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An increased IL-18 level is associated with erosive joint disease, but the measurement of IL-18 does not help to distinguish between RA patients and healthy controls.

mice treated with monoclonal anti-TNF: 5/15 (33%) with TN3 (p=0.03/ controls), 4/12 (33%) with ADA (p=0.054/ controls), 0/15 with ETA and 1/22 (5%) in controls. Conclusions Higher mortality and increased risk of lymphoma were observed in BAFF Tg mice treated with monoclonal anti-TNF compared to etanercept. This result may be linked either to the different mechanism of action between the soluble receptor and the monoclonals or to a difference of trough level observed in the different groups even if higher levels of ADA was mandatory given the difference of effect on mouse TNF. This study demonstrates the negative impact of a prolonged anti-TNF treatment on the risk of lymphoma in the context of BAFF increase. Disclosure of interest None declared P029ABSTRACT WITHDRAWN

BackgroundSmoking is the most extensively studied environmental risk factor of rheumatoid arthritis (RA). We have recently shown that smoking is associated with high serum levels of survivin (Svensson, Hafström et al. 2014). Survivin is a novel biomarker for RA that can predict severe joint destruction as well as treatment outcome for RA patients (Levitski et al, 2015). We hypothesized cytotoxic activity to be the reason for the increased serum levels of survivin observed in RA patients and we wished to further investigate possible molecular mechanisms behind cytotoxicity in RA.ObjectivesWe have studied the effect of nicotine on cytotoxic activity of T lymphocytes during RA paying special attention to the expression of PD-1, a receptor that inhibits activation of T cells.MethodsWe used female Balb/c mice that received 0.03% nicotine in drinking water or regular tap water as controls, after 18 days mice were immunized with collagen and subsequently developed arthritis (CIA). At the end of experiment bone marrow, lymph nodes and serum were collected and analyzed using flow cytometry (FACS), qPCR and ELISA. To confirm nicotine-dependent nature of experimental findings, we analyzed blood samples of female RA patients and healthy women with known smoking status.ResultsThe proportion of CD8+ cells was 1.9 times larger in nicotine treated mice compared to control (p=0.00020). Meanwhile, the nicotine treated mice had a 2.3 times less PD-1 expressing CD8+ cells in the bone marrow (p=0.032), but PD-1 expression in the lymph nodes was not affected by nicotine. This resulted in an accumulation of the CD8+PD-1- population in the bone marrow of the nicotine treated mice (p=0.0074). The nicotine treated mice had higher levels of serum survivin (0.0 vs 0.29 ng/ml, p=0.017) which also correlated to the size of CD8+PD-1- population in the bone marrow (r=0.52, p=0.024). The decrease in PD-1 expression of CD8+ T cells caused by nicotine was confirmed in smoking women. Smokers had a 1.7 times less PD-1 positive CD8+ T cells compared to non-smokers (p=0.041). In patients, the serum levels of survivin correlated to the expression of the cytotoxic marker CD107 on CD8+ T cells (r=0.52, p=0.047).ConclusionsNicotine exposure supports cytotoxic phenotype of CD8+ T cells characterized by high CD107 and low PD-1 expression in experimental arthritis and RA patients. Increased cytotoxic activity of CD8+ T cells is a plausible mechanism for the enrichment of survivin in serum in RA patients. See graphical abstract.ReferencesSvensson B, Hafström I, Erlandsson MC, Forslind K, Bokarewa MI. Smoking in combination with antibodies to cyclic citrullinated peptides is associated with persistently high levels of survivin in early rheumatoid arthritis: a prospective cohort study. Arthritis Res Ther. 2014;16(1):R12. doi: 10.1186/ar4438.Levitsky A, Erlandsson MC, van Vollenhoven RF, Bokarewa MI, Serum survivin predicts responses to treatment in active rheumatoid arthritis: a post hoc analysis from the SWEFOT trial. BMC Med. 2015;13:247. doi: 10.1186/s12916-0...

BackgroundRheumatoid arthritis (RA) is an established risk factor for premature development of cardiovascular disease. Adipokines are signal molecules originating from adipose tissue and exhibit strong proinflammatory effects. We have previously shown that resistin utilizes IGF-1R (1) and TLR4 (2) pathway to induce inflammation in RA leukocytes and synovia.ObjectivesIn the present study we evaluated the role of adipokines and adipokine-related genes on the cardiovascular risk in female RA patients.MethodsThe estimated cardiovascular risk was calculated in 187 female RA patients, using the modified Systematic Coronary Risk Evaluation (mSCORE). Serum levels of adipokines and IGF-1 and transcription of genes affected by Resistin and IGF-1 signalling in peripheral blood leukocytes and in subcutaneous fat tissue were analyzed in relation to mSCORE. To assess the predictive value of adipokines and gene transcription for the increased mSCORE, two independent binary logistic regression models were designed where high mSCORE or high resistin were chosen as the dependent variables.ResultsmSCORE was directly related to the age, disease duration, smoking habits and blood fat profile (cholesterol and triglycerides). These parameters were higher in the group with mSCORE≥1 (n=96) indicative for the increased cardiovascular risk. The patients with mSCORE≥1 had significantly higher levels of leptin (p=0.007), and resistin (p=0.03), while the levels of IGF-1 were significantly lower (p<0.0001) compared to the patients with lower cardiovascular risk (mSCORE<1, n=91). The overall transcriptional activity of the fat tissue adipocytes was prominently higher compared to peripheral blood leucocytes in patients with mSCORE≥1. In patients with mSCORE≥1, the relative transcription of RELA, AKT1 and TLR4 was higher compared to the patients with mSCORE<1.The logistic regression analysis with mSCORE as a dependent variable showed that high serum levels of resistin and leptin were independently associated with the increased cardiovascular risk. Similar associations were observed for adipocyte expression of resistin-triggering genes TLR4 (OR 1.15 [95% CI 1.01-2.15]; p=0.03) and STAT3 (OR 2.39 [95% CI 1.00-5.74]; p=0.05). The logistic regression model with high serum resistin as a dependent variable revealed an association to high transcription of STAT3 (OR 1.12 [95% CI 1.00-3.30]; p=0.02), and low transcription of AKT1 in leukocytes and in adipocytes.ConclusionsThe results of our study indicate that transcriptional activity of subcutaneous adipose tissue in women with RA is associated with the increased cardiovascular risk. High transcriptional activity of resistin-triggering genes may be a sufficient force driving premature cardiovascular disease in RA patients.ReferencesBoström EA, Svensson M, Andersson S, Jonsson IM, Ekwall AK, Eisler T, Dahlberg LE, Smith U, Bokarewa MI. Resistin and insulin/insulin-like growth factor signaling in rheumatoid arthritis. Arthritis Rheum. 2011,63:2894-904Tarkowski A, Bjersing J, Shestakov A, Bokarewa MI. Resist...