Session Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis
Session Type: Abstract Submissions (ACR)
Background/Purpose: Recent studies indicate that the breach of immune tolerance that occurs in rheumatoid arthritis (RA) extends beyond the citrullination of arginines (as recognized by anti-citrullinated protein antibodies; ACPA) to homocitrullination of lysines. Since 2011, humoral responses to homocitrullinated proteins (subsequently referred to as anti-carbamylated protein antibodies; ACarP Ab) have been reported in both early and established seropositive RA. We analyzed the relationship of serum/plasma levels of ACarP Ab to several clinical and serologic parameters, using both established and early RA cohorts.
Methods: Carbamylation of fetal calf sera was performed as previously described . Patients with established RA (n=212) were recruited at Dartmouth-Hitchcock Medical Center (Lebanon, NH, USA). Serum and/or plasma ACarP Ab, anti-Sa Ab, CXCL13, rheumatoid factor (RF), ACPA (specifically, anti-CCP2 Ab) and total IgG were measured by ELISA. Seropositivity (positive for RF, anti-CCP or both) and C-Reactive Protein level were determined by the clinical lab. A confirmatory analysis was performed using samples from early RA patients included in the Sherbrooke, QC (Canada) cohort. T-test, ANOVA and correlation analysis were utilized to evaluate relationships between variables. 63 healthy controls were also evaluated for levels of ACarP Ab.
Results: Among seropositive patients in the Dartmouth cohort (n=164), 46.6% exhibited elevated levels of ACarP Ab. ACarP Ab titers correlated with levels of ACPA (p=0.004) and IgM-RF (p=0.04). Seropositive patients in the early RA Sherbrooke cohort (n=173) displayed similar trends; 38.2% had elevated ACarP Ab levels, and ACarP Ab titer was highly associated with levels of ACPA (p=0.005) and weakly associated with IgM-RF (p=0.06). The relationship of ACarP Ab levels with baseline clinical parameters (age, DAS28-CRP, erosions, etc.) was either weak or absent in both cohorts. Intriguingly, we observed a highly significant correlation between anti-Sa status and ACarP Ab titer among seropositive patients in the Sherbrooke cohort (p<0.0002), with 47.9% of anti-Sa-positive patients harboring elevated levels of ACarP Ab versus 25.4% of anti-Sa-negative patients. This observation led us to test seropositive RA samples in the Dartmouth cohort for anti-Sa status; once again, a highly significant relationship was observed (p<0.000001); 62.6% of anti-Sa-positive patients showed elevated ACarP Ab levels versus 26.9% of anti-Sa-negative patients.
Conclusion: This is the first investigation of ACarP Ab levels in a population of established RA patients in the US, comparing it with an early RA Canadian cohort. A large proportion of each seropositive RA cohort exhibited elevated levels of ACarP Ab (38.2-46.6%). Most compellingly, we identified a strong relationship between levels of ACarP Ab and anti-Sa reactivity that raises the mechanistic question of how antibody responses to carbamylated proteins and citrullinated vimentin (Sa) are linked in vivo.
1. Shi, J., et al., Autoantibodies Recognizing Carbamylated Proteins Are Present in Sera of Patients with Rheumatoid Arthritis and Predict Joint Damage. PNAS, 2011. 108(42): p. 17372-77.
G. J. Challener,
J. D. Jones,
B. J. Hamilton,
A. J. de Brum-Fernandes,
H. A. Ménard,
W. F. C. Rigby,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-carbamylated-protein-antibody-levels-are-elevated-in-seropositive-rheumatoid-arthritis-and-correlate-with-anti-sacitrullinated-vimentin-antibody-levels/