Cigarette smoking and risk of rheumatoid arthritis: a dose-response meta-analysis

Introduction

Although previous studies found that cigarette smoking is associated with risk of rheumatoid arthritis (RA), the dose-response relationship remains unclear. This meta-analysis quantitatively summarizes accumulated evidence regarding the association of lifelong exposure to cigarette smoking assessed as pack-years with the risk of RA.

Methods

Relevant studies were identified by a search of MEDLINE and EMBASE from 1966 to October 2013, with no restrictions. Reference lists from retrieved articles were also reviewed. Studies that reported relative risks (RR) or odds ratio (OR) estimates with 95% confidence intervals (CIs) for the association between pack-years of cigarette smoking and rheumatoid arthritis were included in a dose-response random-effects meta-regression analysis.

Results

We included 3 prospective cohorts and 7 case-control studies in the meta-analysis. They included a total of 4,552 RA cases. There was no indication of heterogeneity (P_{heterogeneity} = 0.32) and publication bias did not affect the results. Compared to never smokers, the risk of developing RA increased by 26% (RR = 1.26, 95% CI 1.14 to 1.39) among those who smoked 1 to 10 pack-years and doubled among those with more than 20 pack-years (RR for 21 to 30 pack years = 1.94, 95% CI 1.65 to 2.27). The risk of RA was not increasing further for higher exposure levels (RR for >40 pack-years = 2.07, 95% CI 1.15 to 3.73). The risk of RA was statistically significantly higher among rheumatoid factor (RF)-positive RA cases (RR = 2.47, 95% CI 2.02 to 3.02) compared to RF-negative (RR = 1.58, 95% CI 1.15 to 2.18) when comparing the highest versus lowest category of pack-years for the individual studies.

Conclusions

Lifelong cigarette smoking was positively associated with the risk of RA even among smokers with a low lifelong exposure. The risk of RA did not further increase with an exposure higher than 20 pack-years.     

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.     

Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent

BackgroundObservational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.MethodsWe applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases  =  46,325, controls  =  42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.ResultsIn the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR]  =  0.65 per 5 kg/m² increase, 95% confidence interval [CI]: 0.56–0.75, p = 3.32 × 10⁻¹⁰). The associations were similar for both premenopausal (OR   =   0.44, 95% CI:0.31–0.62, p  =  9.91 × 10⁻⁸) and postmenopausal breast cancer (OR  =  0.57, 95% CI: 0.46–0.71, p  =  1.88 × 10⁻⁸). This association was replicated in the data from the DRIVE consortium (OR  =  0.72, 95% CI: 0.60–0.84, p   =   1.64 × 10⁻⁷). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk.ConclusionsBMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.     

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.     

Genetic variant in IL33 is associated with susceptibility to rheumatoid arthritis

Introduction

Interleukin (IL)-33 is a proinflammatory cytokine contributing to the pathogenesis of rheumatoid arthritis (RA). The gene encoding IL-33 may serve as a genetic factor and be associated with the risk of RA. To investigate the potential association between IL33 and RA, we performed a case–control study based on Chinese Han population.

Methods

A three-stage case–control study was performed. Two tag single-nucleotide polymorphisms (SNPs) (rs7044343 and rs10975514), mapping to the IL33 gene, were first genotyped in the discovery population. We further genotyped rs7044343 and rs10975514 in the validation and replication population. The associations between the two tag SNPs and phenotypic subgroups of RA and levels of serum IL-33 were assessed with a logistic regression model.

Results

In the discovery population, the CC genotype of rs7044343 was associated with RA patients (odds ratio (OR) = 0.777, 95% confidence interval (CI), 0.611 to 0.988; P = 0.040). After anti-citrullinated peptide antibody (ACPA) stratification, the CC genotype of rs7044343 was also shown to be a protective genotype in RA without ACPA (OR = 0.610; 95% CI, 0.379 to 0.982; P = 0.042). In the validation population and replication population, the association between rs7044343 and RA, especially ACPA-negative RA, was still significant. A meta-analysis of discovery, validation, and replication panels confirmed the association between CC genotype of rs7044343 and RA (P_combined = 0.0004; OR_combined = 0.77; 95% CI, 0.67 to 0.89). No evidence was found for heterogeneity between three sample sets (P_het = 0.99; I² = 0%). Similar results were also obtained in ACPA-negative RA (P_combined = 0.0002; OR_combined = 0.57; 95% CI, 0.43 to 0.77). No association was detected between rs10975514 polymorphism and RA susceptibility in the discovery and validation population. The serum levels of IL-33 were significantly lower in the patients with the rs7044343 CC genotype.

Conclusion

The CC genotype of rs7044343 in IL33 is associated with RA patients and downregulates IL-33 expression in RA.     

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.     

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.     

Carotid artery plaque in women with rheumatoid arthritis and low estimated cardiovascular disease risk: a cross-sectional study

IntroductionWe previously reported that most patients with rheumatoid arthritis (RA) and moderate cardiovascular disease (CVD) risk according to the Systematic COronary Evaluation score (SCORE) experience carotid artery plaque. In this study, we aimed to identify patient characteristics that can potentially predict carotid plaque presence in women with RA and a concurrent low CVD risk according to the SCORE.MethodsA cohort of 144 women with an evaluated low risk of CVD (SCORE value of zero) was assembled amongst 550 consecutive patients with RA that underwent CVD risk factor recording and carotid artery ultrasound. Participants had no established CVD, moderate or severe chronic kidney disease, or diabetes. We assessed carotid plaque(s) presence and its associated patient characteristics.ResultsCarotid artery plaque was present in 35 (24.3%) of women with RA. Age, the number of synthetic disease-modifying agents (DMARDs) and total cholesterol concentrations were independently associated with plaque in multivariable stepwise backward regression analysis (odds ratio (95% confidence interval) = 1.15 (1.07 to 1.24), P <0.0001, 1.51 (1.05 to 2.17), P = 0.03 and 1.66 (1.00 to 2.73) P = 0.04), respectively). The area under the curve (AUC) of the receiver operating curve (ROC) for the association with plaque was 0.807 (P <0.0001), 0.679 (P = 0.001) and 0.599 (P = 0.08) for age, total cholesterol concentrations and number of synthetic DMARDs used, respectively. The optimal cutoff value in predicting plaque presence for age was 49.5 years with a sensitivity and specificity of 74% and 75%, respectively, and for total cholesterol concentration, it was 5.4 mmol/l with a sensitivity and specificity of 63% and 70%, respectively. The plaque prevalence was 37.5% in patients (n = 80; 55.6%) with age >49.5 years or/and total cholesterol concentration of >5.4 mmol/l, respectively, compared to only 7.8% in those (n = 64; 44.4%) with age ≤49.5 years or/and total cholesterol concentration of ≤5.4 mmol/l, respectively.ConclusionsApproximately one-third of women with RA who experience a low SCORE value and are aged >49.5 years or/and have a total cholesterol concentration of >5.4 mmol/l, experience high-risk atherosclerosis, which requires intensive CVD risk management.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0576-7) contains supplementary material, which is available to authorized users.     

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.     

Anti-citrullinated peptide/protein antibody (ACPA)-negative RA shares a large proportion of susceptibility loci with ACPA-positive RA: a meta-analysis of genome-wide association study in a Japanese population

IntroductionAlthough susceptibility genes for anti-citrullinated peptide/protein antibodies (ACPA)-positive rheumatoid arthritis (RA) have been successfully discovered by genome-wide association studies (GWAS), little is known about the genetic background of ACPA-negative RA. We intended to elucidate genetic background of ACPA-negative RA.MethodWe performed a meta-analysis of GWAS comprising 670 ACPA-negative RA and 16,891 controls for 1,948,138 markers, followed by a replication study of the top 35 single nucleotide polymorphisms (SNPs) using 916 cases and 3,764 controls. Inverse-variance method was applied to assess overall effects. To assess overlap of susceptibility loci between ACPA-positive and -negative RA, odds ratios (ORs) of the 21 susceptibility markers to RA in Japanese were compared between the two subsets. In addition, SNPs were stratified by the p-values in GWAS meta-analysis for either ACPA-positive RA or ACPA-negative RA to address the question whether weakly-associated genes were also shared. The correlations between ACPA-positive RA and the subpopulations of ACPA-negative RA (rheumatoid factor (RF)-positive and RF-negative subsets) were also addressed.ResultsRs6904716 in LEMD2 of the human leukocyte antigen (HLA) locus showed a borderline association with ACPA-negative RA (overall p = 5.7 × 10⁻⁸), followed by rs6986423 in CSMD1 (p = 2.4 × 10⁻⁶) and rs17727339 in FCRL3 (p = 1.4 × 10⁻⁵). ACPA-negative RA showed significant correlations of ORs with ACPA-positive RA for the 21 susceptibility SNPs and non-HLA SNPs with p-values far from significance. These significant correlations with ACPA-positive RA were true for ACPA-negative RF-positive and ACPA-negative RF-negative RA. On the contrary, positive correlations were not observed between the ACPA-negative two subpopulations.ConclusionMany of the susceptibility loci were shared between ACPA-positive and -negative RA.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0623-4) contains supplementary material, which is available to authorized users.     

Subjective and objective levels of physical activity and their association with cardiorespiratory fitness in rheumatoid arthritis patients

IntroductionThe aims of the present study were: (a) to examine the agreement between subjective (assessed via the International Physical Activity Questionnaire; IPAQ) and objective (accelerometry; GT3X) physical activity (PA) levels in patients with rheumatoid arthritis (RA), and (b) to evaluate the associations of RA patients’ subjective and objective PA to their scores on the maximal oxygen uptake test (VO2max).MethodsThe participants wore the GT3X for seven days before completing the IPAQ and VO2max test. The Bland-Altman plot was used to illustrate the agreement between the objective and subjective PA data, and the Wilcoxon test was employed to examine the differences. The association between the PA measurement and VO2max test was examined via the correlations and the magnitude was presented by the Steiger’s Z value.ResultsSixty-eight RA patients (age = 55 ± 13 years, body mass index: 27.8 ± 5.4 kg/m2, median of disease duration = 5 (2–8) yrs) were recruited. Smaller differences between the subjective and objective measures were found when PA was assessed at the moderate level. Wilcoxon tests revealed that patients reported less time spent engaged in sedentary behaviours (Z = −6.80, P < 0.01) and light PA (Z = −6.89, P < 0.01) and more moderate PA (Z = −6.26, P < 0.01) than was objectively indicated. Significant positive correlations were revealed between VO2max with all PA levels derived from accelerometry (light PA rho = .35, P < .01; moderate PA rho = .34, P = .01; moderate and vigorous PA, (MVPA) rho = .33, P = .01), and a negative association to sedentary time (ST) emerged (rho = −.27, P = .04). IPAQ-reported moderate PA and MVPA positively correlated with maxV02 (rho = .25, P = .01, rho = .27, P = .01, respectively). Differences between the magnitude of correlations between the IPAQ-VO2 max and GT3X-VO2 max were only significant for ST (Z = 3.43, P < .01).ConclusionsVia responses to the IPAQ, RA patients reported that they were less sedentary and engaged in more higher intensity PA than what was objectively assessed. Accelerometry data correlated with VO2max at all PA levels. Only subjective moderate and MPVA correlated with VO2max. Findings suggest that self-reported PA and ST should be interpreted with caution in people with RA and complemented with accelerometry when possible.

Trial registration

Trial registration: ClinicalTrials.gov ISRCTN04121489. Registered 5 September 2012.     

Reappraisal of the diagnostic and prognostic value of morning stiffness in arthralgia and early arthritis: results from the Groningen EARC,Leiden EARC,ESPOIR, Leiden EAC and REACH

IntroductionMorning stiffness is assessed daily in the diagnostic process of arthralgia and arthritis, but large-scale studies on the discriminative ability are absent. This study explored the diagnostic value of morning stiffness in 5,202 arthralgia and arthritis patients and the prognostic value in early rheumatoid arthritis (RA).MethodsIn arthralgia patients referred to the Early Arthritis Recognition Clinics (EARC) of Leiden (n = 807) and Groningen (n = 481) or included in the Rotterdam Early Arthritis Cohort (REACH) study (n = 353), the associations (cross-sectional analyses) between morning stiffness and presence of arthritis at physical examination were studied. In early arthritis patients, included in the Leiden Early Arthritis Clinic (EAC) (n = 2,748) and Evaluation et Suivi de POlyarthrites Indifférenciées Récentes (ESPOIR) (n = 813), associations with fulfilling the 2010-RA criteria after one year were assessed. In 2010-RA patients included in the EAC (n = 1,140) and ESPOIR (n = 677), association with the long-term outcomes of disease-modifying antirheumatic drug (DMARD)-free sustained remission and radiological progression were determined. Morning stiffness was defined as a duration ≥60 minutes; sensitivity analyses were performed for other definitions.ResultsIn arthralgia, morning stiffness (≥60 minutes) associated with the presence of arthritis; Leiden EARC odds ratio (OR) 1.49 (95% CI 1.001 to 2.20), Groningen EARC OR 2.21 (1.33 to 3.69) and REACH OR 1.55 (0.97 to 2.47) but the areas under the receiver operating characteristic curve (AUCs) were low (0.52, 0.57, 0.54). In early arthritis, morning stiffness was associated with 2010-RA independent of other predictors (Leiden EAC OR 1.72 (95% CI 1.31 to 2.25, AUC 0.68), ESPOIR OR 1.68 (1.03 to 2.74, AUC 0.64)). Duration of ≥30 minutes provided optimal discrimination for RA in early arthritis. Morning stiffness was not associated with radiological progression or DMARD-free sustained remission.ConclusionsMorning stiffness in arthralgia and early arthritis is associated with arthritis and RA respectively. This supports the incorporation of morning stiffness in the diagnostic process.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0616-3) contains supplementary material, which is available to authorized users.     

Visceral fat obesity is highly associated with primary gout in a metabolically obese but normal weighted population: a case control study

IntroductionGout is a chronic inflammatory disease the development of which is associated with obesity-induced metabolic abnormalities. However, a substantial number of non-obese patients (body mass index [BMI] <25 kg/m²) also develop gout in Korea. It was suggested that accumulation of visceral fat rather than subcutaneous fat is associated with metabolic abnormalities and hyperuricemia in patients with gout; therefore, we hypothesized that visceral fat accumulation was increased in non-obese gout patients.MethodsOne hundred and three male patients with primary gout and 204 age-matched healthy controls who attended a health check-up examination were recruited after the review of medical charts. The visceral fat area (VFA) was measured using the bioelectrical impedance analysis (BIA) method, and a VFA >100 cm² was defined as visceral fat obesity (VFO). The frequency of VFO was compared in patients and control groups. The frequencies of metabolic syndrome and related parameters were also investigated.ResultsBMI, waist circumference, total fat mass, serum triglycerides, and serum glucose levels were significantly greater in patients compared with controls. VFA and the prevalence of VFO was increased in gout patients compared with controls. There were positive correlations between VFA and serum triglyceride levels and serum glucose levels. Multivariate regression analysis revealed that VFO is an independent risk factor for gout (odds ratio 2.488, 95% confidence interval 1.041–4.435). In non-obese subgroup analyses (gout patients, n = 38; healthy controls, n = 150), VFA (98.7 ± 19.3 vs. 91.0 ± 16.7, P = 0.016) and the frequency of VFO (47.4 vs. 27.3%, P = 0.017) remained significantly higher in gout patients. There was no difference in either BMI or total fat mass between patients and controls in the non-obese subgroup. The prevalence of metabolic syndrome in patients with gout was 31.7% (33/104), compared with 13.2% (5/38) in the non-obese subgroup according to modified ATP III criteria.ConclusionVFO, measured using BIA, is observed more frequently in patients with primary gout compared with healthy controls, even in non-obese individuals. Therefore, VFO might more properly represent metabolic derangements in patients with gout than general obesity.     

CYB5A polymorphism increases androgens and reduces risk of rheumatoid arthritis in women

IntroductionRheumatoid arthritis (RA) is characterized by decreased androgen levels, which was the first hormonal abnormality described. Several studies indicated that steroidogenesis is directed towards endogenous glucocorticoids at the expense of androgens. The decisive step governing androgen synthesis is the 17,20-lyase activity of the CYP17A1 gene-encoded enzyme cytochrome P450 17A1. Here, we focused on the role in RA of the critical cofactor for 17,20-lyase activity, cytochrome b5, encoded by the CYB5A gene.MethodsData sets of two genome wide RA association studies (GWAS) were screened for single nucleotide polymorphisms (SNP) in the CYB5A gene. Candidate SNPs in CYB5A were studied in a case–control study population of Slovakia. Expression analyses were done in synovial fibroblasts from RA patients by quantitative real-time polymerase chain reaction, and cytochrome b5–expression was detected by immunohistochemistry. Real-life androgen production after steroid conversion was measured using radiolabeled substrates.ResultsThe study identified the RA-associated intronic SNP rs1790834 in the CYB5A gene in one GWAS and confirmed the same SNP in our study. The minor allele reduced RA risk selectively in women (P = 4.1*10⁻³; OR = 0.63, 95% CI [0.46-0.86]). The protective effect was confined to rheumatoid factor-positive (OR = 0.53, [0.37-0.75]) and anti-cyclic citrullinated peptide-positive (OR = 0.58, [0.41-0.83]) cases, respectively. The protective allele doubles CYB5A mRNA-expression resulting in 2-3fold activation of steroid 17,20-lyase activity, and protective allele was accompanied by a higher density of cytochrome b5-positive cells in synovial tissue.ConclusionsCYB5A is the first RA susceptibility gene involved in androgen synthesis. Our functional analysis of SNP rs1790834 indicates that it contributes to the sex bias observed in RA.     

Lack of Association between Insulin Receptor Substrate2 rs1805097 Polymorphism and the Risk of Colorectal and Breast Cancer: A Meta-Analysis

Background

Insulin receptor substrate-2 (IRS-2), a signaling adaptor protein, was involved in two cancer-related pathways (the phosphatidylinositol 3′-kinase (PI3K) and the extracellular signal-regulated kinase (ERK) pathways). Several studies have evaluated the association between IRS2 rs1805097 (G>A) polymorphisms and the risk of colorectal and breast cancer. However, the results were inconsistent.

Methodology/Principal Findings

A meta-analysis of seven published case-control studies (4 studies with 4798 cases and 5478 controls for colorectal cancer and 3 studies with 2108 cases and 2507 controls for breast cancer) were conducted to assess the strength of association using crude odd ratios (ORs) with 95% confidence intervals (CIs). For colorectal cancer, no obvious associations were found for all genetic models (homozygote comparison OR = 0.96, 95%CI 0.85–1.08, P_{heterogeneity} = 0.97; heterozygote comparison: OR = 0.91, 95%CI 0.73–1.13, P_{heterogeneity}<0.01; dominant model: OR = 0.92, 95%CI 0.80–1.06, P_{heterogeneity} = 0.05; recessive model: OR = 1.02, 95%CI 0.91–1.14, P_{heterogeneity} = 0.60). In the subgroup analysis by ethnicity, control source and consistency of frequency with Hardy-Weinberg equilibrium (HWE), still no significant associations were observed. For breast cancer, also no obvious associations were found for all genetic models (homozygote comparison: OR = 0.95, 95%CI 0.71–1.26, P_{heterogeneity} = 0.10; heterozygote comparison: OR = 1.00, 95%CI 0.89–1.14, P_{heterogeneity} = 0.71; dominant model: OR = 0.98, 95%CI 0.87–1.10, P_{heterogeneity} = 0.55; recessive model: OR = 0.95, 95%CI 0.72–1.25, P_{heterogeneity} = 0.07). We performed subgroup analyses by sample size and did not find an association.

Conclusions

This meta-analysis indicated that IRS2 rs1805097polymorphism was not associated with colorectal and breast cancer risk.     

Peripheral blood CD4+CD25+CD127low regulatory T cells are significantly increased by tocilizumab treatment in patients with rheumatoid arthritis: increase in regulatory T cells correlates with clinical response

IntroductionTocilizumab (TCZ), an anti-interleukin-6 receptor antibody, is clinically effective against rheumatoid arthritis (RA), and several reports have indicated how TCZ influences a number of mechanisms underlying RA pathogenesis. However, it is still unclear whether TCZ affects inflammatory cells in peripheral blood and whether any such changes are associated with clinical response. We evaluated associations between proportions of subsets of peripheral immune cells and clinical response in patients with RA treated with TCZ.MethodsThirty-nine consecutive patients with RA who started to receive TCZ as their first biologic between March 2010 and April 2012 were enrolled. The proportions of several subsets of peripheral cells with their levels of expression of differentiation markers, activation markers and costimulatory molecules were measured sequentially from baseline to week 52 by flow cytometry analysis.ResultsClinical Disease Activity Index (CDAI) remission was achieved in 53.8% of patients at week 52 of TCZ therapy. The proportions of CD4⁺CD25⁺CD127^low regulatory T cells (T_reg) and HLA-DR⁺ activated T_reg cells significantly increased with TCZ therapy (P < 0.001 and P < 0.001, respectively), whereas proportions of CD3⁺CD4⁺CXCR3⁻CCR6⁺CD161⁺ T helper 17 cells did not change over the 52 weeks. The proportions of CD20⁺CD27⁺ memory B cells, HLA-DR⁺CD14⁺ and CD69⁺CD14⁺ activated monocytes, and CD16⁺CD14⁺ monocytes significantly decreased (P < 0.001, P < 0.001, P < 0.001 and P < 0.001, respectively). Among them, only the change in T_reg cells was inversely correlated with the change in CDAI score (ρ = −0.40, P = 0.011). The most dynamic increase in T_reg cells was observed in the CDAI remission group (P < 0.001).ConclusionThis study demonstrates that TCZ affected proportions of circulating immune cells in patients with RA. The proportion of T_reg cells among CD4⁺ cells correlated well with clinical response.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0526-4) contains supplementary material, which is available to authorized users.     

Association analyses confirm five susceptibility loci for systemic lupus erythematosus in the Han Chinese population

IntroductionSystemic lupus erythematosus (SLE) is a multisystem autoimmune disease. Currently, numerous genetic loci of SLE have been confirmed. Here we try to further explore additional genes contributing to SLE susceptibility in this study.MethodsForty nine single nucleotide polymorphisms (SNPs) with moderate-risk for SLE in previous study were genotyped in a large-scale replication study with a total of 3,522 cases and 8,252 controls using the Sequenom Massarray system. Association analyses were performed using logistic regression with gender or sample cohorts as a covariate through PLINK 1.07 software.ResultsThis replication effort confirmed five reported SLE susceptibility loci reaching genome-wide levels of significance (P_meta <5.00 × 10⁻⁰⁸): TNFSF4 (rs1418190, odds ratio (OR) = 0.81, P_meta = 1.08 × 10⁻⁰⁸; rs4916219, OR = 0.80, P_meta = 7.77 × 10⁻⁰⁹), IRF8 (rs2934498, OR = 1.25, P_meta = 4.97 × 10⁻⁰⁹), miR-146a (rs2431697, OR = 0.69, P_meta = 1.15 × 10⁻²²), CD44 (rs2732547, OR = 0.82, P_meta = 1.55 × 10⁻¹¹), and TMEM39A (rs12494314, OR = 0.84, P_meta = 1.01 × 10⁻⁰⁹). Further logistic regression analysis indicated that the genetic effects within TNFSF4 detected in this study are independent from our previously reported signals.ConclusionsThis study increases the number of established susceptibility loci for SLE in Han Chinese population and highlights the contribution of multiple variants of modest effect. Although further studies will be required to identify the causal alleles within these loci, the findings make a significant step forward in our understanding of the genetic contribution to SLE in Chinese population.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0602-9) contains supplementary material, which is available to authorized users.     

Tumor characteristics and family history in relation to mammographic density and breast cancer: The French E3N cohort

BackgroundMammographic density is a known heritable risk factor for breast cancer, but reports how tumor characteristics and family history may modify this association are inconsistent.MethodsDense and total breast areas were assessed using Cumulus™ from pre-diagnostic mammograms for 820 invasive breast cancer cases and 820 matched controls nested within the French E3N cohort study. To allow comparisons across models, percent mammographic density (PMD) was standardized to the distribution of the controls. Odds ratios (OR) and 95% confidence intervals (CI) of breast cancer risk for mammographic density were estimated by conditional logistic regression while adjusting for age and body mass index. Heterogeneity according to tumor characteristic and family history was assessed using stratified analyses.ResultsOverall, the OR per 1 SD for PMD was 1.50 (95% CI, 1.33–1.69). No evidence for significant heterogeneity by tumor size, lymph node status, grade, and hormone receptor status (estrogen, progesterone, and HER2) was detected. However, the association of PMD was stronger for women reporting a family history of breast cancer (OR_1SD = 2.25; 95% CI, 1.67–3.04) than in women reporting none (OR_1SD = 1.41; 95% CI, 1.24–1.60; p_{heterogeneity} = 0.002). Similarly, effect modification by FHBC was observed using categories of PMD (p_{heterogeneity} = 0.02) with respective ORs of 15.16 (95% CI, 4.23–54.28) vs. 3.14 (95% CI, 1.89–5.22) for ≥50% vs. <10% PMD.ConclusionsThe stronger association between mammographic density and breast cancer risk with a family history supports the hypothesis of shared genetic factors responsible for familial aggregation of breast cancer and the heritable component of mammographic density.     

Characterising deviation from treat-to-target strategies for early rheumatoid arthritis: the first three years

IntroductionTreat-to-target (T2T) strategies using a protocol of pre-defined adjustments of disease-modifying anti-rheumatic drugs (DMARDs) according to disease activity improve outcomes for patients with rheumatoid arthritis (RA). However, successful implementation may be limited by deviations from the protocol. The aim of this study was to determine the prevalence of protocol deviation, explore the reasons and identify subsets of patients in whom treatment protocols are more difficult to follow.MethodsIn this retrospective cohort study, treatment-naïve patients with RA of less than one year’s duration, attending a dedicated early arthritis clinic between 2001 and 2013, were followed for three years from initiation of combination therapy with conventional DMARDs which was subsequently modified according to a T2T protocol. At each clinic visit, whether deviation from the protocol occurred, the type of deviation and the reasons for deviation were assessed. The relationship between protocol deviations and baseline variables was determined using linear regression analysis.ResultsIn total, 198 patients contributed 3,654 clinic visits. The prevalence of protocol deviations was 24.5% and deviation in at least at one clinic visit was experienced by 90.4% of patients. The median time to first deviation was 30 weeks. Continuing existing treatment rather than intensifying therapy was the most common type of deviation (59.9%). Patient and physician related factors were the most common reasons for deviation, each accounting for 24.7% of deviations, followed by toxicities (23.3%) and comorbidities (20.0%). The prevalence of protocol deviations was lower among patients who achieved remission after three years (13.1%; 162 deviations out of 1,228 visits) compared with those who were not in remission (30.9%; 523/1692) (P <0.0001). On multivariate analysis, only body mass index (P = 0.003) and helplessness score (P = 0.04) were independent predictors of protocol deviations although the predictive power of the model was not strong (R² = 0.17).ConclusionsDeviation from a T2T protocol occurred in one quarter of visits, indicating that applying the T2T approach is feasible in clinical practice. Failure to escalate dose when indicated was commonly encountered, and just under half of the observed deviations were related to either toxicities or comorbidities and were therefore justifiable on clinical grounds.     

Rheumatoid arthritis response to treatment across IgG1 allotype – anti-TNF incompatibility: a case-only study

IntroductionWe have hypothesized that incompatibility between the G1m genotype of the patient and the G1m1 and G1m17 allotypes carried by infliximab (INX) and adalimumab (ADM) could decrease the efficacy of these anti-tumor necrosis factor (anti-TNF) antibodies in the treatment of rheumatoid arthritis (RA).MethodsThe G1m genotypes were analyzed in three collections of patients with RA totaling 1037 subjects. The first, used for discovery, comprised 215 Spanish patients. The second and third were successively used for replication. They included 429 British and Greek patients and 393 Spanish and British patients, respectively. Two outcomes were considered: change in the Disease Activity Score in 28 joint (ΔDAS28) and the European League Against Rheumatism (EULAR) response criteria.ResultsAn association between less response to INX and incompatibility of the G1m1,17 allotype was found in the discovery collection at 6 months of treatment (P = 0.03). This association was confirmed in the replications (P = 0.02 and 0.08, respectively) leading to a global association (P = 0.001) that involved a mean difference in ΔDAS28 of 0.4 units between compatible and incompatible patients (2.3 ± 1.5 in compatible patients vs. 1.9 ± 1.5 in incompatible patients) and an increase in responders and decrease in non-responders according to the EULAR criteria (P = 0.03). A similar association was suggested for patients treated with ADM in the discovery collection, but it was not supported by replication.ConclusionsOur results suggest that G1m1,17 allotypes are associated with response to INX and could aid improved therapeutic targeting in RA.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0571-z) contains supplementary material, which is available to authorized users.