Risk Of Rheumatoid Arthritis Research Articles

Effect of Chronic Rhinosinusitis on the Risk of Development of Rheumatoid Arthritis.

Several studies have reported a possible link between chronic rhinosinusitis (CRS) and rheumatoid arthritis (RA). However, it remains unclear whether CRS could influence the risk of developing RA. Therefore, in this study, we focused on examining the association between CRS and RA. A total of 14,867 individuals with CRS and 14,867 without CRS were enrolled after 1:1 propensity score match from a nationwide longitudinal cohort database in South Korea. RA incidence was assessed using person-years at risk, and the hazard ratio (HR) was examined using the Cox proportional hazards model. The incidence of RA (per 1,000 person-years) was 6.51 for those with CRS, 6.55 for those with CRS without nasal polyps (CRSsNP), and 5.96 for those with CRS with nasal polyps (CRSwNP). We found that CRS individuals had a significantly increased risk of subsequent RA development with an adjusted HR of 1.41, regardless of the phenotype (adjusted HR was 1.42 in CRSsNP and 1.37 in CRSwNP patients). Moreover, the risk of developing RA over time was relatively higher within the first 4 years after the diagnosis of CRS. Our nationwide population-based cohort study suggests that CRS may be associated with a subsequent increase in RA events, regardless of the phenotype. Therefore, physicians should consider RA risk when diagnosing and treating CRS patients.

Alcohol drinking and rheumatoid arthritis risk: A systematic review and dose-response meta- analysis of prospective cohort studies

Alcohol drinking and rheumatoid arthritis risk: A systematic review and dose-response meta- analysis of prospective cohort studies

Prevention vs treatment of rheumatoid arthritis.

Whether a yet chronic and not curable disease like rheumatoid arthritis (RA) can be subject to prevention or whether available resources should be focused on treatment is a classical dilemma. Similar to the case in most other chronic diseases, the focus in research as well as in clinical practice has been on the treatment of established diseases, resulting in drugs that are efficient in eliminating most joint damage but not able to cure the disease or stop needs for continuous treatment of the disease. Less effort has been spent on identifying and implementing ways to prevent the disease. We argue in this review that knowledge concerning the longitudinal evolvement of the major, 'seropositive' subset of RA has now come to a stage where prevention should be a large part of the research agenda and that we should prepare for prevention as part of clinical practice in RA. We describe briefly the knowledge basis for broad public health-based prevention as well as for a 'precision prevention' strategy. In the latter, individuals at high risk for RA will be identified, monitored, and ultimately provided with advice on how to change lifestyle/environment or be given treatment with drugs able to delay and ultimately stop the development of RA. Whether this potential of precision prevention for RA will change the broader clinical practice will depend on whether specific and long-lasting interference with disease-inducing immunity, ultimately 'tolerance therapy', will become a reality.

Retracted: Construction of Rheumatoid Arthritis Risk Prediction and Medical Image Applications from Rheumatoid Factor Levels.

[This retracts the article DOI: 10.1155/2022/8617467.].

Importance of STAT3 Polymorphisms on the Risk and Clinical Characteristics of Rheumatoid Arthritis.

Signal transducer and activator of transcription 3 (STAT3) has been introduced as one of the critical genetic factors in the pathogenesis of rheumatoid arthritis (RA). Single nucleotide polymorphisms (SNPs) in microRNA binding sites, known as miRSNPs, are a class of common variants in the 3' untranslated regions of genes targeted by miRNAs. miRSNPs unbalance gene expression by disrupting the binding regions of microRNAs. In this study, we intended to evaluate the association of two miRSNPs with the risk of RA development and its clinical features. We studied 120 Iranian patients with RA and 125 non-RA subjects as controls. The genotypes and alleles of rs1053005 and rs1053023 in each individual were assessed by the high-resolution melting method. The distribution of STAT3 variants did not differ markedly in RA patients compared to healthy controls. Stratification analysis revealed that rs1053005 was linked with a higher concentration of C-reactive protein and an increased erythrocyte sedimentation rate, two indicators of inflammation and disease activity in RA patients. The rs1053023 variant was correlated with higher levels of creatinine as an indicator of renal involvement. Our data demonstrate an association between STAT3 variants and clinical characteristics of RA, such as disease activity and probably kidney impairment. However, we did not observe a significant relationship between the two targeted variants and a predisposition to RA.

Association between 19 dietary fatty acids intake and rheumatoid arthritis: Results of a nationwide survey

BackgroundThe relationship between dietary fatty acid intakes and rheumatoid arthritis (RA) is unclear and the available studies have focused on only a few fatty acids. This study investigated the association between the intake of 19 dietary fatty acids and RA in U.S. adults. MethodsThis cross-sectional study using nationally representative data from the 2010-2020 National Health and Nutrition Examination Survey (NHANES). Multivariate linear regression model, multivariate logic regression models, smoothing curve fitting, and two-segment linear regression model were used to explore the relationships between 19 dietary fatty acids intakes with high-sensitivity C-reactive protein (Hs-CRP) and RA risk. ResultsA total of 16,530 participants were included (1053 participants with RA). Intake of hexadecanoic acid and octadecanoic acid were significantly associated with higher Hs-CRP levels, intake of hexadecenoic acid was significantly associated with higher RA risk, and intake of docosahexaenoic acid was significantly associated with lower RA risk. In addition, there was an inverted U-shaped relationship between total monounsaturated fatty acids (MUFAs) intake and RA risk, with the inflection point reached at 15.77% . ConclusionsAmong the 19 dietary fatty acids, only 4 subclasses were significantly associated with Hs-CRP or RA risk. The inverted U-shaped relationship between MUFAs and RA risk may provide insights to find potential prevention strategies for RA.

Association of class II HLA alleles with susceptibility to develop immune-mediated diseases in Paraguayan patients.

Genetic and nongenetic factors are involved in the pathogenesis of immune-mediated inflammatory diseases (IMIDs). The best-known genetic factor for susceptibility to IMIDs is the human leukocyte antigen (HLA). The aim of the present study was to evaluate the association of HLA class II genes with the risk of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and systemic sclerosis (SSc) in the Paraguayan population. We included 254 patients with IMIDs (101 SLE, 103 RA, and 50 SSc) and 50 healthy controls. The haplotypes of five genes corresponding to HLA class II genes and their relationship to the IMIDs studied were determined. Note that 84.6% were women, with a mean age of 43.4 ± 14 years. Among the associated HLA alleles, we found the previously identified risk factors in other populations like HLA-DRB1*03:01 and HLA-DRB1*14:02 for RA, as well as new ones not previously identified, such as DPA1*02:01 for SLE and, DB1*02:01 for RA and SSc. In the genetic association analysis, already known associations have been replicated, and unpublished associations have been identified in Paraguayan patients with IMIDs. This is the first genetic association study in Paraguayan patients with IMIDs.

Cancer risks in rheumatoid arthritis patients who received immunosuppressive therapies: Will immunosuppressants work?

Exploring the cancer risks of rheumatoid arthritis (RA) patients with disease-modifying anti-rheumatic drugs (DMARDs) can help detect, evaluate, and treat malignancies at an early stage for these patients. Thus, a comprehensive analysis was conducted to determine the cancer risk of RA patients using different types of DMARDs and analyze their relationship with tumor mutational burdens (TMBs) reflecting immunogenicity. A thorough search of PubMed, EMBASE, Web of Science, and Medline was conducted up to 20 August 2022. Standardized incidence ratios (SIRs) were constructed with a random-effect model to determine risks for different types of malignancies in comparison with the general population. We also analyzed the correlation between SIRs and TMBs using linear regression (LR). From a total of 22 studies, data on 371,311 RA patients receiving different types of DMARDs, 36 kinds of malignancies, and four regions were available. Overall cancer risks were 1.15 (SIR 1.15; 1.09-1.22; p < 0.001) and 0.91 (SIR 0.91; 0.72-1.14; p = 0.402) in RA populations using conventional synthetic DMARDs (csDMARDs) and biologic DMARDs (bDMARDs), respectively. RA patients taking csDMARDs displayed a 1.77-fold lung cancer risk (SIR 1.77; 1.50-2.09; p < 0.001), a 2.15-fold lymphoma risk (SIR 2.15; 1.78-2.59; p < 0.001), and a 1.72-fold melanoma risk (SIR 1.72; 1.26-2.36; p = 0.001). Correlation coefficients between TMBs and SIRs were 0.22 and 0.29 from those taking csDMARDs and bDMARDs, respectively. We demonstrated a cancer risk spectrum of RA populations using DMARDs. Additionally, TMBs were not associated with elevated cancer risks in RA patients following immunosuppressive therapy, which confirmed that iatrogenic immunosuppression might not increase cancer risks in patients with RA. Changes were similar in cancer risk after different immunosuppressive treatments, and there was a lack of correlation between SIRs and TMBs. These suggest that we should look for causes of increased risks from the RA disease itself, rather than using different types of DMARDs.

Genetically predicted C-reactive protein mediates the association between rheumatoid arthritis and atlantoaxial subluxation.

Investigating the causal relationship between rheumatoid arthritis (RA) and atlantoaxial subluxation (AAS) and identifying and quantifying the role of C-reactive protein (CRP) as a potential mediator. Using summary-level data from a genome-wide association study (GWAS), a two-sample Mendelian randomization (MR) analysis of genetically predicted rheumatoid arthritis (14,361 cases, and 43,923 controls) and AAS (141 cases, 227,388 controls) was performed. Furthermore, we used two-step MR to quantitate the proportion of the effect of c-reactive protein-mediated RA on AAS. MR analysis identified higher genetically predicted rheumatoid arthritis (primary MR analysis odds ratio (OR) 0.61/SD increase, 95% confidence interval (CI) 1.36-1.90) increased risk of AAS. There was no strong evidence that genetically predicted AAS had an effect on rheumatoid arthritis risk (OR 1.001, 95% CI 0.97-1.03). The proportion of genetically predicted rheumatoid arthritis mediated by C-reactive protein was 3.7% (95%CI 0.1%-7.3%). In conclusion, our study identified a causal relationship between RA and AAS, with a small proportion of the effect mediated by CRP, but a majority of the effect of RA on AAS remains unclear. Further research is needed on additional risk factors as potential mediators. In clinical practice, lesions of the upper cervical spine in RA patients need to be given more attention.

Association of distance to swine concentrated animal feeding operations with immune-mediated diseases: An exploratory gene-environment study

BackgroundConcentrated animal feeding operations (CAFOs) are a source of environmental pollution and have been associated with a variety of health outcomes. Immune-mediated diseases (IMD) are characterized by dysregulation of the normal immune response and, while they may be affected by gene and environmental factors, their association with living in proximity to a CAFO is unknown. ObjectivesWe explored gene, environment, and gene-environment (GxE) relationships between IMD, CAFOs, and single nucleotide polymorphisms (SNPs) of prototypical xenobiotic response genes AHR, ARNT, and AHRR and prototypical immune response gene PTPN22. MethodsThe exposure analysis cohort consisted of 6,464 participants who completed the Personalized Environment and Genes Study Health and Exposure Survey and a subset of 1,541 participants who were genotyped. We assessed the association between participants’ residential proximity to a CAFO in gene, environment, and GxE models. We recombined individual associations in a transethnic model using METAL meta-analysis. ResultsIn White participants, ARNT SNP rs11204735 was associated with autoimmune diseases and rheumatoid arthritis (RA), and ARNT SNP rs1889740 was associated with RA. In a transethnic genetic analysis, ARNT SNPs rs11204735 and rs1889740 and PTPN22 SNP rs2476601 were associated with autoimmune diseases and RA. In participants living closer than one mile to a CAFO, the log-distance to a CAFO was associated with autoimmune diseases and RA. In a GxE interaction model, White participants with ARNT SNPs rs11204735 and rs1889740 living closer than eight miles to a CAFO had increased odds of RA and autoimmune diseases, respectively. The transethnic model revealed similar GxE interactions. ConclusionsOur results suggest increased risk of autoimmune diseases and RA in those living in proximity to a CAFO and a potential role of the AHR-ARNT pathway in conferring risk. We also report the first association of ARNT SNPs rs11204735 and rs1889740 with RA. Our findings, if confirmed, could allow for novel genetically-targeted or other preventive approaches for certain IMD.

Occupational inhalable agents constitute major risk factors for rheumatoid arthritis, particularly in the context of genetic predisposition and smoking

ObjectivesTo assess the effects of occupational inhalable exposures on rheumatoid arthritis (RA) development and their interactions with smoking and RA-risk genes, stratifying by presence of anticitrullinated protein antibodies (ACPA).MethodsData came...

Predictors of perceived risk in first-degree relatives of patients with rheumatoid arthritis

ObjectivesTo define variables associated with perceived risk of developing rheumatoid arthritis (RA) in first-degree relatives (FDRs) of patients with RA.MethodsPatients with RA and their FDRs were invited to complete cross-sectional...

Bidirectional two-sample Mendelian randomization study of causality between rheumatoid arthritis and myocardial infarction.

Epidemiological evidence suggests an association between rheumatoid arthritis (RA) and myocardial infarction (MI). However, causality remains uncertain. Therefore, this study aimed to explore the causal association between RA and MI. Using publicly available genome-wide association study summary datasets, bidirectional two-sample Mendelian randomization (TSMR) was performed using inverse-variance weighted (IVW), weighted median, MR-Egger regression, simple mode, and weighted mode methods. The MR results for the causal effect of RA on MI (IVW, odds ratio [OR] = 1.041, 95% confidence interval [CI]: 1.007-1.076, P = 0.017; weighted median, OR = 1.027, 95% CI: 1.006-1.049, P = 0.012) supported a causal association between genetic susceptibility to RA and an increased risk of MI. MR results for the causal effect of MI on RA (IVW, OR = 1.012, 95% CI: 0.807-1.268, P = 0.921; weighted median, OR = 1.069, 95% CI: 0.855-1.338, P = 0.556) indicated that there was no causal association between genetic susceptibility to MI and an increased risk of RA. Bidirectional TSMR analysis supports a causal association between genetic susceptibility to RA and an increased risk of MI but does not support a causal association between genetic susceptibility to MI and an increased risk of RA.

Acceptable risks of treatments to prevent rheumatoid arthritis among first-degree relatives: demographic and psychological predictors of risk tolerance

ObjectivesTo quantify tolerance to risks of preventive treatments among first-degree relatives (FDRs) of patients with rheumatoid arthritis (RA).MethodsPreventive treatments for RA are under investigation. In a preference survey, adult FDRs...

Association of Fc Gamma Receptor 3B Gene Copy Number Variation with Rheumatoid Arthritis Susceptibility.

Structural variations such as copy number variants (CNVs) have been associated with multiple autoimmune diseases. In this study, we explored the association of the Fc gamma receptor 3B gene (FCGR3B) copy number variation (CNV) with rheumatoid arthritis (RA) susceptibility and related serological traits in the Pakistani population. We also performed a meta-analysis of four published FCGR3B CNV studies along with the current study. A total of 927 subjects (597 RA cases, 330 healthy controls) were recruited from three rheumatology centers in Pakistan. Anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor (RF) were measured in RA patients. FCGR3B copy number was assayed using the TaqMan® CN assay (Hs04211858_cn, Applied Biosystems, Foster City, CA, USA) and the copy number was estimated by using CopyCaller® software (version 2.1; Applied Biosystems, USA). Logistic regression was applied to calculate the odds ratio (OR) of RA risk associated with FCGR3B CNV using sex and age as covariates in R. Meta-analysis on four previously published studies and the current study was performed using the random-effect model. We observed a significant association between FCGR3B copy number &lt; 2 and RA susceptibility (OR = 1.53; 95% CI: 1.05 to 2.22; p = 0.0259) and anti-CCP seropositivity (OR 2.56; 95% CI: 1.34 to 4.89; p = 0.0045). A non-significant association of FCGR3B copy number &lt; 2 was also observed between increased rheumatoid factor (RF) seropositivity (OR = 1.74; 95% CI:0.93 to 3.26; p = 0.0816). Meta-analysis on 13,915 subjects (7005 RA cases and 6907 controls) also showed significant association of copy number &lt; 2 with the increased risk of RA (OR = 1.30; 95% CI: 1.07 to 1.56; p = 0.00671). FCGR3B copy number &lt; 2 is associated with increased RA risk and anti-CCP seropositivity.

Higher skin autofluorescence in individuals at risk for rheumatoid arthritis: results from a large population based cohort.

To investigate skin autofluorescence (SAF) levels, an early indicator for cardiovascular disease, in relation to the presence of anticitrullinated protein antibodies (ACPA), joint complaints and rheumatoid arthritis (RA) in a large population-based cohort. Cross-sectional data were used from 17346 participants of the Dutch Lifelines Cohort Study, of whom baseline SAF and ACPA levels were available. Individuals were divided into four groups: ACPA-negative controls (n=17211), ACPA-positive without joint complaints (n=49), ACPA-positive RA risk (n=31) and defined RA (n=52). Multinomial regression was used to compare SAF levels and correct for potential confounders. SAF levels were higher in the ACPA-positive RA risk group (OR 2.04, p=0.034) and the defined RA group (OR 3.10, p<0.001) compared to controls, but not in the ACPA-positive without joint complaints group (OR 1.07, p=0.875). The difference in SAF levels remained statistically significant in the defined RA group after adjusting for age (OR 2.09, p=0.011), smoking status, renal function or HbA1c. In the ACPA-positive RA risk group, the effect was found to be comparable (corrected for age: OR 2.09). Our results indicate that ACPA-positive individuals with RA risk have elevated SAF levels, which is regarded as a non-invasive marker for oxidative stress and a possible indicator for development of cardiovascular disease. Therefore, it is important to conduct further studies to explore if, in ACPA-positive individuals with RA risk and no diagnosis of RA, cardiovascular risk management should be considered in future clinical practice.

Genetic link between rheumatoid arthritis and autoimmune liver diseases: A two-sample Mendelian randomization study

BackgroundAn association between rheumatoid arthritis (RA) and autoimmune liver diseases (AILDs) was found in observational studies. However, neither the direction nor the cause-effect chain was clear. This study aimed to assess the causal associations between AILDs and RA. MethodsWe performed a two-sample Mendelian randomization (MR) analysis. Following a strict assessment, genome-wide association study (GWAS) datasets were used to select potential candidate single-nucleotide polymorphisms. The inverse-variance weighted (IVW) was used as the primary analysis approach, supplemented with four sensitive analysis methods applied to assess the robustness of the results. ResultsWe discovered that a genetically increased primary biliary cholangitis (PBC) risk had a positive causal effect on RA (IVW OR=1.149, 95% CI=1.063–1.241, P<0.001). According to the MR-Egger regression, horizontal pleiotropy was unlikely to impact causality (intercept = -0.028, P = 0.263). Using the leave-one-out strategy, sensitivity studies revealed that the MR analysis results were robust and reliable. Genetically determined primary sclerosing cholangitis (PSC) was not linked with the risk of RA (IVW OR=1.071, 95%CI=0.984–1.166, P = 0.111). The results of the MR analysis were further validated by sensitivity analyses utilizing the leave-one-out approach. In the other direction, there was no causal relationship between RA and PBC (OR=1.132, 95% CI=0.881–1.454, P = 0.333) or PSC (OR=1.067, 95% CI=0.891–1.279, P = 0.088). ConclusionsUsing a two-sample MR analysis, we investigated the relationship between AILDs and RA and revealed first that PBC increases the risk of RA. Large-scale cross-disease GWAS are required to further illuminate the genomic landscape of AILDs and RA.

Identification of novel meQTLs strongly associated with rheumatoid arthritis by large-scale epigenome-wide analysis.

Rheumatoid arthritis (RA) is highly heritable, and previous studies have suggested that genetic variation may affect susceptibility to RA by altering epigenetic modifications (e.g. DNA methylation). Here we examined how genetic variation influences DNA methylation (DNAm) in RA by integrating individual genetic variation and DNAm data. Epigenome-wide meQTL (methylation quantitative trait loci) analysis was performed on 354 RA patients and 335 controls, scanning 30,101,744 relationships between 62 SNPs and 485,512 DNA methylation sites. Two regulatory relationship pairs (FDR < 0.05) showed very strong associations with RA risk. One was rs10796216-cg00475509, and the DNAm decreased by 0.0168 per addition of allele rs10796216-A. The other was rs6546473-cg13358873, for which a 0.0365 reduction of DNAm at cg13358873 was observed for each addition of allele rs6546473-A, and lower DNAm was found to be significantly associated with RA risk (P=2.0407e-28). Moreover, both pairs of meQTL showed a strong regulatory relationship only in RA samples, so they can be subsequently considered as risk markers for RA. In conclusion, our integrated analysis of genetic and epigenetic variation suggests that genetic variation may affect the risk of RA by regulating DNA methylation levels. Alterations of DNAm at cg00475509 and cg13358873 loci conferred by rs10796216-A and rs6546473-A allele may suggest a potential risk for RA. Our results deepen our understanding of the genetic and epigenetic mechanisms of RA and provide novel associations that can be further investigated in future studies.

A Mendelian randomization study on causal effects of leisure sedentary behaviour on the risk of rheumatoid arthritis.

The causal inference between leisure sedentary behaviour (LSB) and rheumatoid arthritis (RA) is still controversial because of potential residual confounding and reverse causality. The present study used publicly available large-scale genome-wide association studies (GWAS) of LSB (television watching, computer use, and driving) and RA to perform a two-sample Mendelian randomization (MR) study to evaluate the causal effect of LSB on the risk of RA. We detected significant causal associations using the multiplicative random effects-inverse variance weighted (MRE-IVW) method, the maximum likelihood, robust adjusted profile scores, the weighted median, MR-Egger regression, and several complementary sensitivity analyses. Risk factor analysis was also conducted to further investigate potential mediators linking causal inference. Increased genetic liability to leisure television watching was significantly associated with a higher risk of RA (MRE-IVW method; OR=2.46, 95% CI 1.77-3.41; p=8.35 × 10-8 ). MR estimates indicated that prolonged leisure computer use was causally associated with a lower risk of RA (MRE-IVW method; OR=0.23, 95% CI 0.12-0.46; p=2.19 × 10-5 ). However, we found no evidence for a causal effect of leisure driving on the risk of RA (MRE-IVW method; OR=0.59, 95% CI 0.10-3.41; p=0.557). No pleiotropy was detected by the sensitivity analysis. This study supports a causal association between prolonged leisure television watching and an increased risk of RA. Additionally, prolonged computer use might be a protective factor for RA.

Periodontitis and risk of immune-mediated systemic conditions: A systematic review and meta-analysis.

The aim of this review is to examine and quantify the long-term risk of immune-mediated systemic conditions in people with periodontitis compared to people without periodontitis. Medline, EMBASE and Cochrane databases were searched up to June 2022 using keywords and MeSH headings. The 'Risk of Bias in Non-Randomised Studies of Interventions' tool was used to assess bias. Cohort studies comparing incident metabolic/autoimmune/inflammatory diseases in periodontitis to healthy controls were included. Meta-analysis and meta-regression quantified risks and showed impact of periodontitis diagnosis type and severity. The search retrieved 3354 studies; 166 studies were eligible for full-text screening, and 30 studies were included for review. Twenty-seven studies were eligible for meta-analysis. The risks of diabetes, rheumatoid arthritis (RA) and osteoporosis were increased in people with periodontitis compared to without periodontitis (diabetes-relative risk [RR]: 1.22, 95% CI: 1.13-1.33; RA-RR: 1.27, 95% CI: 1.07-1.52; osteoporosis-RR: 1.40, 95% CI: 1.12-1.75). Risk of diabetes showed gradient increase by periodontitis severity (moderate-RR=1.20, 95% CI=1.11-1.31; severe-RR=1.34, 95% CI=1.10-1.63). People with moderate-to-severe cases of periodontitis have the highest risk of developing diabetes, while the effect of periodontal severity on risk of other immune-mediated systemic conditions requires further investigation. More homologous evidence is required to form robust conclusions regarding periodontitis-multimorbidity associations.