- Email: [email protected]
Risk of coronary artery disease in patients with idiopathic inflammatory myopathies: A systematic review and meta-analysis of observational studies
Seminars in Arthritis and Rheumatism ] (2014) ]]]–]]]
Contents lists available at ScienceDirect
Seminars in Arthritis and Rheumatism journal homepage: www.elsevier.com/locate/semarthrit
Risk of coronary artery disease in patients with idiopathic inflammatory myopathies: A systematic review and meta-analysis of observational studies Patompong Ungprasert, MDa,n, Promporn Suksaranjit, MDb, Ittikorn Spanuchart, MDc, Napat Leeaphorn, MDd, Nitipong Permpalung, MDd a
Department of Medicine, Faculty of medicine Siriraj hospital, Mahidol University, Bangkok 10700, Thailand Department of Cardiology, University of Utah School of Medicine, Salt Lake City, UT Department of Internal Medicine, John A. Burns School of medicine, University of Hawaii, Honolulu, HI d Department of Internal Medicine, Bassett Medical Center, Columbia University College of Physicians and Surgeons, Cooperstown, NY b c
a r t i c l e in fo
Keywords: Dermatomyositis Polymyositis Idiopathic inflammatory myopathies Coronary artery disease Atherosclerosis Meta-analysis
a b s t r a c t Objectives: To investigate the risk of coronary artery disease in patients with idiopathic inflammatory myopathies (IIM). Methods: We conducted a systematic review and meta-analysis of observational studies that reported odds ratios, relative risks, hazard ratios, or standardized incidence ratios comparing the risk of coronary artery disease in patients with IIM versus non-IIM participants. We searched published studies indexed in MEDLINE, EMBASE, and the Cochrane database from inception to December 2013 using the terms “coronary artery disease” OR “coronary heart disease” OR “myocardial infarction” OR “atherosclerosis” combined with the terms “dermatomyositis” OR “polymyositis” OR “Idiopathic inflammatory myopathy.” Pooled risk ratio and 95% confidence interval were calculated using a random-effect, generic inverse variance method. Result: Overall, four studies were identified and included for data analysis. The pooled risk ratio of CAD in patients with IIM was 2.24 (95% CI: 1.02–4.92). The statistical heterogeneity of this meta-analysis was high with an I2 of 97%. Conclusion: Our study demonstrated a statistically significant increased risk of CAD among patients with IIM. & 2014 Elsevier Inc. All rights reserved.
Introduction Idiopathic inflammatory myopathies (IIM) are a group of chronic systemic inflammatory disorders that primarily affect the skeletal muscle. The most common subtypes are dermatomyositis (DM) and polymyositis (PM) [1–3]. The association between chronic inflammation and accelerated atherosclerosis is wellestablished [4,5], and several chronic inflammatory disorders, including rheumatoid arthritis (RA), psoriasis, and systemic lupus erythematosus, have been shown to be associated with an increased risk of coronary artery disease (CAD) in large epidemiological studies [6–8]. Nevertheless, the data on CAD in patients
Authors' contributions: All authors had access to the data and a role in writing the manuscript. n Corresponding author. E-mail addresses: [email protected], Patompong.Ungprasert@bassett. org (P. Ungprasert). http://dx.doi.org/10.1016/j.semarthrit.2014.03.004 0049-0172/& 2014 Elsevier Inc. All rights reserved.
with IIM is unclear, and the results from large epidemiological studies are conflicting. Thus, to further investigate this association, we conducted a systematic review and meta-analysis of case– control and cohort studies that compared the risk of coronary artery disease in patients with IIM versus non-IIM.
Materials and methods Search strategy Two investigators (P.U. and P.S.) independently searched published studies indexed in MEDLINE, EMBASE, and the Cochrane database from inception to December 2013 using the terms “coronary artery disease” OR “coronary heart disease” OR “myocardial infarction” OR “atherosclerosis” combined with the terms “dermatomyositis” OR “polymyositis” OR “Idiopathic inflammatory myopathy.” A manual search of references of selected retrieved
2
P. Ungprasert et al. / Seminars in Arthritis and Rheumatism ] (2014) ]]]–]]]
Potenally relevant arcles idenfied from search of MEDLINE, EMBASE and the Cochrane database and screened for retrieval (n=392)
Detailed review of potenally relevant arcles
379 articles were excluded since they were not observaonal study or were not done in paents with IIM
13 potenally relevant arcles included for fulllength arcle review
5 arcles were excluded since they do not report the outcome of interest (coronary artery disease) 4 arcles were excluded since they were review arcle
4 arcles were included in the meta-analysis Fig. 1. Studies identification.
studies was also performed. Abstract and unpublished studies were not included. The details of our search strategy are provided in the Appendix.
estimates with 95% CI, and confounders. The two investigators independently performed this data extraction. Any disagreement, again, were resolved by consensus.
Study selection Statistical analysis The inclusion criteria were as follows: (1) observational studies (case–control or cohort studies) published as original studies to evaluate the association between DM or PM and the risk of CAD, (2) odds ratios (ORs), relative risks (RRs), hazard ratios (HRs), or standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were provided, and (3) random, non-IIM participants were used as a reference group. Study eligibility was independently determined by each investigator noted above. Any disagreements were resolved by consensus. The quality of the included studies was independently evaluated by each investigator using the Newcastle–Ottawa quality assessment scale [9]. Data extraction A standardized data collection form was used to extract the following information: last name of the first author, title of the article, year of publication, country where the study was conducted, calendar year of the study, study design, study size, study population, criteria used for the diagnosis of IIM, adjusted effect
Review Manager 5.2 software from the Cochrane Collaboration was used to perform the data analysis. We reported the pooled effect estimate of CAD. We combined the data from case–control and cohort analyses to increase the precision of our estimates. As the outcome of the studies was relatively uncommon, we used the OR of case–control studies as the estimate of the RR to pool this data with the RR or HR of cohort studies. Point estimates and standard errors were extracted from individual studies and were combined by the generic inverse variance method. We used a random-effect model rather than a fixed-effect model because of the high likelihood of between-study variance given different study designs and populations. Cochran's Q test was used to assess the statistical heterogeneity. This statistic 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 0–25% represents insignificant heterogeneity, 25–50% low heterogeneity, 50–75% moderate heterogeneity, and 75–100% high heterogeneity [10].
P. Ungprasert et al. / Seminars in Arthritis and Rheumatism ] (2014) ]]]–]]]
3
Table Main characteristics of studies included in the meta-analysis Tisseverasinghe et al. [11]
Zoller et al. [12]
Lai et al. [13]
Linos et al. [14]
Country Study design Year Cases
Canada Retrospective cohort 2009 Hospitalized or non-hospitalized patients who were diagnosed with DM or PM (without previous or co-existing coronary artery disease) between 1994 and 2003. Cases were identified by using the Quebec provincial database.
Sweden Retrospective cohort 2012 All patients who were hospitalized with a main diagnosis of DM or PM (without previous or co-existing coronary artery disease) between 1964 and 2008. Cases were identified by using the Swedish national registry.
Taiwan Prospective cohort 2013 Ambulatory patients who were diagnosed with DM between January 1, 2001 and December 31, 2001. Cases were identified by using the National health insurance database (which covers 97% of entire population).
Diagnosis of IIM
Diagnostic code from the registry. Diagnostic code from the registry.
Diagnostic code from the registry for at least two visits.
Controls
Using Swedish age- and sex-specific Using Canadian age- and sexgeneral population incidence rates specific general population for AMI, angina, and chronic incidence rates for AMI as the coronary heart disease as the comparator for the calculation comparator for the calculation of of standardized incidence ratio. standardized incidence ratio. AMI AMI, angina, and chronic coronary heart disease Until the first of outcome event, Until hospitalization for CAD, death, death, or December 31, 2003. emigration from the system, or December 31, 2008. 62.4 Data not provided 70.0 61.7 607 1531 NA NA 4 Data not provided
Sex- and age-matched subjects randomly selected from same database.
USA Case–control 2013 All patients who were hospitalized with a primary or secondary diagnosis of DM between 1993 and 2007. Cases were identified by using the Healthcare Cost and Utilization Project Nationwide Inpatient Sample database (which covers 20% of the US community hospitals). Diagnostic code from the registry without concurrent diagnostic code of PM, systemic sclerosis, SLE, or RA. Sex- and age-matched subjects randomly selected from same database.
Selection: 4 stars Comparability: 1 star Outcome: 2 stars
Coronary artery disease Follow-up
Mean age, year Woman, % Number of cases Number of control Average range of follow-up, year Quality assessment (Newcastle–Ottawa scale)
Selection: 4 stars Comparability: 1 star Outcome: 3 stars
AMI Two years after the index date.
AMI, angina, CHF, and coronary intervention NA
53.2 58.9 907 4535 2
58.3 73.2 10,156 76,440 NA
Selection: 3 stars Comparability: 1 star Outcome: 2 stars
Selection: 2 stars Comparability: 1 star Exposure: 3 stars
USA, United States of America; DM, dermatomyositis; PM, polymyositis; IIM, idiopathic inflammatory myopathy; SLE, systemic lupus erythematosus; RA, rheumatoid arthritis; AMI, acute myocardial infarction; CHF, congestive heart failure; CAD, coronary artery disease; NA, not applicable.
Result
Discussion
Our search strategy yielded 392 potentially relevant articles. A total of 379 articles was excluded as they were not observational studies or were not done in patients with IIM. Therefore, 13 articles underwent full-length article review. Of them, five were excluded as they did not report the outcome of interest (coronary artery disease) while four of them were excluded as they were review articles. Overall, four studies (three cohort studies and one case– control study) with 13,201 patients with IIM met our eligibility criteria and were included in the analysis [11–14]. Figure 1 outlines our search methodology and selection process. The detailed characteristics and quality assessment of the included studies are described in the Table. Our meta-analysis demonstrated a statistically significant increased CAD risk among patient with IIM with a pooled risk ratio of 2.24 (95% CI: 1.02–4.92). The statistical heterogeneity was high with an I2 of 97%. Figure 2 demonstrates the forest plot of our findings. We performed a sensitivity analysis by excluding the only case–control study [14]. The pooled risk ratio of the remaining cohort studies was 2.99 (95% CI: 1.80–4.97) with a lower statistical heterogeneity (I2 of 76%). Since only four studies were included in this meta-analysis, we did not perform an evaluation for publication bias.
This is the first systematic review and meta-analysis of published observational studies assessing the risk of CAD in patients with DM or PM. Our study demonstrates a significant association between IIM and CAD with an overall 2.24-fold increased risk compared with nonIIM participants. All cohort studies reported a positive association between IIM and CAD, and in fact, the relative risks were fairly consistent among the cohort studies [11–13] while the only case– control study did not reveal an increased risk [14]. Heterogeneity between studies was present in this metaanalysis. We suspect that the difference in study design, population, and case selection was the main source of heterogeneity as two studies were done in hospitalized subjects [12,14], one study was done in the ambulatory setting [13] while another study included both ambulatory and hospitalized subjects [11]. Two studies included only patients with DM while the other two studies included either patients with DM or patients with PM. It should be noted that these four studies were conducted in four different countries (Canada, Sweden, Taiwan, and United States). The role of inflammation in the initiation and development of atherosclerosis is well-recognized [4,5,15]. It is hypothesized that the effect of inflammatory cytokine, oxidative stress, and
P. Ungprasert et al. / Seminars in Arthritis and Rheumatism ] (2014) ]]]–]]]
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Fig. 2. Forest plot of included studies.
activated-T lymphocytes, macrophages, and dendritic cells resulting in endothelial dysfunction and direct endovascular injury may accelerate the progression of atherosclerosis [16–19]. Furthermore, chronic inflammation related to autoimmune disease has been demonstrated to promote pro-coagulation, impair the anticoagulation pathway, and inhibit the fibrinolytic process resulting in a hypercoagulable state [20,21]. These factors may serve as the fundamental pathophysiology of the development of premature coronary artery disease. In addition, other traditional cardiovascular risk factors, including diabetes, hypertension, and metabolic syndrome, are more prevalent in patients with IIM compared with healthy individuals [22,23] which, again, might be a result of the underlying inflammatory process in conjunction with decreased functional capacity and physical activity secondary to muscle weakness. The effect of corticosteroids, the most commonly used immunosuppressive agent in IIM, on the pathogenesis of atherosclerosis is unclear as epidemiological studies assessing the cardiovascular effect of corticosteroid in patients with inflammatory autoimmune diseases yielded inconsistent results [24–26]. Use of corticosteroids is associated with adverse effects on atherosclerotic risk factors, including diabetes mellitus, hypertension, and dyslipidemia [27]. However, their anti-inflammatory activity might provide a protective effect on the cardiovascular system in patients with chronic inflammatory disorders [28]. Even though the four studies included in this meta-analysis were of high quality, there are some limitations, and thus, the result should be interpreted with caution. First, the statistical heterogeneity is high in this study. Second, all of the included studies were conducted using a medical registry-based database, thus the possibility of coding inaccuracy. The issue of coding inaccuracy is of particular concern for this study as myocardial involvement of IIM might be misinterpreted or miscoded as CAD. Third, this is a meta-analysis of observational studies, and this type of study can only demonstrate an association, not establish cause and effect, so we cannot be certain that IIM itself versus other potential confounders increase the risk of CAD. Furthermore, the higher detection rate of CAD in patients with IIM might be partly due to the fact that they have chronic illness and, thus, are exposed to medical community more frequently.
Conclusion The results of our meta-analysis demonstrate a statistically significant increased CAD risk among patients with IIM. A physician should be aware of this association, and traditional cardiovascular risk factors modification should be part of standard of care in this group of patients. Appendix Database: Ovid MEDLINE 1. exp Dermatomyositis/ 2. dermatomyositis.mp.
3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33.
exp Polymyositis/ polymyositis.mp. exp Myositis/ myositis.mp. or/1-6 exp Coronary Disease/ coronary disease$.mp. exp Coronary Artery Disease/ coronary arter$ disease$.mp. exp Coronary Stenosis/ coronary stenos$.mp. coronary atheroscleros$.mp. coronary arterioscleros$.mp. (coronary adj3 disease$).mp. (coronary adj3 syndrome$).mp. cad.mp. exp Myocardial Infarction/ myocardial infarct$.mp. exp Coronary Thrombosis/ coronary thrombos$.mp. exp Angina, Unstable/ unstable angina.mp (unstable adj3 angina).mp. exp Angina, Stable/ stable angina.mp. exp Angina Pectoris/ angina pectoris.mp. acs.mp. ami.mp. or/8-31 7 and 32 Database: EMBASE
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
exp Dermatomyositis/ dermatomyositis.mp. exp Polymyositis/ polymyositis.mp. exp Myositis/ myositis.mp. or/1-6 exp Heart Disease/ heart disease$.mp. exp Coronary Artery Disease/ coronary arter$ disease$.mp. exp Coronary Artery Atherosclerosis/ coronary arter$ atheroscleros$.mp. exp Coronary Artery Obstruction/ coronary arter$ obstruction$.mp. (coronary arter$ adj5 stenos$).mp. coronary atheroscleros$.mp. coronary arterioscleros$.mp. (coronary adj3 disease$).mp. (coronary adj3 syndrome$).mp.
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21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34.
cad.mp. exp Heart Infarction/ heart infarction.mp exp Coronary Artery Thrombosis/ coronary thrombosis.mp. exp Angina Pectoris/ angina pectoris.mp. myocardial infarct$.mp. acs.mp. ami.mp. acute angina.mp. (unstable adj3 angina).mp. or/8-32 7 and 33
Reference [1] Ungprasert P, Leeaphorn N, Hosiriluck N, Chaiwatcharayut W, Ammannagari N, Raddatz D.A. Clinical features of inflammatory myopathies and their association with malignancy: a systematic review in Asian population. ISRN Rheumatol 2013;2013:509354. [2] Bohan A, Peter JB. Polymyositis and dermatomyositis-I. New Engl J Med 1975; 292:344–7. [3] Bohan A, Peter JB. Polymyositis and dermatomyositis (second of tow parts). New Engl J Med 1975;292:403–7. [4] Frostegard J. Atherosclerosis in patients with autoimmune disorders. Arterioscler Thromb Vasc Biol 2005;25:1776–85. [5] Libby P. Inflammation in atherosclerosis. Nature 2002;420:868–74. [6] Maradit-Kremers H, Nicola PJ, Crowson CS, Ballman KV, Gabreil SE. Cardiovascular death in rheumatoid arthritis: a population-based study. Arthritis Rheum 2005;52:722–32. [7] Bessant R, Hingorani A, Patel L, MacGregor A, Isenberg DA, Rahman A. Risk of coronary heart disease and stroke in a large British cohort of patients with systemic lupus erythematosus. Rheumatology (Oxford) 2004;43:924–9. [8] Vizzardi E, Raddino R, Teli M, Gorga E, Brambilla G, Dei Cas L. Psoriasis and cardiovascular diseases. Acta Cardiol 2010;65:337–40. [9] Stang A. Critical evaluation of the Newcastle–Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010;25:603–5. [10] Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in metaanalyses. Br Med J 2003;327:557–60. [11] Tisseverasinghe A, Bernatsky S, Pineau CA. Arterial events in persons with dermatomyositis and polymyositis. J Rheumatol 2009;36:1943–6.
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[12] Zoller B, Li X, Sundquist J, Sunquist K. Risk of subsequent coronary heart disease in patients hospitalized for immune-mediated diseases: a nationwide follow-up study from Sweden. PLoS One 2012;7:e33442. [13] Lai YT, Dai YS, Yen MF, Chen LS, Chen HH, Cooper RG, et al. Dermatomyositis is associated with an increased risk of cardiovascular and cerebrovascular events: a Taiwanese population-based longitudinal follow up study. Br J Dermatol 2013;168:1054–9. [14] Linos E, Fiorentino D, Lingala B, Krishnan E, Chung L. Atherosclerotic cardiovascular disease and dermatomyositis: an analysis of nationwide inpatient sample survey. Arthritis Res Ther 2013;15:R7. [15] Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685–95. [16] Montecucco F, Mach F. Common inflammatory mediators orchestrate pathophysiological processes in rheumatoid arthritis and atherosclerosis. Rheumatology (Oxford) 2009;48:11–22. [17] Rho YH, Chung CP, Oeser A, Solus JF, Gebretsadik T, Shintani A, et al. Interaction between oxidative stress and high-density lipoprotein cholesterol is associated with severity of coronary artery calcification in rheumatoid arthritis. Arthritis Care Res 2010;62:1473–80. [18] Niessner A, Sato K, Chaikof EL, Colmegna I, Goronzy JJ, Weyand CM. Pathogensensing plasmacytoid dendritic cells stimulate cytotoxic T-cell function in atherosclerotic plaque through interferon-alpha. Circulation 2006;114:2482–9. [19] Hansen S, Lassig G, Pistrosch E, Passauer J. Endothelial dysfunction in young patients with long-term rheumatoid arthritis and low disease activity. Atherosclerosis 2003;170:177–80. [20] Xu J, Lupu F, Esmon CT. Inflammation, innate immunity and blood coagulation. Hamostaseologie 2010;30:8–9. [21] Esmon CT. The interactions between inflammation and coagulation. Br J Haematol 2005;131:417–30. [22] de Moraes MT, de Souza FH, de Barros TB, Shinjo SK. Analysis of metabolic syndrome in adult dermatomyositis with a focus on cardiovascular disease. Arthritis Care Res 2013;65:793–9. [23] Limaye VS, Lester S, Blumbergs P, Roberts-Thompson PJ. Idiopathic inflammatory myositis is associated with a high incidence of hypertension and diabetes mellitus. Int J Rheum Dis 2010;13:132–7. [24] Wei L, MacDonald TM, Walker BR. Taking glucocorticoid by prescription is associated with subsequent cardiovascular disease. Ann Intern Med 2004;141: 764–70. [25] Maradit-Kremers H, Reinalda MS, Crowson CS, Davis JM 3rd, Hunder GG, Gabriel SE. Glucocorticoids and cardiovascular and cerebrovascular events in polymyalgia rheumatic. Arthritis Rheum 2007;57:279–86. [26] Toms TE, Panoulas VF, Douglas KM, Griffitths HR, Kitas GD. Lack of association between glucocorticoid use and presence of the metabolic syndrome in patients with rheumatoid arthritis: a cross-sectional study. Arthritis Res Ther 2008;10:R145. [27] Sholter DE, Armstrong PW. Adverse effects of corticosteroids on cardiovascular system. Can J Cardiol 2000;16:505–11. [28] Voisard R, Seitzer U, Baur R, Dartsch PC, Osterhues H, et al. Corticosteroid agents inhibit proliferation of smooth muscle cells from human atherosclerotic arteries in vitro. Int J Cardiol 1994;43:257–67.
Contents lists available at ScienceDirect
Seminars in Arthritis and Rheumatism journal homepage: www.elsevier.com/locate/semarthrit
Risk of coronary artery disease in patients with idiopathic inflammatory myopathies: A systematic review and meta-analysis of observational studies Patompong Ungprasert, MDa,n, Promporn Suksaranjit, MDb, Ittikorn Spanuchart, MDc, Napat Leeaphorn, MDd, Nitipong Permpalung, MDd a
Department of Medicine, Faculty of medicine Siriraj hospital, Mahidol University, Bangkok 10700, Thailand Department of Cardiology, University of Utah School of Medicine, Salt Lake City, UT Department of Internal Medicine, John A. Burns School of medicine, University of Hawaii, Honolulu, HI d Department of Internal Medicine, Bassett Medical Center, Columbia University College of Physicians and Surgeons, Cooperstown, NY b c
a r t i c l e in fo
Keywords: Dermatomyositis Polymyositis Idiopathic inflammatory myopathies Coronary artery disease Atherosclerosis Meta-analysis
a b s t r a c t Objectives: To investigate the risk of coronary artery disease in patients with idiopathic inflammatory myopathies (IIM). Methods: We conducted a systematic review and meta-analysis of observational studies that reported odds ratios, relative risks, hazard ratios, or standardized incidence ratios comparing the risk of coronary artery disease in patients with IIM versus non-IIM participants. We searched published studies indexed in MEDLINE, EMBASE, and the Cochrane database from inception to December 2013 using the terms “coronary artery disease” OR “coronary heart disease” OR “myocardial infarction” OR “atherosclerosis” combined with the terms “dermatomyositis” OR “polymyositis” OR “Idiopathic inflammatory myopathy.” Pooled risk ratio and 95% confidence interval were calculated using a random-effect, generic inverse variance method. Result: Overall, four studies were identified and included for data analysis. The pooled risk ratio of CAD in patients with IIM was 2.24 (95% CI: 1.02–4.92). The statistical heterogeneity of this meta-analysis was high with an I2 of 97%. Conclusion: Our study demonstrated a statistically significant increased risk of CAD among patients with IIM. & 2014 Elsevier Inc. All rights reserved.
Introduction Idiopathic inflammatory myopathies (IIM) are a group of chronic systemic inflammatory disorders that primarily affect the skeletal muscle. The most common subtypes are dermatomyositis (DM) and polymyositis (PM) [1–3]. The association between chronic inflammation and accelerated atherosclerosis is wellestablished [4,5], and several chronic inflammatory disorders, including rheumatoid arthritis (RA), psoriasis, and systemic lupus erythematosus, have been shown to be associated with an increased risk of coronary artery disease (CAD) in large epidemiological studies [6–8]. Nevertheless, the data on CAD in patients
Authors' contributions: All authors had access to the data and a role in writing the manuscript. n Corresponding author. E-mail addresses: [email protected], Patompong.Ungprasert@bassett. org (P. Ungprasert). http://dx.doi.org/10.1016/j.semarthrit.2014.03.004 0049-0172/& 2014 Elsevier Inc. All rights reserved.
with IIM is unclear, and the results from large epidemiological studies are conflicting. Thus, to further investigate this association, we conducted a systematic review and meta-analysis of case– control and cohort studies that compared the risk of coronary artery disease in patients with IIM versus non-IIM.
Materials and methods Search strategy Two investigators (P.U. and P.S.) independently searched published studies indexed in MEDLINE, EMBASE, and the Cochrane database from inception to December 2013 using the terms “coronary artery disease” OR “coronary heart disease” OR “myocardial infarction” OR “atherosclerosis” combined with the terms “dermatomyositis” OR “polymyositis” OR “Idiopathic inflammatory myopathy.” A manual search of references of selected retrieved
2
P. Ungprasert et al. / Seminars in Arthritis and Rheumatism ] (2014) ]]]–]]]
Potenally relevant arcles idenfied from search of MEDLINE, EMBASE and the Cochrane database and screened for retrieval (n=392)
Detailed review of potenally relevant arcles
379 articles were excluded since they were not observaonal study or were not done in paents with IIM
13 potenally relevant arcles included for fulllength arcle review
5 arcles were excluded since they do not report the outcome of interest (coronary artery disease) 4 arcles were excluded since they were review arcle
4 arcles were included in the meta-analysis Fig. 1. Studies identification.
studies was also performed. Abstract and unpublished studies were not included. The details of our search strategy are provided in the Appendix.
estimates with 95% CI, and confounders. The two investigators independently performed this data extraction. Any disagreement, again, were resolved by consensus.
Study selection Statistical analysis The inclusion criteria were as follows: (1) observational studies (case–control or cohort studies) published as original studies to evaluate the association between DM or PM and the risk of CAD, (2) odds ratios (ORs), relative risks (RRs), hazard ratios (HRs), or standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were provided, and (3) random, non-IIM participants were used as a reference group. Study eligibility was independently determined by each investigator noted above. Any disagreements were resolved by consensus. The quality of the included studies was independently evaluated by each investigator using the Newcastle–Ottawa quality assessment scale [9]. Data extraction A standardized data collection form was used to extract the following information: last name of the first author, title of the article, year of publication, country where the study was conducted, calendar year of the study, study design, study size, study population, criteria used for the diagnosis of IIM, adjusted effect
Review Manager 5.2 software from the Cochrane Collaboration was used to perform the data analysis. We reported the pooled effect estimate of CAD. We combined the data from case–control and cohort analyses to increase the precision of our estimates. As the outcome of the studies was relatively uncommon, we used the OR of case–control studies as the estimate of the RR to pool this data with the RR or HR of cohort studies. Point estimates and standard errors were extracted from individual studies and were combined by the generic inverse variance method. We used a random-effect model rather than a fixed-effect model because of the high likelihood of between-study variance given different study designs and populations. Cochran's Q test was used to assess the statistical heterogeneity. This statistic 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 0–25% represents insignificant heterogeneity, 25–50% low heterogeneity, 50–75% moderate heterogeneity, and 75–100% high heterogeneity [10].
P. Ungprasert et al. / Seminars in Arthritis and Rheumatism ] (2014) ]]]–]]]
3
Table Main characteristics of studies included in the meta-analysis Tisseverasinghe et al. [11]
Zoller et al. [12]
Lai et al. [13]
Linos et al. [14]
Country Study design Year Cases
Canada Retrospective cohort 2009 Hospitalized or non-hospitalized patients who were diagnosed with DM or PM (without previous or co-existing coronary artery disease) between 1994 and 2003. Cases were identified by using the Quebec provincial database.
Sweden Retrospective cohort 2012 All patients who were hospitalized with a main diagnosis of DM or PM (without previous or co-existing coronary artery disease) between 1964 and 2008. Cases were identified by using the Swedish national registry.
Taiwan Prospective cohort 2013 Ambulatory patients who were diagnosed with DM between January 1, 2001 and December 31, 2001. Cases were identified by using the National health insurance database (which covers 97% of entire population).
Diagnosis of IIM
Diagnostic code from the registry. Diagnostic code from the registry.
Diagnostic code from the registry for at least two visits.
Controls
Using Swedish age- and sex-specific Using Canadian age- and sexgeneral population incidence rates specific general population for AMI, angina, and chronic incidence rates for AMI as the coronary heart disease as the comparator for the calculation comparator for the calculation of of standardized incidence ratio. standardized incidence ratio. AMI AMI, angina, and chronic coronary heart disease Until the first of outcome event, Until hospitalization for CAD, death, death, or December 31, 2003. emigration from the system, or December 31, 2008. 62.4 Data not provided 70.0 61.7 607 1531 NA NA 4 Data not provided
Sex- and age-matched subjects randomly selected from same database.
USA Case–control 2013 All patients who were hospitalized with a primary or secondary diagnosis of DM between 1993 and 2007. Cases were identified by using the Healthcare Cost and Utilization Project Nationwide Inpatient Sample database (which covers 20% of the US community hospitals). Diagnostic code from the registry without concurrent diagnostic code of PM, systemic sclerosis, SLE, or RA. Sex- and age-matched subjects randomly selected from same database.
Selection: 4 stars Comparability: 1 star Outcome: 2 stars
Coronary artery disease Follow-up
Mean age, year Woman, % Number of cases Number of control Average range of follow-up, year Quality assessment (Newcastle–Ottawa scale)
Selection: 4 stars Comparability: 1 star Outcome: 3 stars
AMI Two years after the index date.
AMI, angina, CHF, and coronary intervention NA
53.2 58.9 907 4535 2
58.3 73.2 10,156 76,440 NA
Selection: 3 stars Comparability: 1 star Outcome: 2 stars
Selection: 2 stars Comparability: 1 star Exposure: 3 stars
USA, United States of America; DM, dermatomyositis; PM, polymyositis; IIM, idiopathic inflammatory myopathy; SLE, systemic lupus erythematosus; RA, rheumatoid arthritis; AMI, acute myocardial infarction; CHF, congestive heart failure; CAD, coronary artery disease; NA, not applicable.
Result
Discussion
Our search strategy yielded 392 potentially relevant articles. A total of 379 articles was excluded as they were not observational studies or were not done in patients with IIM. Therefore, 13 articles underwent full-length article review. Of them, five were excluded as they did not report the outcome of interest (coronary artery disease) while four of them were excluded as they were review articles. Overall, four studies (three cohort studies and one case– control study) with 13,201 patients with IIM met our eligibility criteria and were included in the analysis [11–14]. Figure 1 outlines our search methodology and selection process. The detailed characteristics and quality assessment of the included studies are described in the Table. Our meta-analysis demonstrated a statistically significant increased CAD risk among patient with IIM with a pooled risk ratio of 2.24 (95% CI: 1.02–4.92). The statistical heterogeneity was high with an I2 of 97%. Figure 2 demonstrates the forest plot of our findings. We performed a sensitivity analysis by excluding the only case–control study [14]. The pooled risk ratio of the remaining cohort studies was 2.99 (95% CI: 1.80–4.97) with a lower statistical heterogeneity (I2 of 76%). Since only four studies were included in this meta-analysis, we did not perform an evaluation for publication bias.
This is the first systematic review and meta-analysis of published observational studies assessing the risk of CAD in patients with DM or PM. Our study demonstrates a significant association between IIM and CAD with an overall 2.24-fold increased risk compared with nonIIM participants. All cohort studies reported a positive association between IIM and CAD, and in fact, the relative risks were fairly consistent among the cohort studies [11–13] while the only case– control study did not reveal an increased risk [14]. Heterogeneity between studies was present in this metaanalysis. We suspect that the difference in study design, population, and case selection was the main source of heterogeneity as two studies were done in hospitalized subjects [12,14], one study was done in the ambulatory setting [13] while another study included both ambulatory and hospitalized subjects [11]. Two studies included only patients with DM while the other two studies included either patients with DM or patients with PM. It should be noted that these four studies were conducted in four different countries (Canada, Sweden, Taiwan, and United States). The role of inflammation in the initiation and development of atherosclerosis is well-recognized [4,5,15]. It is hypothesized that the effect of inflammatory cytokine, oxidative stress, and
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Fig. 2. Forest plot of included studies.
activated-T lymphocytes, macrophages, and dendritic cells resulting in endothelial dysfunction and direct endovascular injury may accelerate the progression of atherosclerosis [16–19]. Furthermore, chronic inflammation related to autoimmune disease has been demonstrated to promote pro-coagulation, impair the anticoagulation pathway, and inhibit the fibrinolytic process resulting in a hypercoagulable state [20,21]. These factors may serve as the fundamental pathophysiology of the development of premature coronary artery disease. In addition, other traditional cardiovascular risk factors, including diabetes, hypertension, and metabolic syndrome, are more prevalent in patients with IIM compared with healthy individuals [22,23] which, again, might be a result of the underlying inflammatory process in conjunction with decreased functional capacity and physical activity secondary to muscle weakness. The effect of corticosteroids, the most commonly used immunosuppressive agent in IIM, on the pathogenesis of atherosclerosis is unclear as epidemiological studies assessing the cardiovascular effect of corticosteroid in patients with inflammatory autoimmune diseases yielded inconsistent results [24–26]. Use of corticosteroids is associated with adverse effects on atherosclerotic risk factors, including diabetes mellitus, hypertension, and dyslipidemia [27]. However, their anti-inflammatory activity might provide a protective effect on the cardiovascular system in patients with chronic inflammatory disorders [28]. Even though the four studies included in this meta-analysis were of high quality, there are some limitations, and thus, the result should be interpreted with caution. First, the statistical heterogeneity is high in this study. Second, all of the included studies were conducted using a medical registry-based database, thus the possibility of coding inaccuracy. The issue of coding inaccuracy is of particular concern for this study as myocardial involvement of IIM might be misinterpreted or miscoded as CAD. Third, this is a meta-analysis of observational studies, and this type of study can only demonstrate an association, not establish cause and effect, so we cannot be certain that IIM itself versus other potential confounders increase the risk of CAD. Furthermore, the higher detection rate of CAD in patients with IIM might be partly due to the fact that they have chronic illness and, thus, are exposed to medical community more frequently.
Conclusion The results of our meta-analysis demonstrate a statistically significant increased CAD risk among patients with IIM. A physician should be aware of this association, and traditional cardiovascular risk factors modification should be part of standard of care in this group of patients. Appendix Database: Ovid MEDLINE 1. exp Dermatomyositis/ 2. dermatomyositis.mp.
3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33.
exp Polymyositis/ polymyositis.mp. exp Myositis/ myositis.mp. or/1-6 exp Coronary Disease/ coronary disease$.mp. exp Coronary Artery Disease/ coronary arter$ disease$.mp. exp Coronary Stenosis/ coronary stenos$.mp. coronary atheroscleros$.mp. coronary arterioscleros$.mp. (coronary adj3 disease$).mp. (coronary adj3 syndrome$).mp. cad.mp. exp Myocardial Infarction/ myocardial infarct$.mp. exp Coronary Thrombosis/ coronary thrombos$.mp. exp Angina, Unstable/ unstable angina.mp (unstable adj3 angina).mp. exp Angina, Stable/ stable angina.mp. exp Angina Pectoris/ angina pectoris.mp. acs.mp. ami.mp. or/8-31 7 and 32 Database: EMBASE
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
exp Dermatomyositis/ dermatomyositis.mp. exp Polymyositis/ polymyositis.mp. exp Myositis/ myositis.mp. or/1-6 exp Heart Disease/ heart disease$.mp. exp Coronary Artery Disease/ coronary arter$ disease$.mp. exp Coronary Artery Atherosclerosis/ coronary arter$ atheroscleros$.mp. exp Coronary Artery Obstruction/ coronary arter$ obstruction$.mp. (coronary arter$ adj5 stenos$).mp. coronary atheroscleros$.mp. coronary arterioscleros$.mp. (coronary adj3 disease$).mp. (coronary adj3 syndrome$).mp.
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21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34.
cad.mp. exp Heart Infarction/ heart infarction.mp exp Coronary Artery Thrombosis/ coronary thrombosis.mp. exp Angina Pectoris/ angina pectoris.mp. myocardial infarct$.mp. acs.mp. ami.mp. acute angina.mp. (unstable adj3 angina).mp. or/8-32 7 and 33
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