I. E. van der Horst-Bruinsma

Improvement of Lipid Profile Is Accompanied by Atheroprotective Alterations in High-Density Lipoprotein Composition Upon Tumor Necrosis Factor Blockade A Prospective Cohort Study in Ankylosing Spondylitis

OBJECTIVE Cardiovascular mortality is increased in ankylosing spondylitis (AS), and inflammation plays an important role. Inflammation deteriorates the lipid profile and alters high-density lipoprotein cholesterol (HDL-c) composition, reflected by increased concentrations of serum amyloid A (SAA) within the particle. Anti-tumor necrosis factor (anti-TNF) treatment may improve these parameters. We therefore undertook the present study to investigate the effects of etanercept on lipid profile and HDL composition in AS. METHODS In 92 AS patients, lipid levels and their association with the inflammation markers C-reactive protein (CRP), erythrocyte sedimentation rate, and SAA were evaluated serially during 3 months of etanercept treatment. HDL composition and its relationship to inflammation markers was determined in a subgroup of patients, using surface-enhanced laser desorption/ionization time-of-flight analysis. RESULTS With anti-TNF treatment, levels of all parameters of inflammation decreased significantly, whereas total cholesterol, HDL-c, and apolipoprotein A-I (Apo A-I) levels increased significantly. This resulted in a better total cholesterol:HDL-c ratio (from 3.9 to 3.7) (although the difference was not statistically significant), and an improved Apo B:Apo A-I ratio, which decreased by 7.5% over time (P=0.008). In general, increases in levels of all lipid parameters were associated with reductions in inflammatory activity. In addition, SAA was present at high levels within HDL particles from AS patients with increased CRP levels and disappeared during treatment, in parallel with declining plasma levels of SAA. CONCLUSION Our results show for the first time that during anti-TNF therapy for AS, along with favorable changes in the lipid profile, HDL composition is actually altered whereby SAA disappears from the HDL particle, increasing its atheroprotective ability. These findings demonstrate the importance of understanding the role of functional characteristics of HDL-c in cardiovascular diseases related to chronic inflammatory conditions.

Study on the Protective Effect of the KIR3DL1 Gene in Ankylosing Spondylitis

Ankylosing spondylitis (AS) is an autoimmune disease that mainly affects the sacroiliac joints and the spine of the lower back. The disease is strongly associated with HLA–B27. Additional genes, single‐nucleotide polymorphisms, and molecular components have been identified to be associated with AS, but the exact mechanism that drives disease development remains poorly understood. The killer cell immunoglobulin‐like receptors (KIRs) are regulators of cytotoxicity of natural killer cells and T cell subsets and may be relevant in binding to HLA–B27 and the development of AS. We undertook this study to identify possible associations of KIR genotype with susceptibility to AS and disease characteristics including the presence of the HLA–B27 allele, disease severity, and uveitis.

SAT0415 Diastolic Left Ventricular Dysfunction in Ankylosing Spondylitis Improves during Tumor Necrosis Factor Alpha Blocking Therapy

Background Ankylosing spondylitis (AS) is associated with concomitant cardiac pathology, such as diastolic left ventricular (LV) dysfunction (1), valvular dysfunction, and aortic disease (2), all presumably caused by inflammation. The precise prevalence of diastolic left ventricular (LV) dysfunction and the effects of anti-inflammatory treatment thereon are currently unknown. Objectives To investigate the prevalence of diastolic LV dysfunction compared to controls and the effects of tumor necrosis factor (TNF) -α blocking therapy on ventricular function in AS patients. Methods Forty consecutive AS patients were included and treated for one year with TNF-α blocking therapy. Transthoracic echocardiography was performed at baseline and at one year. Forty age and gender matched asymptomatic random controls were included from an established echocardiographic cohort. Diastolic LV function (normal, dysfunction grade I, II, or III) and systolic LV function (ejection fraction, EF) were assessed. Valvular and aortic pathology was documented. Disease activity was measured with C-reactive protein (CRP), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score–CRP (ASDAS). Results At baseline, diastolic LV dysfunction (all grades) was present in nine patients (23%) vs one (3%) control (p=0.011). Systolic LV dysfunction was present in 0 (0%) patients vs one (3%) control (p=0.625). In total, 13 (33%) AS patients and six (15%) controls (p=0.066) had some form of cardiac pathology (i.e. one or more of the following: diastolic and/or systolic LV dysfunction, aortic valve dysfunction, aortic dilatation; one AS patient and one control had two disorders). Treatment with TNF-α blocking therapy had no effect on systolic LV function, but diastolic LV dysfunction (n=3 grade I, n=1 grade II) improved to normal in four patients (p=0.125), and neither worsened nor developed in the other patients. After the start of TNF-α blocking therapy CRP decreased from 4.0 (1.3–12.0) mg/l to 2.0 (1.9–3.2) mg/l (p<0.001), BASDAI decreased from 5.2±1.6 to 3.7±2.0 (p=0.001) and ASDAS decreased from 3.1±1.2 to 2.0±1.0 (p<0.001). Conclusions AS patients had a significantly increased prevalence of diastolic LV dysfunction compared to controls which improved during treatment with TNF-α blocking therapy. This appears to be related to the anti-inflammatory effects of TNF-blocking therapy. References Heslinga SC, Van Dongen CJ, Konings TC, Peters MJ, van der Horst-Bruinsma IE, Smulders YM, et al. Diastolic left ventricular dysfunction in ankylosing spondylitis–a systematic review and meta-analysis. Semin Arthritis Rheum 2014 Aug;44(1):14–9. Nurmohamed MT, van der Horst-Bruinsma I, Maksymowych WP. Cardiovascular and cerebrovascular diseases in ankylosing spondylitis: current insights. Curr Rheumatol Rep 2012 Oct;14(5):415–21. Acknowledgement This is an investigator initiated study partially supported by an unrestricted grant from MSD, The Netherlands Disclosure of Interest None declared

SAT0416 Significantly Reduced Recurrence Rate of Acute Anterior Uveitis in Ankylosing Spondylitis during Treatment with Golimumab

Background Acute anterior uveitis (AAU) is common in ankylosing spondylitis (AS) (1). Golimumab, a tumor necrosis factor alpha (TNF-α) blocker, has proven to be effective in the treatment of AS (2). We have shown earlier that treatment with adalimumab, another TNF-α blocker, leads to a significant decrease in the recurrence rate of AAU (3) in AS. At present, the effect of golimumab on the recurrence rate of AAU in AS is unknown. Objectives To investigate the effect of golimumab treatment on the recurrence rate of AAU attacks in AS patients. Methods Consecutive AS patients were enrolled who all fulfilled the 1984 Modified New York criteria, and fulfilled the criteria for initiating treatment with a TNF-α blocker in the Netherlands. All patients were treated with golimumab 50mg once a month for 12 months. During treatment, all occurring AAU attacks were assessed. The historic presence of AAU attacks was assessed from the year before baseline for non-biological treated patients, or the year before the first treatment with a TNF-α blocker in case of a switch from another TNF-α blocker to golimumab. Disease activity was measured with the Ankylosing Spondylitis Disease Activity Score – C-reactive protein (ASDAS). Response to treatment was assessed with the ASAS-20. Results In total, 93 patients (65% male) were evaluable as per protocol, with a mean age of 44±13 years and a median disease duration of 7 (0–53) years. Fifty-one patients (55%) were TNF-α blocker naive. Median ASDAS score at baseline was 3.1 (0.7–5.5), which decreased to 1.9 (0.1–5.1) at 12 months. ASAS-20 response was achieved by 36% of patients at month three (p<0.001), and by 49% of patients at month twelve (p<0.001). Six patients (7%) had a prior history of AAU with a total of nine attacks in the year prior to the first TNF-α blocker use (9.8/100 patient years). During golimumab treatment, the rate of recurring AAU attacks was reduced to two new attacks (2.2/100 patient years), a significant reduction of 78% (p<0.001). These two AAU attacks occurred in two separate patients, of whom one had no history of AAU. Conclusions Treatment of AS patients with golimumab leads to a significant decrease in disease activity. Simultaneously, the rate of recurring AAU attacks decreased significantly during golimumab treatment. References Stolwijk C, van TA, Castillo-Ortiz JD, Boonen A. Prevalence of extra-articular manifestations in patients with ankylosing spondylitis: a systematic review and meta-analysis. Ann Rheum Dis 2015 Jan;74(1):65–73. Inman RD, Davis JC, Jr., Heijde D, Diekman L, Sieper J, Kim SI, et al. Efficacy and safety of golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, phase III trial. Arthritis Rheum 2008 Nov;58(11):3402–12. Van Denderen JC, Visman IM, Nurmohamed MT, Suttorp-Schulten MS, van der Horst-Bruinsma IE. Adalimumab significantly reduces the recurrence rate of anterior uveitis in patients with ankylosing spondylitis. J Rheumatol 2014 Sep;41(9):1843–8. Disclosure of Interest S. Heslinga: None declared, M. Nurmohamed: None declared, A. Gerards: None declared, E. Griep: None declared, C. Koehorst: None declared, M. Kok: None declared, A. Schilder: None declared, M. Verhoef Employee of: Merck Sharp & Dohme the Netherlands, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA., I. Van der Horst-Bruinsma Grant/research support from: This study was funded by Merck Sharp & Dohme the Netherlands, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

THU0228 Reduction of Inflammation Drives Lipid Changes in Ankylosing Spondylitis

Background In inflammatory diseases, including ankylosing spondylitis (AS), systemic inflammation induces secondary dyslipidaemia with lower total cholesterol (TC) and lower high density cholesterol (HDL-C) levels. Effective anti-inflammatory treatment with tumor necrosis factor (TNF) alpha-blocking therapy has been shown to increase lipid levels, which as a result, may affect cardiovascular (CV) risk. It is still unclear whether lipid changes following TNF-alpha blocking therapy are due to suppressed inflammation, or due to a specific effect of TNF-alpha blocking therapy. Objectives We investigated the effects of changing inflammation levels during treatment with TNF-alpha blocking therapy on the lipid profile in AS patients. Methods 230 consecutive AS patients with an indication for TNF-alpha blocking therapy with etanercept or adalimumab were enrolled. Data was collected at baseline and after 52 weeks of treatment. Serum C-reactive protein (CRP) was measured at each visit. High inflammatory status was defined as CRP≥10mg/L. Non-fasting lipid samples were collected at baseline and at 52 weeks. Results CRP decreased significantly during treatment from 8 (3-22) to 2 (1-6) mg/l (p<0.01). TC, HDL-C and low density lipoprotein cholesterol (LDL-C) increased significantly with 4.6%, 3.7%, and 4.3% respectively. Apolipoprotein A-1 increased with 5.3%, while apolipoprotein B did not change. The TC/HDL-C ratio was not significantly changed after 52 weeks of TNF-alpha blocking therapy. Regression analyses yielded an inverse association between changes in CRP and changes in TC (+0.104 mmol/l per 10mg/l reduction in CRP) and HDL-C (+0.024mmol/l per 10mg/l reduction in CRP) but not TC/HDL-C ratio. Significant changes in TC (+8.2%) and HDL-C (+8.3%) levels were only seen in patients whom CRP levels decreased during treatment from ≥10 mmol/l to <10mmol/l, but again, the TC/HDL-C ratio did not change. Conclusions TNF-alpha blocking therapy is associated with a modest, but broadly parallel increase in TC, LDL-C, and HDL-C that might affect CV risk. Also, our data show, for the first time, that lipid changes following TNF-alpha blocking therapy are mostly due to suppressing inflammation and not to a specific TNF-alpha blocking therapy effect. Finally, consistent with previous findings, our data illustrate that the TC/HDL-C ratio is not appreciably altered by TNF-alpha blocking therapy and is therefore currently the most appropriate marker to determine CV risk in patients with an inflammatory condition. Disclosure of Interest None declared

SAT0266 Very High Prevalence of Cardiac Disease in Ankylosing Spondylitis Patients

Background Ankylosing spondylitis (AS) is associated with increased risk of cardiac disease, such as valvular regurgitation, conduction disturbances and decreased ventricular function [1]. However, contemporary data are not available and therefore we investigated the prevalence of cardiac manifestations in AS patients between 50 and 75 years old. Objectives To determine the prevalence of cardiac disease in older AS patients with and without a cardiovascular history. Methods We performed a cross sectional study in randomly selected AS patients between 50 and 75 years old. Patients were screened for cardiac disease using standard transthoracic echocardiography (TTE) that included two-dimensional, three-dimensional and M-mode echocardiography, spectral Doppler, color Doppler and tissue Doppler imaging. Systolic left ventricular (LV) dysfunction was defined as an ejection fraction <50%. Diastolic LV dysfunction (DD) was graded into three categories: mild (grade I), pseudonormal (grade II) and restrictive (grade III). Valvular parameters and aortic diameters were evaluated according to the current echocardiographic guidelines Results Sixty-nine AS patients (18 females, 26%) with a mean age of 60±7 years and a mean disease duration of 22±13 years were included. 16 patients (23%) had a history of cardiovascular disease, including stroke (n=2), myocardial infarction (n=3), rhythm disorders (n=5), or a combination (n=6). Of all patients, 33% had DD grade I, 13% DD grade II and 0% DD grade III and 3 patients (4%) had systolic LV dysfunction. In patients without a history of cardiovascular disease, a new cardiac abnormality was found on TTE in 14 (20%) which required treatment or follow-up by a cardiologist: ventricular dysfunction (n=2), aortic (root) dilatation (n=7), valvular regurgitation (n=2), rhythm disorders (n=1), other (n=1) or a combination (n=1). Conclusions In patients with a long duration of AS, without a history of cardiac disease or symptoms, there is a high prevalence of cardiac manifestations, with high prevalences of LV dysfunction, valvular disease and aortic (root) dilatation. This high prevalence might ultimately translate into increased cardiovascular morbidity and mortality. Obviously, the potential clinical impact and effect on cardiovascular mortality remains to be determined. References Nurmohamed MT, van der Horst-Bruinsma I, Maksymowych WP. Cardiovascular and cerebrovascular diseases in ankylosing spondylitis: current insights. Curr Rheumatol Rep 2012 Oct;14(5):415-21. Acknowledgements This study was partially financed by the Dutch Arthritis Association, The Netherlands Disclosure of Interest None declared

SAT0282 C-reactive protein (CRP) polymorphisms and haplotypes influence serum CRP levels independent of disease activity (BASDAI) in ankylosing spondylitis

Background C-reactive protein (CRP) levels are used more frequently for determination of disease activity in patients with Ankylosing Spondylitis (AS), but these levels do not necessarily reflect disease activity in each patient. Objectives We investigated whether CRP levels were influenced by common single-nucleotide polymorphisms (SNPs) and haplotypes in the CRP gene in AS patients. Additionally, we studied the relation between CRP levels and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Methods In this exploratory cross-sectional study, 189 unrelated anti-tumour necrosis factor naïve Dutch Caucasian AS patients were included and CRP SNPs rs2794521, rs3091244, rs1800947, and rs876538 were genotyped and haplotypes constructed. We used a multivariate linear and logistic regression model to investigate the relation between the SNPs and baseline CRP levels (mg/l), controlling for NSAID use, BMI, smoking, age, sex, and using the BASDAI to correct for disease activity. Results CRP levels were significantly positively correlated with the BASDAI (p=0.001). AS patients with genotype CA of the tri-allelic (C>T>A) SNP rs3091244 were associated with significantly higher CRP levels when compared with genotype CC (CA: 18.6 mg/l vs. CC: 8.3 mg/l; p=0.02). Heterozygous carriers of haplotype 5 (tagged by allele A of rs3091244) had a significantly higher odd when compared with non-carriers to have a CRP value >10 mg/l (OR=2.9, 95%CI 1.0 to 8.3; p=0.05) in the multivariate regression model. Figure 1. Baseline CRP values in mg/l for the SNP rs3091244 observed genotypes. CRP values were backtransformed after natural logarithmic correction. Data are represented as mean ± upper 95% CI. P values are indicated. Conclusions Certain CRP polymorphisms (SNP rs3091244 genotypes) and the haplotype tagged by allele A are associated with high CRP levels in AS, independent of the BASDAI and other confounders. Therefore, carrying distinct genetic variants might explain the lack of elevated CRP levels despite high disease activity in certain AS patients. This observation can be important to interpret disease activity scores that incorporate CRP levels, like the Ankylosing Spondylitis Disease Activity Score (ASDAS). Disclosure of Interest None Declared