Bozena Möller

Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease caused by both genetic and environmental factors. Genome scans in families with SLE point to multiple potential chromosomal regions that harbor SLE susceptibility genes, and association studies in different populations have suggested several susceptibility alleles for SLE. Increased production of type I interferon (IFN) and expression of IFN-inducible genes is commonly observed in SLE and may be pivotal in the molecular pathogenesis of the disease. We analyzed 44 single-nucleotide polymorphisms (SNPs) in 13 genes from the type I IFN pathway in 679 Swedish, Finnish, and Icelandic patients with SLE, in 798 unaffected family members, and in 438 unrelated control individuals for joint linkage and association with SLE. In two of the genes--the tyrosine kinase 2 (TYK2) and IFN regulatory factor 5 (IRF5) genes--we identified SNPs that displayed strong signals in joint analysis of linkage and association (unadjusted P<10(-7)) with SLE. TYK2 binds to the type I IFN receptor complex and IRF5 is a regulator of type I IFN gene expression. Thus, our results support a disease mechanism in SLE that involves key components of the type I IFN system.

Cardiovascular events in early RA are a result of inflammatory burden and traditional risk factors: a five year prospective study

IntroductionCo-morbidity and mortality due to cardiovascular disease (CVD) are increased in patients with rheumatoid arthritis (RA). Most published studies in this field are retrospective or cross sectional. We investigated the presence of traditional and disease related risk factors for CVD at the onset of RA and during the first five years following diagnosis. We also evaluated their potential for predicting a new cardiovascular event (CVE) during the five-year follow-up period and the modulatory effect of pharmacological treatment.MethodsAll patients from the four northern-most counties of Sweden with early RA are, since December 1995, consecutively recruited at diagnosis (T0) into a large survey on the progress of the disease. Information regarding cardiovascular co-morbidity and related predictors was collected from clinical records and supplemented with questionnaires. By April 2008, 700 patients had been included of whom 442 patients had reached the five-year follow-up (T5).ResultsAmong the 442 patients who reached T5 during the follow-up period, treatment for hypertension increased from 24.5 to 37.4% (P < 0.001)), diagnosis of diabetes mellitus (DM) from 7.1 to 9.5% (P < 0.01) whilst smoking decreased from 29.8 to 22.4% (P < 0.001) and the BMI from 26.3 to 25.8 (P < 0.05), respectively. By T5, 48 patients had suffered a new CVE of which 12 were fatal. A total of 23 patients died during the follow-up period. Age at disease onset, male sex, a previous CVE, DM, treatment for hypertension, triglyceride level, cumulative disease activity (area under the curve (AUC) disease activity score (DAS28)), extra-articular disease, corticosteroid use, shorter duration of treatment with disease modifying anti-rheumatic drugs (DMARDs) and use of COX-2 inhibitors increased the hazard rate for a new CVE. A raised erythrocyte sedimentation rate (ESR) at inclusion and AUC DAS28 at six months increased the hazard rate of CVE independently whilst DMARD treatment was protective in multiple Cox extended models adjusted for sex and CV risk factors. The risk of a CVE due to inflammation was potentiated by traditional CV risk factors.ConclusionsThe occurrence of new CV events in very early RA was explained by traditional CV risk factors and was potentiated by high disease activity. Treatment with DMARDs decreased the risk. The results may have implications for cardio-protective strategies in RA.

Oestrogen receptor α gene polymorphisms in systemic lupus erythematosus

Objective: To analyse associations of two oestrogen receptor α (ORα) gene polymorphisms in 260 patients with SLE from northern Sweden. The two polymorphisms, PvuII T/C and the XbaI A/G, are located in the first intron of the ORα gene. Methods: All patients fulfilling at least four of the ACR criteria for SLE were consecutively recruited during one year. The SLEDAI score and SLICC damage index were recorded. 670 individuals from the same geographical area served as controls. DNA from the patients and controls was extracted and genotyped using the 5′ nuclease assay with an ABI PRISM 7900HT instrument. The genotype/phenotype relationships were calculated using SPSS. Results: The unusual PvuII C allele was associated with malar rash and the unusual XbaI G allele with photosensitivity (p = 0.001, OR = 2.53, 95% CI = 1.43 to 4.47 and p = 0.007, OR = 2.12, 95% CI = 1.22 to 3.66, respectively). The common XbaI AA genotype was associated with serositis (p = 0.013, OR = 1.92, 95% CI = 1.15 to 3.22). Based on the SLICC damage index associations of the common TT genotype and AA genotype with cognitive impairment were identified (p = 0.018, OR = 2.47, 95% CI = 1.17 to 5.25 and p = 0.018, OR = 2.75, 95% CI = 1.19 to 6.38 respectively). There was also an association of the XbaI AA genotype with the angina/coronary artery bypass variable (p = 0.042, OR = 2.58, 95% CI = 1.03 to 6.43). Of the variables describing disease severity and duration it was found that carriers of the unusual PvuII C allele showed a later onset of SLE (p = 0.02) and carriers of the unusual XbaI G allele a lower SLICC damage index. Conclusions: The unusual PvuII C and XbaI G alleles were associated with a milder form of SLE characterised by skin manifestations, later onset, and less organ damage.

Age at onset determines severity and choice of treatment in early rheumatoid arthritis: a prospective study

IntroductionDisease activity, severity and comorbidity contribute to increased mortality in patients with rheumatoid arthritis (RA). We evaluated the impact of age at disease onset on prognostic risk factors and treatment in patients with early disease.MethodsIn this study, 950 RA patients were followed regularly from the time of inclusion (<12 months from symptom onset) for disease activity (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), tender and/or swollen joints, Visual Analogue Scale pain and global scores, and Disease Activity Score in 28 joints (DAS28)) and function (Health Assessment Questionnaire (HAQ)). Disease severity, measured on the basis of radiographs of the hands and feet (erosions based on Larsen score), extraarticular disease, nodules, and comorbidities and treatment (disease-modifying antirheumatic drugs (DMARDs), corticosteroids, biologics and nonsteroidal anti-inflammatory drugs) were recorded at the time of inclusion and at 5 years. Autoantibodies (rheumatoid factor, antinuclear antibodies and antibodies against cyclic citrullinated peptides (ACPAs)) and genetic markers (human leucocyte antibody (HLA) shared epitope and protein tyrosine phosphatase nonreceptor type 22 (PTPN22)) were analysed at the time of inclusion. Data were stratified as young-onset RA (YORA) and late-onset RA (LORA), which were defined as being below or above the median age at the time of onset of RA (58 years).ResultsLORA was associated with lower frequency of ACPA (P < 0.05) and carriage of PTPN22-T variant (P < 0.01), but with greater disease activity at the time of inclusion measured on the basis of ESR (P < 0.001), CRP (P < 0.01) and accumulated disease activity (area under the curve for DAS28 score) at 6 months (P < 0.01), 12 months (P < 0.01) and 24 months (P < 0.05), as well as a higher HAQ score (P < 0.01) compared with YORA patients. At baseline and 24 months, LORA was more often associated with erosions (P < 0.01 for both) and higher Larsen scores (P < 0.001 for both). LORA was more often treated with corticosteroids (P < 0.01) and less often with methotrexate (P < 0.001) and biologics (P < 0.001). YORA was more often associated with early DMARD treatment (P < 0.001). The results of multiple regression analyses supported our findings regarding the impact of age on chosen treatment.ConclusionYORA patients were more frequently ACPA-positive than LORA patients. LORA was more often associated with erosions, higher Larsen scores, higher disease activity and higher HAQ scores at baseline. Nevertheless, YORA was treated earlier with DMARDs, whilst LORA was more often treated with corticosteroids and less often with DMARDs in early-stage disease. These findings could have implications for the development of comorbidities.

The Extent of Subclinical Atherosclerosis Is Partially Predicted by the Inflammatory Load: A Prospective Study over 5 Years in Patients with Rheumatoid Arthritis and Matched Controls.

Objective. This prospective followup study investigated subclinical atherosclerosis in relation to traditional cardiovascular disease (CVD) risk factors and inflammation in patients with rheumatoid arthritis (RA) recruited at diagnosis compared with controls. Methods. Patients diagnosed with early RA were consecutively recruited into a prospective study. From these, a subgroup aged ≤ 60 years (n = 71) was consecutively included for ultrasound measurement of intima-media thickness (IMT) and flow-mediated dilation (FMD) at inclusion (T0) and after 5 years (T5). Age- and sex-matched controls (n = 40) were also included. Results. In the Wilcoxon signed-rank test, both IMT and FMD were significantly aggravated at T5 compared to baseline in patients with RA, whereas only IMT was significantly increased in controls. In univariate linear regression analyses among patients with RA, the IMT at T5 was significantly associated with age, systolic blood pressure (BP), cholesterol, triglycerides, Systematic Coronary Risk Evaluation (SCORE), and Reynolds Risk Score at baseline (p < 0.05). Similarly, FMD at T5 was significantly inversely associated with age, smoking, systolic BP, SCORE, and Reynolds Risk Score (p < 0.05). A model with standardized predictive value from multiple linear regression models including age, smoking, BP, and blood lipids at baseline significantly predicted the observed value of IMT after 5 years. When also including the area under the curve for the 28-joint Disease Activity Score over 5 years, the observed value of IMT was predicted to a large extent. Conclusion. This prospective study identified an increased subclinical atherosclerosis in patients with RA. In the patients with RA, several traditional CVD risk factors at baseline significantly predicted the extent of subclinical atherosclerosis 5 years later. The inflammatory load over time augmented this prediction.

Is Lipoprotein-Associated Phospholipase A2 a Link between Inflammation and Subclinical Atherosclerosis in Rheumatoid Arthritis?

Objective. Lipoprotein-associated phospholipase A2 (Lp-PLA2), a marker of vascular inflammation, is associated with cardiovascular disease. This prospective study of an inception cohort aimed to investigate whether the level of Lp-PLA2 is associated with subclinical atherosclerosis in patients with rheumatoid arthritis (RA). Methods. Patients from northern Sweden diagnosed with early RA were consecutively recruited into an ongoing prospective study. From these, all patients ≤60 years (n = 71) were included for measurements of subclinical atherosclerosis at inclusion (T0) and five years later (T5). Forty age- and sex-matched controls were included. The patients were clinically assessed, SCORE, Reynolds Risk Score, and Larsen score were calculated, and blood samples were drawn from all individuals at T0 and T5. Results. There was no significant difference in the level of Lp-PLA2 between patients with RA and controls (p > 0.05). In simple linear regression models among patients with RA, Lp-PLA2 at T0 was significantly associated with intima media thickness (IMT) at T0 and T5, flow mediated dilation (FMD) at T0 and T5, ever smoking, male sex, HDL-cholesterol (inversely), non-HDL-cholesterol, SCORE, Reynolds Risk Score, and Larsen score (p < 0.05). Conclusion. In this cohort of patients with early RA, the concentration of Lp-PLA2 was associated with both subclinical atherosclerosis and disease severity.

Performance of the Expanded Cardiovascular Risk Prediction Score for Rheumatoid Arthritis Is Not Superior to the ACC/AHA Risk Calculator

Objective. Cardiovascular (CV) risk estimation calculators for the general population do not perform well in patients with rheumatoid arthritis (RA). An RA-specific risk calculator has been developed, but did not perform better than a risk calculator for the general population when validated in a heterogeneous multinational cohort. Methods. In a cohort of patients with new-onset RA from northern Sweden (n = 665), the risk of CV disease was estimated by the Expanded Cardiovascular Risk Prediction Score for Rheumatoid Arthritis (ERS-RA) and the American College of Cardiology/American Heart Association algorithm (ACC/AHA). The ACC/AHA estimation was analyzed, both as crude data and when adjusted according to the recommendations by the European League Against Rheumatism (ACC/AHA × 1.5). ERS-RA was calculated using 2 variants: 1 from patient and physician reports of hypertension (HTN) and hyperlipidemia [ERS-RA (reported)] and 1 from assessments of blood pressure (BP) and blood lipids [ERS-RA (measured)]. The estimations were compared with observed CV events. Results. All variants of risk calculators underestimated the CV risk. Discrimination was good for all risk calculators studied. Performance of all risk calculators was poorer in patients with a high grade of inflammation, whereas ACC/AHA × 1.5 performed best in the high-inflammatory patients. In those patients with an estimated risk of 5–15%, no risk calculator performed well. Conclusion. ERS-RA underestimated the risk of a CV event in our cohort of patients, especially when risk estimations were based on patient or physician reports of HTN and hyperlipidemia instead of assessment of BP and blood lipids. The performance of ERS-RA was no better than that of ACC/AHA × 1.5, and neither performed well in high-inflammatory patients.

FRI0069 Comorbidity in Early Rheumatoid Arthritis - Which is the Role of Inflammation?

Background Patients with rheumatoid arthritis (RA) suffer from comorbidities that contribute to a shortened lifespan. Inflammation is of importance for the development of cardiovascular disease, but little is known on its relationship with other comorbidities in RA. Objectives To examine the prevalence of comorbidities in early RA and the role of inflammation in this context. Methods All patients with early RA (symptom duration <12 months) in Northern Sweden are since 1995 included in a prospective study on co-morbidities. By now 950 patients have been included. At the time of this compilation, 715 patients were followed-up of whom 498 had been ill for ≥5 years. Data on comorbidities, disease activity, x-ray (hands/feet), laboratory samples (autoantibodies, inflammatory variables) and pharmacological therapy were collected in record studies and further validated using a questionnaire at RA onset (T0) and after 5 years of disease (T5). Results 53% had one or more comorbidities at RA onset. By then, the most common comorbidities were hypertension (26.3%), obstructive pulmonary disease (13.9%), diabetes (8.0%), hypothyroidism (6.3%) and malignancy (5.0%). After 5 years, 41% had developed at least one new comorbidity; most common were hypertension (15.1%), malignancy (7.8%), stroke/TIA (5.1%), myocardial infarction (4.3%) and osteoporosis (3.7%). Univariate regression analyses showed that age (p<0.001), ESR (p<0.01), extra-articular RA (p<0.01), corticosteroids (p<0.001) were associated with a new comorbidity during 5 years. Female gender and biologics reduced this risk (p<0.01 for both). In a multiple regression model adjusted for age, sex, smoking and corticosteroids, ESR were associated with a new comorbidity at follow-up. In a similar model, the relationship between ESR and endocrine comorbidity approached significance (p=0,10). Conclusions There was substantial comorbidity among RA patients already at disease onset and considerable new comorbidity during the first five years of disease. Measures of disease activity were associated with occurrence of comorbidity. References Innala et al. Arthritis Res Ther 2011; 13: R131, Charlson et al. J Chron Dis, 1987; 40: 373-383, 25: 469-483, Norton et al. Rheumatol. 2013;52:99-110. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4651

FRI0134 Progression of subclinical atherosclerosis over five years in patients with early rheumatoid arthritis

Background Patients with rheumatoid arthritis (RA) have an increased mortality and morbidity due to cardiovascular disease (CVD). Premature atherosclerosis can be measured by ultrasound of intima media thickness (IMT) and of flow-mediated dilation (FMD). In patients with RA of recent onset, we have found IMT and FMD to be similar as in controls at diagnosis. Objectives In this prospective 5-year follow up, we aimed to investigate for increased progression of atherosclerosis in the patients with early RA compared to the controls. We also aimed to analyze the relationship between IMT and FMD and traditional CVD risk factors as well as markers of inflammation. Methods Patients from northern Sweden diagnosed with early RA are consecutively recruited into a ongoing prospective study of co-morbidity. From these patients, a subgroup aged ≤60 years (n=71), was consecutively included for measurements of IMT of a. carotis communis and FMD of a. brachialis. The ultrasound measurements were taken at inclusion (T0) and after 5 years (T5). 40 age-sex matched controls were included. The patients were clinically assessed (DAS28, TJC, SJC, DMARDs) and blood was analysed for cholesterol, HDL-cholesterol, triglycerides, ESR and CRP. SCORE and Reynolds Risk Score were calculated at T0 and T5. Results Patients with RA had a significant aggravation in both IMT (0.52 at T0 and 0.58 at T5, p<0.001) and FMD (109.2% at T0 and 107.0 at T5, p<0.001). In controls the increase was only significant for IMT (0.55 at T0 and 0.60 at T5, p<0.001). In simple linear regression analyses among RA-patients, the IMT at T5 was significantly associated with several variables at T0: systolic blood pressure (BP), cholesterol, triglycerides, SCORE and Reynolds Risk Score. In the corresponding analyses of FMD at T5, it was significantly inversely associated with age, smoking, SCORE as well as Reynolds Risk Score at T0 and area under the curve (AUC) for DAS28 over 60 months. In controls, the IMT at T5 was significantly associated with gender, age, systolic BP, cholesterol, triglycerides, HDL (inversly), BMI and SCORE at T0, whilst FMD was not significantly associated with any of the variables at T0. In a multiple regression model among RA-patients with age, systolic BP, triglycerides, cholesterol, HDL at T0 and AUC for DAS28 over 60 months, IMT at T5 was significantly associated with the BP and cholesterol. In another multiple regression model with age, smoking, cholesterol and AUC for DAS 28 over 60 months, FMD at T5 was significantly associated only with the AUC DAS28. Conclusions After five years, the increase in subclinical atherosclerosis tended to be more evident among patients with early RA compared to the controls. Both traditional CVD risk factors as well as inflammatory load over time seems to contribute to this increased atherosclerotic findings among patients with RA. Disclosure of Interest None Declared

SAT0086 Extent of Atherosclerosis is Associated with Biomarkers for Unstable Plaques: A Prospective Study Over Five Years in Rheumatoid Arthritis Patients and Matched Controls

Background In the general population several serological biomarkers, for example phospholipase A2 group 7 (PLA2G7), macrophage inhibitory cytokine 1 (MIC-1), soluble CD40 ligand (sCD40L), myeloperoxidase (MPO) and interleukin 18 (IL-18), have been found to be associated with unstable atherosclerotic plaques and hence with an increased risk of cardiovascular disease (CVD). These biomarkers are not well studied among patients with rheumatoid arthritis (RA). After five years of follow-up in patients with a recent onset of RA, we have found sub-clinical atherosclerosis, when measured as intima media thickness (IMT) and flow-mediated dilation (FMD), to be more progressive than in controls. Objectives The aim of the present study was to investigate whether this sub-clinical atherosclerosis could be associated with serological biomarkers of unstable plaques. Methods Patients from northern Sweden diagnosed with early RA are followed in an ongoing prospective study of co-morbidity. From these patients a subgroup aged ≤60 years (n=71), was consecutively included for measurements of IMT of a. carotis communis and FMD of a. brachialis. The ultrasound measurements were taken at inclusion (T0) and after 5 years (T5). 40 age/sex matched controls were included. The patients were clinically assessed (DAS28, TJC, SJC, DMARDs, ESR and CRP) and blood was drawn from all individuals at T0 and T5 for analysis of cholesterol, HDL-cholesterol, triglycerides, PLA2G7, MIC-1, sCD40L, MPO and IL-18. SCORE and Reynolds Risk Score were calculated at T0 and T5. Larsen score was calculated on x-rays taken at inclusion. Results At inclusion as well after 5 years, i.e. at T0 and T5, patients with RA had significantly higher levels of MIC-1 (1773 vs. 1216 at T0 and 1941 vs 1331 at T5, p<0.05) and IL-18 (334 vs 286, p<0.05, at T0 and 356 vs 303, p=0.062, at T5) compared with the controls. There were no difference between patients with RA and controls regarding any of the other biomarkers measured. In simple linear regression models at T0 among patients with RA the biomarkers were significantly associated with several other variables at T0: PLA2G7 with IMT, FMD, male sex, HDL-cholestrol (inversely), SCORE, Reynolds Risk score as well as the Larsen score (p<0.05); IL-18 with systolic and diastolic blood pressure as well as Reynolds Risk score (p<0.05); sCD40L with CRP (p<0.01). In the same simple regression models but after 5 years of follow up the biomarkers were significantly associated with other variables at T5: PLA2G7 with cholesterol, HDL-cholestrol (inversely), BMI and Reynolds Risk score at T5 (p<0.05); MIC-1 with IMT, smoking, age, BMI, SCORE as well as Reynolds Risk score (p<0.05); MPO with systolic blood pressure as well as BMI (p<0.05); sCD40L with area under the curve for CRP over 60 months (p=0.05). Conclusions Among patients with RA, followed prospectively over 5 years, biomarkers of unstable plaques were associated with sub-clinical atherosclerosis as well as with traditional CVD risk factors and inflammation. This might, in part, clarify the increased risk of CVD among patients with RA. Disclosure of Interest None Declared