Cardiovascular Disease in Rheumatoid Arthritis: A Systematic Literature Review in Latin America

Background. Cardiovascular disease (CVD) is the major predictor of poor prognosis in rheumatoid arthritis (RA) patients. There is an increasing interest to identify “nontraditional” risk factors for this condition. Latin Americans (LA) are considered as a minority subpopulation and ethnically different due to admixture characteristics. To date, there are no systematic reviews of the literature published in LA and the Caribbean about CVD in RA patients. Methods. The systematic literature review was done by two blinded reviewers who independently assessed studies for eligibility. The search was completed through PubMed, LILACS, SciELO, and Virtual Health Library scientific databases. Results. The search retrieved 10,083 potential studies. A total of 16 articles concerning cardiovascular risk factors and measurement of any cardiovascular outcome in LA were included. The prevalence of CVD in LA patients with RA was 35.3%. Non-traditional risk factors associated to CVD in this population were HLA-DRB1 shared epitope alleles, rheumatoid factor, markers of chronic inflammation, long duration of RA, steroids, familial autoimmunity, and thrombogenic factors. Conclusions. There is limited data about CVD and RA in LA. We propose to evaluate cardiovascular risk factors comprehensively in the Latin RA patient and to generate specific public health policies in order to diminish morbi-mortality rates.

Life expectancy of patients with RA is three to ten years less than that of the general population [29]. Although it is well established that cardiovascular mortality is higher in RA, the reasons for this remain elusive [30]. Currently, ischemic heart disease (IHD) secondary to atherosclerosis is the most prevalent cause of death associated with CVD in patients with RA [31]. CVD accounts for 30-50% of all deaths in RA patients [3]. Thus, RA added to CVD as the leading cause of death around the world [32,33] requires us to take these diseases more seriously. Therefore, doctors need to be more committed to assessing, monitoring, and treating cardiovascular risk factors in the early stages as well as to promoting lifestyle changes in order to diminish morbimortality rates in RA individuals.
Hispanics are considered a minority group due to a mixed ethnicity (so called mestizos) that is mainly derived from a European and Amerindian inheritance [34]. Therefore, they represent a unique population. So far, some studies of RA have documented differences in health status, disease prevalence, treatment outcomes, and healthcare use among different ethnic groups [35,36] which suggest that minority health disparities influence RA. Moreover, CVD is still one of the most important comorbidities in this subpopulation due to augmented mortality secondary to accelerated atherosclerosis, systemic inflammation, and MI or stroke [37][38][39].
RA is not uncommon in LA, the geographical area defined by Mexico, Central America, South America, and the islands of the Caribbean [1]. Overall,RA affects 0.5% of LA [40]. In Argentina, Spindler et al. [41] reported an overall prevalence ratio (per 1,000) of 1.97 (95% CI: 1.8-2) for both sexes, 0.6 (95% CI: 0.49-0.73) for men and 3.2 (95% CI: 2.9-3.5) for women. Peláez-Ballestas et al. [42] found a prevalence of 0.7-2.8% in Mexican patients. In an isolated African Colombian population, a prevalence of 0.01% was reported [43]. However, CVD has not been systematically assessed in LA and only a few studies have evaluated some of the traditional and nontraditional risk factors, cardiovascular subphenotypes, and mechanisms underlying the accelerated atherosclerosis that is characteristic of this population. Therefore, in this study, a systematic review of CVD in LA patients with RA was done.

Search Strategy.
A systematic literature review of articles on CVD and RA in LA was carried out in the following databases: PubMed, LILACS, SciELO, and Virtual Health Library (VHL). It included articles published between January 1947 and May 2012. Two reviewers did the search independently (SMJC and HDAC) while applying the same selection criteria described below. The search results were compared and disagreements were resolved by consensus. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed in data extraction, analysis, and reporting [44].
A similar strategy was followed for the other databases. Each MeSH term was translated into DeCS (Health Sciences Descriptors) in order to explore sources of information in Portuguese, Spanish, and English through SciELO, LILACS and VHL databases. The following terms were selected: "Artritis Reumatoide," "América Latina," "Salud de Minorias," "GruposÉtnicos," "Brasil," and "Haití" (24 countries, as well as PubMed). Then each of the terms was crossreferenced with the following: "Enfermedades Cardiovasculares," "Hipertension," "Embolia y Trombosis," "Accidente Cerebrovascular," "Infarto del Miocardio," and "Enfermedad Coronaria" for the first search. Each term was crossreferenced for the greatest number of results. Once again, no limits were used. For the second search in SciELO, some of the DeCS terms and keywords included were Artritis Reumatoid, América Latina, Salud de Minorias, GruposÉtnicos, "Enfermedades Cardiovasculares," "Hipertension," "Embolia y Trombosis," "Accidente Cerebrovascular," "Infarto del Miocardio," and "Enfermedad Coronaria." Both Spanish (Artritis Reumatoide) and English (Rheumatoid Arthritis) key words were matched with every country (Brazil to Haiti). "Artrite Reumatoide" was included as an additional term for Brazil in the search for articles published about CVD in this country. Likewise, in two remaining databases-LILACS and VHL (all sources)-both Spanish (Artritis Reumatoide) and English (Rheumatoid Arthritis) key words were matched with every country (Brazil to Haiti). As in SciELO, "Artrite Reumatoide" was included as an additional term for Brazil. Arthritis 3

Study Selection, Data Extraction, and Quality Assessment.
A study was included if (a) the abstract was available, (b) it contained original data, and (c) it used accepted classification criteria for RA and measured cardiovascular risk factors (traditional, nontraditional) and/or any of the cardiovascular subphenotypes. Articles were excluded from the analysis if they dealt with juvenile idiopathic arthritis or were done on animal models (i.e., murine models) instead of RA patients. Studies were also excluded if they were reviews or case reports, if they discussed topics not related to CVD, and/or were not done on an LA population. Those references from the articles that seemed to be relevant for the present paper were hand-searched and were included in the discussion. Abstracts and full text articles were reviewed to find eligible studies. Duplicate papers were excluded.
Three blinded reviewers (SMJC, AAJC, and HDAC) organized selected articles on the basis of publication source, author, cardiovascular outcome, and traditional and nontraditional cardiovascular risk factors as well as subphenotypes evaluated. Moreover, a descriptive analysis from these data was completed. Articles were not included in the analysis when there was a lack of inclusion criteria, insufficient data, and statistical significance. A database with pertinent information from these studies which included authors, name of study, country, language, study design, number of patients, objective, cardiovascular outcome, method of hypothesis testing, results, limits/bias of the study, and reference was created. Disagreements between the reviewers were resolved by consensus. Each record was classified based on the quality score of the studies that was assigned by applying the levels established by the Oxford Centre for Evidence-based Medicine 2011 in order to evaluate the risk of bias [45].

Systematic Literature
Review. There were 3,897 articles identified in the first and 1,285 articles in the second search in PubMed (total of 5,182). Additional records identified through other sources included 206 articles from SciELO in the first search and 273 in the second one, 34 and 465 from LILAC, and 2,496 and 1,427 from VHL. Therefore, the database searches provided a total of 10,083 publications. Of these, 9,998 studies were discarded because they did not meet the eligibility criteria. After this exclusion, 85 articles were assessed and duplicates were identified (64 papers). A total of 21 full text articles were assessed for eligibility. Finally, only 16 articles [25,30,[46][47][48][49][50][51][52][53][54][55][56][57][58][59] that had interpretable data and fulfilled the eligibility criteria were included. Of the selected articles, there were 5 from Mexico, 3 from Brazil and Colombia, 2 from Argentina, and 1 from Chile, Cuba and Puerto Rico, respectively. Seven were cross-sectional, 6 were case controls, 2 descriptive/retrospective, and only one corresponded to a cohort study. Half the studies had a sample size that was less than 100 patients. The flow chart for systematic literature review and articles included in the analysis are shown in Figure 1.

Discussion
To date, the literature evaluating CVD outcomes in LA individuals with RA is scarce. Only a few studies have assessed the classic and nontraditional risk factors in this subpopulation.

Cardiovascular Disease as the Leading Cause of Mortality in LA.
CVD is the leading cause of mortality worldwide. On the American continent, the prevalence and incidence of CVD is growing at an alarming rate. The World Health Organization (WHO) forecasts that the number of deaths in the region attributed to CVD will increase by more than 60% between 2000 and 2020 unless preventive measures are taken [60]. Thus, this chronic disease is one of the major causes of death around the world [33]. Thanks to the CARMELA initiative study, many traditional factors have been described in LA population such as hypertension, dyslipidemia, obesity, smoking, T2DM, and MetS [61]. Table 2, which was adapted from the Pan American Health Organization report [62], shows the mortality rates of CVD in the Americas as of 2007-2009 in terms of IHD and cerebrovascular disease. The data on this table is organized by country and region thus making it possible to contrast mortality rates from these two diseases in the United States of America (USA) and Canada with LA and the Caribbean. Generally, high rates of death were mostly observed in developed countries such as USA and Canada 136.3/100,000 people. Incidence of mortality in LA and the Caribbean due to IHD and cerebrovascular disease is 55.8/100,000 and 44.8/100,000 people, respectively. Individuals living in developed countries have more risk factors, for example, inappropriate life styles, that contribute to a higher rate of death from CVD. Thus, it is important to promote healthy habits among the general population and in patients with an early diagnosis of RA in order to prevent CVD. In specific LA countries, numbers show high rates of IHD in countries such as Cuba (140.1/100,000 people) and Puerto Rico (100.7/100,000 population). The importance of the numbers lies in the fact that they can be analyzed from the perspective of increased risk of CVD in RA in comparison to the general population. Therefore, it is important to discriminate mortality CVD rates by patients with chronic inflammatory diseases (i.e., RA).
LA has a growing population and it is a very dynamic region with an estimated population of 515 million. As mentioned before, the RA prevalence reported in LA is considered to be less than 0.5% [63,64]. The heterogeneity across LA is expected due to the high degree of admixture between subpopulations. Hispanic/Latino populations are the result of a two-way admixture between Amerindian     and European populations or of three-way admixture of Amerindian, European, and West African populations [65]. Some studies have documented differences in the health status of, disease prevalence in, treatment outcome in, and healthcare use by different ethnic groups. Yazici et al. [35] compared patients from different ethnic groups with early RA using disease activity measures, identifying possible differences in patterns of clinical severity. They found that Hispanic patients with RA scored the worst in all self-report measures compared to Caucasians and African Americans with statistically significant differences in the Modified Health Assessment Questionnaire (MHAQ) functional score, psychological distress, and morning stiffness [35]. In a study of RA patients, Bruce et al. [36] demonstrated disparities between Caucasians and African Americans and Hispanics in disability, pain, and global health. Pain was worse in the latter two groups and global health was worse in Hispanics. The results of this exploratory study suggest that in a relatively similar cohort of patients with RA, minority health disparities exist [36]. Moreover, the prevalence of MI is high in Hispanics living in the USA, and coronary events are presented by people younger than in other minorities [48]. Nevertheless, only two studies in LA assessed mortality in RA patients. Orozco-Alcalá et al. [46] showed that there were no differences between RA patients and the general population concerning causes of death. Acosta et al. [58] demonstrated a mortality rate of 5.2% in a six-year followup. For both, the most frequent cause of death was CVD in 44.7% and 22.2% of the cases, respectively. In the other selected articles, a wide range of prevalence for CVD was reported (13.8-80.6%). The highest prevalence was indicated by Santiago-Casas et al. [59] in Puerto Rican patients (55.9%) when the demographic characteristics, clinical manifestations, comorbidities, pharmacological profile, and functional status of different age groups were determined. Nevertheless, the fact that elderly people (>60 years) have a higher probability of developing CVD whether or not they have RA had to be taken into account for calculating the prevalence of CVD in Puerto Rico. Cisternas et al. [30] evaluated cardiovascular risk factors in Chilean patients with RA and reported a prevalence of 46.4% for CVD. For Brazil [51,53], Colombia [25,54,55], and Argentina [56,57], a similar prevalence was indicated (47.4, 35.1 and 30.5%, resp.). In Mexico, five studies [46][47][48][49][50] reported an overall prevalence of 20.9% for CVD in RA patients.

Traditional Risk Factors, CVD, and RA.
RA is a relatively frequent AD, which is chronic in nature, and these patients are doubly at risk of developing any CVD subphenotype with respect to the non-RA population [66,67]. In fact, IHD secondary to atherosclerosis is the most prevalent cause of death associated with CVD in patients with RA [30]. The worldwide prevalence of hypertension in RA is between 49 and 77% [5]. It is considered the most common comorbiditiy in Hispanic patients with RA. The most frequent classic risk factor for CVD in this systematic literature review (with more than 2,000 RA patients included) was hypertension as well. Nevertheless, a lower prevalence (27.9%) than that reported previously in other countries was found. Many of these predisposing factors have been described in LA studies: hypertension [30, 36, 53-55, 58, 59, 61, 68, 69], T2DM [25,48,50,53,56,58], dyslipidemia [25,58,59,70], MetS [17,25,50,53,68,69,71], and hyperhomocysteinemia [22,25,48,72]. For details, see Table 3.

Nontraditional Risk Factors, CVD, and RA.
Since there is no classification system for nontraditional risk factors, we would like to propose one. Our recommendation is to divide them into genetic, AD associated, and others. The genetic group includes both HLA and non-HLA genes. HLA-DRB1 SE alleles are related to chronic inflammation, endothelial dysfunction, premature death, and CVD itself [25,[73][74][75][76][77][78][79][80]. The non-HLA genes include polymorphisms in the endothelin-1 and methylene tetrahydrofolate reductase genes. Endothelin-1 enhances CVD by endothelial dysfunction and hypertension [81]. Methylene tetrahydrofolate reductase has been related to atherosclerosis and the clinical response to some Disease-Modifying Antirheumatic Drugs (DMARDs) [82]. Others genes are TNFA rs1800629 and NFKB1-94ATTG ins/del polymorphisms. These are associated with predisposition to cardiovascular complications in patients with RA, as subclinical and accelerated atherosclerosis [83,84]. However, other gene polymorphisms placed outside the HLA region and not strongly associated with susceptibility to RA and CVD. Rodríguez-Rodríguez et al. [85] showed a potential influence of the CCR5Δ32 deletion on the risk of CV disease among patients with RA. This may be due to a protective effect of this allelic variant against the development of vascular endothelial dysfunction.
Other issues, such as thrombogenic factors, which include vWF and fibrinogen levels, are related to CVD as well [49,96,97]. Several new cardiovascular risk factors in RA have received only modest attention and the different studies have shown contradictory results in LA patients. Each of these factors contribute to an impaired endothelial function, increased IMT, accelerated atherosclerosis, and finally, manifest CVD. For details, see Table 3.

Discovering Novel Nontraditional Risk Factors.
Despite of all the traditional risk factors that have been associated with CVD in RA patients, the literature on it with respect to LA and the Caribbean is still scarce. Even though it has been generally accepted that systemic activity is related to chronic inflammation and accelerated pathogenic processes leading to cardiovascular compromise, it is important to assess other novel factors in patients that may also contribute. Therefore, we believe further research is needed in order to establish other factors that are not currently taken into account. To date, there are no systematic reviews of literature involving LA patients as a minority group.
After the systematic search was done, 2,119 RA patients from different LA countries were included and evaluated for cardiovascular outcomes in studies ranging from 1993 to 2012 (see Supplementary Table 1 in Supplementary Material available online at doi:1155/2012/371909). Common limiting factors in the sixteen studies analyzed included a lack of prospective follow up of RA patients and a general limitation on sample sizes. Most of the studies were either cross-sectional or case-control which in terms of evidence place them at level 4 [45]. Moreover, 50% of the studies included in the analysis had sample sizes of more than 100 RA patients. The rest of them had limited numbers of patients included, which was another common limit or bias found in the retrieved studies. Furthermore, the lack of adequate statistical methods and hypothesis testing in some of the studies should be noted. This was the case for four of the studies, which were descriptive or did not calculate P values, adjusted odds ratio or confidence intervals.
There is insufficient literature regarding CVD in LA patients with RA. Although the number of patients assessed is not negligible, when the geographical area of LA, the diversity, and the admixture of the population are considered, there is a need to include true cohorts to ensure more decisive conclusions. Dyslipidemia Altered lipid profiles in RA patients are related with higher probability of IHD by accelerating atherosclerosis [25,70] Is characterized for an alteration in production/secretion of proinflammatory adipokines and leads to increased activity of RA and accelerating atherosclerosis [68,71] MetS Studies about the prevalence of MetS in LA patients have not achieved definitive conclusions, although its presence has been directly associated with a worse prognosis [53] In RA patients, was related with pain and functional status, suggesting disease activity. Therefore, a better control of disease activity may reduce CVD risk [50] Hyperhomocysteinemia Homocysteine is considered as biomarker for atherosclerosis and a risk factor related with CAD and stroke [22,72] There is still controversy about whether hyperhomocysteinemia is a causative agent of cardiovascular damage or only an epiphenomenon of inflammation [48] A high prevalence of this biomarker in Mexican patients with RA had a statistical association with male gender and higher radiological damage [48] High homocysteine concentration can be an important risk marker for CVD in Chilean patients with RA, as it was significantly associated [30] Nontraditional Related with chronic inflammation, endothelial dysfunction, and premature death for CVD [73][74][75] Genetic HLA-DRB1 SE alleles Associated with severe RA and with more EAM, high activity, and systemic inflammation [74][75][76][77]79] Being a carrier of a single copy of HLA-DRB1 SE were significantly associated with an increased risk of atherosclerotic plaque in RA Colombian patients [25] Polyautoimmunity Some articles included patients with poliautoimmunity, but no correlation with CVD subphenotypes was described [25,46,55,58] Familial autoimmunity Was associated with presence of atherosclerotic plaque in RA Colombian patients. [25] High titers have been established to be a predictor of CVD due to immune complex formation and tissue injury. It has been shown that such immune complexes from RF can be deposited in the endothelium and through inflammatory reactions generate endotelial disfunction and atherosclerotic process [86] RF positivity RF seropositivity was significantly associated with an increased risk of endothelial dysfunction in RA Colombian patients [25] A statistical association between increased IMT, atherosclerosis plaque, and presence of RF was described in Mexican population with RA [49] anti-oxLDL Promote instability and rupture of the atheromatous plaque within the coronary arteries [24,88] Only one LA study evaluated this antibodies, but no correlation with CVD was found [30] Other autoantibodies The presence of plaques was higher in Brazilian patients with RA, but no correlation between IMT or plaques and autoantibodies were found [51] AD associated Other autoantibodies were assessed in LA population, such as aCL, anti-β2GPI, anti-HSP 60/6, and anti-CCP antibodies with no association regarding CVD outcomes [25,30,51,55] Inflammatory markers The association of inflammatory pathways with CVD is complex and is composed of several intermediate factors, including dyslipidemia, homocysteinemia, insulin resistance, and endothelial dysfunction [89]  May accelerate atherogenic processes, either by the accentuation of known pathways of plaque formation or by the onset of additional immune pathways [90] Disease activity The lipid profile in RA depends on disease activity. Higher disease activity leads to depressed levels of total cholesterol. However, HDL cholesterol levels are even more depressed, resulting in a more unfavourable atherogenic index [90] Long duration of RA (>10 years) Implies more time for chronic inflammatory process to generate sequelae such as atherosclerosis and endothelial dysfunction [39] Were significantly associated with an increased risk of atherosclerotic plaque in RA Colombian patients [25] EAM Is an indirect indicator of disease severity and systemic compromise.
Patients are considered to have three times higher risk to develop CVD [55,76] GC Could enhance cardiovascular risk owing to their potentially deleterious effects on lipids, glucose tolerance, insulin production and resistance, blood pressure, and obesity. On the other hand, it may actually decrease the risk of atherosclerosis and CVD by suppressing inflammation, which paradoxically may improve glucose intolerance and dyslipidaemia [93] Others Thrombogenic factors vWF has been recognized to induce a procoagulant state Represent a biomarker of endothelial dysfunction [96,97] The measurements of the IMT together with the vWF serum levels could give valuable information about the artery status and the atherosclerosis process in early stages in Mexican patients with RA without cardiovascular risk factors [49]  (3) What should be the target of all these efforts? That question raises more questions. Inflammation in RA is a risk factor for CVD which can be treated effectively, but can targeting "inflammation" decrease CVD risk in RA? Should the target be remission, a low CRP level, or lack of swollen joints? Is targeting specific inflammatory pathways more effective for reducing cardiovascular risk than other therapies? There are many unanswered questions and a lot of controversy about how to best address cardiovascular risk in patients with RA. Therefore, a comprehensive multidisciplinary approach is the first step towards addressing this complex issue and to optimize patient outcomes [98].

Conclusions
RA and CVD share common pathophysiology mechanisms (i.e., systemic and chronic inflammation) with secondary accelerated atherosclerosis that can explain the high mortality rates and augmented risk of ischemic events in these patients. Therefore, early or subclinical atherosclerosis should be assessed in every patient through the measurement of IMT in carotid arteries and other inflammatory markers on a regular clinical basis. LA patients are ethnically different from other populations and have a worse disease course due to their different genetic burden that could be the cause of a higher prevalence of EAM. Trying to extrapolate previous results from countries with patients from a different ethnic group to our subpopulation could be a mistake.
Although there is an evident association of traditional risk factors and cardiovascular compromise in RA patients, they do not completely explain the high rates of CVD in these patients. Thus, novel risk factors which are related to autoimmunity are now becoming a more important focus of attention. This is the reason why we propose to separate traditional and nontraditional risk factors and evaluate them comprehensively and in a multidisciplinary fashion.
There is a lack of literature about CVD in Hispanic patients as demonstrated by this systematic search. To make matters worse, literature evaluating nontraditional risk factors is scarce. This should be a challenge to the rheumatologist to do research in these fields in order to elucidate the underlying mechanisms involved for the benefit of the patient.
Unfortunately, LA patients receive lower quality diagnostic assessment and treatment choices than Caucasian patients due to difficulties in access to health services and delayed diagnosis. Cardiovascular compromise in RA patients is a therapeutic challenge and doctors need to be committed to assessing, monitoring, and treating cardiovascular risk factors in the early stages as well as generating effective public health policies in developing LA countries so that morbimortality rates can be decreased promptly.