Background/Purpose: Rheumatoid arthritis (RA) develops as a result of the dysregulation of immune activating and inhibitory pathways. Several lines of evidence indicate that inhibitory receptors on circulating leukocytes are potential predictors of disease activity, seropositivity and/or inflammation markers. Although myeloid cells play an important role in the pathogenesis of RA, less is known about the correlation between the expression of their inhibitory receptors and clinical outcomes in RA compared to inhibitory receptors on lymphocytes. CLEC12A is a myeloid inhibitory receptor that negatively regulates neutrophil activation in vitro and whose polymorphisms have been associated with RA. Moreover, CLEC12A knock-out mice with collagen-induced arthritis exhibit enhanced joint inflammation and impaired resolution of joint injury indicative of a potential role for this inhibitory receptor in RA. The goal of this study was to determine whether CLEC12A is differentially expressed in circulating neutrophils and monocytes of human early RA (eRA) patients and if its expression correlates with clinical parameters and cytokine production.

Methods: Seventeen patients with early RA (eRA), symptom duration of >6 weeks but less than 15 months of symptoms, were recruited as part of the Systemic Autoimmune Rheumatic Disease biobank and database repository of the CHU de Québec-Université Laval. Clinical data and serum samples were obtained at the first visit (baseline), 3, 6, 12 and 18 months and a one-time control sample was obtained from healthy donors. Simple disease activity index (SDAI) was determined at each visit, and autoantibody levels at baseline and 12 months. CLEC12A receptor expression was determined on circulating neutrophils and monocytes by flow cytometry at baseline and 3, 6, 12 and 18 months follow-up. Serum cytokines were quantified at baseline. Group generalized estimating equations model, Student’s t test and Spearman’s correlations were performed to identify correlations between CLEC12A expression and clinical parameters.

Results: Cell-surface expression of CLEC12A is significantly higher on neutrophils of early rheumatoid arthritis patients at baseline compared to healthy donors (p = 0.014). Cross-sectional analyses indicate a negative correlation of CLEC12A expression at baseline with the SDAI at baseline (r_s = -0.55; p = 0.032). The same observation was observed at 3 months (r_s = -0.65; p = 0.01). CLEC12A expression at baseline was predictive of the SDAI score at 6 months (r_s = -0.52; p = 0.046) and correlated positively with eotaxin levels at baseline (r_s = 0.71; p = 0.003). Similar observations were made for monocytes. No correlations were identified between CLEC12A expression and autoantibodies.

Conclusion: Our observations provide further support to the recurring theme that the expression of inhibitory receptors on circulating leukocytes changes during disease and predictive of disease parameters. The correlations we observed in this discovery cohort between CLEC12A expression and disease activity as well as cytokines strongly suggests that CLEC12A modulates the immune response that drives the early stages of this autoimmune disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/clec12a-expression-as-a-potential-predictor-of-disease-activity-in-early-rheumatoid-arthritis/