Front. Med. Frontiers in Medicine Front. Med. 2296-858X Frontiers Media S.A. 10.3389/fmed.2022.855141 Medicine Systematic Review Prevalence of Metabolic Syndrome in Patients With Rheumatoid Arthritis: An Updated Systematic Review and Meta-Analysis Cai Wei 1 * Tang Xuemi 2 Pang Min 2 1Pediatric Department, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, China 2Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China

Edited by: Rossella De Angelis, Università Politecnica delle Marche, Italy

Reviewed by: Miguel Angel González-Gay, University of Cantabria, Spain; Hèctor Corominas, Hospital de la Santa Creu i Sant Pau, Spain

 *Correspondence: Wei Cai veners_55@163.com

This article was submitted to Rheumatology, a section of the journal Frontiers in Medicine

 08 04 2022 2022 9 855141 14 01 2022 03 03 2022 Copyright © 2022 Cai, Tang and Pang. 2022 Cai, Tang and Pang

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

 Introduction

Rheumatoid arthritis (RA) due to systemic inflammation and insulin resistance increases the risk of cardiovascular disease and reduces life expectancy. In order to develop cardiac death prevention strategies, it is necessary to estimate the prevalence of metabolic syndrome (MetS) in these patients.

 Methods

This systematic review and meta-analysis was performed to estimate the prevalence of MetS among patients with RA. International databases (i.e., Scopus, PubMed, Web of Science, and Google Scholar) were searched during the period of October 1 and October 10, 20121. Heterogeneity among the included studies was assessed through the Cochrane Q test statistics and I2 test. Finally, a random-effects meta-analysis model was computed to estimate the pooled prevalence of MetS.

 Results

Sixty-one articles with 96 groups and a sample size of 13,644 people were analyzed. The pooled prevalence of MetS was 32% (95% CI: 29.6–34.4). The highest prevalence of MetS is related to studies conducted in Asia (32.7%, 95% CI: 29–36.3) and Europe (32.7%, 95% CI: 27.5.37.9) and the lowest Prevalence was also related to studies conducted in Africa (28%, 95% CI: 28.8–32.2). The prevalence of MetS in men was 33% (95% CI: 26–39) and 34% (95% CI: 29–40) in women. Findings by diagnostic criteria showed that the highest and lowest prevalence of MetS was related to ATP III (37.5%, 95% CI: 30.9–44.2) and EGIR (14.4%, 95% CI: 10.5–18.5), respectively.

 Conclusions

MetS is highly prevalent in patients with RA and identification of high-risk patients is necessary to prevent cardiovascular mortality.

 metabolic syndrome rheumatoid arthritis prevalence systematic review meta-analysis Introduction

Rheumatoid arthritis is a chronic inflammatory disease of unknown etiology characterized by systemic symptoms, especially joint involvement and deformity (1). Patients with rheumatoid arthritis are at high risk for cardiovascular disease and premature death due to systemic inflammation, which reduces their life expectancy by 5 to 10 years (2, 3). Rheumatoid arthritis is associated with insulin resistance, dyslipidemia, and changes in adipokines profiles that are components of the metabolic syndrome (MetS) (4). Insulin resistance is a constant risk factor for cardiovascular disease and the central mechanism in metabolic syndrome, which is present in 70% of patients with RA (5, 6).

MetS, also known as syndrome X and insulin resistance syndrome, refers to a set of cardiovascular risk factors (obesity, glucose intolerance, dyslipidemia, and high blood pressure) that can lead to cardiovascular disease (7). MetS increases cardiovascular outcomes and mortality by 2 and 1.5 times, respectively (8, 9). The increased risk of cardiovascular disease in patients with rheumatoid arthritis has been well established, so that the European League Against Rheumatism (EULAR) recommends that screening and management of cardiovascular risk in these patients be performed immediately (10, 11).

Various studies have shown that the prevalence of metabolic syndrome in these patients varies between 10 and 56% (12, 13). In this systematic review and meta-analysis, the cumulative prevalence of metabolic syndrome in patients with rheumatoid arthritis has been estimated.

 Methods Search Strategy

The present systematic review and meta-analysis study was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (14). To access articles examining the prevalence of metabolic syndrome in patients with rheumatoid arthritis, a comprehensive search with no data limit was performed in the following databases: PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar. The search was conducted between October 1 and October 10, 2021. All article published until August 30, 2021 were included. Articles were searched with keywords (“Metabolic Syndrome”[Mesh] OR “Metabolic Syndrome*”[tiab] OR “Insulin Resistance Syndrome*”[tiab] OR “Metabolic X Syndrome*”[tiab] OR “Dysmetabolic Syndrome*”[tiab] OR “Reaven Syndrome*”[tiab] OR “Metabolic Cardiovascular Syndrome*”[tiab]) AND (“rheumatic diseases”[Mesh] OR “Arthritis, Rheumatoid”[Mesh] OR “Rheumatic disease*”[tiab] OR “Rheumatism*”[tiab] OR “Rheumatoid Arthritis”[tiab] OR “Rheumatic symptom*”[tiab]) AND (“Prevalence”[Mesh] OR “Prevalence*”[tiab] OR “Period Prevalence*”[tiab] OR “Point Prevalence*”[tiab]). The reference lists of the included articles were also reviewed to find other eligible articles.

 Selection of Studies and Data Extraction

All observational studies published in English that reported the prevalence or frequency of metabolic syndrome in patients with rheumatoid arthritis were analyzed. Interventional, review, and replication studies, as well as studies investigating the prevalence of metabolic syndrome in other rheumatic diseases, were excluded. According to the inclusion and exclusion criteria, the titles and abstracts of the articles were independently reviewed by two researchers and the required information such as first author, year of publication, country of study, sample size, prevalence or frequency of metabolic syndrome in patients with rheumatoid arthritis were extracted and recorded in a pre-prepared form. To evaluate the quality of articles, the modified Newcastle-Ottawa Scale (NOS) was used, which has three main sections. The first part, rated on a scale of one to five stars, focuses on the methodological quality of each study (i.e., sample size, response rate, and sampling technique). The second section considers the comparability of the study cases or cohorts with a possibility of two stars to be gained. The last section is concerned with the outcomes and statistical analysis of the original study with a possibility of three stars to be gained. Two authors extracted the information and evaluated the methodological quality of the articles, independently. Any disagreements between the two reviewers were resolved consensus (15, 16).

 Statistical Analysis

Point estimation and 95% confidence interval (CI) of metabolic syndrome due to binomial distribution formula and heterogeneity between studies was evaluated by Cochran Q test with a significance level of less than 0.1 and I2 index. The degree of heterogeneity was assessed using the I2 index. Heterogeneities were divided into three categories: less than 25% (low heterogeneity), 25 to 75% (moderate heterogeneity) and more than 75% (high heterogeneity). Pooled prevalence was estimated using a random-effects model. Subgroup analysis was performed based on diagnostic criteria and continent. To investigate the potential publication bias, funnel plot based on Egger's regression test was used. Univariate meta-regression was used to investigate the relationship between the prevalence of metabolic syndrome and the year of study and the mean age of patients. Data analysis was performed using Stata software version 16.

 Results

In the initial search, 938 potentially relevant articles were retrieved. Of these articles, 431 articles were excluded due to duplications and removing duplicate articles, 507 articles remained. The titles and abstracts of the remaining articles were reviewed and 411 irrelevant articles were removed. Of the remaining 96 articles, 34 articles were deleted for not reporting the prevalence of MetS (Figure 1).

Study selection following PRISMA guidelines.

 Study Characteristics

In this study, 62 articles with a sample size of 13,644 people were analyzed, the characteristics of which are listed in Table 1. Most studies were performed in Morocco (n = 9) and Iran (n = 9). Most studies were based on NCEP/ATP III (n = 42) and IDF (n = 21) diagnostic criteria. Thirty-nine studies were conducted in Asia, 25 in Europe, 18 in the United States and 14 in Africa. All selected articles had good methodological quality.

Characteristics of included articles.

First author Year Country Sample size Diagnostic criteria Mean age RA patients (%)
Total M/F Total Male Female
Turgunova et al. (17) 2021 Kazakhstan 101 31/70 IDF - 40.5 - -
Hee et al. (18) 2021 Singapore 561 0/561 NCEP/ATP III - 44.9 - -
JC 2009 - 49.4 - -
Giraud et al. (19) 2021 France 75 20/55 WHO 59.2 28 - -
Kong et al. (20) 2021 China 717 152/565 CDS 61 31.2 - -
Cioffi et al. (21) 2021 Italy 228 - IDF 58 15 - -
Mobini et al. (13) 2020 Iran 200 - NCEP/ATP III - 54.5 - -
IDF 56 - -
Garcia-Chagollan et al. (4) 2020 Mexico 216 22/194 NCEP/ATP III 46 30.6 - -
ALAD 28.7 - -
Xu et al. (22) 2020 Korea 247 48/199 NCEP/ATP III 58 15 - -
Shaikh et al. (23) 2020 Pakistan 104 10/94 NCEP/ATP III 33.4 32.7 - -
Ozkul et al. (24) 2019 Turkey 50 11/39 IDF 56.9 36 - -
Mulumba et al. (3) 2019 Congo 75 15/60 NCEP/ATP III 51.8 25.3 - -
Ene et al. (25) 2019 Romania 120 31/89 IDF-NCEP/ATP III 52.7 39.2 45.2 37.1
Naidu et al. (26) 2019 India 114 21/93 NCEP/ATP III 44.8 31.6 - -
Kuriya et al. (27) 2019 USA 1543 443/1100 WHO 54 30.8 42 26
Akbal et al. (28) 2019 Turkey 53 12/41 ATP III 51 47.1 - -
Aleksic et al. (29) 2019 Serbia 81 19/62 IDF 59.7 54.3 - -
Mobini et al. (30) 2018 Iran 140 25/115 NCEP/ATP III 44.7 31.4 - -
IDF 35 - -
Gomes et al. (7) 2018 Brazil 338 31/307 NCEP/ATP III 53.5 51.3 - -
Burggraaf et al. (31) 2017 Netherland 212 65/147 NCEP/ATP III 54 40.1 - -
Slimani et al. (32) 2017 Algeria 249 36/213 NCEP/ATP III 50.1 13.9 14.3 13.8
Pandey et al. (33) 2017 India 84 18/66 ATP III 2004 44.8 39.2 - -
Ostojic et al. (34) 2016 Serbia 36 6/30 - 36 30.6 - -
Lee et al. (35) 2016 Korea 598 110/488 AHA/NHLBI 63.6 36.4 34.5 36.9
Hugo et al. (36) 2016 France 57 15/42 IDF 57.6 24 25 24
Zafar et al. (37) 2016 Pakistan 384 97/277 NCEP/ATP III 43.8 31.3 18.5 35.5
Oliveira et al. (38) 2016 Brazil 107 0/107 NCEP/ATP III 55.5 51.4 - 51.4
IDF 53.4 - 53.4
Muller et al. (39) 2016 Estonia 91 66/25 NCEP/ATP III 51.6 35 - -
Dihingia et al. (40) 2016 India 72 6/66 NCEP/ATP III 41.5 16.7 - -
Ghazaly et al. (41) 2015 Egypt 80 13/67 ATP III 40.7 50 53 49.2
Salamon et al. (42) 2015 Croatia 583 100/483 ATP III 59 43.1 40 43.7
Tantayakom et al. (43) 2015 Thailand 267 31/236 NCEP/ATP III 59 16.1 12.9 16.5
Parra-Salcedo et al. (44) 2015 Mexico 160 18/142 AHA/NHLBI 38.1 28 - -
IDF 18 - -
NCEP/ATP III 24 - -
Craciun et al. (12) 2014 Romania 51 7/44 IDF-AHA 55.2 19 10.5 82.4
NCEP/ATP III 23 - -
IDF 18 - -
AHA 14 - -
Bilecik et al. (45) 2014 Turkey 100 0/100 IDF 52 33 - 33
NCEP/ATP III 27 - 27
Ozmen et al. (46) 2014 Turkey 52 15/37 NCEP/ATP III 51 17.3 - -
WHO 28.8 - -
Kumar et al. (47) 2014 India 54 6/48 IDF 46 29 - -
NCEP/ATP III 31 - -
Abourazzak et al. (48) 2014 Morocco 179 22/157 IDF 49 30.7 - -
NCEP/ATP III 29 - -
AACE 2003 24 - -
Salinas et al. (49) 2013 Argentina 409 69/340 ATP III 55.5 30 62 23.8
IDF 35 - -
Abdul-Qaharr et al. (50) 2013 Iraq 203 41/162 NCEP/ATP III 46.9 51.2 12 92
Rostom et al. (51) 2013 Morocco 120 10/110 NCEP/ATP III 2004 49 30.8 10 32.7
NCEP/ATP III 2001 24.6 - -
WHO 20 - -
IDF 48.6 - -
EGIR 18 - -
JC 2009 32.3 - -
Lee et al. (52) 2013 Korea 84 0/84 NCEP/ATP III 50.6 19 - 19
Ormseth et al. (53) 2013 USA 162 18/144 ATP III 54 26 - -
Karakoc et al. (1) 2012 Turkey 54 7/47 IDF 49.8 42.6 - -
Manka et al. (54) 2012 Slovakia 87 4/83 IDF 58.8 48.3 - -
NCEP/ATP III 44.8 - -
AHA/NHLBI 47.1 - -
Da Cunha et al. (55) 2012 Brazil 283 50/233 NCEP/ATP III 56.8 39.2 - -
Goshayeshi et al. (56) 2012 Iran 120 14/106 NCEP/ATP III 45.5 45.2 - -
Baker et al. (57) 2012 USA 499 83/416 IDF 49.5 10.6 - -
Crowson et al. (58) 2011 USA 232 58/174 NCEP/ATP III 58.8 33 36 32
Sahebari et al. (59) 2011 Iran 120 14/106 IDF 45.5 30.8 28.6 41.5
NCEP/ATP III 45.2 28.6 37.7
Karimi et al. (60) 2011 Iran 92 0/92 NCEP 48.3 27.2 - 27.2
WHO 19.6 - 19.6
Mok et al. (61) 2011 Hong Kong 699 133/566 JS 2009 53.3 20 - -
Dao et al. (62) 2010 Vietnam 105 0/105 IDF 56.3 40.9 - -
NCEP/ATP III 2004 32.4 - -
NCEP/ATP III 2001 24.7 - -
JS 2009 32.4 - -
WHO 19 - -
EGIR 16.2 - -
Raterman et al. (63) 2010 Netherland 236 79/157 NCEP 62.1 19.9 - -
Solomon et al. (64) 2010 South Africa 291 32/259 NCEP/ATP III 27.2 31.3 - -
335 65/270 NCEP/ATP III 27.2 20.3 - -
Giles et al. (65) 2010 USA 131 51/80 NCEP/ATP III 61 36 - -
Santos et al. (66) 2010 Portugal 98 0/98 ATP III 49.2 25.5 - -
Toms et al. (67) 2009 UK 387 105/282 IDF 63.1 45.3 52.7 42.6
NCEP/ATP III 2004 40.1 42.5 39.2
NCEP/ATP III 2001 38.3 40 37.7
WHO 19.4 25.5 17.2
EGIR 12.1 22.6 8.2
Chung et al. (2) 2008 USA 66 18/48 WHO 59 42 - -
Zonana-Nacach et al. (68) 2008 Mexico 107 - NCEP/ATP III 42.9 18.7 - -
Karvounaris et al. (69) 2007 Greece 200 53/147 ATP III 63 44 39.6 45.6
Montagna et al. (70) 2007 Italy 45 3/42 NCEP/ATP III 53.8 55.5 - -

The prevalence of MetS in patients with rheumatoid arthritis was 32% (95% CI: 29.6–34.4%). The prevalence of metabolic syndrome was 33% (95% CI: 26–39%) in men and 34% (95% CI: 29–40%)in women. The findings demonstrated that the highest prevalence of MetS was related to studies in Asia (32.7%, 95% CI: 29–36.3%) and Europe (32.7%, 95% CI: 27.5–37.9%) and the lowest prevalence was related to studies in Africa (28%, 95% CI: 22.8–33.2%) (Figure 2). Findings by diagnostic criteria of metabolic syndrome showed that the highest and lowest prevalence were related to ATP III (37.5%, 95% CI: 30.9–44.2%) and EGIR (14.4%, 95% CI: 10.5–18.5%) criteria, respectively (Table 2).

Subgroup prevalence of MetS among patients with RA.

Subgroups Number of studies Prevalence (95% CI) Between studies Subgroup
Pheterogeneity Q Q Pheterogeneity I2
Continent
Asia 39 32.7 (29–36.3) 91.25% 0.001 505.13 2.39 0.495
Europe 25 32.7 (27.5–38) 93.37% 0.001 418.57
America 18 32.3 (27–37.5) 94.66% 0.001 345.11
Africa 14 28 (22.8–33.2) 88.24% 0.001 155.11
Criteria
WHO 8 25.2 (20–30.4) 81% 0.004 42.19 79.69 0.001
IDF 21 35.2 (29.4–41.1) 93.1% 0.017 482.13
JS 4 33.5 (21–46) 95.6% 0.015 128.65
NCEP/ATP III 42 32 (28.5–35.5) 91.2% 0.012 518.62
ATP III 8 37.5 (31–44) 85.9% 0.007 47.09
AACE 4 26.2 (17.3–35.2) 87.8% 0.007 25.17
EGIR 3 14.4 (10.5–18.4) 36.75 0.001 2.92

WHO, World Health Organization; IDF, International Diabetes Federation; EGIR, European Group against Insulin Resistance; NCEP ATPIII, National Cholesterol Education Program Adult Treatment Panel; AACE, American Association of Clinical Endocrinologists; AHA/NHLBI, The American Heart Association / National Heart, Lung, and Blood Institute; JS, Joint Statement.

Forest plot of the pooled prevalence of MetS in patients with RA in Europe.

 Meta-Regression

The results of meta-regression showed that the prevalence of MetShad increased significantly with increasing age (in studies in the Americas) (p = 0.006) (Figure 3). Also, the prevalence of MetS over time in studies in Asia was significantly increased (p = 0.024). Also, publication bias was not significant in the analyzed studies (p = 0.569).

Meta-regression of the prevalence of MetS among patients with RA based on year of study (A) and mean age (B). Circles indicate the weight of studies.

 Discussion

The results of this study showed that one third of patients with RA have MetS. The results of a previous meta-analysis of 38 articles (with 70 groups) between 2007 and 2016 showed that the prevalence of MetS in patients with RA was 30.65%, which is almost consistent with the results of the present study (71). The reason for the high prevalence of metabolic syndrome in these patients can be attributed to traditional risk factors such as smoking, body mass index, gender, dyslipidemia and hypertension, although the role of continuous inflammation and activation of endothelial cells cannot be ignored (41). Inflammatory cytokines such as TNFα also reduce insulin function and facilitate insulin resistance (2). On the other hand, these patients use non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids to control the disease, which can cause metabolic disorders such as high blood pressure, obesity and diabetes (27). Serum levels of some biomarkers associated with metabolic syndrome, adipokines such as adiponectin, and biomarkers of endothelial cell activation and inflammation may appear to be useful in predicting cardiovascular risk in patients with RA (72).

The highest prevalence of metabolic syndrome was related to studies in Asia and Europe and the lowest prevalence was related to studies in Africa. Given that nutritional, ethnic and sociodemographic status are the determinants of the prevalence of metabolic syndrome, the reason for this finding can be attributed to these differences in these communities.

In a study by Park et al. (73) the prevalence of metabolic syndrome in Korean and American adults was compared, and the results showed that the prevalence of metabolic syndrome and all its components (except low high density lipoprotein-cholesterol) was higher in American adults than in Korean. The two groups were not different in terms of blood pressure (73). The results of our study differ from those of Park et al. (73); in that they examined the prevalence of metabolic syndrome among patients with rheumatoid arthritis, not the general population. Therefore, further studies in this regard seem necessary.

The highest and lowest prevalence of metabolic syndrome were related to ATP III and EGIR criteria, respectively. In all diagnostic criteria, blood pressure, triglycerides, HDL cholesterol and fasting glucose are measured, and the difference between them is in the selection of the cut-off points and the measure of obesity. In WHO and EGIR criteria, the presence of hyperinsulinemia as an indicator of insulin resistance is the starting point, while in ATP III, the number of abnormalities is considered (69). These differences have led to different prevalence being reported in a group of patients (same patients) based on different criteria, so appropriate standards should be used to diagnose MetS in different regions. In a meta-analysis performed to estimate the prevalence of metabolic syndrome in postmenopausal women, the highest prevalence of metabolic syndrome was based on the ATP III screening criterion (74). The prevalence of metabolic syndrome increased significantly with age (in studies in the Americas). The prevalence of metabolic syndrome in the general population also increases with age (27), which can be due to redistribution of adipose tissue, weight gain, insulin resistance, and lipid changes (75).

Given that the prevalence of metabolic syndrome in patients with rheumatoid arthritis has not been studied in some countries and therefore has not been analyzed, the findings of this study should be generalized with caution worldwide.

 Conclusion

Metabolic syndrome is so common in patients with RA that one-third of these patients have MetS, so identifying at-risk patients is essential to prevent cardiovascular events.

 Data Availability Statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

 Author Contributions

WC: concept, design, and drafting of the manuscript. WC, MP, and XT: acquisition, analysis, or interpretation of data. XT: critical revision of the manuscript for important intellectual content. MP: statistical analysis. All authors gave their final approval of this version of the manuscript.

 Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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