Rheumatology
Rheumatol Int DOI 10.1007/s00296-014-3166-0
INTERNATIONAL
ORIGINAL ARTICLE - OBSERVATIONAL RESEARCH
Risk of ischemic stroke in patients with polymyositis and dermatomyositis: a systematic review and meta‑analysis Patompong Ungprasert · Wisit Cheungpasitporn · Karn Wijarnpreecha · Wasin Ahuja · Praveen Ratanasrimetha · Charat Thongprayoon
Received: 21 July 2014 / Accepted: 24 October 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Several chronic inflammatory disorders, such as rheumatoid arthritis and systemic lupus erythematosus, have been demonstrated to increase ischemic stroke risk, but the data on polymyositis (PM) and dermatomyositis (DM) remain unclear. We conducted a systematic review and meta-analysis of observational studies that reported odds ratio, relative risk, hazard ratio or standardized incidence ratio comparing ischemic risk in patients with PM/DM versus non-PM/DM participants. Pooled risk ratio and 95 % confidence intervals were calculated using a random-effect, generic inverse variance method of DerSimonian and Laird. Three cohort studies were identified
Electronic supplementary material The online version of this article (doi:10.1007/s00296-014-3166-0) contains supplementary material, which is available to authorized users. P. Ungprasert (*) Division of Rheumatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA e-mail: [email protected] W. Cheungpasitporn · C. Thongprayoon Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA K. Wijarnpreecha Cardiac Electrophysiology Unit, Department of Physiology, and Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand W. Ahuja Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand P. Ratanasrimetha Department of Internal Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
and included in our data analysis. The pooled risk ratio of ischemic stroke in patients with PM/DM was 1.61 (95 % CI 1.28–2.02). The statistical heterogeneity of this metaanalysis was insignificant with an I2 of 0 %. Our study demonstrated a statistically significant increased ischemic stroke risk among patients with PM/DM. Keywords Meta-analysis · Ischemic stroke · Idiopathic inflammatory myositis · Dermatomyositis · Polymyositis
Introduction Chronic inflammation is well recognized as a cause of premature atherosclerosis as inflammatory cytokine, reactive oxygen species and activated inflammatory cells have been demonstrated to cause endothelial dysfunction and endovascular injury, resulting in an acceleration of the progression of atherosclerosis [1–3]. Moreover, several chronic inflammatory disorders, such as rheumatoid arthritis and systemic lupus erythematosus, and idiopathic inflammatory myositis (IIM) have been shown to increase coronary artery disease and cerebrovascular disease risk in large epidemiological studies [4–6]. Polymyositis (PM) and dermatomyositis (DM), two major subtypes of IIM, are other relatively uncommon chronic inflammatory disorders characterized by weakness of limb-girdle muscle [7]. Accelerated atherosclerosis is also documented in patients with PM/DM. In fact, an increased risk of clinically significant CAD among these patients is well demonstrated in a recent meta-analysis of epidemiological studies [8]. Moreover, vasculopathy is one of the hallmarks of the pathogenesis of IIM, particularly in patients with DM. Thus, patients with PM/DM might be a higher risk of developing ischemic stroke. However, the
13
epidemiological data on this are unclear as the results from previous studies are inconclusive. Thus, to further investigate this association, we conducted a systematic review and meta-analysis of observational studies that compared the risk of ischemic stroke in patients with PM/DM versus non-PM/DM participants.
Methods Search strategy Two investigators (P.U. and K.W.) independently searched published studies indexed in MEDLINE and EMBASE from inception to April 2014 using the terms IIM combined with the terms for cerebrovascular disease. Detailed search strategy is provided in Supplemental data 1. A manual search of references of selected retrieved articles was also performed. Conference abstract and unpublished studies were not included.
Rheumatol Int
adjusted effect estimates with 95 % CI. Three investigators (P.U., K.W. and W.A.) independently performed this data extraction. Statistical analysis Review Manager 5.2 software from the Cochrane Collaboration was used for the data analysis. Point estimates and standard errors were extracted from individual studies and were combined by the generic inverse variance method of DerSimonian and Laird [10]. In light of the high likelihood of between study variance, we used a random-effect model rather than a fixed-effect model. Cochran’s Q test was used to assess the statistical heterogeneity. This statistic is 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, 26–50 % low heterogeneity, 51–75 % moderate heterogeneity and >75 % high heterogeneity [11].
Inclusion criteria
Results
The inclusion criteria were as follows: (1) Observational studies (case–control or cohort studies) published as original studies to evaluate the association between PM/DM and ischemic stroke, (2) odds ratios (OR’s), relative risk (RR’s) or hazard ratio (HR’s) or standardized incidence ratio (SIR’s) with 95 % confidence intervals (CI’s) were provided (3) non-PM/DM participants were used as the reference group cohort studies, and participants without ischemic stroke were used as the reference group in case– control studies. Study eligibility was independently determined by the two investigators noted above. Different decisions were resolved by consensus with the senior investigator. The quality of each study was, again, independently evaluated by each investigator using Newcastle–Ottawa quality assessment scale. Using this scale, each study is assessed on eight items, which are categorized into three groups including (1) the selection of the study groups (2) the comparability of the groups and (3) the ascertainment of the exposure or outcome of interest for case–control or cohort studies, respectively [9].
Our search strategy yielded 116 potentially relevant articles. A total of 105 articles were excluded based on title
Poten ally relevant ar cles iden fied from search of MEDLINE and EMBASE and screened for retrieval (n=116).
Title and abstract reviewed for screening.
105 ar cles were excluded based on tle and abstract for clearly not fulfilling inclusion criteria on basis of type of ar cle, study design, popula on or outcome of interest. 11 poten ally relevant ar cles included for fulllength ar cle review.
7 ar cles were excluded because they were review ar cle. 1 ar cle was excluded because it reported only subclinical atherosclero c diseases.
Data extraction A standardized data collection form was used to extract the following information: last name of the first author, title of the article, study design, year of publication, country of origin, year of publication, sample size, characteristics of included participants, method used to diagnose PM/DM and ischemic stroke, mean duration of follow-up and
13
3 ar cles were included in the meta-analysis.
Fig. 1 Outline of the search methodology
50.0 1,071 NA NA
70.0 607 NA 4
Outcome: 2 stars
Outcome: 3 stars
Outcome: 2 stars
None
Selection: 4 stars Comparability: 1 star
53.2
Until the first occurrence of ischemic stroke or 2 years after the index date
Taiwan Prospective cohort 2013 Ambulatory patients who were diagnosed with DM between January 1, 2001, and December 31, 2001. Cases were identified from the National Health Insurance claim database (which covers 97 % of entire population) Diagnostic code from the registry for at least two visits Sex and age-matched subjects randomly selected from same database
Lai et al. [14]
58.9 907 4,535 2 Age, sex, HTN, diabetes, hyperlipidemia, coroAge, socioeconomic status, region of resinary heart disease, other heart diseases dence, obesity, HTN, diabetes, atrial fibrillation, heart failure, coronary heart disease Selection: 4 stars Selection: 3 stars Comparability: 1 star Comparability: 1 star
62.4
Using Swedish age- and sex-specific general population incidence rates for ischemic stroke as the comparator for the calculation of standardized incidence ratio Diagnostic code from the registry Until hospitalization for ischemic or hemorrhagic stroke, death, emigration from the system or December 31, 2008 NA
Sweden Retrospective cohort 2012 All hospitalized patient with a diagnosis of DM or PM (without previous or co-existing ischemic stroke) between 1987 and 2008. Cases were identified from the Swedish national registry Diagnostic code from the registry
Using Canadian age- and sex-specific general population incidence rates for ischemic stroke as the comparator for the calculation of standardized incidence ratio Diagnostic code from the registry Until the first of outcome event, death, or December 31, 2003
Canada Retrospective cohort 2009 Hospitalized or non-hospitalized patients who were diagnosed with DM or PM (without previous or co-existing ischemic stroke) between 1994 and 2003. Cases were identified by from the Quebec provincial database Diagnostic code from the registry
Zoller et al. [13]
DM indicates dermatomyositis, PM polymyositis, IIM idiopathic inflammatory myopathy, NA not available, HTN hypertension
Quality assessment (Newcastle-Ottawa scale)
Average range of follow-up, Y Confounder adjusted
Mean age, Y Female, % Number of cases Number of control
Diagnosis of ischemic stroke Follow-up
Controls
Diagnosis of PM/DM
Country Study design Year Cases
Tisseverasinghe et al. [12]
Table 1 Main characteristics of studies included in the meta-analysis
Rheumatol Int
13
Rheumatol Int
Fig. 2 Forest plot of the included studies
and abstract for clearly not fulfilling inclusion criteria on basis of type of article, study design, population or outcome of interest. Eleven articles underwent full-length article review. Seven of them were excluded, because they were review articles, while a study was excluded, because it reported only subclinical atherosclerotic diseases. Three studies (two retrospective cohort studies and a prospective cohort study) with 2,585 patients with PM/DM met our inclusion criteria and were included in the data analysis [12–14]. Figure 1 summarizes our search methodology and selection process. Table 1 describes the detailed characteristics and quality assessment of the three included studies. The pooled risk ratio of ischemic stroke of subjects with PM/DM versus control subjects was 1.61 (95 % CI, 1.28– 2.02). The statistical heterogeneity was insignificant with an I2 of 0 %. Figure 2 demonstrates the forest plot of the included studies. Evaluation for publication bias Since only three studies were included in this meta-analysis, the evaluation for publication bias was not performed.
Discussions Our meta-analysis demonstrated a significant association between IIM and ischemic stroke with an overall 1.61-folds (95 % CI 1.28–2.02) increased risk compared with nonPM/DM participants. The increased risk was consistently observed across the studies though did not reach a statistical significance in a study [12]. The magnitude of risk was similar to ischemic stroke risk observed in other chronic autoimmune disorders including systemic lupus erythematosus, rheumatoid arthritis and ankylosing spondylitis (RR’s of 2.01, 1.32 and 1.93, respectively) [15–17]. Why patients with PM/DM have an increased risk of cerebrovascular events are not well understood. The widely accepted hypothesis is related endothelial dysfunction, which is pivotal to the pathogenesis of atherosclerosis, secondary to the chronic inflammation. The role of Inflammation in the initiation and progression of atherosclerosis is well recognized as the detrimental effects of inflammatory cytokines, free radical species and activated inflammatory cells on endothelial function have been extensively
13
documented [1–3, 18]. Moreover, chronic inflammation has been demonstrated to impair the anticoagulation pathway, promote the coagulation cascade and inhibit the fibrinolytic process resulting in a thrombophilic state [19, 20]. These factors may well serve as the fundamental pathophysiology of the development of premature atherosclerosis resulting in cerebrovascular disease. In addition, other traditional cardiovascular risk factors, such as diabetes, hypertension and dyslipidemia are more prevalent in patients with PM/DM compared with general population. This increased prevalence is thought to be a result of, again, the underlying chronic inflammation in conjunction with the use of corticosteroid and decreased level of physical activity secondary to muscle weakness [21, 22]. Vasculopathy is another potential cause of the increased risk as it is a hallmark of the pathogenesis of the disease, particularly in patients with DM [7]. The patency of cerebral vasculature could potentially be compromised by this vasculopathy and, thus, renders patients high risk of developing ischemic stroke. The effect of corticosteroids, the most commonly used immunosuppressive drug in PM/DM, on the pathogenesis of atherosclerosis is unclear as epidemiological studies evaluating the cardiovascular effect of corticosteroid in patients with chronic inflammatory diseases yielded inconsistent results [23–25]. Use of corticosteroids is associated with an increased incidence of traditional atherosclerotic risk factors, as mentioned before. However, their antiinflammatory activity might provide a protective effect on the cardiovascular system in patients with chronic inflammatory disorders [26]. Even though the three included studies were of high quality and the statistical heterogeneity was very low in this meta-analysis, there are some limitations and, thus, the result should be interpreted with caution. First, all of the included studies were conducted using medical registry-based database, so coding inaccuracies may have been presented. Second, this is a meta-analysis of observational studies which, at the best, can demonstrate an association but cannot establish cause-and-effect. Therefore, we cannot be certain that PM/DM itself versus other potential confounders was the cause of the increased ischemic stroke risk. Furthermore, these studies were at risk of detection bias as the patients in their cohorts, because of their myopathy, were exposed to more medical examinations
Rheumatol Int
and investigations and, thus, more likelihood of stroke detection. In conclusion, our meta-analysis demonstrated a statistically significant increased ischemic stroke risk among patients with PM/DM with 61 % excess risk. Physician should be aware of this association and an appropriate intervention to control other traditional cardiovascular risk factors should be emphasized in these patients. Conflict of interest We do not have any financial or non-financial potential conflicts of interest.
References 1. Frostegard J (2005) Atherosclerosis in patients with autoimmune disorders. Arterioscler Thromb Vasc Biol 25:1776–1785 2. Libby P (2002) Inflammation in atherosclerosis. Nature 420:868–874 3. Montecucco F, Mach F (2009) Common inflammatory mediators orchestrate pathophysiological processes in rheumatoid arthritis and atherosclerosis. Rheumatology (Oxford) 48:11–22 4. Maradit-Kremers H, Nicola PJ, Crowson CS, Ballman KV, Gabreil SE (2005) Cardiovascular death in rheumatoid arthritis: a population-based study. Arthritis Rheum 52:722–732 5. Bessant R, Hingorani A, Patel L et al (2004) Risk of coronary heart disease and stroke in a large British cohort of patients with systemic lupus erythematosus. Rheumatology (Oxford) 43:924–929 6. Timlin H, Petri M (2013) Transient ischemic attack and stroke is systemic lupus erythematosus. Lupus 22:1251–1258 7. Iaccarino L, Ghirardello A, Bettio S et al (2014) The clinical features, diagnosis and classification of dermatomyositis. J Autoimmun 48–49:122–127 8. Ungprasert P, Suksaranjit P, Spanuchart I et al (2014) Risk of coronary artery disease in patients with idiopathic inflammatory myopathies: a systematic review and meta-analysis of observational studies. Semin Arthritis Rheum 44:63–67 9. Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25:603–605 10. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trial 7:177–188 11. Higgins JP, Thompson SG, Deeks JJ et al (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560
12. Tisseverasinghe A, Bernatsky S, Pineau CA (2009) Arterial events in persons with dermatomyositis and polymyositis. J Rheumatol 36:1943–1946 13. Zoller B, Li X, Sundquist J, Sunquist K (2012) Risk of subsequent ischemic and hemorrhagic stroke in patients hospitalized for immune-mediated diseases: a nationwide follow-up study from Sweden. BMC Neurol 12:41 14. Lai YT, Dai YS, Yen MF et al (2013) Dermatomyositis is associated with an increased risk of cardiovascular and cerebrovascular events: a Taiwanese population-based longitudinal follow up study. Br J Dermatol 168:1054–1059 15. Krishnan E (2005) Stroke subtypes among young patients with systemic erythematosus. Am J Med 118:1415.e1–1415.e7 16. Lindhardsen J, Ahlehoff O, Gislason GH et al (2012) Risk of atrial fibrillation and stroke in rheumatoid arthritis: Danish nationwide cohort study. BMJ 344:e1257 17. Lin CW, Huang YP, Chiu YH et al (2014) Increased risk of ischemic stroke in young patients with ankylosing spondylitis: a population based longitudinal follow-up study. PLoS One 9:e94027 18. Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352:1685–1695 19. Xu J, Lupu F, Esmon CT (2010) Inflammation, innate immunity and blood coagulation. Hamostaseologie 30(5–6):8–9 20. Esmon CT (2005) The interactions between inflammation and coagulation. Br J Haematol 131:417–430 21. de Moraes MT, de Souza FH, de Barros TB et al (2013) Analysis of metabolic syndrome in adult dermatomyositis with a focus on cardiovascular disease. Arthritis Care Res (Hoboken) 65:793–799 22. Limaye VS, Lester S, Blumbergs P et al (2010) Idiopathic inflammatory myositis is associated with a high incidence of hypertension and diabetes mellitus. Int J Rheum Dis 13:132–137 23. Wei L, MacDonald TM, Walker BR (2004) Taking glucocorticoid by prescription is associated with subsequent cardiovascular disease. Ann Intern Med 141:764–770 24. Maradit-Kremers H, Reinalda MS et al (2007) Glucocorticoids and cardiovascular and cerebrovascular events in polymyalgia rheumatic. Arthritis Rheum 57:279–286 25. Toms TE, Panoulas VF, Douglas KM et al (2008) Lack of association between glucocorticoid use and presence of the metabolic syndrome in patients with rheumatoid arthritis: a cross-sectional study. Arthritis Res Ther 10:R145 26. Voisard R, Seitzer U, Baur R, Dartsch PC, Osterhues H et al (1994) Corticosteroid agents inhibit proliferation of smooth muscle cells from human atherosclerotic arteries in vitro. Int J Cardiol 43:257–267
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Rheumatol Int DOI 10.1007/s00296-014-3166-0
INTERNATIONAL
ORIGINAL ARTICLE - OBSERVATIONAL RESEARCH
Risk of ischemic stroke in patients with polymyositis and dermatomyositis: a systematic review and meta‑analysis Patompong Ungprasert · Wisit Cheungpasitporn · Karn Wijarnpreecha · Wasin Ahuja · Praveen Ratanasrimetha · Charat Thongprayoon
Received: 21 July 2014 / Accepted: 24 October 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Several chronic inflammatory disorders, such as rheumatoid arthritis and systemic lupus erythematosus, have been demonstrated to increase ischemic stroke risk, but the data on polymyositis (PM) and dermatomyositis (DM) remain unclear. We conducted a systematic review and meta-analysis of observational studies that reported odds ratio, relative risk, hazard ratio or standardized incidence ratio comparing ischemic risk in patients with PM/DM versus non-PM/DM participants. Pooled risk ratio and 95 % confidence intervals were calculated using a random-effect, generic inverse variance method of DerSimonian and Laird. Three cohort studies were identified
Electronic supplementary material The online version of this article (doi:10.1007/s00296-014-3166-0) contains supplementary material, which is available to authorized users. P. Ungprasert (*) Division of Rheumatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA e-mail: [email protected] W. Cheungpasitporn · C. Thongprayoon Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA K. Wijarnpreecha Cardiac Electrophysiology Unit, Department of Physiology, and Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand W. Ahuja Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand P. Ratanasrimetha Department of Internal Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
and included in our data analysis. The pooled risk ratio of ischemic stroke in patients with PM/DM was 1.61 (95 % CI 1.28–2.02). The statistical heterogeneity of this metaanalysis was insignificant with an I2 of 0 %. Our study demonstrated a statistically significant increased ischemic stroke risk among patients with PM/DM. Keywords Meta-analysis · Ischemic stroke · Idiopathic inflammatory myositis · Dermatomyositis · Polymyositis
Introduction Chronic inflammation is well recognized as a cause of premature atherosclerosis as inflammatory cytokine, reactive oxygen species and activated inflammatory cells have been demonstrated to cause endothelial dysfunction and endovascular injury, resulting in an acceleration of the progression of atherosclerosis [1–3]. Moreover, several chronic inflammatory disorders, such as rheumatoid arthritis and systemic lupus erythematosus, and idiopathic inflammatory myositis (IIM) have been shown to increase coronary artery disease and cerebrovascular disease risk in large epidemiological studies [4–6]. Polymyositis (PM) and dermatomyositis (DM), two major subtypes of IIM, are other relatively uncommon chronic inflammatory disorders characterized by weakness of limb-girdle muscle [7]. Accelerated atherosclerosis is also documented in patients with PM/DM. In fact, an increased risk of clinically significant CAD among these patients is well demonstrated in a recent meta-analysis of epidemiological studies [8]. Moreover, vasculopathy is one of the hallmarks of the pathogenesis of IIM, particularly in patients with DM. Thus, patients with PM/DM might be a higher risk of developing ischemic stroke. However, the
13
epidemiological data on this are unclear as the results from previous studies are inconclusive. Thus, to further investigate this association, we conducted a systematic review and meta-analysis of observational studies that compared the risk of ischemic stroke in patients with PM/DM versus non-PM/DM participants.
Methods Search strategy Two investigators (P.U. and K.W.) independently searched published studies indexed in MEDLINE and EMBASE from inception to April 2014 using the terms IIM combined with the terms for cerebrovascular disease. Detailed search strategy is provided in Supplemental data 1. A manual search of references of selected retrieved articles was also performed. Conference abstract and unpublished studies were not included.
Rheumatol Int
adjusted effect estimates with 95 % CI. Three investigators (P.U., K.W. and W.A.) independently performed this data extraction. Statistical analysis Review Manager 5.2 software from the Cochrane Collaboration was used for the data analysis. Point estimates and standard errors were extracted from individual studies and were combined by the generic inverse variance method of DerSimonian and Laird [10]. In light of the high likelihood of between study variance, we used a random-effect model rather than a fixed-effect model. Cochran’s Q test was used to assess the statistical heterogeneity. This statistic is 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, 26–50 % low heterogeneity, 51–75 % moderate heterogeneity and >75 % high heterogeneity [11].
Inclusion criteria
Results
The inclusion criteria were as follows: (1) Observational studies (case–control or cohort studies) published as original studies to evaluate the association between PM/DM and ischemic stroke, (2) odds ratios (OR’s), relative risk (RR’s) or hazard ratio (HR’s) or standardized incidence ratio (SIR’s) with 95 % confidence intervals (CI’s) were provided (3) non-PM/DM participants were used as the reference group cohort studies, and participants without ischemic stroke were used as the reference group in case– control studies. Study eligibility was independently determined by the two investigators noted above. Different decisions were resolved by consensus with the senior investigator. The quality of each study was, again, independently evaluated by each investigator using Newcastle–Ottawa quality assessment scale. Using this scale, each study is assessed on eight items, which are categorized into three groups including (1) the selection of the study groups (2) the comparability of the groups and (3) the ascertainment of the exposure or outcome of interest for case–control or cohort studies, respectively [9].
Our search strategy yielded 116 potentially relevant articles. A total of 105 articles were excluded based on title
Poten ally relevant ar cles iden fied from search of MEDLINE and EMBASE and screened for retrieval (n=116).
Title and abstract reviewed for screening.
105 ar cles were excluded based on tle and abstract for clearly not fulfilling inclusion criteria on basis of type of ar cle, study design, popula on or outcome of interest. 11 poten ally relevant ar cles included for fulllength ar cle review.
7 ar cles were excluded because they were review ar cle. 1 ar cle was excluded because it reported only subclinical atherosclero c diseases.
Data extraction A standardized data collection form was used to extract the following information: last name of the first author, title of the article, study design, year of publication, country of origin, year of publication, sample size, characteristics of included participants, method used to diagnose PM/DM and ischemic stroke, mean duration of follow-up and
13
3 ar cles were included in the meta-analysis.
Fig. 1 Outline of the search methodology
50.0 1,071 NA NA
70.0 607 NA 4
Outcome: 2 stars
Outcome: 3 stars
Outcome: 2 stars
None
Selection: 4 stars Comparability: 1 star
53.2
Until the first occurrence of ischemic stroke or 2 years after the index date
Taiwan Prospective cohort 2013 Ambulatory patients who were diagnosed with DM between January 1, 2001, and December 31, 2001. Cases were identified from the National Health Insurance claim database (which covers 97 % of entire population) Diagnostic code from the registry for at least two visits Sex and age-matched subjects randomly selected from same database
Lai et al. [14]
58.9 907 4,535 2 Age, sex, HTN, diabetes, hyperlipidemia, coroAge, socioeconomic status, region of resinary heart disease, other heart diseases dence, obesity, HTN, diabetes, atrial fibrillation, heart failure, coronary heart disease Selection: 4 stars Selection: 3 stars Comparability: 1 star Comparability: 1 star
62.4
Using Swedish age- and sex-specific general population incidence rates for ischemic stroke as the comparator for the calculation of standardized incidence ratio Diagnostic code from the registry Until hospitalization for ischemic or hemorrhagic stroke, death, emigration from the system or December 31, 2008 NA
Sweden Retrospective cohort 2012 All hospitalized patient with a diagnosis of DM or PM (without previous or co-existing ischemic stroke) between 1987 and 2008. Cases were identified from the Swedish national registry Diagnostic code from the registry
Using Canadian age- and sex-specific general population incidence rates for ischemic stroke as the comparator for the calculation of standardized incidence ratio Diagnostic code from the registry Until the first of outcome event, death, or December 31, 2003
Canada Retrospective cohort 2009 Hospitalized or non-hospitalized patients who were diagnosed with DM or PM (without previous or co-existing ischemic stroke) between 1994 and 2003. Cases were identified by from the Quebec provincial database Diagnostic code from the registry
Zoller et al. [13]
DM indicates dermatomyositis, PM polymyositis, IIM idiopathic inflammatory myopathy, NA not available, HTN hypertension
Quality assessment (Newcastle-Ottawa scale)
Average range of follow-up, Y Confounder adjusted
Mean age, Y Female, % Number of cases Number of control
Diagnosis of ischemic stroke Follow-up
Controls
Diagnosis of PM/DM
Country Study design Year Cases
Tisseverasinghe et al. [12]
Table 1 Main characteristics of studies included in the meta-analysis
Rheumatol Int
13
Rheumatol Int
Fig. 2 Forest plot of the included studies
and abstract for clearly not fulfilling inclusion criteria on basis of type of article, study design, population or outcome of interest. Eleven articles underwent full-length article review. Seven of them were excluded, because they were review articles, while a study was excluded, because it reported only subclinical atherosclerotic diseases. Three studies (two retrospective cohort studies and a prospective cohort study) with 2,585 patients with PM/DM met our inclusion criteria and were included in the data analysis [12–14]. Figure 1 summarizes our search methodology and selection process. Table 1 describes the detailed characteristics and quality assessment of the three included studies. The pooled risk ratio of ischemic stroke of subjects with PM/DM versus control subjects was 1.61 (95 % CI, 1.28– 2.02). The statistical heterogeneity was insignificant with an I2 of 0 %. Figure 2 demonstrates the forest plot of the included studies. Evaluation for publication bias Since only three studies were included in this meta-analysis, the evaluation for publication bias was not performed.
Discussions Our meta-analysis demonstrated a significant association between IIM and ischemic stroke with an overall 1.61-folds (95 % CI 1.28–2.02) increased risk compared with nonPM/DM participants. The increased risk was consistently observed across the studies though did not reach a statistical significance in a study [12]. The magnitude of risk was similar to ischemic stroke risk observed in other chronic autoimmune disorders including systemic lupus erythematosus, rheumatoid arthritis and ankylosing spondylitis (RR’s of 2.01, 1.32 and 1.93, respectively) [15–17]. Why patients with PM/DM have an increased risk of cerebrovascular events are not well understood. The widely accepted hypothesis is related endothelial dysfunction, which is pivotal to the pathogenesis of atherosclerosis, secondary to the chronic inflammation. The role of Inflammation in the initiation and progression of atherosclerosis is well recognized as the detrimental effects of inflammatory cytokines, free radical species and activated inflammatory cells on endothelial function have been extensively
13
documented [1–3, 18]. Moreover, chronic inflammation has been demonstrated to impair the anticoagulation pathway, promote the coagulation cascade and inhibit the fibrinolytic process resulting in a thrombophilic state [19, 20]. These factors may well serve as the fundamental pathophysiology of the development of premature atherosclerosis resulting in cerebrovascular disease. In addition, other traditional cardiovascular risk factors, such as diabetes, hypertension and dyslipidemia are more prevalent in patients with PM/DM compared with general population. This increased prevalence is thought to be a result of, again, the underlying chronic inflammation in conjunction with the use of corticosteroid and decreased level of physical activity secondary to muscle weakness [21, 22]. Vasculopathy is another potential cause of the increased risk as it is a hallmark of the pathogenesis of the disease, particularly in patients with DM [7]. The patency of cerebral vasculature could potentially be compromised by this vasculopathy and, thus, renders patients high risk of developing ischemic stroke. The effect of corticosteroids, the most commonly used immunosuppressive drug in PM/DM, on the pathogenesis of atherosclerosis is unclear as epidemiological studies evaluating the cardiovascular effect of corticosteroid in patients with chronic inflammatory diseases yielded inconsistent results [23–25]. Use of corticosteroids is associated with an increased incidence of traditional atherosclerotic risk factors, as mentioned before. However, their antiinflammatory activity might provide a protective effect on the cardiovascular system in patients with chronic inflammatory disorders [26]. Even though the three included studies were of high quality and the statistical heterogeneity was very low in this meta-analysis, there are some limitations and, thus, the result should be interpreted with caution. First, all of the included studies were conducted using medical registry-based database, so coding inaccuracies may have been presented. Second, this is a meta-analysis of observational studies which, at the best, can demonstrate an association but cannot establish cause-and-effect. Therefore, we cannot be certain that PM/DM itself versus other potential confounders was the cause of the increased ischemic stroke risk. Furthermore, these studies were at risk of detection bias as the patients in their cohorts, because of their myopathy, were exposed to more medical examinations
Rheumatol Int
and investigations and, thus, more likelihood of stroke detection. In conclusion, our meta-analysis demonstrated a statistically significant increased ischemic stroke risk among patients with PM/DM with 61 % excess risk. Physician should be aware of this association and an appropriate intervention to control other traditional cardiovascular risk factors should be emphasized in these patients. Conflict of interest We do not have any financial or non-financial potential conflicts of interest.
References 1. Frostegard J (2005) Atherosclerosis in patients with autoimmune disorders. Arterioscler Thromb Vasc Biol 25:1776–1785 2. Libby P (2002) Inflammation in atherosclerosis. Nature 420:868–874 3. Montecucco F, Mach F (2009) Common inflammatory mediators orchestrate pathophysiological processes in rheumatoid arthritis and atherosclerosis. Rheumatology (Oxford) 48:11–22 4. Maradit-Kremers H, Nicola PJ, Crowson CS, Ballman KV, Gabreil SE (2005) Cardiovascular death in rheumatoid arthritis: a population-based study. Arthritis Rheum 52:722–732 5. Bessant R, Hingorani A, Patel L et al (2004) Risk of coronary heart disease and stroke in a large British cohort of patients with systemic lupus erythematosus. Rheumatology (Oxford) 43:924–929 6. Timlin H, Petri M (2013) Transient ischemic attack and stroke is systemic lupus erythematosus. Lupus 22:1251–1258 7. Iaccarino L, Ghirardello A, Bettio S et al (2014) The clinical features, diagnosis and classification of dermatomyositis. J Autoimmun 48–49:122–127 8. Ungprasert P, Suksaranjit P, Spanuchart I et al (2014) Risk of coronary artery disease in patients with idiopathic inflammatory myopathies: a systematic review and meta-analysis of observational studies. Semin Arthritis Rheum 44:63–67 9. Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25:603–605 10. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trial 7:177–188 11. Higgins JP, Thompson SG, Deeks JJ et al (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560
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