D. Greco

Newly identified antiatherosclerotic activity of methotrexate and adalimumab: complementary effects on lipoprotein function and macrophage cholesterol metabolism.

Rheumatoid arthritis (RA) is associated with accelerated atherosclerosis. The reduction in cardiovascular risk that is induced by methotrexate (MTX) and anti–tumor necrosis factor α agents in RA is considered secondary to their anti‐inflammatory action, but their effects on serum lipoprotein function and foam cell formation are unknown. The reduced capacity of high‐density lipoprotein (HDL) to promote cell cholesterol efflux and the increased serum cell cholesterol‐loading capacity (CLC) demonstrated in RA may contribute to foam cell development. The aim of this study was to investigate the influence of MTX and adalimumab treatment on serum cholesterol efflux capacity (CEC) and CLC in RA patients and to study the in vitro effects of the two drugs on macrophage cholesterol handling.

Cyclosporine A Impairs the Macrophage Reverse Cholesterol Transport in Mice by Reducing Sterol Fecal Excretion

Despite the efficacy in reducing acute rejection events in organ transplanted subjects, long term therapy with cyclosporine A is associated with increased atherosclerotic cardiovascular morbidity. We studied whether this drug affects the antiatherogenic process of the reverse cholesterol transport from macrophages in vivo. Cyclosporine A 50 mg/kg/d was administered to C57BL/6 mice by subcutaneous injection for 14 days. Macrophage reverse cholesterol transport was assessed by following [3H]-cholesterol mobilization from pre-labeled intraperitoneally injected macrophages, expressing or not apolipoprotein E, to plasma, liver and feces. The pharmacological treatment significantly reduced the amount of radioactive sterols in the feces, independently on the expression of apolipoprotein E in the macrophages injected into recipient mice and in absence of changes of plasma levels of high density lipoprotein-cholesterol. Gene expression analysis revealed that cyclosporine A inhibited the hepatic levels of cholesterol 7-alpha-hydroxylase, concomitantly with the increase in hepatic and intestinal expression of ATP Binding Cassette G5. However, the in vivo relevance of the last observation was challenged by the demonstration that mice treated or not with cyclosporine A showed the same levels of circulating beta-sitosterol. These results indicate that treatment of mice with cyclosporine A impaired the macrophage reverse cholesterol transport by reducing fecal sterol excretion, possibly through the inhibition of cholesterol 7-alpha-hydroxylase expression. The current observation may provide a potential mechanism for the high incidence of atherosclerotic coronary artery disease following the immunosuppressant therapy in organ transplanted recipients.

AB0730 Cell cholesterol transport in spondyloarthritides and its response to anti-rheumatic drugs

Background Spondyloarthritis is associated to accelerated atherosclerosis, possibly due to chronic inflammation and lipid metabolism disturbances. Circulating lipoprotein function may be more important than concentration. In particular, cholesterol efflux capacity (CEC) of high density lipoproteins (HDL) opposes to foam cell formation and correlates inversely with cardiovascular risk1. Instead, the capacity of low density lipoproteins (LDL) to load cells with cholesterol (CLC) favors atherosclerosis. CEC and CLC may be altered independently from lipoprotein serum levels, e.g. due to chronic autoimmune inflammation or to medical therapies2. Objectives Our aim was to compare CEC and CLC in patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA). We also aimed to evaluate CEC and CLC modification upon anti-rheumatic therapy and their relationship to lipoprotein levels. Methods Patients with AS (n=24) and PsA (n=36) were from the observational PSARA study. Treatment was: anti-TNF agents for AS; MTX alone or in combination with an anti-TNF agent for PsA. Serum was drawn before, after 6 weeks and after 6 months of anti-rheumatic therapy to measure CEC with a validated cell model (radioisotopic technique to measure % cholesterol efflux on total cell cholesterol3) and CLC (with a macrophage model and fluorimetric measurement of cell cholesterol2). Results At baseline serum LDL and total cholesterol were higher in PsA than in AS patients. LDL, total cholesterol and HDL increased after treatment in AS, but not in PsA. In AS, CEC increased after 6 weeks of treatment (4.9±0.3 vs. 5.5±0.3, 95% CI: -1.09 to -0.03, p<0.05), in parallel with HDL serum levels. In PsA, CEC did not differ between any of the time points. CLC did not change with treatment in AS nor in PsA, but was overall higher in PsA than in AS patients. Despite the LDL serum level increase in AS, after 6 months of treatment the difference between CLC in PsA and AS was the most significant (34.0±1.8 in PsA vs 27.8±1.5 in AS, CI 95%: 3.28 to 6.67, p<0.05). In addition, after 6 months of therapy the correlation of CLC with LDL levels, present before treatment, was lost in the AS group. In the PSA group CLC did not correlate with LDL serum levels at any time point. Conclusions Our novel data indicate that pro-atherogenic lipoprotein dysfunction is more marked, and less responsive to anti-rheumatic treatment, in PsA than AS patients. In AS, CEC improved significantly during anti-TNF therapy, probably due to increase in anti-atherogenic HDL. Despite the LDL increase associated with the anti-TNF therapy in AS patients, CLC stayed constant, standing against a hypothetical pro-atherogenic effect of such LDL increase. These data may be useful for atherosclerosis prevention and treatment with tailored strategies for AS and PsA patients. References Khera AV, et al. N Engl J Med 364(2):127–35, 2011. Ronda N et al. Arthritis Rheumatol 67(5):1155–64, 2015. Zanotti I et al. Curr Pharm Biotechnol 13(2):292–302, 2012. Disclosure of Interest None declared

FRI0258 Improvement of Cell Cholesterol Trafficking-Related Lipoprotein Functions in Rheumatoid Arthritis Patients Treated with Adalimumab

Background RA is associated with accelerated atherosclerosis. HDL in RA have reduced capacity to promote cell cholesterol efflux (CEC) while LDL have increased cholesterol loading capacity on macrophages (CLC). Inflammation and immune disturbances are among the mechanisms proposed. Anti-TNFa agents appear to reduce cardiovascular risk in RA, but their effects on serum lipid profile is variable. Objectives We studied modifications of lipoprotein function with respect to cell cholesterol trafficking after adalimumab therapy in RA. Methods Serum was drawn from 56 patients with RA, 34 treated with methotrexate (MTX), 22 starting with adalimumab in addition to ongoing MTX (MTX/ADA), before and after 6 weeks and 6 months of treatment. We measured: serum lipid profile; CLC with cholesterol measurement by fluorimetric technique; CEC with radioisotopic technique. Results HDL, LDL and total cholesterol serum levels increased in the MTX group after treatment, while HDL levels only increased in the MTX/ADA group. CLC significantly decreased after treatment in the MTX/ADA group only (mean ± SE, 7.16±0.28 vs 7.92±0.48 mg cholesterol/mg protein, p<0.05). In MTX group ATP-binding cassette G1 (ABCG1) and Scavenger receptor-BI (SR-BI)-mediated CEC increased after treatment; in MTX/ADA group SR-BI-mediated CEC increased. No modifications in ATP-binding cassette A1-mediated CEC occurred in either MTX or MTX/ADA group. Conclusions Adalimumab addition to MTX treatment results in decreased cell cholesterol loading serum capacity and slight improvement in HDL promotion of cell cholesterol efflux, both potentially inhibiting foam cell formation. These effects may be especially relevant in RA patients with aggressive disease needing anti-TNFa, particularly prone to accelerated atherosclerosis. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2441