Gunnbjorg Hjeltnes

Anti-CCP and RF IgM: predictors of impaired endothelial function in rheumatoid arthritis patients

Objective: To determine whether the presence of anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor immunoglobulin M (RF IgM) is associated with endothelial dysfunction in patients with rheumatoid arthritis (RA). Methods: We studied the presence of anti-CCP antibodies and RF IgM and endothelial function in terms of the reactive hyperaemic index (RHI) in 53 consecutive RA patients. Endothelial function was measured by using a finger plethysmograph. Results: RHI was significantly lower in anti-CCP-positive RA patients (n  =  33, RHI  =  1.78, SD  =  0.30) than in anti-CCP-negative RA patients (n  =  20, RHI  =  2.19, SD = 0.59; p  =  0.008). A similar result was found in RF IgM-positive patients (n  =  34, RHI  =  1.77, SD  =  0.30) vs. RF IgM-negative patients (n  =  19, RHI  =  2.23, SD  =  0.58; p  =  0.003). There were no significant differences between the groups regarding age, gender, traditional cardiovascular risk markers, Disease Activity Score using 28 joint counts (DAS28), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), extra-articular manifestations (EAMs), use of glucocorticosteroids, statins, angiotensin-converting enzyme (ACE) inhibitors, and non-steroidal anti-inflammatory drugs (NSAIDs). Conclusion: The presence of anti-CCP antibodies and RF IgM was related to impaired endothelial function independent of other cardiovascular risk factors in RA patients. Thus, these autoantibodies might reflect an early reversible stage of the atherosclerotic process, and may indicate increased risk of cardiovascular disease (CVD). Further studies are needed to explore whether anti-CCP antibodies and RF IgM may act directly or indirectly to cause endothelial dysfunction, or merely reflect endothelial dysfunction in RA patients.

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.

Endothelial function improves within 6 weeks of treatment with methotrexate or methotrexate in combination with a TNF-α inhibitor in rheumatoid arthritis patients

Cardiovascular disease (CVD), mainly caused by premature atherosclerosis, is the main cause of reduced life expectancy in rheumatoid arthritis (RA) patients (1). Endothelial dysfunction (ED) is regarded as the initial step in the atherosclerotic process, and independently predicts cardiovascular events (2). Non-invasive methods for detecting andmonitoring endothelial function (EF) are preferred (3). Inflammation appears to play an important role in causing ED and may contribute to the premature pathogenesis of atherosclerosis in RA (4). Thus, in theory, anti-inflammatory drugs may both reduce cardiovascular risk and improve the EF. The aim of the present study was to examine the effect of methotrexate (MTX) and MTX combined with antitumour necrosis factor (anti-TNF)-α treatment on the EF in RA patients as measured by the reactive hyperaemic index (RHI), using the non-invasive technique EndoPAT 2000 (5). This uses a finger plethysmograph, is easy to handle in a standardized manner, and the calculation of the RHI is made independently of the operator. RHI values below 1.7 indicate ED. We also explored associations between EF, the presence of autoantibodies, including anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor immunoglobulin M (RF IgM), and inflammatory biomarkers during treatment. Fifty-two consecutive patients with RA according to the American College of Rheumatology (ACR; formerly the American Rheumatism Association) 1987 criteria (6) were enrolled and completed the ongoing PSARA study at Lillehammer Hospital for Rheumatic Diseases in the period October 2008–May 2010 (5). The decision about treatment modality was based on conventional clinical judgement by rheumatologists not involved in the study. None of the 52 patients were treated with any other disease-modifying anti-rheumatic drugs (DMARDs) at baseline or during the follow-up at 6 weeks and 6 months. RA patients starting with MTX plus TNF-α inhibitor had a marginally higher body mass index (BMI), longer RA duration, and had a lower proportion of smokers than those starting with MTX as monotherapy (Table 1). Otherwise, the demographic data, inflammatory clinical scores and biomarker levels, adjunct medication, any form of CVD or family history of CVD, hypertension and hyperlipidaemia were similar in the RA treatment groups at baseline. Of the 52 RA patients, 38% (n 1⁄4 20) had abnormal EF at baseline (RHI < 1.7), with a mean RHI of 1.50 (sd 1⁄4 0.13) in the ED group, whereas the mean RHI was 2.14 (sd 1⁄4 0.35) in the RA patients with normal EF. The improvement in RHI at 6 weeks and 6 months was similar in the two treatment arms (p6weeks 1⁄4 0.890, p6months 1⁄4 0.569). Furthermore, changes in C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), RF IgM level, anti-CCP antibody level, triglycerides, cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), lipoprotein a [Lp(a)], apoprotein (apo) A1, white blood cell (WBC) count, glycosylated haemoglobin (HbA1c), Health Assessment Questionnaire (HAQ) score, and pain and fatigue on a visual analogue scale (VAS) did not differ between the two treatment arms at any points of the follow-up. Compared to baseline values, reduction in the disease activity score in 28 joints (DAS28) based on ESR (DAS28-ESR) was significantly greater at 6 weeks in the MTXþTNF-α inhibitor group (DAS28-ESR p 1⁄4 0.007) compared to the MTX group, whereas the reduction was similar in the groups after 6 months of treatment. When we analysed all 52 RA patients as one group, a significant improvement in RHI after 6 weeks of treatment was found (RHIbaseline 1⁄4 1.90, RHI6weeks 1⁄4 2.21; p 1⁄4 0.004). This improvement remained steady at 6 monthsfollow-up (RHI6months 1⁄4 2.16; p 1⁄4 0.014). The RHI in women increased significantly more than in men both at 6 weeks (p 1⁄4 0.029) and at 6 months (p 1⁄4 0.020). A total of 69% of the RA patients were positive for RF IgM. At baseline, the RF IgM-positive patients had a 240 Scand J Rheumatol 2012;41:240–248

Anti-rheumatic treatment is not associated with reduction of pentraxin 3 in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis

Background Pentraxin 3 is proposed to be a marker of inflammation and cardiovascular risk, but its role in inflammatory rheumatic diseases (IRDs) is still uncertain. Therefore, we wanted to examine if anti-rheumatic treatment reduced serum PTX3 (s-PTX3) levels in IRDs, and if s-PTX3 levels were related to other markers of inflammation and to endothelial function (EF). Methods We examined s-PTX3, EF and established inflammatory biomarkers in 114 IRD patients from the PSARA study before and after 6 weeks and 6 months of treatment with methotrexate (MTX) or anti-tumor necrosis factor alpha (anti-TNF) therapy with or without MTX co-medication. Results s-PTX3 levels in all IRD diagnoses were above the upper limit of the reference range. In contrast to established inflammatory markers, in particular CRP and ESR, s-PTX3 levels did not change significantly after 6 weeks and 6 months of anti-rheumatic therapy. There was no difference in change in s-PTX3 levels from baseline to 6 weeks and 6 months between MTX monotherapy and anti-TNF regimens. CRP, ESR and EF were not related to changes in s-PTX3 neither in crude nor adjusted analyses. Conclusion IRD patients have increased s-PTX3 levels, which, in contrast to other inflammatory markers, do not seem to improve within 6 months of therapy with MTX and/or anti-TNF. Thus, s-PTX3 might reflect a persisting immune process, even a causal factor of inflammation, not inhibited by the standard anti-rheumatic treatment. Furthermore, even though s-PTX3 is thought to be a strong predictor of cardiovascular prognosis, it was not related to EF.

Effect of anti-rheumatic treatment on selenium levels in inflammatory arthritis

OBJECTIVES The reason for increased cardiovascular risk in inflammatory arthritis (IA) is unclear. Interestingly, selenium-deficiency is suspected to contribute to the development of cardiovascular disease (CVD) in the general population. Although the reference range of serum selenium (s-selenium) is 50-120 μg/L, there are indications that levels up to 85 μg/L might not be sufficient for optimal cardioprotection. Our aim was to examine s-selenium levels in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), to evaluate the effect of anti-rheumatic treatment on s-selenium levels, and to assess relationships between s-selenium levels and clinical and laboratory parameters including markers of disease activity and CVD risk. METHODS We examined 64 patients with RA, 40 with PsA and 26 with AS starting with methotrexate (MTX) monotherapy or anti-tumor necrosis factor therapy (anti-TNF) with or without methotrexate (anti-TNF ± MTX) due to active disease. S-selenium, inflammatory biomarkers, endothelial function (EF) and other variables were examined at baseline and after 6 weeks and 6 months of treatment. RESULTS In the total IA group, s-selenium increased within 6 weeks of anti-rheumatic treatment, and thereafter the levels remained stable until the end of the 6 months follow-up period. There were no significant differences in s-selenium changes between the three diagnostic groups and between the two treatment regimens. Changes in s-selenium were negatively related to changes in C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), but there were no significant relationships to any other of the examined risk parameters for CVD including EF. CONCLUSION IA patients had s-selenium within the reference range, but below the level that might be necessary for optimal CVD protection. Anti-rheumatic treatment had a relatively rapid and sustained effect on s-selenium levels. The increase in s-selenium was related to reduction in inflammatory activity. In theory, anti-rheumatic drugs might improve s-selenium levels through inhibition of pro-inflammatory processes or through other mechanisms. Although we have not revealed any significant relationships between s-selenium and CVD risk parameters, the role of suboptimal s-selenium levels in pathogenesis of premature CVD in IA cannot be ruled out.

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

AB0272 Anti-Rheumatic Treatment Is Not Associated with Reduction of Pentraxin 3 (PTX3) in Rheumatoid Arthritis (RA), Psoriatic Arthritis (PSA) and Ankylosing Spondylitis (AS)

Background PTX3, an important component of the innate immune system,has been proposed as a useful biomarker of inflammation and cardiovascular (CV) risk, but its role in inflammatory rheumatic diseases (IRDs) is still uncertain [1,2]. Objectives The aim of this study was to examine if methotrexate (MTX) and/or anti-tumor necrosis factor treatment (anti-TNF) treatment reduced serum PTX3 (s-PTX3) levels in IRDs (RA, PsA and AS), and if s-PTX3 levels were related to other markers of inflammation and to endothelial function (EF). Methods From the biobank of PSARA, an observational study, we examined samples from 114 IRD patients starting with either MTX or anti-TNF with or without MTX (anti-TNF±MTX) due to active disease, who completed a 6 months follow up. s-PTX3 (enzyme-linked immunosorbent assay), EF (finger plethysmography) and established inflammatory biomarkers were evaluated at baseline and after 6 weeks and 6 months of therapy. Results The s-PTX3 levels in IRD and all the diagnostic subgroups were above the upper limit of the reference range. In contrast to established inflammatory markers, in particular C- reactive protein (CRP) and erythrocyte sedimentation rate (ESR) (all p-values <0.05), s-PTX3 levels did not change significantly after 6 weeks and 6 months of anti-rheumatic therapy (all p>0.2). The effect of MTX monotherapy and anti-TNF±MTX on s-PTX3 levels was similar. Changes in CRP, ESR and EF were not related to changes in s-PTX3 levels neither in univariate analyses nor in analyses adjusted for potential confounders. Conclusions IRD patients have increased s-PTX3 levels, which, in contrast to other inflammatory markers, do not seem to improve within 6 months of therapy with MTX and/or anti-TNF. Thus, in theory, s-PTX3 might reflect a persisting immune process, even a causal factor of the inflammation, not inhibited by the standard anti-rheumatic treatment. Furthermore, even though PTX3 is thought to be a strong predictor of CV prognosis, it was not related to EF. References Bottazzi, B., et al., An integrated view of humoral innate immunity: pentraxins as a paradigm. Annu.Rev.Immunol., 2010. 28: p. 157–183. Jylhävä, J., et al., Pentraxin 3 (PTX3) is associated with cardiovascular risk factors: the Health 2000 Survey. Clinical and Experimental Immunology, 2011. 164(2): p. 211–217. Disclosure of Interest None declared

AB0355 Anti-Rheumatic Therapy Reduces Syndecan-1 Shedding in Rheumatoid Arthritis (RA)

Background Intact glycocalyx is of importance for healthy endothelial function. Changes in the endothelial glycocalyx, characterized by increased levels of circulating syndecan-1, might be related to accelerated atherosclerosis in RA. Objectives To examine the effect of anti-rheumatic treatment on serum syndecan-1 levels. Methods From the Norwegian observational PSARA study, we selected 32 patients starting with methotrexate (MTX) and/or anti-tumor necrosis factor (anti-TNF) treatment due to active RA. S-syndecan-1 was measured by ELISA at baseline and after 6 weeks of the treatment. Results The mean age of the patients was 59±8 years, and 27% were men. 12 patients received MTX and 20 received MTX and anti-TNF. S-syndecan-1 significantly decreased during the treatment (49±52 ng/ml vs. 45±50 ng/ml, p=0.047). The difference was independent of age, sex and DAS28. The s-syndecan-1 reduction was greater in the MTX than MTX+anti-TNF group (10±13 vs. 1±1 ng/ml, p=0.048). Conclusions Anti-rheumatic treatment reduces s-syndecan-1 in RA. Thus, a glycocalyx ameliorating effect may contribute to the reduction of cardiovascular morbidity due to anti-rheumatic treatment. In theory, the greater reduction of s-syndecan-1 in the MTX than in the combined group might be due to differences in patient population (less severe RA and a shorter disease duration in patients treated with MTX compared to anti-TNF). Interestingly, although MTX is considered a less potent anti-rheumatic drug than anti-TNF, it may have an important cardioprotective effect caused by its protective effect on glycocalyx etc. This effect might be at least partially independent of its anti-inflammatory properties. 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