-antibodies (AAPA and/or anti-CarP), indicating that SE is only associated with ACPA.

Conclusion: This in-depth analysis of the exact association between risk factors and AMPA presence revealed striking differences regarding the associations for smoking versus SE. Since smoking is associated with the concurrent presence of multiple AMPA, this implies that smoking is involved in a general process of auto-antibody development. However SE is solely associated with the presence of ACPA, and not with anti-CarP or AAPA. This suggests that, despite the similarity in antigenic targets and partial cross reactivity between AMPA responses, the pathophysiological mechanisms underlying their development differ for the various AMPA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/lessons-learnt-from-associations-between-anti-modified-protein-antibodies-and-risk-factors-human-leukocyte-antigen-shared-epitope-alleles-solely-associate-with-anti-citrullinated-protein-antibodies/