Risk Of Rheumatoid Arthritis Research Articles

Mendelian randomization identifies causal associations between GWAS-associated bacteria and their metabolites and rheumatoid arthritis.

Accumulating evidence suggests that an imbalance of gut microbiota is commonly observed in patients with rheumatoid arthritis (RA). However, it remains unclear whether gut microbiota dysbiosis is a cause or consequence of RA, and the mechanisms by which gut dysbiosis contributes to RA have not been fully understood. This study aimed to investigate the causal relationship between gut microbiota and metabolites with RA. A two-sample Mendelian randomization analysis was performed to estimate the causality of gut microbiota and metabolites on RA. A genome-wide association study (GWAS) of 211 gut microbiota and 217 metabolites was used as the exposure, whereas RA was treated as the outcome. Inverse variance weighted (IVW) was regarded as the primary approach for calculating causal estimates. MR Egger method, Weighted median method, Simple mode method, and weighted mode method were used for sensitive analysis. Metabolic pathway analysis was performed via the web-based Metaconflict 5.0. Additionally, an animal study was undertaken to evaluate the results inferred by Mendelian randomization. This study indicated that six gut microbiota taxa (RuminococcaceaeUCG013, Erysipelotrichia, Erysipelotrichaceae, Erysipelotrichales, Clostridia, and Veillonellaceae) were estimated to exert a positive impact on RA. Conversely, seven gut microbiota taxa (Oxalobacter, Cyanobacteria, RuminococcaceaeUCG002, LachnospiraceaeUCG010, Christensenellaceae, Oxalobacteraceae, Anaerostipes) were estimated to exert a negative impact on RA. Three metabolites, namely indole-3-propionate (IPA), glycine and sphingomyelin (SM 16:1), were found to be linked to lower RA risk, while five metabolites (argininosuccinate, CE 20_4, TAG 58_8, PC 40_6, and LPC 20_4) were linked to higher RA risk. Additionally, four metabolic pathways were identified by metabolic pathway analysis. The collagen-induced arthritis (CIA) rats exhibited a higher relative abundance of Class_Clostridia and a lower abundance of Genus_Lachnospiraceae (p < 0.05) than the healthy controls. This study identified causal associations between specific gut microbiota, metabolites, and RA. These findings support the significant role of gut microbiota and metabolites in RA pathogenesis.

Sleep pattern, genetic risk, and the risk of incident rheumatoid arthritis: A cohort study

ObjectiveTo investigate the associations of sleep behaviors with the risk of rheumatoid arthritis, and whether the associations differ among individuals with low, intermediate, or high genetic risk. MethodsWe included participants who were free of rheumatoid arthritis at baseline based the UK Biobank. We evaluated the associations of five sleep behaviors with the risk of rheumatoid arthritis using Cox proportional hazard regression models. We then generated a sleep risk score which combined five sleep behaviors and assessed its association with the risk of rheumatoid arthritis. We finally generated a genetic risk score and examined the joint effects of sleep patterns and genetic susceptibility on the risk of rheumatoid arthritis. ResultsOf the 375,133 participants at baseline, 4913 incident rheumatoid arthritis cases were identified over a median follow-up of 11.73years. We found that insomnia and daytime sleepiness were associated with a 33% and a 38% increased risk of rheumatoid arthritis. A U-shaped association was observed between sleep duration and the risk of rheumatoid arthritis, with a 29% higher risk for those with short sleep and a 30% higher risk for those with long sleep. Participants with unfavorable sleep patterns had a 63% increased risk of rheumatoid arthritis compared with those with favorable sleep patterns. Participants with unfavorable sleep patterns and high genetic risk showed the highest risk of rheumatoid arthritis although no statistically significant multiplicative or additive interaction was found. ConclusionsOur study suggested that insomnia, daytime sleepiness, and short or long sleep duration, as well as sleep risk score were associated with an increased risk of rheumatoid arthritis.

Genetic causality between modifiable risk factors and the risk of rheumatoid arthritis: Evidence from Mendelian randomization.

Emerging research has investigated the potential impact of several modifiable risk factors on the risks of rheumatoid arthritis (RA), but the findings did not yield consistent results. This study aimed to comprehensively explore the genetic causality between modifiable risk factors and the susceptibility of RA risk using the Mendelian randomization (MR) approach. Genetic instruments for modifiable risk factors were selected from several genome-wide association studies at the genome-wide significance level (p < 5 × 10-8), respectively. Summary-level data for RA were sourced from a comprehensive meta-analysis. The causal estimates linking modifiable risk factors to RA risk were assessed using MR analysis with inverse variance weighting (IVW), MR-Egger, weighted, and weighted median methods. After Bonferroni correction for multiple tests, we found the presence of causality between educational attainment and RA, where there were protective effects of educational attainment (college completion) (odds ratio [OR] = 0.50, 95% CI = 0.36, 0.69, p = 2.87E-05) and educational attainment (years of education) (OR = 0.93, 95% CI = 0.90, 0.96, p = 4.18E-06) on the lower RA risks. Nevertheless, smoking initiation was observed to be associated with increased RA risks (OR = 1.27, 95% CI = 1.09, 1.47, p = .002). Moreover, there was no indication of horizontal pleiotropy of genetic variants during causal inference between modifiable risk factors and RA. Our study reveals the genetic causal impacts of educational attainment and smoking on RA risks, suggesting that the early monitoring and recognition of modifiable risk factors would be beneficial for the preventive counseling/treatment strategies for RA.

Cardiovascular Risk in Rheumatoid Arthritis: Considerations on Assessment and Management.

In the context of holistic therapeutic practices, the cardiovascular risk of patients with rheumatoid arthritis (RA) needs to be addressed as a major factor of compromised disease prognosis and increased mortality. The elevated prevalence of cardiovascular disease (CVD) by more than twofold in RA has been attributed, inter alia, to chronic inflammation exacerbating arterial stiffness, increased onset of hypertension, dyslipidaemia and diabetes mellitus, sedentary lifestyle, and antirheumatic drug complications. CVD risk in RA can be currently assessed by practitioners through accessible adapted calculators, but it remains problematic as their diagnostic accuracy is not superior to calculators designed for the general population. Implementation of guideline-oriented personalised interventions remains the cornerstone for cardiovascular risk management in RA. Remarkably, there is lack of a consortium that brings together different health care providers engaged in the care of patients with RA (e.g., rheumatologists, cardiologists, general practitioners, etc), to guide cardiovascular risk assessment and management. This narrative review aims at providing an overview of current CVD risk assessment and management options, highlighting their pivotal role in the comprehensive treatment of RA patients.

Development of rheumatoid arthritis after methotrexate in anticitrullinated protein antibody-negative people with clinically suspect arthralgia at risk of rheumatoid arthritis: 4-year data from the TREAT EARLIER trial

Prevention of rheumatoid arthritis has become a definitive target. However, whether prevention of anti-citrullinated protein antibody (ACPA)-negative rheumatoid arthritis is possible is still unknown. We aimed to assess the efficacy of a 1-year course of methotrexate on the development of rheumatoid arthritis in ACPA-negative people with clinically suspect arthralgia and predicted increased risk of rheumatoid arthritis. For this follow-up analysis, we used 4-year data from the TREAT EARLIER trial, a randomised, double-blind, placebo-controlled, proof-of-concept trial conducted in the southwest region of the Netherlands from which we analysed data collected between April 16, 2015, and Sept 11, 2023. ACPA-positive and ACPA-negative adults aged 18 years or older with arthralgia and subclinical joint inflammation who were at risk of developing rheumatoid arthritis were eligible for enrolment. For TREAT EARLIER, participants were randomly assigned (1:1) to active treatment or placebo. Active treatment consisted of a single intramuscular glucocorticoid injection (120 mg of methylprednisolone) upon inclusion, then a 1-year course of methotrexate. Placebo consisted of a single placebo injection followed by a 1-year course of placebo tablets. Trial visits occurred every 4 months during the first 2 years, at which clinical and questionnaire data were collected. Total follow-up was 4 years. For this analysis, participants were stratified via a prediction model into low risk, increased risk, and high risk of developing persistent, clinically apparent inflammatory arthritis. The primary outcome was development of rheumatoid arthritis, defined as the presence of clinically apparent inflammatory arthritis and clinical diagnosis of rheumatoid arthritis, and was assessed in all TREAT EARLIER participants. Severity of subclinical joint inflammation, physical functioning, and grip strength in ACPA-negative participants was studied in each risk group over a period of 2 years. 901 people with clinically suspect arthralgia were assessed for eligibility and 236 were enrolled in TREAT EARLIER. All 236 participants were included in the intention-to-treat analysis and 217 (92%) completed 4-year follow-up. 154 (65%) of 236 participants were women and 82 (35%) were men, 182 (77%) were ACPA-negative and 54 (23%) were ACPA-positive. Of the 182 randomly assigned ACPA-negative participants, none were predicted to be at high risk of developing persistent, clinically apparent inflammatory arthritis, 66 (36%) at increased risk, and 116 (64%) at low risk. Of the 54 ACPA-positive participants, 24 (44%) were predicted to be at high risk, 30 (56%) at increased risk, and none at low risk. After 4 years, 52 (22%) of 236 participants had developed the primary outcome of rheumatoid arthritis (25 [21%] of 119 in the treatment group and 27 [23%] of 117 in the placebo group). Of the 66 ACPA-negative participants predicted to be at increased risk, three (9%) of 35 in the treatment group developed the primary outcome compared with nine (29%) of 31 in the placebo group (hazard ratio 0·27, 95% CI 0·07-0·99; p=0·034). Of the 116 ACPA-negative participants predicted to be at low risk, four (8%) of 53 in the treatment group met the primary outcome compared with six (10%) of 63 in the placebo group (0·79, 0·22-2·80; p=0·71). Thus, after risk stratification, a 1-year course of methotrexate was associated with a reduced rate of development of ACPA-negative rheumatoid arthritis in participants with predicted increased risk of developing the disease. Subclinical joint inflammation, physical functioning, and grip strength persistently improved upon treatment in ACPA-negative participants with increased risk of developing rheumatoid arthritis, but not in those with low risk. Risk stratification can be helpful in trials of ACPA-negative people with clinically suspect arthralgia to identify participants who could benefit from treatment to prevent development of rheumatoid arthritis. Dutch Research Council-ZonMw, Dutch Arthritis Society.

Targeting Therapeutic Windows for Rheumatoid Arthritis Prevention.

Rheumatoid arthritis (RA) is a worldwide public health problem. Interventions to delay or prevent the onset of RA have attracted much attention in recent years, and researchers are now exploring various prevention strategies. At present, there is still no unified consensus for RA prevention, but targeting therapeutic windows and implementing interventions for at-risk individuals are extremely important. Due to the limited number of clinical trials on pharmacologic interventions, further studies are needed to explore and establish optimal intervention regimens and effective measures to prevent progression to RA. In this review, we introduce the RA disease process and risk factors, and present research on the use of both Western and Chinese medicine from clinical perspectives regarding RA prevention. Furthermore, we describe several complete and ongoing clinical studies on the use of Chinese herbal formulae for the prevention of RA.

Genetically Predicted Iron Status Is a Causal Risk of Rheumatoid Arthritis: A Mendelian Randomization Study.

Background Current knowledge on iron's role in rheumatoid arthritis (RA) development is very limited, with studies yielding inconsistent findings. We conducted a two-sample Mendelian randomization study to assess the associations of iron status with the risk of RA. Methods This study leveraged genetic data from a large genome-wide association study (GWAS) of 257,953 individuals to identify single nucleotide polymorphisms (SNPs) associated with iron status. We then analyzed these data in conjunction with summary-level data on RA from the IEU open GWAS project, which included 5,427 RA cases and 479,171 controls. An inverse-variance weighted method with random effects was employed, along with sensitivity analyses, to assess the relationship between iron status and RA risk. Results Genetic predisposition to high ferritin and serum iron status was causally associated with lower odds of RA. Ferritin had an odds ratio (OR) of 0.997 (95% confidence interval [CI]: 0.995-0.997; p = 0.010), indicating that a one-unit increase in ferritin is associated with a 0.3% decrease in the odds of RA. Similarly, serum iron had an OR of 0.997 (95% CI: 0.995-0.999; p = 0.014). However, MR analyses found no significant causal associations between total iron-binding capacity (OR = 1.0, 95% CI: 0.999-1.002; p = 0.592) or transferrin saturation percentage (OR = 0.998, 95% CI: 0.996-1.000; p = 0.080) and risk of developing RA. Conclusions This study suggests that individuals with genes linked to higher iron levels may have a lower risk of developing RA. Our findings indicate that the total amount of iron in the body, rather than how it is distributed, might be more important for RA. This raises the intriguing possibility that iron supplementation could be a preventative strategy, but further research is necessary.

Association of HDL and LDL levels with osteoporosis in rheumatoid arthritis: a retrospective cohort study

ObjectivesA correlation exists between lipids and osteoporosis (OP), as well as between lipids and rheumatoid arthritis (RA). However, lipids, the relationship between RA and OP is still unclear. This study mainly investigates the relationship between lipid levels and OP risk in RA patients.MethodsRetrospective collection of RA patient data from July 2017 to May 2022, encompassing baseline demographics, treatment regimens, laboratory results, and bone mineral density (BMD) measurements. Analyses, stratified by BMD subgroups, were conducted using propensity score matching (PSM) based on age, sex, and baseline duration, and binary logistic regression to examine the interplay between lipoprotein levels and other risk factors. The relationship between continuous variables and OP risk was assessed using restricted cubic spline (RCS), followed by a reanalysis of the correlation between varying lipoprotein levels and different factors, segmented according to RCS-determined cutoffs.ResultsThe study included 2673 RA patients. Binary logistic regression revealed significant associations between high-density lipoprotein (HDL), low-density lipoprotein (LDL), and RA–OP (p < 0.01). Specifically, HDL emerged as a protective factor against OP (OR = 0.40, 95% CI 0.250–0.629; p < 0.001), whereas LDL was identified as a risk factor (OR = 1.56, 95% CI 1.290–1.890; p < 0.001). Furthermore, HDL (RCS cutoff point 1.28 mmol/L) showed a negative, linear correlation with RA-related OP, while LDL (RCS cutoff point 2.63 mmol/L) demonstrated a positive, linear correlation.ConclusionsThe levels of HDL and LDL may be indicators of OP occurrence in RA patients.

The Risk of Lung Cancer in Rheumatoid Arthritis and Rheumatoid Arthritis-Associated Interstitial Lung Disease.

We aimed to evaluate lung cancer risk in patients with rheumatoid arthritis (RA) and RA-interstitial lung disease (ILD). We performed a retrospective, matched cohort study of RA and RA-ILD within the Veterans Health Administration (VA) between 2000 and 2019. Patients with RA and RA-ILD were identified with validated administrative-based algorithms, then matched (up to 1:10) on age, gender, and VA enrollment year to individuals without RA. Lung cancers were identified from a VA oncology database and the National Death Index. Conditional Cox regression models assessed lung cancer risk adjusting for race, ethnicity, smoking status, Agent Orange exposure, and comorbidity burden among matched individuals. Several sensitivity analyses were performed. We matched 72,795 patients with RA with 633,937 patients without RA (mean age 63 years; 88% male). Over 4,481,323 patient-years, 17,099 incident lung cancers occurred. RA was independently associated with an increased lung cancer risk (adjusted hazard ratio [aHR] 1.58 [95% confidence interval (CI) 1.52-1.64]), which persisted in never smokers (aHR 1.65 [95% CI 1.22-2.24]) and in those with incident RA (aHR 1.54 [95% CI 1.44-1.65]). Compared to non-RA controls, prevalent RA-ILD (n = 757) was more strongly associated with lung cancer risk (aHR 3.25 [95% CI 2.13-4.95]) than RA without ILD (aHR 1.57 [95% CI 1.51-1.64]). Analyses of both prevalent and incident RA-ILD produced similar results (RA-ILD vs non-RA aHR 2.88 [95% CI 2.45-3.40]). RA was associated with a >50% increased risk of lung cancer, and those with RA-ILD represented a particularly high-risk group with an approximate three-fold increased risk. Increased lung cancer surveillance in RA, and especially RA-ILD, may be a useful strategy for reducing the burden posed by the leading cause of cancer death.

Association between dietary retinol intake and rheumatoid arthritis based on NHANES database

ObjectiveThis study focused on the investigation of the correlation between dietary retinol intake and rheumatoid arthritis (RA) using the National Health and Nutrition Examination Survey (NHANES) database.MethodsData from five NHANES cycles from 2003 to 2012 were utilized for this study. Dietary retinol intake was considered as the independent variable, and RA was the dependent variable. A weighted logistic regression method was applied to construct the relational model of the two variables. Stratified analysis without adjusting for confounding factors and subgroup analysis with confounding factors adjusted were conducted to explore the association between dietary retinol intake and RA. The optimal intake of dietary retinol was determined by the restricted cubic splines (RCS) analysis.Results22,971 samples were included in this study. The weighted logistic regression model was employed to construct the relational model of dietary retinol intake and RA (OR: 0.95, 95% CI: 0.91–0.99, p = 0.019). Stratified analysis displayed a great influence on the relational model exerted by the interaction between gender and retinol intake (p for interaction = 0.014). A significant association between retinol intake and RA was also indicated in the model adjusted for demographic characteristics (OR: 0.95, 95% CI: 0.90-1.00, p = 0.029). Subgroup analysis by gender showed that in the female population, unadjusted model (OR: 0.90, 95% CI: 0.84–0.96, p = 0.002), model adjusted for demographic characteristics only (OR: 0.89, 95% CI: 0.83–0.96, p = 0.002), and model adjusted for all confounding factors (OR: 0.91, 95% CI: 0.85–0.99, p = 0.019) indicated dietary retinol intake as a protective factor against RA. RCS analysis demonstrated that in the female population, regardless of the model used (Crude, Model I, and Model II), an intake of dietary retinol > 354.86 mcg was associated with RA disease reduction (OR < 1.0, p-non-linear < 0.05, p-overall < 0.05).ConclusionIncreased dietary retinol intake was associated with RA disease reduction, particularly in the female population. Women are recommended to increase their dietary retinol intake (> 354.86 mcg) to reduce the risk of RA.

Role of Selected Genetic Polymorphisms in the Development of Rheumatoid Arthritis in a British White Population.

Rheumatoid arthritis (RA) is a complex autoimmune disease that negatively affects synovial joints, leading to the deterioration of movement and mobility of patients. This chronic disease is considered to have a strong genetic inheritance, with genome-wide association studies (GWAS) highlighting many genetic loci associated with the disease. Moreover, numerous confounding and non-genetic factors also contribute to the risk of the disease. This study investigates the association of selected genetic polymorphisms with rheumatoid arthritis risk and develops a polygenic risk score (PRS) based on selected genes. A case-control study recruited fully consenting participants from the East Midlands region of the UK. DNA samples were genotyped for a range of polymorphisms and genetic associations were calculated under several inheritance models. PRS was calculated at crude (unweighted) and weighted levels, and its associations with clinical parameters were determined. There were significant associations with the risk of RA at six genetic markers and their associated risk alleles (TNRF2*G, TRAF1*A, PTPN22*T, HLA-DRB1*G, TNFα*A, and IL4-590*T). The TTG haplotype at the VDR locus increased the risk of RA with an OR of 3.05 (CI 1.33-6.98, p = 0.009). The GA haplotype of HLADRB1-TNFα-308 was a significant contributor to the risk of RA in this population (OR = 2.77, CI 1.23-6.28, p = 0.01), although linkage disequilibrium was low. The polygenic risk score was significantly higher in cases over controls in both unweighted (mean difference = 1.48, t285 = 5.387, p < 0.001) and weighted (mean difference = 2.75, t285 = 6.437, p < 0.001) results. Several genetic loci contribute to the increased risk of RA in the British White sample. The PRS is significantly higher in those with RA and can be used for clinical applications and personalised prevention of disease.

Association of ultraprocessed food consumption with risk of rheumatoid arthritis: a retrospective cohort study in the UK Biobank

BackgroundLimited studies explored the association between consumption of ultraprocessed food (UPF) and rheumatoid arthritis (RA). ObjectivesThis study aimed to examine the association between UPF consumption and RA risk and explore the potential mediating effects of RA-related biomarkers. MethodsThis retrospective cohort study included 207,012 participants without RA at recruitment and completed 24-h dietary recalls. UPF was defined based on the NOVA food classification system. Incident RA was ascertained using the International Classification of Diseases version 10. Cox regression models were used to examine the association between UPF consumption and the incidence of RA. Additionally, mediation analyses were conducted to evaluate the contribution of biomarkers related to the lipid profile, systemic inflammatory factors, serum liver enzymes, and glucose metabolism to the observed associations. ResultsThe participants’ mean (standard deviation [SD]) age at recruitment was 56.08 (7.95) y. During a median follow-up of 12.24 (interquartile range: 11.66–13.03) y, 1869 RA events were recorded. Compared with the lowest quintile of UPF consumption (weight percentage of the UPF), the adjusted hazard ratio (HR) of RA in the highest quintile was 1.17 (95% confidence interval (CI): 1.01, 1.36). There was a 6% elevated risk of RA incidence per SD increase in UPF intake (HR: 1.06; 95% CI: 1.01, 1.11). In the mediation analyses, the biomarkers explained 3.07%–14.80% of the association between UPF intake and RA. ConclusionsHigher UPF consumption was associated with an increased risk of RA, which may be mediated by inflammation, lipids, and liver enzymes. Lower UPF consumption is recommended to reduce RA incidence.

Haplotype-based Analysis of 6q24-25 for Association with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a multisystem inflammatory disorder. Family history of RA is an important risk factor as it is strongly linked with the inherited HLA-DR4 (most specifically DR0401 and 0404). The aim of this study is to conduct the haplotype-based analysis of 6q24-25 and evaluate its association with RA. Case-control study which included all patients attending outpatient department (OPD) at Sardar Patel Medical College, Bikaner, Rajasthan and volunteers (only for blood samples). Blood samples of patients were collected. As per inclusion and exclusion criteria, a total of 103 subjects lacking history of disease were included under control group, while 48 cases were recruited as study group. Any significant departure of genotype distribution is evaluated using Hardy-Weinberg equilibrium by Chi-squared test. Case-control association was done using data from 151 genomic deoxyribonucleic acid (DNA) samples, which were allele typed. RA is significantly associated with >305bp (the longer allele of D6S1053 corresponding to 11 tetramer (GATA) repeats. Differences in individual allele frequency within the control population and RA cases were observed which shows the bimodal distribution of the 10 alleles of D6S1053 short tandem repeat (STR) marker observed in the cohort tested by us. No significant association with the risk for RA is shown by the allele for D6S1053 and the mutant allele 118G. Similarly, OPRM1 gene's haplotype frequency for rs1799972 for D6S1053 allele has not shown any added risk with the wild allele 17C compared to controls. The polymorphism showed that 17T depicted a higher odds ratio of 1.3 with an associated risk of 1.15 in the presence of longer allele of DS61053. Significance observed between short allele and RA was lost when haplotype analysis for the two genes were taken together. There was no difference observed between the short or long allele and 17T/C while there was a significant difference observed when haplotype frequencies were compared with alleles of A118G and the long and short allele of DS61053. We concluded that the short allele of µ-opioid receptor (MOR) gene offered a clear protection from a risk of getting RA.

Gastroesophageal reflux disease increases the risk of rheumatoid arthritis: a bidirectional two-sample Mendelian randomization study

Rheumatoid arthritis (RA) is a common autoimmune disease, and some observational studies have indicated an association between Gastroesophageal Reflux Disease (GERD) and RA. However, the causal relationship between the two remains uncertain. We used Mendelian randomization (MR) to assess the causal relationship between GERD and RA. Two-sample Mendelian randomization analysis was performed using pooled data from large-scale genome-wide association studies. In addition, we performed multivariate MR analyses to exclude confounding factors between GERD and RA, including smoking quantity, drinking frequency, BMI, depression, and education attainment. The MR results for GERD on RA suggested a causal effect of the genetic susceptibility of GERD on RA (discovery dataset, IVW, odds ratio [OR] = 1.41, 95% confidence interval [CI] 1.22–1.63, p = 2.81 × 10−6; validation dataset, IVW, OR = 1.38, 95% CI 1.23–1.55, P = 1.76 × 10−8). Multivariate MR analysis also supports this result. But the results of the reverse MR analysis did not reveal compelling evidence that RA can increase the risk of developing GERD. Our bidirectional Two-Sample Mendelian randomization analysis and multivariate MR analysis provide support for the causal effect of GERD on RA. This discovery could offer new insights for the prevention and treatment of RA.

Rheumatoid arthritis and adverse pregnancy outcomes: a bidirectional two-sample mendelian randomization study

BackgroundThere is growing evidence of bidirectional associations between rheumatoid arthritis and adverse pregnancy outcomes (APOs) in observational studies, but little is known about the causal direction of these associations. Therefore, we explored the potential causal relationships between rheumatoid arthritis and APOs using a bidirectional two-sample Mendelian randomization (MR) in European and Asian populations.MethodsWe conducted a bidirectional two-sample Mendelian randomization analysis using available summary statistics from released genome-wide association studies. Summary statistics for instrument–outcome associations were retrieved from two separate databases for rheumatoid arthritis and adverse pregnancy outcomes, respectively. The inverse-variance weighted method was used as the primary MR analysis, and cML-MA-BIC was used as the supplementary analysis. MR-Egger, MR pleiotropy residual sum and outlier (MR-PRESSO), and Cochran Q statistic method were implemented as sensitivity analyses approach to ensure the robustness of the results.ResultsOur study showed that a higher risk of rheumatoid arthritis in the European population was associated with gestational hypertension (OR: 1.04, 95%CI: 1.02–1.06), pre-eclampsia (OR: 1.06, 95%CI: 1.01–1.11), fetal growth restriction (OR: 1.08, 95%CI: 1.04–1.12), preterm delivery (OR:1.04, 95%CI: 1.01–1.07). Furthermore, we found no evidence that APOs had causal effects on rheumatoid arthritis in the reverse MR analysis. No association between rheumatoid arthritis and APOs was found in East Asian population. There was no heterogeneity or horizontal pleiotropy.ConclusionsThis MR analysis provides the positive causal association from rheumatoid arthritis to gestational hypertension, pre-eclampsia, fetal growth restriction and preterm delivery genetically. It highlights the importance of more intensive prenatal care and early intervention among pregnant women with rheumatoid arthritis to prevent potential adverse obstetric outcomes.

Does the use of statins alter the risk of rheumatoid arthritis? A systematic review and meta-analysis.

Statins have anti-inflammatory and immune-modulatory effects which could alter the risk of rheumatoid arthritis (RA). We reviewed published literature and conducted a meta-analysis to examine if statins have an impact on the risk of RA. Case-control studies, cohort studies, or randomized controlled trials (RCT) published on the PubMed, Scopus, and EMBASE databases up to 30th October 2023 were searched. The association between statin use and risk of RA was pooled in a random-effects meta-analysis. Nine studies (four cohort, four case-control, and one RCT) were included. Overall, the analysis failed to note an association between the use of statins and the risk of RA with the pooled OR being 0.93 (95% CI 0.82, 1.06). High heterogeneity was noted with I2 = 75%. Results were consistent across study types with no association noted between prior statin use and risk of RA in case-control studies (OR: 0.88 95% CI: 0.69, 1.13), cohort studies (OR: 1.01 95% CI: 0.92, 1.10), and the lone RCT (OR: 1.40 95% CI: 0.50, 3.92). Current literature shows that there is no association between the use of statins and the risk of RA. Further rigorous studies taking into account patient factors, duration of statin exposure, and other confounders are needed to generate better evidence.

Biological use influences the impact of inflammation on risk of major adverse cardiovascular events in rheumatoid arthritis

ObjectivesChronic inflammation promotes cardiovascular risk in rheumatoid arthritis (RA). Biological disease-modifying antirheumatic drugs (bDMARDs) improve disease activity and cardiovascular disease outcomes. We explored whether bDMARDs influence the impact of disease...

Does Adding Single-Nucleotide Polymorphisms to Risk Algorithms Improve Cardiovascular Disease Risk Prediction in Rheumatoid Arthritis? An Internal and External Validation of a Clinical Risk Score.

Current risk algorithms do not accurately predict cardiovascular disease (CVD) risk in rheumatoid arthritis (RA). An area of interest is that of single-nucleotide polymorphisms (SNPs), of which several have been associated with CVD in the general population. We investigated whether these SNPs are associated with CVD in RA and whether SNPs could improve CVD risk prediction in RA. Sixty SNPs were genotyped in 353 patients with RA. Logistic and Cox regression analyses were performed to identify SNPs that were associated with CVD (n = 99). A prediction model with clinical variables was made. SNPs were added to investigate the additional predictive value. Both models were internally validated. External validation was done in a separate cohort (n = 297). rs3184504, rs4773144, rs12190287, and rs445925 were significantly associated with new CVD. The clinical prediction model consisted of age, sex, body mass index, systolic blood pressure, high-density lipoprotein cholesterol (HDLc), and creatinine, with an area under the curve (AUC) of 0.74 (P = 0.03). Internal validation resulted in an AUC of 0.76 (P < 0.01). A new model was made including SNPs and resulted in a model with rs17011666 and rs801426, age, total cholesterol, and HDLc, which performed slightly better with an AUC of 0.77 (P < 0.01). External validation resulted in a good fit for the clinical model, but a poor fit for the SNP model. Several SNPs were associated with CVD in RA. Risk prediction slightly improved after adding SNPs to the models, but the clinical relevance is debatable. However, larger studies are needed to determine more accurately the additional value of these SNPs to CVD risk prediction algorithms.

Association of Cardiovascular Outcomes With Low-Dose Glucocorticoid Prescription in Patients With Rheumatoid Arthritis.

Many guidelines recommend limiting glucocorticoids in patients with rheumatoid arthritis (RA), but 40% of patients remain on glucocorticoids long term. We evaluated the cardiovascular risk of long-term glucocorticoid prescription by studying patients on stable disease-modifying antirheumatic drugs (DMARDs). Using two claims databases, we identified patients with RA on stable DMARD therapy for >180 days. Proportional hazards models with inverse-probability weights and clustering to account for multiple observations were used to estimate the effect of glucocorticoid dose on composite cardiovascular outcomes (stroke or myocardial infarction [MI]). There were 135,583 patients in Medicare and 39,272 in Optum's de-identified Clinformatics Data Mart (CDM) database. Medicare and CDM patients had an incidence of 1.3 and 0.8 composite cardiovascular outcomes per 100 person-years, respectively. In the older, comorbid Medicare cohort, glucocorticoids were associated with a dose-dependent increase in composite cardiovascular outcomes in adjusted models with predicted one-year incidence of 1.4% (95% confidence interval [CI] 1.2%-1.6%) for ≤5 mg, 1.6% (95% CI 1.4%-1.9%) for >5 to 10 mg, and 1.8% (95% CI 1.2%-2.5%) for >10 mg versus 1.1% (95% CI 1.1%-1.2%) among patients not receiving glucocorticoids. There was no significant association among the CDM cohort. However, in the subgroup of younger patients with RA and higher cardiovascular risk, glucocorticoids were associated with a dose-dependent increase in composite cardiovascular outcomes. Among older patients with more comorbidities and younger patients with higher cardiovascular risk with RA on stable DMARD therapy, glucocorticoids were associated with a dose-dependent increased risk of MI and stroke, even at doses ≤5 mg/day. By contrast, no association was noted among younger, healthier patients with RA.

Treating Cardiovascular Disease in the Inflammatory Setting of Rheumatoid Arthritis: An Ongoing Challenge.

Despite progress in treating rheumatoid arthritis, this autoimmune disorder confers an increased risk of developing cardiovascular disease (CVD). Widely used screening protocols and current clinical guidelines are inadequate for the early detection of CVD in persons with rheumatoid arthritis. Traditional CVD risk factors alone cannot be applied because they underestimate CVD risk in rheumatoid arthritis, missing the window of opportunity for prompt intervention to decrease morbidity and mortality. The lipid profile is insufficient to assess CVD risk. This review delves into the connection between systemic inflammation in rheumatoid arthritis and the premature onset of CVD. The shared inflammatory and immunologic pathways between the two diseases that result in subclinical atherosclerosis and disrupted cholesterol homeostasis are examined. The treatment armamentarium for rheumatoid arthritis is summarized, with a particular focus on each medication's cardiovascular effect, as well as the mechanism of action, risk-benefit profile, safety, and cost. A clinical approach to CVD screening and treatment for rheumatoid arthritis patients is proposed based on the available evidence. The mortality gap between rheumatoid arthritis and non-rheumatoid arthritis populations due to premature CVD represents an urgent research need in the fields of cardiology and rheumatology. Future research areas, including risk assessment tools and novel immunotherapeutic targets, are highlighted.