Accelerated atherosclerosis in rheumatoid arthritis: a systematic review

Background: Rheumatoid arthritis (RA) is a highly prevalent, chronic inflammatory condition of the synovial joints that affects approximately 1% of the global population. The pathogenesis of RA is predominantly inflammatory in nature, thereby accelerating the co-occurrence of other immunoinflammatory conditions such as atherosclerosis. Apart from traditional cardiovascular risk factors, RA patients possess a multitude of other factors that predispose them to early atherosclerotic disease. The aim of this systematic review is to assess the prevalence of premature atherosclerosis in RA patients and elucidate the role that proinflammatory cytokines, RA-related autoantibodies, and endothelial dysfunction play in the pathophysiology of RA-mediated atherosclerosis. We also discussed novel biomarkers that can be used to predict early atherosclerosis in RA and current guidelines used to treat RA. Methods: This review followed the PRISMA guidelines to select and analyze relevant articles. A literature search for articles was performed on February 25, 2022, through three research databases including PubMed, ProQuest, and ScienceDirect. The query used to identify relevant publications was “Rheumatoid arthritis and atherosclerosis” and the search duration was set from 2012-2022. Relevant articles were selected based on the inclusion and exclusion criteria. Results: Our initial search generated 21,235 articles. We narrowed our search according to the inclusion and exclusion criteria. After assessing eligibility based on the full content of the articles, 73 articles were ultimately chosen for this review. Conclusion: There is an increased prevalence of accelerated atherosclerosis among RA patients. We found evidence to explain the role of proinflammatory cytokines, RA-related autoantibodies, and endothelial dysfunction in the pathophysiology RA-mediated atherosclerosis. Therapies targeting either the inflammatory load or traditional CV risk-factors seem to improve vascular outcomes in RA patients. Novel markers of atherosclerosis in RA may be useful in predicting premature atherosclerosis and serve as new targets for therapeutic intervention.

Introduction and background Rheumatoid arthritis (RA) is an autoimmune disorder, often described as a debilitating condition, that severely impairs quality of life by causing extra-articular manifestations. [1][2][3] RA affects approximately 1% of the global population and poses a significant societal and economic burden in terms of cost and disability. 4, 5 The incidence of comorbidities such as atherosclerosis-related cardiovascular diseases, lung cancer, osteoporosis, and depression are higher among individuals with RA, making it a multisystem disease. 6 RA is described as a chronically progressive inflammatory condition that affects the synovial lining of joints in the fingers, wrists, feet, and ankles. 1 Since the pathological mechanism that lead to RA is predominantly inflammatory in nature, it facilitates the co-occurrence of other immunoinflammatory conditions such as atherosclerosis. 7,8 Atherosclerosis refers to the hardening of an artery due to the buildup of fatty, cholesterol-rich plaque within the intimal lining of the vessel wall. 8,9 The pathophysiological link between RA and atherosclerosis has its roots in complex inflammatory pathways that interconnect the two conditions and serve as an explanation for the increased cardiovascular morbidity in RA patients. 10,11 Tumor necrosis factor alpha (TNF-α), is a proinflammatory cytokine that is highly elevated in the synovial fluid of individuals with RA. 12,13 TNF-α, along with interleukin-6 (IL-6), promotes the accumulation of oxidized low density lipoprotein (oxLDL) within the vessel wall, which directly contributes to the formation of lipid-laden macrophages, also known as foam cells. [13][14][15] Macrophagic foam cells are considered to be the prototypical cells involved in the development of atherosclerotic plaques. 15,16 Interleukin-1 (IL-1) is another cytokine associated with RA that shares its proinflammatory properties with TNF-α as they both upregulate the expression of adhesion molecules on vascular endothelial surfaces, stimulate cytokine production, and induce the expression of proinflammatory genes, all of which favor the initiation of atherogenesis. [17][18][19][20] The role of neutrophil extracellular traps (NETs) in the pathogenesis of RA has been increasingly gaining attention. 21 NETs are a complex network of granular proteins, nuclear chromatin, and extracellular fibers that eliminate pathogens through the activation of the ROS-mediated suicidal NETosis pathway. [21][22][23] The role of neutrophils in atherogenesis has been historically denied, but recent evidence shows that neutrophils are involved in progressive endothelial damage, recruitment of proinflammatory monocytes, and foam cell formation, thus implicating them in the process of atherosclerosis. [24][25][26] The presence of citrullinated proteins within the synovia of patients with RA has been recognized as a target for anti-citrullinated peptide antibodies (ACPAs). 27,28 Citrullinated fibrinogen within atherosclerotic plaques have also shown to be targeted by RA-derived ACPAs, contributing to the development of atherosclerosis in the setting of RA. 27,29 It is well known that atherosclerosis is a consequence of progressive endothelial damage and dysfunction. 30 There is ample evidence to support the presence of both micro-and macrovascular endothelial dysfunction in RA which helps to strengthen the pathophysiological link between the two entities. 31 Our systematic review will assess the prevalence of premature atherosclerosis in RA patients and elucidate the role that proinflammatory cytokines, RA-related autoantibodies, and endothelial dysfunction play in the pathophysiology of RA-mediated atherosclerosis through analysis of available literature. We will also discuss carotid intima media thickness, flow mediated dilation, lipoprotein-associated phospholipase A2 enzyme activity, osteocalcin and osteoprotegerin levels as markers of predicting atherosclerosis in RA patients.

Methods
This review strictly follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines as this is a widely accepted and validated methodology for choosing relevant publications to be included in systematic reviews. 32 A literature search for articles was performed on February 25, 2022, through three research databases: PubMed, ProQuest, and ScienceDirect. The query used to identify relevant publications was "Rheumatoid arthritis and atherosclerosis" and the search duration was set from 2012-2022. We included primary case-control studies, cohort studies, cross-sectional studies, observational studies, comparative studies, and meta-analyses. Once the search was complete, three co-authors worked independently to screen the results and extract data from each article. We acknowledge that despite our maximum efforts, some relevant articles may have been left off accidently. Our initial search generated 21,235 articles. Using manual screening, we narrowed the search according to the inclusion and exclusion criteria and a total of 73 articles were ultimately included in this systematic review ( Figure 1).

REVISED Amendments from Version 1
We implemented the changes suggested by the reviewers.
-Added a paragraph on current treatment guidelines for RA.
-Elaborated on the selection/inclusion criteria for articles included in the systematic review and discussion.
-Edited the conclusion to make it more concise.
-Corrected errors in dates and used full-forms for various acronyms.
Any further responses from the reviewers can be found at the end of the article

Inclusion criteria
The following inclusion criteria were used: research studies conducted on humans and written in English, studies published in or after 2011, studies relevant to our topic of interest (accelerated atherosclerosis in rheumatoid arthritis), and articles that were full text, peer-reviewed, and primary or original research publications. The articles that were ultimately chosen were manually screened and read before being considered for this review.

Exclusion criteria
The following criteria were used for exclusion: animal studies, articles that were not primary research studies i.e. case reports, reviews or systematic reviews, abstracts, letters to the editor, book chapters, articles published outside of range (2011-2022), and articles not relevant to our review. All duplicates and non-full-text articles were also excluded. This information is visually presented in the PRISMA flow diagram (Figure 1).

Data items
The information collected from each study included the name of the first author, year of publication, study design, study population, study aim, findings, and conclusion.

Risk of bias in selected studies
Once studies were selected, three co-authors were to grade the risk of bias in individual studies using using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system. GRADE evaluates study flaws such as bias risk, indirectness, imprecision, and publication bias. Two reviewers would have used these criteria on a study-bystudy basis, with a third reviewer assessing and providing an outcome if there was any inconsistency.

Results
Our literature search yielded 21,235 articles: 1,041 from PubMed, 4121 from ScienceDirect, and 16,073 from ProQuest. 16,955 articles were excluded based on the exclusion criteria (animal studies, articles that were not primary research studies i.e. case reports, reviews or systematic reviews, abstracts, letters to the editor, book chapters, articles published outside of range, and articles not relevant to our review). All duplicates and non-full-text articles were also excluded. This resulted in 4,280 articles to be checked for eligibility. After manual screening of full-text articles, 73 articles were considered relevant and included in this review. We acknowledge that some relevant articles may have been accidently left off. Ultimately, there were 37 prospective studies, 10 case-control studies, eight cross-sectional studies, five comparative studies, three observational studies, three prospective observational studies, three meta-analyses, three retrospective studies, and one cohort analysis included in this review. Study characteristics are tabulated in Table 1.

Discussion
The role of inflammatory cytokines The pathophysiology of accelerated atherosclerosis in RA is due to a complex interplay between various proinflammatory mediators. Tumor necrosis factor-alpha (TNF-α) is an inflammatory cytokine that is highly elevated in the synovial fluid of individuals with RA and is involved in mediating premature atherogenesis by complex signaling pathways involving the p38 mitogen-activated protein kinase (MAPK) and the transcription factor nuclear factor-κB (NF-κB). 11,106 As described earlier, TNF-α acts synergistically with interleukin-6 (IL-6) to form lipid-laden macrophages (foam cells), which are prototypic in the development of atherosclerotic plaques. [13][14][15][16] The mechanistic pathway that contributes to this process involves the upregulation of the human scavenger receptor-A (SR-A) and lectin-like oxidized Low density lipoprotein receptor-1 (LOX1) on macrophages. 15 Anti-TNF-α therapy has become a mainstay for treatment of RA. 106,107 Some studies reported that TNF-α inhibition was found to significantly improve vascular function in RA patients. 42,43,45,78 Davies et al. found a positive correlation between RA disease activity and soluble vascular adhesion molecule-1 (sVCAM-1), and associated it with the role of IL-6 in mediating atherosclerosis in RA. 88 They went on to conclude that IL-6 trans-signaling plays an important role in vascular dysfunction in RA and blocking this pathway may be useful for RA patients. IL-1 is considered to be a proatherogenic cytokine as it stimulates smooth muscle cell (SMC) proliferation by autocrine induction of the platelet-derived growth factor (PDGF). 20,108 SMCs contribute to the initiation of atherosclerosis by producing an extracellular matrix (ECM), precipitating lipid uptake, and inducing foam cell formation to ultimately form a fibrous cap within the vessel wall. 109 IL-1 also induces its own gene expression, thus creating a powerful positive feedback loop to maintain a proatherogenic milieu. 20 Lo Gullo et al. reported that RA patients had a higher expression of IL-1β and elevated levels of C-reactive protein (CRP) compared with the control group, suggesting a proinflammatory milieu mediated by this cytokine 73 54,63 Other studies also found significantly elevated levels of inflammatory biomarkers and proinflammatory cytokines in RA patients, further supporting the role of cytokines in premature atherosclerosis in RA. 60,80 Individuals with RA have elevated circulating levels of IL-17 as a result of T-helper 17 (Th17) cell activation and differentiation. 10,11,110 Although the pathomechanisms that implicate IL-17 as a mediator of atherogenesis in the setting of RA remain unclear, Marder et al. proposed that IL-17 may disrupt normal endothelial function, stimulate myocardial fibrosis, and lower arterial compliance, thus promoting atherosclerosis. 86 Yamamoto et al. reported that both traditional cardiovascular disease (CVD) risk-factors and inflammatory mediators influence the development of atherosclerosis in RA patients and concluded that the management of RA should involve controlling CVD risk factors and RA disease activity. 64 A wealth of data shows that the role of inflammatory cytokines is pivotal when considering the pathomechanisms that explain the increased incidence of premature atherosclerosis in RA. Age is implicated as the major determinant of premature atherosclerosis in arthritis.

The role of neutrophil extracellular traps
The role of neutrophil extracellular traps (NETs) in autoimmune disorders is explained by the process of NETosis, which is described as an imbalance between NET formation and NET breakdown. 10 In patients with RA, NET formation is thought to be triggered by autoantibodies and immunostimulatory molecules. 21 NETs contain citrullinated vimentin (cVim), which is involved in secreting proinflammatory cytokines such as TNF-α and IL-1, thus continually maintaining a state of inflammation in RA. 21,111 Even though the role of neutrophils in mediating atherosclerosis has been historically denied, recent evidence shows that neutrophils are involved in progressive endothelial damage, recruitment of proinflammatory monocytes, and foam cell formation. [24][25][26] Researchers have detected the presence of NETs in atherosclerotic plaques of both humans and mice, which may contribute to the pathophysiology of RA-related atherosclerosis. 23,112,113 Pérez-Sánchez et al. found that RA patients had enhanced NETosis, which correlated with disease activity and inflammatory and oxidative profiles in these patients. They concluded that NETosis-derived products play a role in mediating atherosclerosis in RA and may be used as a diagnostic tool. 44 The lack of primary research studies on this topic area make it difficult to draw definitive conclusions about the role NETosis in RA and atherosclerosis. More research in this particular field would be beneficial in evaluating the diagnostic potential of NETosis-derived products and assessing whether the inhibition of NETs would hold therapeutic value in RA.
The role of RA-related autoantibodies Citrullinated proteins within the synovia of patients with RA are a target for anti-citrullinated peptide antibodies (ACPAs). 27,28 Sokolove et al. found that citrullinated fibrinogen within atherosclerotic plaques are also targeted by RA-derived ACPAs. 28 Clavel et al. found that RA-specific ACPA immune complexes have the potential of inducing macrophage-driven TNF-α secretion via the Fc-gamma receptor IIa (FcγRIIa). 114 As detailed earlier, the contribution of TNF-α as an inflammatory mediator of atherosclerosis is remarkable, which provides evidence to support the pathophysiology of RA autoantibody-derived atherosclerosis. RA-derived autoantibodies like ACPAs were found in the serum of patients with RA and were considered an independent risk factor for the development of subclinical and clinical atherosclerosis. 51 Nowak et al. found that the presence of anti-CCP antibodies were associated with greater cIMT values, as also confirmed by Vázquez-Del Mercado et al. 48,75 Wahab et al. also found higher levels of anti-CCP antibodies in RA patients compared to controls and suggested its use as a useful indicator of subclinical atherosclerosis. 92 A number of studies included in this review found similar results concerning RA-derived autoantibodies and atherosclerosis. 51,55,84,85,87 An interesting phenomenon was reported by Jacobsen et al., who found polymorphic variations in the mannose-binding lectin gene (MBL) were associated with high scores of RA disease activity, C-reactive protein-based DAS28, and physical disability in anti-CCP-positive RA patients. 115 MBL, a serum protein, plays an instrumental role in regulating innate immunity by binding to repeating sugar motifs to activate the complement system via MBL-associated serum proteases. 116 Barbara et al. found that RA patients had a significantly lower MBL serum concentration in relation to controls and found no statistically significant association between MBL and disease activity, ESR, autoantibodies, or IMT. 105 A cross-sectional study found that both high and low levels of MBL in RA patients were associated with an increased common carotid artery intima-media thickness (cc-IMT), indicating a quadratic U-shaped relation between serum MBL and ccIMT. 117 More studies would be valuable to assess whether MBL truly plays a role in mediating atherosclerosis in RA patients.

The role of endothelial dysfunction
Atherosclerosis is a consequence of progressive endothelial damage and dysfunction. 30 The endothelium, as an organ, functions as an intimate vascular barrier that is involved with maintaining vascular tone, blood hemostasis, leukocyte migration, and antigen presentation, among other physiological processes. 118,119 Endothelial dysfunction is heavily involved in the pathogenesis of atherosclerosis by inducing cell adhesion molecules, facilitating leukocyte emigration, promoting cytokine production, platelet activation, and SMC proliferation 120 A number of studies have found elevated serum levels of asymmetric dimethylarginine (ADMA) in RA patients. [121][122][123][124] ADMA is a potent inhibitor of endothelial nitric oxide synthase (eNOS), an enzyme responsible for the synthesis of vasoprotective nitric oxide (NO) 125 NO serves as a cardioprotective molecule due to its vasodilatory properties and its ability to inhibit platelet aggregation, suppress adhesion molecules, maintain endothelial barrier integrity, and regulate SMC proliferation. 126 Di Franco et al. found that RA patients had elevated levels of ADMA and proposed its use as a biomarker of vascular endothelial dysfunction, as also concluded by Dimitroulas et al. and Chandrasekharan et al. 50,77,83 Endothelial progenitor cells (EPCs) have also been implicated in RA-related atherogenesis. 10 An inverse relationship between circulating EPCs and endothelial function has been established by numerous studies. [127][128][129] When considering RA, a reduction in EPCs has been reported, possibly due to C-reactive protein-mediated apoptosis of EPCs 130 Rodríguez-Carrio et al. reported long-standing RA was correlated with a reduction in EPCs and concluded that EPC imbalance is associated with endothelial dysfunction and subsequent CVD in RA. 47 Similar findings were also reported by other studies included in this review. 53,57 Progressive endothelial dysfunction along with a reduction in EPCs in RA results in the creation of a proatherogenic environment, thus facilitating atherosclerosis and CVD in affected individuals.
Prevalence of accelerated atherosclerosis in RA Carotid intima media thickness (cIMT) has popularly been used as a marker for subclinical atherosclerosis. In our review, a number of studies utilized cIMT to assess the prevalence of subclinical atherosclerosis in RA. In a cross-sectional study by Hannawi et al., patients with RA had significantly higher cIMT values and a higher carotid plaque burden compared to healthy controls. 38 Krajnc et al. also found that patients with RA had a higher cIMT compared with controls, suggesting atherosclerotic plaque build-up and increased risk for subsequent CVD. 39 A plethora of other studies included in this review reported similar findings and concluded that there is a high prevalence of premature atherosclerosis in patients with RA. 33,34,36,40,41,52,56,[58][59][60][61][62]65,66,71,81,99,100,104 However, in a cross-sectional study by van Breukelen-van der et al., no significant association was found between RA and cIMT. These conflicting findings were attributed to the patients having low disease activity and well-controlled RA, suggesting therapeutic strategies that target CVD risk factors seem to improve overall cardiovascular risk in RA. 89 Flow-mediated dilation (FMD) is a non-invasive method to assess endothelial dysfunction and has been used as a predictor of early atherosclerosis. Verma et al. found that RA patients had lower FMD and higher cIMT compared to controls, consistent with endothelial dysfunction and accelerated atherosclerosis in patients with RA. 37 Adawi et al. also acknowledged the high prevalence of accelerated atherosclerosis in RA patients and proposed the clinical use of FMD as a measure of endothelial function to predict subsequent atherosclerosis. 49 Two other studies also reported similar findings regarding endothelial dysfunction in RA patients and the usefulness of FMD as an early marker of atherosclerosis. 76,93 Coronary calcium score (CS) utilizes computed tomography to detect the presence of vascular calcification. In a prospective study by Liu et al., the CS was found to be significantly increased in the coronary artery, carotid artery, and aorta of RA patients. 68 In another prospective study, coronary artery calcification (CAC) was detected in 46% of RA patients. 69 Other studies also reported similar findings. 72,90 In a prospective study by Wahlin et al., patients with RA who had CAC were found to have increased values of DAS28 and ESR, implying that inflammation plays a role in mediating RA-induced CAC. 79 Contrastingly, Chung et al. found no statistical significance in the incidence of CAC in RA patients compared to controls and concluded that traditional risk-factors for CVD, rather than inflammatory markers are responsible for CAC and atherosclerosis in RA. 74 This study also reported that once RA patients developed CAC, the rate of progression was found to be similar to the progression seen in control participants. This study acknowledges that their results were not concordant with their primary hypothesis, and one explanation offered was that the study focused on subclinical atherosclerosis, and RA patients with prior events, who may have contributed to a greater progression of CAC had been excluded, resulting in differential bias. Overall, there is abundant evidence to conclude that premature atherosclerosis in RA is highly prevalent, and that both traditional CVD risk-factors and inflammatory mediators play a role in mediating this process.
Novel markers associated with accelerated atherosclerosis in RA Postprandial hyperlipidemia (PPHL) has been shown to be an independent predictor of CVD. 131 Mena-Vázquez et al. found that PPHL in RA patients was significantly associated with subclinical atherosclerosis, TNF-α, and high-sensitivity C-reactive protein, suggesting that PPHL in RA is associated with inflammation and subclinical atherosclerosis. 95 Other studies have also found that cIMT is associated with postprandial ApoB48 and total ApoB, providing evidence that atherogenic chylomicron remnants contribute to atherosclerosis in RA. 103,132 Biomarkers associated with bone turnover such as osteoprotegerin (OPG) have been associated with CAC, carotid plaque, and IMT. [133][134][135] Wahlin et al. examined the role of bone turnover markers in mediating atherosclerosis in RA and found that Osteocalcin (OCN) and OPG were significantly associated with IMT after 11 years, especially in patients with joint erosions. However, there was no significant association between collagen markers of ongoing bone turnover and IMT, suggesting that bone turnover and atherosclerosis may have different pathogenic mechanisms in the setting of RA. 96 Beyazal et al. also found higher OPG levels in RA patients than controls and concluded that OPG may be a useful marker to assess CV risk in RA patients. 97 More studies investigating this topic area may be beneficial to clarify whether bone turnover truly plays a role in premature atherosclerosis in RA.
Other novel markers found to be associated with accelerated atherosclerosis in RA patients were von Willebrand factor (vWF), 101 cellular communication network factor 1 (CCN1), 98 human endothelial cell-specific molecule-1 (endocan), 70 PCSK9/LDLR system, 94 and oxLDL. 67,82 Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) is a biomarker used to assess vascular inflammation. 136 Södergren et al. found that Lp-PLA2 is associated with both subclinical atherosclerosis and disease severity in RA patients, 102 however, Bes et al. found no significant difference between Lp-PLA2 enzyme in RA patients and healthy controls, possibly because RA patients were undergoing treatment and had low disease activity scores. 35 Similarly, there are other novel biomarkers being investigated in their role in developing accelerated atherosclerosis in the setting of RA. More studies in this topic area may be beneficial to predict premature atherosclerosis in RA and identify new therapeutic targets.

Current therapies to treat RA
The treatment of RA is individually tailored to each patient to optimize patient care. The goal of treating RA involves reducing joint inflammation and preventing progressive joint damage. The target is to achieve a state of low disease activity within 6 months of RA diagnosis. 137 Non-pharmacologic therapies that can be used to control symptoms and manage RA include physical activity, occupational therapy, lifestyle changes such as quitting smoking and reducing alcohol consumption, and dietary therapies such as implementing a Mediterranean diet. 138 It is recommended that pharmacologic drugs should be started as soon as RA is diagnosed. 139 The mainstay drugs in the treatment of RA are disease-modifying antirheumatic drugs (DMARDs). These are further subdivided into synthetic and biological forms. Methotrexate is a conventional synthetic DMARD (csDMARD) and is considered first-line in treatment of RA and is typically prescribed at a weekly dose of 25 mg in combination with short-term glucocorticoids. 140,141 If first-line treatment fails, patients are given a biological DMARD (bDMARD) in addition to the csDMARD. If remission is not achieved with second-line therapy, third-line treatment involves continuing the csDMARD along with a bDMARD and adding a targeted synthetic DMARD such as tofacitinib which acts on enzymes such as janus kinases to interfere with intracellular cytokine signalling. 137 75% to 80% of patients achieve a state of remission or low disease activity with these therapies and have normal life expectancies. Early diagnosis and intervention is key in preventing disease progression.

Limitations
Due to the rigorous inclusion and exclusion criteria, studies that may contain supportive evidence according to their results were not included because their aim was not in line with our search criteria. Moreover, some studies did not explicitly state information regarding the study setting and type of study. Based on the current literature and evidence, there are various pathophysiological processes involved in accelerating atherosclerosis in RA which made it difficult to draw definitive conclusions on whether inflammation or traditional cardiovascular risk-factors work together or independently to contribute to these findings.

Conclusion
In conclusion, abundant evidence exists to support an increased prevalence of accelerated atherosclerosis among RA patients. Since cardiovascular morbidity and mortality in RA is strikingly high, it is important to understand the mechanisms that initiate and govern atherosclerosis in RA so tailored therapeutic regimens can be developed to reduce the CV burden that RA patients carry. Proinflammatory cytokines such as IL-6 and TNF-α are involved in the formation of atherogenic foam cells. RA-derived autoantibodies are involved in exacerbating the inflammatory potential of macrophages and endothelial dysfunction is involved in disrupting the integrity of the vascular barrier which create a proatherogenic milieu and favour subsequent atherosclerotic disease. The question of whether inflammation and traditional CV risk factors work synergistically to produce atherosclerosis in RA or if one is more significant than the other remains. Nevertheless, therapies targeting both the inflammatory load or traditional CV risk-factors seem to improve vascular outcomes in RA patients. Lastly, novel markers of atherosclerosis in RA may be useful in predicting early atherosclerosis and serve as new targets for pharmacological intervention.

Data availability
No data are associated with this article. I reviewed the article titled "Accelerated atherosclerosis in rheumatoid arthritis: a systematic review." The aim of this study is to assess the prevalence of premature atherosclerosis in RA patients and elucidate the role that proinflammatory cytokines, neutrophil extracellular traps, RArelated autoantibodies, and endothelial dysfunction play in the pathophysiology of RA-mediated atherosclerosis.

Reporting guidelines
The paper presented is interesting, and overall, it is well written. However, I have the following comments: In the first paragraph of the methods section and in the inclusion criteria, it is mentioned that "the search duration was set from 2011-2022. However, in the Prisma table/chart, it mentions the years 2012-2022. Authors should clarify and correct the actual years of inclusion.

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For the results section, it would be better to add all studies with similar study designs in sequence. For example, all prospective studies in sequence. This will be clearer to the readers. Add a letter "n" in the heading of study design and population column.

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In the discussion, please add a paragraph on current therapies to treat RA. In addition, authors can discuss research gaps and add future recommendations before concluding their findings.

Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes
Are sufficient details of the methods and analysis provided to allow replication by others? Yes

Is the statistical analysis and its interpretation appropriate? Not applicable
Are the conclusions drawn adequately supported by the results presented in the review? Yes Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Natural products, osteoporosis, cardiovascular research and Bisphenol A associated toxicity and morphological variations.