Rheumatoid Arthritis And Atrial Fibrillation Connection
Overview
Rheumatoid arthritis (RA), an autoimmune condition affecting multiple organs, has garnered attention for its potential link to adverse cardiovascular outcomes, including atrial fibrillation (AF). Yet, the precise association remains elusive, with conflicting findings in the literature. Our study sought to elucidate this relationship and explore additional clinical implications.
Conducting a meticulous systematic review of literature databases including PubMed, Embase, and Scopus, we identified relevant articles up to September 10, 2023. Our analysis encompassed a substantial cohort comprising 4,679,930 patients, with 81,677 individuals diagnosed with RA and 4,493,993 in the non-rheumatoid arthritis (NRA) group. The patients had a mean age of 57.2 years.
Primary outcomes analysis revealed a noteworthy finding: patients in the rheumatoid arthritis group exhibited a significantly elevated risk of AF compared to their NRA counterparts, with an odds ratio (OR) of 1.53 and a 95% confidence interval (CI) of [1.16–2.03], denoting statistical significance (p < .001).
Delving deeper into secondary outcomes, our investigation unveiled compelling insights. Patients with rheumatoid arthritis demonstrated significantly higher odds of experiencing acute coronary syndrome (ACS) and all-cause mortality (ACM) when compared to those without rheumatoid arthritis. Specifically, the OR for ACS stood at 1.39 (95% CI: [1.26–1.52], p < .001), while for ACM, it was 1.19 (95% CI: [1.03–1.37], p = .02), underscoring the heightened cardiovascular risk associated with rheumatoid arthritis.
Interestingly, however, the likelihood of stroke did not exhibit a significant disparity between the rheumatoid arthritis and NRA cohorts, with comparable ORs of 1.02 (95% CI: [0.94–1.11], p = .61) for both groups.
In essence, our comprehensive analysis sheds light on the heightened cardiovascular risk profile observed in patients with rheumatoid arthritis, underscored by increased susceptibility to AF, ACS, and ACM. These findings underscore the importance of vigilant cardiovascular monitoring and management strategies in individuals with rheumatoid arthritis to mitigate adverse outcomes and improve overall prognosis.
Introduction
Rheumatoid arthritis (RA) stands as a chronic autoimmune condition characterized by progressive polyarthritis primarily affecting small joints, often escalating to larger ones. While less common, manifestations like cutaneous, cardiovascular, and ocular symptoms may also arise. Despite typically affecting individuals aged 35–60, cases of juvenile rheumatoid arthritis, impacting those under 16, have been noted. Etiological factors, including genetic predisposition, environmental exposures, and lifestyle dynamics, intertwine to drive rheumatoid arthritis onset and progression.
Globally, RA prevalence is estimated at 0.24%, with higher rates seen in the US and parts of Northern Europe (0.5–1%), with a predilection for females. Classic rheumatoid arthritis symptoms encompass fever, weight loss, tender joints, and characteristic rheumatoid nodules. The pathogenesis involves complex genetic and environmental interactions leading to immune dysregulation, synovial inflammation, and joint damage.
The multifaceted genetic component of rheumatoid arthritis involves numerous genes, each with varying associations. RA patients also face an increased risk of cardiovascular disease (CVD) due to elevated proinflammatory cytokines, notably TNF-alpha and various interleukins. Disease severity significantly impacts CVD risk and prognosis, with heightened severity correlating with increased CVD risk annually.
Existing literature presents conflicting findings on AF risk and CVD outcomes in rheumatoid arthritis, necessitating a meta-analysis to clarify these associations. The goal is to provide insights into the multifactorial nature of CVD in rheumatoid arthritis, aiding in the development of targeted therapeutic approaches and screening strategies for at-risk populations.
Method
This meta-analysis adhered rigorously to established guidelines, including those outlined by Cochrane and PRISMA (Preferred Reporting Items for Systematic Review and Meta-analysis) 2020, ensuring transparency and methodological consistency. The study protocol was preregistered in PROSPERO (CRD42023424652), enhancing transparency and minimizing bias.
The primary outcome of interest was atrial fibrillation (AF), with secondary endpoints encompassing acute coronary syndrome (ACS), stroke, and all-cause mortality (ACM). A systematic literature search was conducted across multiple databases using predefined MeSH terms, covering relevant topics such as rheumatoid arthritis, arrhythmia, ACS, mortality, and stroke. The search, conducted until September 10, 2023, included studies without language or date restrictions.
Following careful screening and review by multiple authors, data from eligible studies were extracted and synthesized using established methodologies. Baseline variables were summarized, and a conventional, two-arm meta-analysis was performed using appropriate statistical models, including random-effects models for study variations. Effect sizes were determined using hazard ratios (HR) and odds ratios (OR) with corresponding 95% confidence intervals (CI).
The assessment of heterogeneity among studies was conducted using the Higgins I-squared (I^2) statistical model, with values interpreted to gauge the degree of heterogeneity. Statistical significance was determined based on established criteria, with thorough analyses conducted using Review Manager software (RevMan) Version 5.4.
To ensure the quality of included studies, the Newcastle-Ottawa Scale (NOS) was employed, with scores indicating the level of risk of bias. Discrepancies in quality assessment were addressed through group-based discussions, emphasizing the importance of robust evaluation criteria.
Overall, this meta-analysis provides a comprehensive and methodologically sound synthesis of existing literature on the relationship between rheumatoid arthritis and cardiovascular outcomes, offering valuable insights for clinical practice and future research endeavors.
Inclusion Criteria
The inclusion criteria for this study encompassed several key parameters to ensure the relevance and reliability of the research findings. Firstly, studies involving patients aged 18 years or older were considered, thereby focusing on adult populations. Secondly, the study required a comparative design with two arms, distinguishing between patients diagnosed with rheumatoid arthritis (RA) and those without rheumatoid arthritis. This design facilitated the examination of potential differences in outcomes between these groups.
Additionally, the inclusion criteria mandated that studies report at least one of the desired outcomes of interest, ensuring that the research addressed pertinent clinical endpoints. These outcomes could encompass various aspects related to RA, such as disease severity, treatment efficacy, or patient-reported outcomes.
Furthermore, the study sought to include different types of research designs, including propensity score-matched studies, as well as prospective and retrospective studies. By incorporating diverse methodologies, the research aimed to capture a comprehensive understanding of the relationship between rheumatoid arthritis and its outcomes, considering both observational and interventional perspectives.
Overall, these inclusion criteria were carefully selected to gather robust evidence and insights into the impact of rheumatoid arthritis on patient health outcomes, thereby informing clinical practice and guiding future research endeavors in this field.
Exclusion Criteria
The exclusion criteria for this review encompassed a variety of study types and methodologies to ensure the selection of robust and comprehensive research findings. Animal studies, abstracts, editorials, commentaries, systematic reviews, single-patient case studies, letters, and studies lacking sufficient data were all excluded from consideration. Additionally, studies presenting a single arm without comparators and those with noncompliant outcomes were also excluded. By implementing these stringent criteria, the review aimed to focus exclusively on high-quality, comparative studies with adequate data to provide reliable and meaningful insights into the research question at hand.
Result
In our initial search, a thorough examination of 451 articles revealed promising insights into the association between rheumatoid arthritis (RA) and cardiovascular outcomes. After meticulous screening and exclusion processes, seven observational studies met the criteria for quantitative analysis. These studies encompassed a total of 4,679,930 patients, with 81,677 in the RA group and 4,493,993 in the non-rheumatoid arthritis (NRA) group, providing a robust dataset for analysis.
Among the patients included, hypertension (HTN) and diabetes mellitus (DM) emerged as prevalent comorbidities, with HTN being particularly common among RA patients. The mean age of the patient cohort was 57.2 years, indicating a predominantly older population.
The meta-analysis of primary outcomes revealed a significantly higher risk of atrial fibrillation (AF) among rheumatoid arthritis patients compared to the NRA group. This finding underscores the potential impact of RA on cardiovascular health, particularly in predisposing individuals to AF, a condition associated with increased morbidity and mortality.
Furthermore, the analysis of secondary outcomes highlighted a notable association between rheumatoid arthritis and adverse cardiovascular events. RA patients exhibited elevated odds of acute coronary syndrome (ACS) and all-cause mortality (ACM) compared to their non-RA counterparts. This suggests a heightened cardiovascular risk profile in RA patients, warranting vigilant monitoring and targeted interventions to mitigate these risks.
However, the likelihood of stroke was found to be comparable between RA and non-RA patients, indicating that while RA may confer an increased risk of certain cardiovascular outcomes, it may not significantly influence the incidence of stroke.
Overall, these findings underscore the intricate interplay between rheumatoid arthritis and cardiovascular health, emphasizing the importance of holistic management strategies that address both rheumatologic and cardiovascular aspects of care. Further research is warranted to elucidate the underlying mechanisms driving these associations and to inform tailored interventions aimed at optimizing cardiovascular outcomes in rheumatoid arthritis patients.
Conclusion
This study presents compelling evidence indicating a higher risk of adverse cardiovascular events among individuals with rheumatoid arthritis (RA). Specifically, RA patients exhibit elevated odds of atrial fibrillation (AF), acute coronary syndrome (ACS), and all-cause mortality (ACM). However, the risk of stroke did not show significant variation between RA and non-RA patient groups. Previous meta-analyses with limited sample sizes may have hindered a comprehensive understanding of the association between RA and cardiovascular outcomes. Therefore, updated analyses incorporating larger and more diverse studies are essential for more robust conclusions.
The findings of this meta-analysis underscore a strong link between RA and increased cardiovascular risk, particularly regarding AF and ACS, both of which contribute to mortality in RA patients. Variations in study designs, population characteristics, and adjustments for confounding factors may contribute to the observed heterogeneity across studies. While the exact mechanisms underlying the heightened cardiovascular risk in rheumatoid arthritis remain incompletely understood, inflammation, a hallmark feature of rheumatoid arthritis, is believed to play a central role. Additionally, traditional cardiovascular risk factors and RA-specific factors such as anti-citrullinated protein antibodies may collectively contribute to increased cardiovascular risk in RA patients.
RA patients, especially young females, are particularly prone to AF, with smaller cohort studies also mentioning other arrhythmias such as premature ventricular contractions and ventricular tachycardia. Inflammatory processes triggered by rheumatoid arthritis can affect the atrial myocardium and contribute to the development of AF. Structural remodeling induced by inflammatory mediators may lead to atrial fibrosis, electrical remodeling, and alterations in atrial electrophysiology, ultimately facilitating the initiation and perpetuation of AF. Moreover, shared risk factors, genetic predispositions, and the presence of comorbidities such as coronary artery disease (CAD) and congestive heart failure (CHF) further contribute to the heightened risk of AF in rheumatoid arthritis patients.
Regarding ACS, rheumatoid arthritis patients exhibit a significantly increased risk compared to the general population, likely due to a combination of factors including oxidative lipid imbalance, insulin resistance, abnormal blood clotting, and immune activation. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids in RA treatment may also contribute to the elevated risk of ACS. Hence, early screening and aggressive management of traditional cardiovascular risk factors are crucial in rheumatoid arthritis patient care to mitigate the risk of ACS.
While rheumatoid arthritis patients face an elevated risk of cerebrovascular disease, particularly stroke, the likelihood of stroke between RA and non-RA patient groups did not show significant variation in this study. Chronic systemic inflammation in rheumatoid arthritis contributes to the development and progression of atherosclerosis, endothelial dysfunction, and procoagulant states, all of which increase the risk of stroke. Additionally, cardioembolism from conditions such as AF or valvular heart disease plays a significant role in stroke occurrence among RA patients.
In conclusion, this study emphasizes the importance of recognizing and managing cardiovascular risks in rheumatoid arthritis patients. Comprehensive understanding of the underlying mechanisms linking rheumatoid arthritis to adverse cardiovascular outcomes is crucial for the development of targeted prevention and treatment strategies. Collaboration among healthcare professionals from various disciplines is essential to optimize patient care and improve long-term outcomes for rheumatoid arthritis patients with cardiovascular comorbidities. Further research efforts are warranted to elucidate the complex interactions between rheumatoid arthritis and cardiovascular diseases and to explore alternative treatment options that do not exacerbate cardiovascular risk.
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