Original Research
Risk of Cardiovascular Disease in Patients with Juvenile Idiopathic Arthritis: A Systematic Review and Meta-analysis Patompong Ungprasert1-2, Narat Srivali3, Charat Thongprayoon4 Division of Rheumatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA; 2 Division of Rheumatology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; 3 Division of Pulmonary and Critical Care, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA; 4 Department of Medicine, Bassett Medical Center, Cooperstown, New York, USA 1
Abstract Background: An increased risk of cardiovascular disease (CVD) has been observed in several chronic immune-mediated inflammatory disorders. However, the data on juvenile idiopathic arthritis (JIA) is limited and inconclusive. Methods: We conducted a systematic review and meta-analysis of cohort studies that reported relative risks, hazard ratios or standardized incidence ratios with 95% confidence comparing CVD risk in patients with JIA versus non-JIA participants. Pooled risk ratios and 95% confidence intervals were calculated using a random-effect, generic inverse variance method of DerSimonian and Laird. Results: Five cohorts with 3,105 patients with JIA were identified and included in our data analysis. The overall pooled risk ratio of CVD in patients with JIA was 2.37 (95% CI, 1.89 to 2.97). The statistical heterogeneity of this meta-analysis was insignificant with an I2 of 0%. Conclusion: Our study demonstrated a significantly elevated CVD risk among patients with JIA. Key words: Juvenile idiopathic arthritis, cardiovascular disease, meta-analysis, epidemiology Introduction Chronic inflammation is increasingly recognized as a non-traditional risk factor for cardiovascular disease (CVD). Several epidemiological studies have demonstrated an elevated risk of coronary artery disease, cerebrovascular disease and peripheral arterial disease among patients with chronic inflammatory disorders [1-6]. Oxidative stress and inflammatory cytokines are believed to
be the cornerstone of the accelerated atherosclerosis as their deleterious effects on endothelial function have been consistently demonstrated [7, 8]. Chronic inflammation is also known to promote coagulation cascade resulting in a hypercoagulable state [9, 10].The combination of those factors may well serve as the elemental pathophysiology for the development of premature CVD. Juvenile idiopathic arthritis (JIA) is a heterog-
Corresponding Author: Patompong Ungprasert, Division of Rheumatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA e-mail:
[email protected] Received: Jul 16, 2015 Accepted: Jul 30, 2015 Ann Paediatr Rheum 2015;4:48-52 DOI: 10.5455/apr. 073020151756
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enous group of chronic inflammatory arthritides with onset under the age of 16 years. It is the most common rheumatic disease in children with the estimated prevalence of 7 to 400 per 100,000 children and the estimated annual incidence of 1 per 10,000 children [11, 12]. The International League of Associations for Rheumatology classifies JIA into five major categories including systemic arthritis, polyarthritis, oligoarthritis (persistent and extended), enthesitis-related arthritis and psoriatic arthritis [13]. In light of chronic inflammation, patients with JIA may be at an increased risk of premature CVD. However, the data on CVD risk in these patients remain inconclusive due to the limited amount of studies. Thus, to further investigate this possible association, we conducted a systematic review and metaanalysis of cohort studies that compared the risk of CVD in patients with JIA versus non-JIA controls. Methods Search strategy Two investigators (P.U. and N.S.) independently searched published studies indexed in MEDLINE and EMBASE database from inception to June 2015 as well as the American College of Rheumatology Scientific Conference abstract database from 2006-2014, using the search strategy described in supplementary data. A manual search of references of selected retrieved articles was also performed. Inclusion criteria The inclusion criteria were as follows: (1) prospective or retrospective cohort study published as original study or conference abstract reporting risk of CVD in patients with JIA (2) relative risk (RR), hazard ratio (HR) or standardized incidence ratio (SIR) with 95% confidence interval (CI) were provided, and (3) non-JIA participants and were used as a reference group. Study eligibility was independently appraised by the two aforementioned investigators. Difference in eligibility determination was resolved by consensus with the senior investigator. Data extraction A standardized data collection form was used to extract the following information: title of the article, first author’s name, authors’ affiliation, year of publication, country where the study was conducted, year of when the study was conductAnnals of Paediatric Rheumatology
ed, study size, study population, criteria used to diagnose JIA, method used to identify the cohort, definition and verification of CVD, demographic data of the cohorts, average duration of follow up and adjusted effect estimates with 95% CI. This data extraction was independently performed by all investigators. Any discrepancy was resolved by referring back to the original study. Statistical analysis Data analysis was performed using Review Manager 5.3 software from the Cochrane Collaboration. Adjusted point estimates and standard errors were extracted from individual cohorts and were combined by the generic inverse variance method as described by DerSimonian and Laird [14]. We used a random-effect model rather than a fixed-effect model in light of the high likelihood of between study variance. The statistical heterogeneity was assessed by Cochran’s Q test. This test was complemented with the I2 statistic, which quantifies the proportion of total variation across studies that is due to heterogeneity rather than chance. A value of I2 of 0% to 25% indicates insignificant heterogeneity, more than or equal to 25% but less than 50% low heterogeneity, more than or equal to 50% but less than 75% moderate heterogeneity, and more than or equal to 75% high heterogeneity [15]. Results Our search strategy yielded 2,871 potentially relevant articles (2,257 articles from EMBASE and 614 articles from Medline). After exclusion of 584 duplicated articles, 2,287 underwent title and abstract review. 2,261 articles were excluded in this step as they were clearly not cohort studies or were not conducted in patients with JIA, leaving 26 studies for fulllength article review. Sixteen articles were excluded since they were descriptive studies without a control group while eight articles were excluded as they did not report the outcome of interest. Two studies met our inclusion criteria. Both of them were population-based retrospective cohort studies. The first study contained two cohorts that identified from different geographic areas [16] while the second study contained three cohorts from one geographic area but were stratified based on type of treatments [17]. Therefore, five cohorts with 3,105 patients with JIA were used to calculate the pooled estimate effect in this meta-analysis. Figure 1 illustrates the process of Year 2015 | Volume:4 | Issue:3 | 48-52
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study identification and literature review. Our meta-analysis demonstrated a statistically significantly increased CVD risk among patients with JIA with a pooled risk ratio of 2.37 (95% CI, 1.89 to 2.97). The overall statistical heterogeneity was insignificant with an I2 of 0%. Figure 2 demonstrates the forest plots of our findings. Sensitivity analysis To confirm the robustness of our results, we performed jackknife sensitivity analysis by excluding one single study at a time [18]. The sensitivity analysis suggested that our results
Figure 1. Literature review process.
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were robust as the pooled risk ratios remained significantly elevated, ranging from 2.33 to 2.40, with the corresponding 95% CI lower bounds remained above one. Evaluation for publication bias Evaluation for publication bias was not performed as the number of included studies was too small. Discussion Our study is the first systematic review and meta-analysis of cohort studies evaluating the risk of CVD among patients with JIA. We are able to demonstrate a statistically significant association between JIA and CVD with an overall 2.37-fold increased risk compared with non-JIA control. As previously described, an increasing numbers of evidence are suggesting that chronic inflammation is the pathogenic link between CVD and immune-mediated disorder, including JIA. It has been demonstrated that endothelial injury from inflammatory cytokine, activated inflammatory cells and reactive oxygen species can accelerate the progression of atherosclerosis [9, 10]. Furthermore, chronic inflammation related to autoimmune disorders has been linked to a hypercoagulability, another predisposing factor for the development of CVD [19-21]. Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs), one of the first line treatments for patients with JIA, might be another contributory cause of the elevated CVD risk as the detrimental effect of NSAIDs on the cardiovascular system is also well-described [22, 23]. Even though the included studies are of high quality, we acknowledge that there are some limitations and, thus, the results should be cautiously translated. First, three of our five cohorts [17] were constructed us-
Figure 2. Demonstration of forest plots of findings. DOI: 10.5455/apr. 073020151756
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ing medical registry-based database. This type of cohort inherently has a problem with coding inaccuracy. Therefore, the accuracy and completeness of diagnosis of JIA and CVD might be a concern for those cohorts. Second, we cannot conduct an evaluation for publication bias. Third, this is a meta-analysis of observational studies which, at the best, can demonstrate an association but not causality. Therefore, we cannot make a conclusion that JIA itself versus other potential confounders was responsible for the increased risk. Furthermore, these studies were at risk of detection bias as these patients, because of their JIA, exposed to more medical examinations and, thus, the more likelihood of CVD detection Conclusion In conclusion, our meta-analysis demonstrated a significantly increased risk of CVD among patients with JIA. How this elevated risk should be addressed in clinical practice still needs further investigations. Acknowledgement This publication was made possible by CTSA Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH. Disclosure None References 1. Ungprasert P, Suksaranjit P, Spanuchart I, Leeaphorn N, Permpalung N. Risk of coronary artery disease in patients with idiopathic inflammatory myopathies: a systematic review and meta-analysis of observational studies. Semin Arthritis Rheum 2014; 44:63-7. 2. Ungprasert P, Cheungpasitporn W, Wijarnpreecha K, Ahuja W, Ratanasrimetha P, Thongprayoon C. Risk of ischemic stroke in patients with polymyositis and dermatomyositis: a systematic review and meta-analysis. Rheumatol Int 2015; 35:905-9. 3. Ogdie A, Yu Y, Haynes K, Love TJ, Maliha S, Jiang Y, et al. Risk of major cardiovascular events in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a population-based cohort study. Ann Rheum Dis 2015; Annals of Paediatric Rheumatology
4.
5.
6.
7.
8.
9.
10. 11.
12.
13.
14. 15.
74:326-32. Ungprasert P, Wannarong T, Panichsillapakit T, Cheungpasitporn W, Thongprayoon C, Ahmed S, et al. Cardiac involvement in mixed connective tissue disease: a systematic review. Int J Cardiol 2014; 171:326-30. Ungprasert P, Koster MJ, Warrington KJ. Coronary artery disease in giant cell arteritis: A systematic review and meta-analysis. Semin Arthritis Rheum 2015; 44:586-91. Ungprasert P, Charoenpong P, Ratanasrimetha P, Thongprayoon C, Cheungpasitporn W, Suksaranjit P. Risk of coronary artery disease in patients with systemic sclerosis: A systematic review and meta-analysis. Clin Rheumatol 2014; 33:1099-104. Montecucco F, Mach F. Common inflammatory mediators orchestrate pathophysiological processes in rheumatoid arthritis and atherosclerosis. Rheumatology (Oxford) 2009; 48:11-22. Frostegard J. Atherosclerosis in patients with autoimmune disorders. Arterioscler Thromb Vasc Biol 2005; 25:1776-85. Xu J, Lupu F, Esmon CT. Inflammation, innate immunity and blood coagulation. Hamostaseologie 2010;30:5-6, 8-9. Esmon CT. The interactions between inflammation and coagulation. Br J Haematol 2005; 131:417-30. Peterson LS, Mason T, Nelson AM, O’Fallon WM, Gabriel SE. Juvenile rheumatoid arthritis in Rochester, Minnesota 1960 – 1993: is the epidemiology changing? Arthritis Rheum 1996; 39:1385–90. Manners PJ, Bower C. Worldwide prevalence of juvenile arthritis: why does it vary so much? J Rheumatol 2002; 29:1520 –30. Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J. International League of Associations for Rheu-matology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004; 31:390 –2. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trial 1986; 7:177-88. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; Year 2015 | Volume:4 | Issue:3 | 48-52
CVD in JIA
16.
17.
18. 19.
327:557-60. Anderson J, Anderson K, Aulie H, et al. Juvenile rheumatoid arthritis and future risk of cardiovascular disease; A multicenter population-based study. Presented at the American College of Rheumatology Annual Scientific Meeting, Boston, MA, 14-19 November 2014. Abstract no. 304. Kok VC, Horng JT, Huang JL. Juvenile arthritis and shortterm risk for cardiometabolic outcomes. Exp Clin Cardiol 2014; 20:2832-40. Miller RG. The jackknife: a review. Biometrika 1974; 61:1–15. Ungprasert P, Srivali N, Spanuchart I, et al. Risk of venous thromboembolism in patients with rheumatoid arthritis: a systematic review and meta-analysis. Clin Rheumatol 2014; 33:297-304.
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20. Ungprasert P, Sanguankeo A, Upala S, Suksaranjit P. Psoriasis and risk of venous thromboembolism: a systematic review and meta-analysis. QJM 2014; 107:793-7. 21. Ungprasert P, Srivali N, Kittanamongkolchai W. Systemic sclerosis and risk of venous thromboembolism: A systematic review and meta-analysis. Mod Rheumatol 2015 May 28:1-5. [Epub ahead of print] 22. McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective of cyclooxygenase 2. JAMA 2006; 296:1633-44. 23. Ungprasert P, Srivali N, Wijarnpreecha K, Charoenpong P, Knight EL. Non-steroidal anti-inflammatory drugs and risk of venous thromboembolism: a systematic review and meta-analysis. Rheumatology (Oxford) 2015; 54:736-42.
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