Genome-wide analysis identifies novel susceptibility loci for myocardial infarction.

AIMS: While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation. METHODS AND RESULTS: We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1ß (vs. vehicle), and associated with smooth muscle cell migration in vitro. CONCLUSIONS: A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.

No increased cardiovascular mortality among early rheumatoid arthritis patients: a nationwide register study in 2000-2008.

OBJECTIVES: To assess cardiovascular (CV) mortality in early rheumatoid arthritis (RA), and the impact of RA medications on CV mortality. METHODS: We identified all incident RA patients over 18 years of age diagnosed between 2000 and 2007 in Finland. Causes of death were analysed until the end of the year 2008. We used competing-risks regression models to assess the impact of different variables such as RA medications on CV mortality. CV mortality was compared with that of the age- and sex-specific general population. RESULTS: We identified 14,878 incident RA patients (68% women, 63% rheumatoid factor (RF) positive, mean age 55.8/57.5 years in men/women), of whom more than 80% received RA medications for longer than 90% of their individual patient-years. By the end of 2008, 1,157 patients died, 501 (43%) of whom of CV causes. The standardised mortality ratio (SMR) for CV deaths in the entire RA cohort was 0.57 (95% CI 0.52 to 0.62). Along with traditional CV risk factors, the presence of RF and the use of glucocorticoids was associated with a higher risk of CV death, whereas the use of methotrexate was associated with a lower risk. CONCLUSIONS: These nationwide results suggest that patients with recent-onset RA who receive consistent RA medication have no increased risk for CV mortality compared to the general population, at least in the early years of the disease. The use of methotrexate is associated with lower CV mortality, whereas the use of glucocorticoids is associated with a higher than average CV mortality.

Increased risk of levothyroxine-treated hypothyroidism preceding the diagnosis of rheumatoid arthritis: a nationwide registry study.

OBJECTIVES: To evaluate the prevalence of levothyroxine-treated hypothyroidism in rheumatoid arthritis (RA) patients at the time of RA diagnosis in comparison to age- and sex-specific general population. Other objectives were to determine whether the risk of hypothyroidism varies by age at the onset of RA, or by sex or rheumatoid factor (RF) status. METHODS: We identified 7,209 incident RA patients diagnosed between January 2004 and December 2007 from a Finnish nationwide register of special reimbursements for medication costs. The presence of hypothyroidism at RA diagnosis was identified from the same register based on special reimbursement decisions for levothyroxine substitution. The prevalence of levothyroxine-treated hypothyroidism was compared to that of an age- and sex-specific Finnish population, and a standardised rate ratio (SRR) for hypothyroidism was calculated. RESULTS: The SRR for levothyroxine-treated hypothyroidism preceding RA was 1.51 (95% CI 1.35 to 1.67). Neither RF status nor sex modified the risk, although the results did not reach statistical significance among men. The SRR was highest, almost 2.5 among younger female RA patients (20-49 years of age), the excess prevalence of hypothyroidism decreasing steadily and wearing off among patients who were older at the time of diagnosis. The absolute prevalence of hypothyroidism, however, increased with age as it does in the general population. CONCLUSIONS: The risk of hypothyroidism is increased among RA patients already at the disease onset, especially among the young women, regardless of RF status. This calls for attention to screening for hypothyroidism in RA patients, preferably when RA has already been diagnosed.

Cardiovascular comorbidities antedating the diagnosis of rheumatoid arthritis.

OBJECTIVES: To assess the prevalence of coronary heart disease (CHD) and chronic hypertension among patients with rheumatoid arthritis (RA) at the time of diagnosis, in comparison with age-specific and sex-specific non-RA subjects. Furthermore, the impacts of age at the onset of RA, as well as gender and the presence of rheumatoid factor (RF) on the risk of these comorbidities, were evaluated. METHODS: A cohort of 7209 RA patients diagnosed between January 2004 and December 2007 was identified, based on a Finnish nationwide register on special reimbursements for medication costs. The presence of CHD and chronic hypertension antedating the diagnosis of RA was identified from the same register. The prevalence of the cardiovascular comorbidities was compared with the general Finnish population, and a standardised rate ratio (SRR) for both these cardiovascular diseases was calculated. RESULTS: The risk of having CHD at RA diagnosis was slightly elevated, the SRR being 1.10 (95% CI 1.01 to 1.20). Younger age at the onset of RA seemed to be related with higher SRR for CHD. In a subset analysis, an increased prevalence of hypertension (SRR 1.19, 95% CI 1.10 to 1.30) and CHD (SRR 1.15, 95% CI 1.00 to 1.32) was apparent only among the RF negative RA cases. CONCLUSIONS: The SRR for CHD is augmented in RA patients already at disease onset, and more pronouncedly in early onset RA. The findings highlight the importance of early prevention of atherosclerosis, regardless of RF status.

How early in the course of rheumatoid arthritis does the excess cardiovascular risk appear?

Rheumatoid arthritis (RA) is a chronic inflammatory disease which is associated with an increased cardiovascular (CV) burden. Whether the risk is already present at the time of RA diagnosis remains a key area of debate. The aim of this review was to evaluate the existence of both subclinical CV changes, including endothelial dysfunction and atherosclerosis, CV risk factors, as well as CV disease manifestations such as coronary heart disease, myocardial infarction, congestive heart failure and CV death prior to RA diagnosis and during the first few years of the disease. The state of the endothelial function remains controversial in patients with newly diagnosed RA. Studies with impaired brachial artery vasodilatory responses at baseline showed a reversal of the dysfunction after 6-12 months of anti-inflammatory therapy. Morphological evidence of arterial wall atherosclerosis, measured by carotid artery intima-media thickness or the prevalence of carotid plaques, was already present during the first year following RA diagnosis. The risk of coronary heart disease and myocardial infarction is increased even prior to and, at the latest, within 1 year of the clinical onset of RA. The prevalence of hypertension was similar among patients with RA and controls. CV mortality may not increase within the first years of RA diagnosis. In conclusion, the CV risk seems to increase sooner after the RA diagnosis than previously thought. In addition to systematic CV risk assessment, patients with early RA might benefit from being targeted with stricter than conventional CV risk prevention and intervention.

Adalimumab and sulfasalazine in alleviating sacroiliac and aortic inflammation detected in PET/CT in patients with axial spondyloarthritis: PETSPA.

AIM: Inflammatory signals in the sacroiliac (SI) joints and the aorta of patients with axial spondyloarthritis (axSpA) were graded by positron emission tomography/computed tomography (PET/CT) imaging before and after treatment with sulfasalazine (SSZ) or adalimumab (ADA). METHODS: Patients with axSpA, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4, were recruited. Disease-modifying antirheumatic drug-naïve patients started SSZ for 12 weeks, whereas those with prestudy treatment with or contraindication to SSZ commenced ADA for 16 weeks. In addition, those patients in the SSZ group with insufficient response commenced ADA for 16 weeks. 18F-fluorodeoxyglucose PET/CT was performed after inclusion and after treatment with SSZ and ADA. Maximum standardized uptake value (SUVmax) was assessed for the aorta and the SI joints, and maximal target-to-blood-pool ratio (TBRmax) only for the aorta. RESULTS: Among five SSZ patients, mean ± SD BASDAI was 4.7 ± 1.6 before and 3.5 ± 1.4 after treatment (p = .101). In 13 ADA patients, the BASDAI decreased from 5.4 ± 1.6 to 2.8 ± 2.2 (p < .001). Among the SSZ patients, SUVmax in SI joints decreased from 2.35 ± 0.55 to 1.51 ± 0.22 (-35.8%, p = .029). Aortic TBRmax decreased from 1.59 ± 0.43 to 1.26 ± 0.26 (-33.2%, p = .087). In the ADA patients, SUVmax in the SI joints was 1.92 ± 0.65 before and 1.88 ± 0.54 after treatment (-1.8%, p = .808) and TBRmax in the aorta 1.50 ± 0.60 before and 1.40 ± 0.26 after treatment (-6.7%, p = .485). CONCLUSIONS: Our small open-label study showed that SSZ may reduce PET-CT-detectable inflammation in the SI joints, with a trend towards a reduction in the aorta.