SAT0006 T-CELL IMMUNOGLOBULIN AND MUCIN DOMAIN 3 (TIM-3) IS INCREASED IN ACTIVE RHEUMATOID ARTHRITIS AND ASSOCIATED WITH CLINICAL DISEASE ACTIVITY AND RADIOGRAPHIC PROGRESSION

Abstract

Background: Co-inhibitory receptors are important for the regulation of inflammation in autoimmune diseases. Among these, T-cell Immunoglobulin and mucin domain-3 (Tim-3) has recently gained attention, as it is expressed on exhausted T cells co-expressing PD-1 (1). Objectives: To investigate Tim-3's role in rheumatoid arthritis (RA). Methods: Early RA (eRA) patients were randomized to conventional methotrexate (MTX) treatment + placebo or MTX + adalimumab (ADA) (2). Plasma were analysed by ELISA at baseline (n=98) and after 3 and 12 months of treatment. Clinical follow up including 28-joint Disease Activity Score with CRP (DAS28CRP) and Total Sharp Score (TSS) were available. Intrasubject differences in sTim-3 between baseline and 3 months were assessed by parametric paired t tests and compared with plasma from HV (n=44) by parametric unpaired t tests. Spearman correlation and Mann-Whitney test were used to investigate relations between sTim-3 and clinical follow up. From chronic RA (cRA) patients (n=17) plasma and synovial fluid were analysed by ELISA and peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) (n=8) were analysed by flow cytometry. Intrasubject differences were assessed by paired parametric t tests, and comparison with PBMC from HV (n=6) by unpaired parametric t test. Parametric data are reported as mean differences (MD) [95%CI]. P values < 0.05 were considered significant. Results: Among memory prone T cells (CD3+CD4+CD45RO+) in SFMC, the percentage of Tim-3+ cells were increased compared with similar gated PBMC from patients (MD 17.4%, [10.7;24.1], p<0.005) and HV (MD 12.9%, [4.1;21.8], p=0.007). In the joint, more of these Tim-3+ cells co-expressed PD-1 compared with similar gated PBMC (MD 42.8%, [27.8;57.9], p<0.005) (Figure 1). On average, sTim-3 plasma levels were higher in eRA compared with HV (MD 4.6 ng/ml, [3.3;5.9], p<0.005) (Figure 2). In eRA, baseline sTim-3 levels correlated with DAS28CRP (rho=0.28, p=0.005). eRA patients with TSS progression within 24 months of treatment decreased more in plasma sTim-3 during 3 months of treatment compared with patients without TSS progression (median+progression: -1.4 ng/ml, median-progression: -0.5 ng/ml (U=849.5), p=0.048). The decrease in plasma sTim-3 was not influenced by treatment (medianMTX+Placebo:-0.9 ng/ml, medianMTX+ADA: -1.2 ng/ml (U=1015), p=0.4). In SF, sTim-3 levels were increased compared with plasma (MD 37.4 ng/ml, [26.3;48.4], p<0.0001). Conclusion: Tim-3 expression is upregulated in memory prone T cells in RA joints and the majority co-express PD-1. Levels of sTim-3 are increased in SF. In eRA, baseline sTim-3 plasma levels are elevated and correlate with DAS28CRP. Decrease of sTim-3 during treatment associates with future radiographic progression. We suggest, that Tim-3 expression and sTim-3 plasma and SF levels reflect ongoing immune response, thus immune regulation in RA. These data indicate that maintenance of sTim-3 plasma levels during treatment is favourable, consistent with Tim-3 being a co-inhibitory receptor. (Figure presented).