Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease in which the type I interferon pathway has a crucial role. We have previously shown that three genes in this pathway, IRF5, TYK2 and STAT4, are strongly associated with risk for SLE. Here, we investigated 78 genes involved in the type I interferon pathway to identify additional SLE susceptibility loci. First, we genotyped 896 single-nucleotide polymorphisms in these 78 genes and 14 other candidate genes in 482 Swedish SLE patients and 536 controls. Genes with P<0.01 in the initial screen were then followed up in 344 additional Swedish patients and 1299 controls. SNPs in the IKBKE, TANK, STAT1, IL8 and TRAF6 genes gave nominal signals of association with SLE in this extended Swedish cohort. To replicate these findings we extracted data from a genomewide association study on SLE performed in a US cohort. Combined analysis of the Swedish and US data, comprising a total of 2136 cases and 9694 controls, implicates IKBKE and IL8 as SLE susceptibility loci (P(meta)=0.00010 and P(meta)=0.00040, respectively). STAT1 was also associated with SLE in this cohort (P(meta)=3.3 × 10⁻⁵), but this association signal appears to be dependent of that previously reported for the neighbouring STAT4 gene. Our study suggests additional genes from the type I interferon system in SLE, and highlights genes in this pathway for further functional analysis.

OBJECTIVES: Chronic inflammation promotes cardiovascular risk in rheumatoid arthritis (RA). Biological disease-modifying antirheumatic drugs (bDMARDs) improve disease activity and cardiovascular disease outcomes. We explored whether bDMARDs influence the impact of disease activity and inflammatory markers on long-term cardiovascular risk in RA. METHODS: We studied 4370 participants without cardiovascular disease in a 10-country observational cohort of patients with RA. Endpoints were (1) major adverse cardiovascular events (MACE) encompassing myocardial infarction, stroke and cardiovascular death; and (2) any ischaemic cardiovascular events (iCVE) including MACE plus revascularisation, angina, transient ischaemic attack and peripheral arterial disease. RESULTS: Over 26 534 patient-years, 239 MACE and 362 iCVE occurred. The interaction between 28-joint Disease Activity Score with C-reactive protein (DAS28-CRP) and bDMARD use was significant for MACE (p=0.017), suggesting the effect of DAS28-CRP on MACE risk differed among bDMARD users (n=515) and non-users (n=3855). DAS28-CRP (per unit increase) is associated with MACE risk in bDMARD non-users (HR 1.21 (95% CI 1.07 to 1.37)) but not users (HR 0.69 (95% CI 0.40 to 1.20)). The interaction between CRP (per log unit increase) and bDMARD use was also significant for MACE (p=0.011). CRP associated with MACE risk in bDMARD non-users (HR 1.16 (95% CI 1.04 to 1.30)), but not users (HR 0.65 (95% CI 0.36 to 1.17)). No interaction was observed between bDMARD use and DAS28-CRP (p=0.167) or CRP (p=0.237) for iCVE risk. CONCLUSIONS: RA activity and inflammatory markers associated with risk of MACE in bDMARD non-users but not users suggesting the possibility of biological-specific benefits locally on arterial wall independently of effects on systemic inflammation.

The objective was to examine the prevalence of atherosclerotic cardiovascular disease (ASCVD) and its risk factors among patients with RA with diabetes mellitus (RA-DM) and patients with RA without diabetes mellitus (RAwoDM), and to evaluate lipid and blood pressure (BP) goal attainment in RA-DM and RAwoDM in primary and secondary prevention. The cohort was derived from the Survey of Cardiovascular Disease Risk Factors in Patients with Rheumatoid Arthritis from 53 centres/19 countries/3 continents during 2014-2019. We evaluated the prevalence of cardiovascular disease (CVD) among RA-DM and RAwoDM. The study population was divided into those with and without ASCVD, and within these groups we compared risk factors and CVD preventive treatment between RA-DM and RAwoDM. The study population comprised of 10 543 patients with RA, of whom 1381 (13%) had DM. ASCVD was present in 26.7% in RA-DM compared with 11.6% RAwoDM (p<0.001). The proportion of patients with a diagnosis of hypertension, hyperlipidaemia and use of lipid-lowering or antihypertensive agents was higher among RA-DM than RAwoDM (p<0.001 for all). The majority of patients with ASCVD did not reach the lipid goal of low-density lipoprotein cholesterol <1.8 mmol/L. The lipid goal attainment was statistically and clinically significantly higher in RA-DM compared with RAwoDM both for patients with and without ASCVD. The systolic BP target of <140 mm Hg was reached by the majority of patients, and there were no statistically nor clinically significant differences in attainment of BP targets between RA-DM and RAwoDM. CVD preventive medication use and prevalence of ASCVD were higher in RA-DM than in RAwoDM, and lipid goals were also more frequently obtained in RA-DM. Lessons may be learnt from CVD prevention programmes in DM to clinically benefit patients with RA .

Objectives

Cardiovascular disease (CVD) risk calculators developed for the general population do not accurately predict CVD events in patients with RA. We sought to externally validate risk calculators recommended for use in patients with RA including the EULAR 1.5 multiplier, the Expanded Cardiovascular Risk Prediction Score for RA (ERS-RA) and QRISK2.

Methods

Seven RA cohorts from UK, Norway, Netherlands, USA, South Africa, Canada and Mexico were combined. Data on baseline CVD risk factors, RA characteristics and CVD outcomes (including myocardial infarction, ischaemic stroke and cardiovascular death) were collected using standardized definitions. Performance of QRISK2, EULAR multiplier and ERS-RA was compared with other risk calculators [American College of Cardiology/American Heart Association (ACC/AHA), Framingham Adult Treatment Panel III Framingham risk score-Adult Treatment Panel (FRS-ATP) and Reynolds Risk Score] using c-statistics and net reclassification index.

Results

Among 1796 RA patients without prior CVD [mean ( s . d .) age: 54.0 (14.0) years, 74% female], 100 developed CVD events during a mean follow-up of 6.9 years (12430 person-years). Estimated CVD risk by ERS-RA [mean ( s . d .) 8.8% (9.8%)] was comparable to FRS-ATP [mean ( s . d .) 9.1% (8.3%)] and Reynolds [mean ( s . d .) 9.2% (12.2%)], but lower than ACC/AHA [mean ( s . d .) 9.8% (12.1%)]. QRISK2 substantially overestimated risk [mean ( s . d .) 15.5% (13.9%)]. Discrimination was not improved for ERS-RA (c-statistic = 0.69), QRISK2 or EULAR multiplier applied to ACC/AHA compared with ACC/AHA (c-statistic = 0.72 for all) or for FRS-ATP (c-statistic = 0.75). The net reclassification index for ERS-RA was low (-0.8% vs ACC/AHA and 2.3% vs FRS-ATP).

Conclusion

The QRISK2, EULAR multiplier and ERS-RA algorithms did not predict CVD risk more accurately in patients with RA than CVD risk calculators developed for the general population.

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2 - 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses--as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes--to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.