Cumulative inflammatory burden is independently associated with increased arterial stiffness in patients with psoriatic arthritis: a prospective study

IntroductionThe aim of this study was to examine whether the cumulative inflammatory burden is associated with an increase in arterial stiffness in a prospective cohort of psoriatic arthritis (PsA) patients.MethodsIn total, 72 PsA patients were followed for a median of 6.5 years. Cumulative inflammatory burden was represented by the cumulative averages of repeated measures of erythrocyte sedimentation rate (ca-ESR) and C-reactive protein (ca-CRP). Brachial-ankle pulse wave velocity (PWV) was measured at the last visit. We also included 47 healthy controls for PWV assessment.ResultsPWV was significantly higher in PsA patients compared with healthy controls after adjustment for age, gender and body weight (1466 ± 29 cm/s versus 1323 ± 38 cm/s, P = 0.008). PsA patients were divided into two groups based on whether their PWV value is ≥1450 cm/s (High PWV group, N = 38) or <1450 cm/s (Low PWV group, N = 34). The High PWV group had a significantly higher ca-ESR (29 (19 to 44) versus 18 (10 to 32) mm/1st hour, P = 0.005) and ca-CRP (0.7 (0.3 to 1.4) versus 0.4 (0.2 to 0.7) mg/dl, P = 0.029). Using regression analysis, high ca-ESR (defined as ≥75th percentile: 37 mm/1st hour) was associated with a higher likelihood of being in the High PWV group (odds ratio (OR): 9.455 (1.939 to 46.093), P = 0.005, adjusted for baseline clinical and cardiovascular risk factors; and 9.111 (1.875 to 44.275), P = 0.006, adjusted for last visit parameters).ConclusionsCumulative inflammatory burden, as reflected by ca-ESR, was associated with increased arterial stiffness in PsA patients even after adjustment for cardiovascular risk factors, emphasizing the important role of chronic inflammation in accelerating the development of cardiovascular risks in PsA patients.     

Body mass index modulates the relationship of sugar-sweetened beverage intake with serum urate concentrations and gout

IntroductionBoth sugar-sweetened beverage (SSB) intake and body mass index (BMI) are associated with elevated serum urate concentrations and gout risk. The aim of this study was to determine whether the associations of SSB intake with serum urate and gout are moderated by BMI.MethodThe effects of chronic SSB intake on serum urate and gout status were analysed in a large cross-sectional population study. The effects of an acute fructose load on serum urate and fractional excretion of uric acid (FEUA) were examined over 180 minutes in a short-term intervention study. In all analyses, the responses were compared in those with BMI <25 mg/kg² (low BMI) and ≥25 mg/kg² (high BMI).ResultsIn the serum urate analysis (n = 12,870), chronic SSB intake was associated with increased serum urate in the high BMI group, but not in the low BMI group (P_difference = 3.6 × 10⁻³). In the gout analysis (n = 2578), chronic high SSB intake was associated with gout in the high BMI group, but not in the low BMI group (P_difference = 0.012). In the acute fructose loading study (n = 76), serum urate was increased in the high BMI group at baseline and throughout the observation period (P_{BMI group} <0.0001), but there were similar acute serum urate increases in both BMI groups in response to the fructose load (P_interaction = 0.99). The baseline FEUA was similar between the two BMI groups. However, following the fructose load, FEUA responses in the BMI groups differed (P_interaction <0.0001), with increased FEUA at 120 minutes and 180 minutes in the low BMI group and reduced FEUA at 60 minutes in the high BMI group.ConclusionsThese data suggest that BMI influences serum urate and gout risk in response to chronic SSB intake, and renal tubular uric acid handling in response to an acute fructose load. In addition to many other health benefits, avoidance of SSBs may be particularly important in those with overweight/obesity to prevent hyperuricaemia and reduce gout risk.

Trials registration

Australian Clinical Trials Registry ACTRN12610001036000. Registered 24 November 2010.     

Association analysis of the SLC22A11 (organic anion transporter 4) and SLC22A12 (urate transporter 1) urate transporter locus with gout in New Zealand case-control sample sets reveals multiple ancestral-specific effects

Introduction

There is inconsistent association between urate transporters SLC22A11 (organic anion transporter 4 (OAT4)) and SLC22A12 (urate transporter 1 (URAT1)) and risk of gout. New Zealand (NZ) Māori and Pacific Island people have higher serum urate and more severe gout than European people. The aim of this study was to test genetic variation across the SLC22A11/SLC22A12 locus for association with risk of gout in NZ sample sets.

Methods

A total of 12 single nucleotide polymorphism (SNP) variants in four haplotype blocks were genotyped using TaqMan® and Sequenom MassArray in 1003 gout cases and 1156 controls. All cases had gout according to the 1977 American Rheumatism Association criteria. Association analysis of single markers and haplotypes was performed using PLINK and Stata.

Results

A haplotype block 1 SNP (rs17299124) (upstream of SLC22A11) was associated with gout in less admixed Polynesian sample sets, but not European Caucasian (odds ratio; OR = 3.38, P = 6.1 × 10^-4; OR = 0.91, P = 0.40, respectively) sample sets. A protective block 1 haplotype caused the rs17299124 association (OR = 0.28, P = 6.0 × 10^-4). Within haplotype block 2 (SLC22A11) we could not replicate previous reports of association of rs2078267 with gout in European Caucasian (OR = 0.98, P = 0.82) sample sets, however this SNP was associated with gout in Polynesian (OR = 1.51, P = 0.022) sample sets. Within haplotype block 3 (including SLC22A12) analysis of haplotypes revealed a haplotype with trans-ancestral protective effects (OR = 0.80, P = 0.004), and a second haplotype conferring protection in less admixed Polynesian sample sets (OR = 0.63, P = 0.028) but risk in European Caucasian samples (OR = 1.33, P = 0.039).

Conclusions

Our analysis provides evidence for multiple ancestral-specific effects across the SLC22A11/SLC22A12 locus that presumably influence the activity of OAT4 and URAT1 and risk of gout. Further fine mapping of the association signal is needed using trans-ancestral re-sequence data.     

The relationship of apolipoprotein B and very low density lipoprotein triglyceride with hyperuricemia and gout

Introduction

Gout results from an innate immune response to monosodium urate (MSU) crystals deposited in joints. Increased very low-density lipoprotein (VLDL) has been associated with gout. The apolipoprotein B (apo B), which is present on VLDL, regulates neutrophil response to MSU crystals and has been positively associated with gout. Furthermore, the gene (A1CF) encoding the complementation factor for the APOB mRNA-editing enzyme is associated with urate levels. However, the relationship of apo B and VLDL with gout and hyperuricaemia (HU) is still unclear. Therefore, we tested the association of VLDL and apo B with HU and with gout compared to HU.

Methods

New Zealand European (n = 90) and Māori and Pacific Island (Polynesian) (n = 90) male gout case and control sample sets were divided into normouricaemia (NU), asymptomatic HU and gout groups. Size exclusion chromatography and enzyme-linked immunosorbant assay was used to measure VLDL and apo B. Multivariate logistic regression was used to assess the risk of gout and HU per unit change in VLDL and apo B.

Results

Increased levels of VLDL triglycerides (Tg) were observed in the gout sample set compared to NU and HU in Europeans (P = 1.8 × 10^-6 and 1 × 10^-3, respectively), but only compared to NU in Polynesians (P = 0.023). This increase was driven by increased number of VLDL particles in the European participants and by the Tg-enrichment of existing VLDL particles in the Polynesian participants. Each mmol/L increase in VLDL Tg was significantly associated with gout in the presence of HU in Europeans, with a similar trend in Polynesians (OR = 7.61, P = 0.011 and 2.84, P = 0.069, respectively). Each μmol/L increase in total apo B trended towards decreased risk of HU (OR = 0.47; P = 0.062) and, conversely, with increased risk of gout compared to HU (OR = 5.60; P = 0.004).

Conclusions

Increased VLDL Tg is associated with the risk of gout compared to HU. A genetic approach should be taken to investigate the possibility for causality of VLDL in gout. Apolipoprotein B may have pleiotropic effects in determining HU and gout.     

Associations between circulating endostatin levels and vascular organ damage in systemic sclerosis and mixed connective tissue disease: an observational study

IntroductionSystemic sclerosis (SSc) and mixed connective tissue disease (MCTD) are chronic immune-mediated disorders complicated by vascular organ damage. The aim of this study was to examine the serum levels of the markers of neoangiogenesis: endostatin and vascular endothelial growth factor (VEGF), in our unselected cohorts of SSc and MCTD.MethodsSera of SSc patients (N = 298) and MCTD patients (N = 162) from two longitudinal Norwegian cohorts were included. Blood donors were included as controls (N = 100). Circulating VEGF and endostatin were analyzed by enzyme immunoassay.ResultsMean endostatin levels were increased in SSc patients 93.7 (37) ng/ml (P < .001) and MCTD patients 83.2 (25) ng/ml (P < .001) compared to controls 65.1 (12) ng/ml. Median VEGF levels were elevated in SSc patients 209.0 (202) pg/ml compared to MCTD patients 181.3 (175) pg/ml (P = .017) and controls 150.0 (145) pg/ml (P < .001). Multivariable analysis of SSc subsets showed that pulmonary arterial hypertension (coefficient 15.7, 95 % CI: 2.2–29.2, P = .023) and scleroderma renal crisis (coefficient 77.6, 95 % CI: 59.3–100.0, P < .001) were associated with elevated endostatin levels. Multivariable analyses of MCTD subsets showed that digital ulcers were associated with elevated endostatin levels (coefficient 10.5, 95 % CI: 3.2–17.8, P = .005). The risk of death increased by 1.6 per SD endostatin increase (95 % CI: 1.2–2.1, P = .001) in the SSc cohort and by 1.6 per SD endostatin increase (95 % CI: 1.0–2.4, P = .041) in the MCTD cohort after adjustments to known risk factors.ConclusionsEndostatin levels were elevated in patients with SSc and MCTD, particularly SSc patients with pulmonary arterial hypertension and scleroderma renal crisis, and MCTD patients with digital ulcers. Elevated endostatin levels were also associated with increased all-cause mortality during follow-up in both groups of patients. We propose that endostatin might indicate the degree of vascular injury in SSc and MCTD patients.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0756-5) contains supplementary material, which is available to authorized users.     

Impact of Visceral Fat on Skeletal Muscle Mass and Vice Versa in a Prospective Cohort Study: The Korean Sarcopenic Obesity Study (KSOS)

Objectives

Sarcopenia and visceral obesity have been suggested to aggravate each other, resulting in a vicious cycle. However, evidence based on prospective study is very limited. Our purpose was to investigate whether visceral fat promotes a decrease in skeletal muscle mass and vice versa.

Methods

We observed changes in anthropometric and body composition data during a follow-up period of 27.6±2.8 months in 379 Korean men and women (mean age 51.9±14.6 years) from the Korean Sarcopenic Obesity Study (KSOS). Appendicular lean soft tissue (ALST) mass was calculated using dual-energy X-ray absorptiometry, and visceral fat area (VFA) was measured using computed tomography at baseline and follow-up examination.

Results

ALST mass significantly decreased, whereas trunk and total fat mass increased in both men and women despite no significant change in weight and body mass index. In particular, women with visceral obesity at baseline had a greater decrease in ALST mass than those without visceral obesity (P = 0.001). In multiple linear regression analysis, baseline VFA was an independent negative predictor of the changes in ALST after adjusting for confounding factors including age, gender, life style and body composition parameters, insulin resistance, high sensitivity C-reactive protein and vitamin D levels (P = 0.001), whereas the association between baseline ALST mass and changes in VFA was not statistically significant (P = 0.555).

Conclusions

This longitudinal study showed that visceral obesity was associated with future loss of skeletal muscle mass in Korean adults. These results may provide novel insight into sarcopenic obesity in an aging society.     

Early cartilage abnormalities at the hip are associated with obesity and body composition measures – a 3.0T MRI community-based study

IntroductionAlthough obesity is a risk factor for hip osteoarthritis (OA), the role of body composition, if any, is unclear. This study examines whether the body mass index (BMI) and body composition are associated with hip cartilage changes using magnetic resonance imaging (MRI) in community-based adults.Methods141 community-based participants with no clinical hip disease, including OA, had BMI and body composition (fat mass and fat free mass) measured at baseline (1990 to 1994), and BMI measured and 3.0 T MRI performed at follow-up (2009–2010). Femoral head cartilage volume was measured and femoral head cartilage defects were scored in the different hip regions.ResultsFor females, baseline BMI (β = −26 mm³, 95% Confidence interval (CI) -47 to −6 mm³, p = 0.01) and fat mass (β = −11 mm³, 95% CI −21 to −1 mm³, p = 0.03) were negatively associated with femoral head cartilage volume. Also, while increased baseline fat mass was associated with an increased risk of cartilage defects in the central superolateral region of the femoral head (Odds Ratio (OR) = 1.08, 95% CI 1.00–1.15, p = 0.04), increased baseline fat free mass was associated with a reduced risk of cartilage defects in this region (OR = 0.82, 95% CI 0.67–0.99; p = 0.04). For males, baseline fat free mass was associated with increased femoral head cartilage volume (β = 40 mm³, 95% CI 6 to 74 mm³, p = 0.02).ConclusionsIncreased fat mass was associated with adverse hip cartilage changes for females, while increased fat free mass was associated with beneficial cartilage changes for both genders. Further work is required to determine whether modifying body composition alters the development of hip OA.     

Association of the lipoprotein receptor-related protein 2 gene with gout and non-additive interaction with alcohol consumption

Introduction

The T allele of a single nucleotide polymorphism (SNP: rs2544390) in lipoprotein receptor-related protein 2 (LRP2) is associated with higher serum urate and risk of gout in Japanese individuals. SNP rs2544390 also interacts with alcohol consumption in determining hyperuricemia in this population. We investigated the association of rs2544390 with gout, and interaction with all types of alcohol consumption in European and New Zealand (NZ) Māori and Pacific subjects, and a Māori study cohort from the East Coast region of NZ’s North Island.

Methods

Rs2544390 was genotyped by Taqman®. From NZ a total of 1205 controls and 1431 gout cases clinically ascertained were used. Publicly available genotype and serum urate data were utilized from the Atherosclerosis Risk in Communities (ARIC) study and the Framingham Heart Study (FHS). Alcohol consumption data were obtained by consumption frequency questions in all study cohorts. Multivariate adjusted logistic regression was done using STATA.

Results

The T allele of rs2544390 was associated with increased risk of gout in the combined Māori and Pacific Island cohort (OR = 1.20, P = 0.009), and associated with gout in the European subjects, but with a protective effect (OR = 0.79, P_Unadjusted = 0.02). Alcohol consumption was positively associated with risk of gout in Māori and Pacific subjects (0.2% increased risk/g/week, P = 0.004). There was a non-additive interaction between any alcohol intake and the risk of gout in the combined Māori and Pacific cohorts (P_Interaction = 0.001), where any alcohol intake was associated with a 4.18-fold increased risk in the CC genotype group (P = 6.6x10^-5), compared with a 1.14-fold increased risk in the CT/TT genotype group (P = 0.40). These effects were not observed in European subjects.

Conclusions

Association of the T-allele with gout risk in the Māori and Pacific subjects was consistent with this allele increasing serum urate in Japanese individuals. The non-additive interaction in the Māori and Pacific subjects showed that alcohol consumption over-rides any protective effect conferred by the CC genotype. Further exploration of the mechanism underlying this interaction should generate new understanding of the biological role of alcohol in gout, in addition to strengthening the evidence base for reduction of alcohol consumption in the management of gout.     

Concentration of antibodies against Porphyromonas gingivalis is increased before the onset of symptoms of rheumatoid arthritis

BackgroundThe periodontal pathogen Porphyromonas gingivalis is hypothesized to be important in rheumatoid arthritis (RA) aetiology by inducing production of anti-citrullinated protein antibodies (ACPA). We have shown that ACPA precede RA onset by years, and that anti-P. gingivalis antibody levels are elevated in RA patients. The aim of this study was to investigate whether anti-P. gingivalis antibodies pre-date symptom onset and ACPA production.MethodsA case–control study (251 cases, 198 controls) was performed within the Biobank of Northern Sweden. Cases had donated blood samples (n = 422) before the onset of RA symptoms by 5.2 (6.2) years (median (interquartile range)). Blood was also collected from 192 RA patients following diagnosis. Antibodies against P. gingivalis virulence factor arginine gingipainB (RgpB), and a citrullinated peptide (CPP3) derived from the P. gingivalis peptidylarginine deiminase enzyme, were analysed by ELISA.ResultsAnti-RgpB IgG levels were significantly increased in pre-symptomatic individuals (mean ± SEM; 152.7 ± 14.8 AU/ml) and in RA patients (114.4 ± 16.9 AU/ml), compared with controls (p < 0.001). Anti-CPP3 antibodies were detected in 5 % of pre-symptomatic individuals and in 8 % of RA patients, with elevated levels in both subsets (4.33 ± 0.59 and 9.29 ± 1.81 AU/ml, respectively) compared with controls (p < 0.001). Anti-CPP3 antibodies followed the ACPA response, with increasing concentrations over time, whilst anti-RgpB antibodies were elevated and stable in the pre-symptomatic individuals with a trend towards lower levels after RA diagnosis.ConclusionsAnti-P. gingivalis antibody concentrations were significantly increased in RA patients compared with controls, and were detectable years before onset of symptoms of RA, supporting an aetiological role for P. gingivalis in the development of RA.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-016-1100-4) contains supplementary material, which is available to authorized users.     

Characterization of the major histocompatibility complex locus association with Beh?et’s disease in Iran

IntroductionThe aim of this study was to characterize the association of human leukocyte antigen (HLA) B alleles and major histocompatibility complex (MHC) single nucleotide polymorphisms (SNPs) with Behçet’s disease (BD) in an Iranian dataset.MethodsThe association of three SNPs in the MHC region previously identified as the most associated in high-density genotyping studies was tested in a case–control study on 973 BD patients and 825 controls from Iran, and the association of HLA-B alleles was tested in a subset of 681 patients and 414 controls.ResultsWe found that HLA-B*51 (P = 4.11 × 10⁻⁴¹, OR [95% CI] = 4.63[3.66-5.85]) and B*15 confer risk for BD (P = 2.83 × 10⁻², OR [95% CI] = 1.75[1.08-2.84]) in Iranian, and in B*51 negative individuals, only the B*15 allele is significantly associated with BD (P = 2.51 × 10⁻³, OR [95% CI] = 2.40[1.37-4.20]). rs76546355, formerly known as rs116799036, located between HLA-B and MICA (MHC class I polypeptide-related sequence A), demonstrated the same level of association with BD as HLA-B*51 (P_adj = 1.78 × 10⁻⁴⁶, OR [95% CI] = 5.46[4.21-7.09], and P_adj = 8.34 × 10⁻⁴⁸, OR [95% CI] = 5.44[4.20-7.05], respectively) in the HLA-B allelotyped subset, while rs2848713 was less associated (P_adj = 7.14 × 10⁻³⁵, OR [95% CI] = 3.73[2.97-4.69]) and rs9260997 was not associated (P_adj = 1.00 × 10⁻¹). Additionally, we found that B*51 genotype-phenotype correlations do not survive Bonferroni correction, while carriers of the rs76546355 risk allele predominate in BD cases with genital ulcers, positive pathergy test and positive BD family history (2.31 × 10⁻⁴ ≤ P ≤ 1.59 × 10⁻³).ConclusionsWe found that the HLA-B*51 allele and the rs76546355/rs116799036 MHC SNP are independent genetic risk factors for BD in Iranian, and that positivity for the rs76546355/rs116799036 risk allele, but not for B*51, does correlate with specific demographic characteristics or clinical manifestations in BD patients.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0585-6) contains supplementary material, which is available to authorized users.     

Influence of the ABCG2 gout risk 141?K allele on urate metabolism during a fructose challenge

Introduction

Both genetic variation in ATP-binding cassette sub-family G member 2 (ABCG2) and intake of fructose-containing beverages are major risk factors for hyperuricemia and gout. This study aimed to test the hypothesis that the ABCG2 gout risk allele 141 K promotes the hyperuricaemic response to fructose loading.

Methods

Healthy volunteers (n = 74) provided serum and urine samples immediately before and 30, 60, 120 and 180 minutes after ingesting a 64 g fructose solution. Data were analyzed based on the presence or absence of the ABCG2 141 K gout risk allele.

Results

The 141 K risk allele was present in 23 participants (31%). Overall, serum urate (SU) concentrations during the fructose load were similar in those with and without the 141 K allele (P_SNP = 0.15). However, the 141 K allele was associated with a smaller increase in SU following fructose intake (P_SNP <0.0001). Those with the 141 K allele also had a smaller increase in serum glucose following the fructose load (P_SNP = 0.002). Higher fractional excretion of uric acid (FEUA) at baseline and throughout the fructose load was observed in those with the 141 K risk allele (P_SNP <0.0001). However, the change in FEUA in response to fructose was not different in those with and without the 141 K risk allele (P_SNP = 0.39). The 141 K allele effects on serum urate and glucose were more pronounced in Polynesian participants and in those with a body mass index ≥25 kg/m².

Conclusions

In contrast to the predicted responses for a hyperuricemia/gout risk allele, the 141 K allele is associated with smaller increases in SU and higher FEUA following a fructose load. The results suggest that ABCG2 interacts with extra-renal metabolic pathways in a complex manner to regulate SU and gout risk.

Clinical Trials Registration

The study was registered by the Australian Clinical Trials Registry (ACTRN12610001036000).     

Prevalence,incidence and characteristics of the metabolic syndrome (MetS) in a cohort of Mexican Mestizo early rheumatoid arthritis patients treated with conventional disease modifying anti-rheumatic drugs: the complex relationship between MetS and disease activity

IntroductionA higher prevalence of metabolic syndrome (MetS) has been described in rheumatoid arthritis (RA), along with an association with disease activity. Objectives were to describe prevalence of MetS at RA diagnosis in a cohort of Mexican Mestizo early RA patients, and to define a causal association between MetS and disease activity.MethodsThe study population was a prospective cohort. At baseline and at fixed 6-months-intervals, patients had medical evaluations, fasting serum glucose, triglycerides, high-density lipoprotein cholesterol and acute reactant-phase determinations. MetS was defined according to international criteria and body mass index (BMI) ≥30 kg/m² was used as a surrogate of the waist circumference. The study was approved by the internal review board. Appropriated statistics and Cox regression analysis were used. All statistical tests were two-sided and evaluated at the 0.05 significance level.ResultsUp to March 2014, data from 160 patients were analyzed. At baseline, they were more frequently middle-aged females and had moderate to high disease activity. Prevalence of MetS varied from 11.3% to 17.5% in patients and was lower to that from matched controls (versus 26.3% to 30%, P ≤0.01).Up to last follow-up, 39 patients (34.5%) developed incidental MetS. In the Cox regression analysis, cumulative disease activity score (DAS) 28 (odds ratio (OR): 1.81, 95% confidence interval (CI): 1.346 to 2.433, P = 0.000) and baseline BMI (OR: 1.13, 96% CI: 1.035 to 1.236, P = 0.007) were the only predictors for incidental MetS.RA patients with incidental MetS accumulated more disease activity and had less frequent remission than their counterparts. Logistic regression analysis showed that incidental MetS (OR: 0.2, 95% CI: 0.01 to 0.99, P = 0.052) and baseline DAS28 (OR: 0.4, 95% CI: 0.2 to 0.9, P = 0.02) were the only predictors for achieving or maintaining sustained (≥6 months) remission.ConclusionsMetS prevalence in a cohort of early RA patients was lower than that from matched controls. Cumulative disease activity and higher BMI were risk factors for incidental Mets; higher baseline disease activity and incidental MetS prevented sustained remission. In addition to disease activity, MetS needs to be controlled to impact disease outcomes.     

Identification of NF-κB and PLCL2 as new susceptibility genes and highlights on a potential role of IRF8 through interferon signature modulation in systemic sclerosis

IntroductionSystemic sclerosis (SSc) and primary biliary cirrhosis (PBC) are rare polygenic autoimmune diseases (AIDs) characterized by fibroblast dysfunction. Furthermore, both diseases share some genetic bases with other AIDs, as evidenced by autoimmune gene pleiotropism. The present study was undertaken to investigate whether single-nucleotide polymorphisms (SNPs) identified by a large genome-wide association study (GWAS) in PBC might contribute to SSc susceptibility.MethodsSixteen PBC susceptibility SNPs were genotyped in a total of 1,616 patients with SSc and 3,621 healthy controls from two European populations (France and Italy).ResultsWe observed an association between PLCL2 rs1372072 (odds ratio (OR) = 1.22, 95% confidence interval (CI) 1.12 to 1.33, P_adj = 7.22 × 10⁻⁵), nuclear factor-kappa-B (NF-κB) rs7665090 (OR = 1.15, 95% CI 1.06 to 1.25, P_adj = 0.01), and IRF8 rs11117432 (OR = 0.75, 95% CI 0.67 to 0.86, P_adj = 2.49 × 10⁻⁴) with SSc susceptibility. Furthermore, phenotype stratification showed an association between rs1372072 and rs11117432 with the limited cutaneous subgroup (lcSSc) (P_adj = 4.45 × 10⁻⁴ and P_adj = 0.001), whereas rs7665090 was associated with the diffuse cutaneous subtype (dcSSc) (P_adj = 0.003). Genotype-mRNA expression correlation analysis revealed that the IRF8 protective allele was associated with increased interferon-gamma (IFN-γ) expression (P = 0.03) in patients with SSc but decreased type I IFN (IFIT1) expression in patients and controls (P = 0.02). In addition, we found an epistatic interaction between NF-κB and IRF8 (OR = 0.56, 95% CI 0.00 to 0.74, P = 4 × 10⁻⁴) which in turn revealed that the IRF8 protective effect is dependent on the presence of the NF-κB susceptibility allele.ConclusionsAn analysis of pleiotropic genes identified two new susceptibility genes for SSc (NF-κB and PLCL2) and confirmed the IRF8 locus. Furthermore, the IRF8 variant influenced the IFN signature, and we found an interaction between IRF8 and NF-κB gene variants that might play a role in SSc susceptibility.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0572-y) contains supplementary material, which is available to authorized users.     

High mobility group box 1 levels in large vessel vasculitis are not associated with disease activity but are influenced by age and statins

IntroductionTakayasu arteritis (TA) and giant cell arteritis (GCA) are large vessel vasculitides (LVV) that usually present as granulomatous inflammation in arterial walls. High mobility group box 1 (HMGB1) is a nuclear protein that acts as an alarmin when released by dying or activated cells. This study aims to evaluate whether serum HMGB1 can be used as a biomarker in LVV.MethodsTwenty-nine consecutive TA patients with 29 healthy controls (HC) were evaluated in a cross-sectional study. Eighteen consecutive GCA patients with 16 HC were evaluated at the onset of disease and some of them during follow-up. Serum HMGB1 levels were measured by enzyme-linked immunosorbent assay.ResultsIn GCA patients at disease onset mean serum HMGB1 levels did not differ from HC (5.74 ± 4.19 ng/ml vs. 4.17 ± 3.14 ng/ml; p = 0.230). No differences in HMGB1 levels were found between GCA patients with and without polymyalgia rheumatica (p = 0.167), ischemic manifestations (p = 0.873), systemic manifestations (p = 0.474) or relapsing disease (p = 0.608). During follow-up, no significant fluctuations on serum HMGB1 levels were observed from baseline to 3 months (n = 13) (p = 0.075), 12 months (n = 6) (p = 0.093) and at the first relapse (n = 4) (p = 0.202). Serum HMGB1 levels did not differ between TA patients and HC [1.19 (0.45–2.10) ng/ml vs. 1.46 (0.89–3.34) ng/ml; p = 0.181] and no difference was found between TA patients with active disease and in remission [1.31 (0.63–2.16) ng/ml vs. 0.75 (0.39–2.05) ng/ml; p = 0.281]. HMGB1 levels were significantly lower in 16 TA patients on statins compared with 13 patients without statins [0.59 (0.29–1.46) ng/ml vs. 1.93 (0.88–3.34) ng/ml; p = 0.019]. Age was independently associated with higher HMGB1 levels regardless of LVV or control status.ConclusionsPatients with TA and GCA present similar serum HMGB1 levels compared with HC. Serum HMGB1 is not useful to discriminate between active disease and remission. In TA, use of statins was associated with lower HMGB1 levels. HMGB1 is not a biomarker for LVV.     

Aortic valve implantation-induced conduction block as a framework towards a uniform electrocardiographic definition of left bundle branch block

IntroductionNew-onset left bundle branch block (LBBB) following transcatheter or surgical aortic valve replacement (LBBB_AVI) implies a proximal pathogenesis of LBBB. This study compares electrocardiographic characteristics and concordance with LBBB definitions between LBBB_AVI and non-procedure-induced LBBB controls (LBBB_control).MethodsAll LBBB_AVI patients at Ghent University Hospital between 2013 and 2019 were enrolled in the study. LBBB_AVI patients were matched for age, sex, ischaemic heart disease and ejection fraction to LBBB_control patients in a 1:2 ratio. For inclusion, a non-strict LBBB definition was used (QRS duration ≥ 120 ms, QS or rS in V1, absence of Q waves in V5-6). Electrocardiograms were digitally analysed and classified according to three LBBB definitions: European Society of Cardiology (ESC), Strauss and American Heart Association (AHA).ResultsA total of 177 patients (59 LBBB_AVI and 118 LBBB_control) were enrolled in the study. LBBB_AVI patients had more lateral QRS notching/slurring (100% vs 85%, p = 0.001), included a higher percentage with a QRS duration ≥ 130 ms (98% vs 86%, p = 0.007) and had a less leftward oriented QRS axis (−15° vs −30°, p = 0.013) compared to the LBBB_control group. ESC and Strauss criteria were fulfilled in 100% and 95% of LBBB_AVI patients, respectively, but only 18% met the AHA criteria. In LBBB_control patients, concordance with LBBB definitions was lower than in the LBBB_AVI group: ESC 85% (p = 0.001), Strauss 68% (p < 0.001) and AHA 7% (p = 0.035). No differences in electrocardiographic characterisation or concordance with LBBB definitions were observed between LBBB_AVI and LBBB_control patients with lateral QRS notching/slurring.ConclusionNon-uniformity exists among current LBBB definitions concerning the detection of proximal LBBB. LBBB_AVI may provide a framework for more consensus on defining proximal LBBB.Supplementary InformationThe online version of this article (10.1007/s12471-021-01565-8) contains supplementary material, which is available to authorized users.     

Association of CXCL10 and CXCL13 levels with disease activity and cutaneous manifestation in active adult-onset Still’s disease

IntroductionC-X-C motif chemokine 10 (CXCL10) is produced in response to interferon-γ, and tumor necrosis factor-α (TNF-α) triggers the accumulation of activated lymphocytes. CXCL13 is constitutively expressed in secondary lymphoid tissues, and the expression is upregulated by TNF-α, via T cell stimulation. It appears that CXCL10 and CXCL13 could play a potential role in the pathogenesis of adult-onset Still’s disease (AOSD), therefore, we investigated the associations between CXCL10 and CXCL13 levels and clinical manifestations in patients with active AOSD.MethodsBlood samples were collected from 39 active AOSD patients, 32 rheumatoid arthritis (RA) patients and 40 healthy controls (HC). Of the AOSD patients, follow-up samples were collected from 15 9.6 ± 9.2 months later. Serum levels of CXCL10 and CXCL13 were determined using enzyme-linked immunosorbent assay. CXCL10, CXCL13, and C-X-C chemokine receptor type 3 (CXCR3) expression levels in biopsy specimens obtained from 26 AOSD patients with skin rashes were investigated via immunohistochemistry.ResultsThe CXCL10 levels in AOSD patients (1,031.3 ± 2,019.6 pg/mL) were higher than in RA (146.3 ± 91.4 pg/mL, p = 0.008) and HC (104.4 ± 47.9 pg/mL, p = 0.006). Also, the CXCL13 levels of AOSD patients (158.8 ± 151.2 pg/mL) were higher than those of RA (54.4 ± 61.1 pg/mL, p < 0.001) and HC (23.5 ± 18.1 pg/mL, p < 0.001). Serum CXCL10 levels correlated with ferritin and systemic scores. Serum CXCL13 levels correlated with those of hemoglobin, C-reactive protein, ferritin, and albumin, and systemic scores. In follow-up AOSD patients, the levels of CXCL10 and CXCL13 fell significantly (153.7 ± 130.1 pg/mL, p = 0.002, and 89.1 ± 117.4 pg/mL, p = 0.001, respectively). On immunohistochemistry, the percentages of inflammatory cells expressing CXCL10 ranged from 1 to 85 %, CXCL13 from 1 to 72 %, and CXCR3 from 2 to 65 %. The percentage of CXCL10-positive inflammatory cells was higher in skin biopsy samples exhibiting mucin deposition than in those that did not (p = 0.01). CXCL13 levels were correlated with those of CD4 and CD68.ConclusionsSerum CXCL10 and CXCL13 levels may serve as clinical markers for assessment of disease activity in AOSD. CXCL10/CXCR3 and CXCL13 may contribute to the inflammatory response, especially skin manifestations thereof, in AOSD.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0773-4) contains supplementary material, which is available to authorized users.     

Increased carotid artery intima-media thickness and myeloperoxidase level in children with newly diagnosed juvenile idiopathic arthritis

IntroductionJuvenile idiopathic arthritis (JIA) is a frequent childhood rheumatic disease characterized by chronic inflammation. The latter has been related to impairment of arterial functional-structural properties, atherogenesis and later cardiovascular events. The objective of this study was to examine intima-media thickness (IMT) and the parameters of arterial stiffness in children with JIA at diagnosis and their correlation with JIA subtype and markers of inflammation and atherosclerosis.MethodsThirty-nine newly diagnosed patients with JIA (26 girls; mean age, 13.2 ± 2.6 years) and 27 healthy controls (9 girls; mean age, 13.6 ± 3.4 years) were included in the study. Twelve patients had oligoarthritis, fifteen had extended oligoarthritis and twelve had rheumatoid factor–negative polyarthritis. IMT of the common carotid artery was determined by ultrasonography, carotid-femoral pulse wave velocity (cfPWV) and augmentation index adjusted to a heart rate of 75 beats/min (AIx@75) were determined by applanation tonometry. The serum levels of atherosclerosis-related biomarkers, such as asymmetric dimethylarginine (ADMA), myeloperoxidase (MPO) and adiponectin, were measured by enzyme-linked immunosorbent assay.ResultsMean IMT (0.46 ± 0.04 vs. 0.42 ± 0.04 mm; p = 0.0003) and MPO concentration (115.2 [95 % confidence interval {95 % CI}, 97.4–136.3] vs. 57.6 [95 % CI, 47.1–70.3] ng/ml; p < 0.0001) were higher in the patients with JIA than in the control subjects. The cfPWV, AIx@75 and serum ADMA and adiponectin levels did not significantly differ between the groups and JIA subtypes. Serum adiponectin level correlated negatively with AIx@75 in patients with JIA (r = −0.38; p < 0.05).ConclusionsPatients with JIA have increased mean IMT and elevated MPO levels at early stages of the disease. AIx@75 was inversely independently associated with adiponectin level in the patients, suggesting that lower adiponectin levels might influence arterial subclinical stiffening in patients with newly diagnosed JIA.     

Surgical aortic valve replacement in patients older than 75 years: is there really a quality of life benefit?

BackgroundTo evaluate the results of elective isolated surgical aortic valve replacement (SAVR) on quality of life (QoL) in patients > 75 years.Methods138 patients operated between January 2008 and December 2011 were included. The EuroQOL questionnaire (EQ-5D, EQ-VAS) was completed preoperatively, and 1- and 2-years postoperatively. The logistic EuroSCORE was used for risk stratification, the Corpus Christi Heart project criteria to assess physical activity.ResultsMean age was 79.5 ± 2.8 years, mean risk 9.7 ± 5.4, hospital mortality 2.8 %. For 115 patients (83.3 %) the preoperative QoL information was complete. Fifty patients were classified as sedentary. In the first postoperative year 13 patients died, mostly sedentary patients (p = 0.046) with a low EQ-5D (p = 0.017). There was no QoL information on 32 survivors, mostly sedentary patients (p = 0.001). The 70 patients with QoL information showed an increased QoL (NS). Two years postoperatively, 16 patients died, significantly more sedentary patients (p = 0.015) with a low EQ-5D (p = 0.006). For 42 survivors, there was no QoL information; these were mostly sedentary patients (p = 0.021). The 57 patients with 2-year QoL information had an increased EQ-5D (NS) and EQ-VAS (p = 0.024).ConclusionsQoL increases after SAVR. However, the patients lost to follow-up were mostly sedentary or had a low preoperative QoL, which can lead to biased results.     

Transcatheter aortic valve implantation amid the COVID-19 pandemic: a nationwide analysis of the first COVID-19 wave in the Netherlands

IntroductionThe coronavirus disease 2019 (COVID-19) pandemic has put tremendous pressure on healthcare systems. Most transcatheter aortic valve implantation (TAVI) centres have adopted different triage systems and procedural strategies to serve highest-risk patients first and to minimise the burden on hospital logistics and personnel. We therefore assessed the impact of the COVID-19 pandemic on patient selection, type of anaesthesia and outcomes after TAVI.MethodsWe used data from the Netherlands Heart Registration to examine all patients who underwent TAVI between March 2020 and July 2020 (COVID cohort), and between March 2019 and July 2019 (pre-COVID cohort). We compared patient characteristics, procedural characteristics and clinical outcomes.ResultsWe examined 2131 patients who underwent TAVI (1020 patients in COVID cohort, 1111 patients in pre-COVID cohort). EuroSCORE II was comparable between cohorts (COVID 4.5 ± 4.0 vs pre-COVID 4.6 ± 4.2, p = 0.356). The number of TAVI procedures under general anaesthesia was lower in the COVID cohort (35.2% vs 46.5%, p < 0.001). Incidences of stroke (COVID 2.7% vs pre-COVID 1.7%, p = 0.134), major vascular complications (2.3% vs 3.4%, p = 0.170) and permanent pacemaker implantation (10.0% vs 9.4%, p = 0.634) did not differ between cohorts. Thirty-day and 150-day mortality were comparable (2.8% vs 2.2%, p = 0.359 and 5.2% vs 5.2%, p = 0.993, respectively).ConclusionsDuring the COVID-19 pandemic, patient characteristics and outcomes after TAVI were not different than before the pandemic. This highlights the fact that TAVI procedures can be safely performed during the COVID-19 pandemic, without an increased risk of complications or mortality.Supplementary InformationThe online version of this article (10.1007/s12471-022-01704-9) contains supplementary material, which is available to authorized users.