Just Accepted by Modern Rheumatology
Risk of Ischemic Stroke in Patients with Systemic Sclerosis: A Systematic Review and Meta-analysis Patompong Ungprasert, Anawin Sanguankeo, Sikarin Upala Doi: 10.3109/14397595.2015.1056931 Abstract
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Background: Several chronic inflammatory disorders, such as rheumatoid arthritis and idiopathic inflammatory myositis, have been shown to increase risk of ischemic stroke but the data on systemic sclerosis (SSc) remains unclear. Methods: We conducted a systematic review and meta-analysis of observational studies that reported odds ratio, relative risk, hazard ratio or standardized incidence ratio comparing risk of ischemic stroke in patients with SSc versus non-SSc participants. Pooled risk ratio and 95% confidence intervals were calculated using a randomeffect, generic inverse variance method of DerSimonian and Laird. Results: Four retrospective cohort studies were identified and included in our data analysis. We found a statistically significant elevated ischemic stroke risk in patients with SSc with a pooled risk ratio of 1.68 (95% CI, 1.26 to 2.24). The statistical heterogeneity was moderate with an I2 of 69%. Conclusions: Our study demonstrated a statistically significant increased ischemic stroke risk among patients with SSc.
© 2015 Informa UK, Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
IMOR_A_1056931_Coverpage.indd 1
29-05-2015 15:34:22
Original Article
Risk of Ischemic Stroke in Patients with Systemic Sclerosis: A Systematic Review and Meta-analysis
Patompong Ungprasert1,2, Anawin Sanguankeo3, Sikarin Upala3 1
Division of rheumatology, Mayo Clinic, Rochester, MN, USA, 2Department of Internal
Medicine, Faculty of medicine Siriraj hospital, Mahidol University, Bangkok, Thailand, 3
Department of Preventive and Social Medicine, Faculty of medicine Siriraj hospital,
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Mahidol University, Bangkok, Thailand
Correspondence: Patompong Ungprasert, Division of rheumatology, Mayo Clinic, Rochester, MN, USA. E-mail: [email protected] Abstract Background: Several chronic inflammatory disorders, such as rheumatoid arthritis and idiopathic inflammatory myositis, have been shown to increase risk of ischemic stroke but the data on systemic sclerosis (SSc) remains unclear. Methods: We conducted a systematic review and meta-analysis of observational studies that reported odds ratio, relative risk, hazard ratio or standardized incidence ratio comparing risk of ischemic stroke in patients with SSc versus non-SSc participants. Pooled risk ratio and 95% confidence intervals were calculated using a random-effect, generic inverse variance method of DerSimonian and Laird. Results: Four retrospective cohort studies were identified and included in our data analysis. We found a statistically significant elevated ischemic stroke risk in patients with SSc with a pooled risk ratio of 1.68 (95% CI, 1.26 to 2.24). The statistical heterogeneity was moderate with an I2 of 69%. Conclusions: Our study demonstrated a statistically significant increased ischemic stroke risk among patients with SSc.
Keywords: Meta-analysis, Stroke, Systemic Sclerosis, Epidemiology, Inflammation
MORH-D-15-00166 Received: Mar-09-15; Accepted: May-26-15
1
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Introduction Over the past few decades, several large epidemiological studies have demonstrated an increased incidence of cardiovascular disease among patient with chronic inflammatory disorders, such as rheumatoid arthritis, idiopathic inflammatory myositis, vasculitis, systemic lupus erythematosus and autoimmune liver diseases [1-6]. Premature atherosclerosis from chronic inflammation appears to be the cornerstone of these excessive cardiovascular complications [7-9]. Systemic sclerosis (SSc) is another autoimmune connective disease characterized by diffuse fibrosis of the skin and internal organs. Its incidence varies from 0.6 per million person-year to 122 per million person-year [10]. SSc is subcategorized into diffuse and limited form, based on the extent of skin involvement. The pathogenesis of this disorder is complex and not well-understood. Microvascular abnormality is one of the hallmarks of its pathology which is linked to the clinical presentations of Raynaud’s phenomenon, periungual capillary changes, gastric antral vascular ectasia and scleroderma renal sclerosis [11]. Though not originally regarded as a clinical feature of SSc, macrovascular complication has been increasingly recognized in this group of patients as a possible link between coronary artery disease (CAD) and this autoimmune disorder has been suggested in several case reports [12, 13]. Subsequent epidemiological studies and a meta-analysis have confirmed this association with an overall 82% excess risk compared with sex and agedmatch controls [14-16]. Ischemic stroke is another major atherosclerotic macrovascular disease that shares a similar pathogenesis to CAD. Patients with SSc might be at an increased risk of ischemic stroke as well. Nonetheless, the data remains inconclusive as previous epidemiological studies yielded inconsistent results [17-19]. Thus, to further investigate this possible association, we conducted a systematic review and meta-analysis of observational studies that compared the ischemic stroke risk in patients with SSc versus non-SSc participants. Methods Search strategy Two investigators (P.U. and A.S.) independently searched published studies indexed in MEDLINE and EMBASE from inception to February 2015 using the terms for systemic sclerosis combined with the terms for ischemic stroke. Detailed search strategy is available in Supplementary data. References of selected retrieved articles were also manually searched. Inclusion criteria The inclusion criteria were as follows: (1) Population-based, case-control or cohort studies published as original study or abstract to evaluate the risk of incident ischemic stroke in patients with SSc, (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) or enough data to calculated this ratios were provided (3) participants without SSc were used as the reference group in cohort study and participants without ischemic stroke were used as the reference group in case-control study. Study eligibility was independently determined by the two investigators noted above. Any differences in decision were resolved by consensus with the third investigator. The quality of each study was also independently assessed by each investigator using Newcastle-Ottawa quality assessment scale [20]. 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, number of case and control, control selection, characteristics of included participants, method used to diagnose SSc and ischemic stroke, average duration of follow up, confounders and adjusted effect estimates with 95% CI. This data extraction was performed by all three investigators. Any discrepancy in data extraction was also resolved by consensus. Statistical analysis Review Manager (RevMan) 5.3 software from the Cochrane Collaboration was used for the statistical analysis. Point estimates and corresponding standard errors were extracted from individual studies and were combined by the generic inverse variance method of DerSimonian and Laird [21]. We used a random-effect model rather than a fixed-effect
2
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model, in light of the high likelihood of between study variance. Cochran’s Q test was used to determine the study’s statistical heterogeneity. This statistic is complemented with the I2 statistic, which quantifies the proportion of total variation across studies that is due to true heterogeneity rather than chance. A value of I2 of 0% to 25% represents insignificant heterogeneity, 26% to 50% low heterogeneity, 51% to 75% moderate heterogeneity, and > 75% high heterogeneity [22]. Results Our search strategy yielded 209 potentially relevant articles (78 from Medline and 131 articles from EMBASE). After exclusion of 75 duplicated articles, 134 articles underwent title and abstract review. 124 articles were excluded as they clearly did not fulfill our inclusion criteria on the basis of type of article, study design, study population or outcome of interest, leaving nine articles for full-length article review and one conference abstract for detailed review. Five studies were excluded because they reported only subclinical atherosclerotic diseases while a study was excluded as it reported prevalence, not incidence, of ischemic stroke in patients with SSc [23]. Four studies, all of which were retrospective cohorts, with 5,097 patients with SSc met our inclusion criteria and were included in the data analysis [17-19, 24]. The search methodology and literature review process are outlined in Figure 1. The detailed characteristics and Newcastle-Ottawa scale of the included studies are illustrated in Table 1. We found a statistically significantly elevated risk of ischemic stroke in patients with SSc versus control with the pooled risk ratio of 1.68 (95% CI, 1.26 to 2.24). The statistical heterogeneity was moderate with an I2 of 69%. Figure 2 demonstrates the forest plot of the included studies. Sensitivity analysis To further explore the statistical heterogeneity, we performed a sensitivity analysis by excluding the study by Zoller et al. [18] as this study was the only study that included only hospitalized patients, which could potentially lead to a selection of only severe cases. This sensitivity analysis considerably reduced the I2 to 51% without significantly altering the pooled risk ratio (RR 1.88; 95% CI, 1.43 to 2.48). Evaluation for publication bias Funnel plot (Figure 3) was used for the evaluation for publication bias. The plot was asymmetric, suggesting that publication bias in favor of positive studies might be present. Discussions Our meta-analysis demonstrated a significant association between systemic sclerosis and ischemic stroke with an overall 1.68-fold (95% CI 1.26 to 2.24) increased risk compared with non-SSc participants. The increased risk of ischemic stroke was consistently seen across all studies, with the exception of Zoller et al. in which the increased risk was numerically evaluated but not statistically significant. [18]. Why patients with SSc have an increased risk of cerebrovascular events is not wellunderstood. Premature atherosclerosis related to chronic inflammation is the widelyaccepted hypothesis as the deleterious effects of inflammatory mediators and oxidative stress on endothelial function have been extensively documented [7-9, 25]. In fact, increased atherosclerotic burden in patients with SSc has been demonstrated in several studies [26-28]. In addition, chronic inflammation related to autoimmune disorder is known to cause a hypercoagulable state as inflammatory cytokines have been shown to promote the coagulation cascade, inhibit the anticoagulation pathway and impair the fibrinolytic process [29-31]. These factors, in conjunction with the vasculopathy of SSc, may serve as the fundamental pathophysiology of the development of ischemic stroke. Even though the included studies were of high quality, there are some limitations and, therefore, our results should be interpreted with caution. First, all of the included studies were medical registry-based studies. Thus, coding inaccuracies and incompleteness for both SSc and ischemic stroke may have been present. Second, we could not evaluate the risk of each subtypes of SSc (i.e., diffuse and limited SSc) as the primary studies did not provide data for each subgroup. Third, statistical heterogeneity was present in this meta-analysis, though the I2 square considerably decreased after excluding the study with potential selection bias [18]. Fourth, as previously discussed, publication bias in favor of positive studies might be present. Fifth, this is a meta-analysis of observational studies which, at best, can demonstrate only an association, not causality. Therefore, we cannot be certain that SSc
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itself or other potential confounders were responsible for the increased risk. Furthermore, detection bias might have been present in these studies as the patients in SSc cohort, because of their chronic illness, were exposed to more medical examinations and investigations and, thus, more likelihood of stroke detection [32]. In conclusion, our meta-analysis demonstrated a statistically significant increased ischemic stroke risk among patients with SSc with 68% excess risk. Physicians should be aware of this association and a strategy to control other traditional cardiovascular risk factors should be employed as a part of standard of care for these patients. Disclosure None
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Reference 1. Maradit-Kremers H, Nicola PJ, Crowson CS, Ballman KV, Gabreil SE. Cardiovascular death in rheumatoid arthritis: a population-based study. Arthritis Rheum 2005;52(3):722– 32. 2.
Ungprasert P, Suksaranjit P, Spanuchart I, Leeaphorn N, Permpalung N. Risk of
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Ungprasert P, Cheungpasitporn W, Wijarnpreecha K, Ahuja W, Ratanasrimetha P,
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Thongprayoon C. Risk of ischemic stroke in patients with polymyositis and dermatomyositis: a systematic review and meta-analysis. Rheumatol Int 2015;35(5):905-9. 4.
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coronary heart disease and stroke in a large British cohort of patients with systemic lupus erythematosus. Rheumatology (Oxford) 2004;43(7):924–9. 5.
Ungprasert P, Koster MJ, Warrington KJ. Coronary artery disease in giant cell arteritis:
A systematic review and meta-analysis. Semin Arthritis Rheum 2015;44(5):586-91. 6.
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artery disease in primary biliary cirrhosis: A systematic review and meta-analysis of observational studies. Hepatol Res 2014 Nov 19 [Epub ahead of print] 7.
Frostegard J. Atherosclerosis in patients with autoimmune disorders. Arterioscler
Thromb Vasc Biol 2005;25(9):1776–85. 8.
Libby P. Inflammation in atherosclerosis. Nature2002;420(6917):868–74.
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12. Derk CT, Jimenez SA. Acute myocardial infarction in systemic sclerosis patients: a case series. Clin Rheumatol 2007;26(6):965-8. 13. Nair CK, Goli-Bijanki R, Lyckholm L, Sketch MH. Inferior myocardial infarction complicated by mural thrombus and systemic embolization despite anticoagulation in progressive systemic sclerosis with normal coronary arteriograms. Am Heart J 1988;116 (5 pt 1):1357-9. 14. Ngian GS, Sahhar J, Proudman SM, Stevens W, Wicks IP , Doornum SV. Prevalence of
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coronary heart disease and cardiovascular risk factors in a national cross-sectional cohort study of systemic sclerosis. Ann Rheum Dis 2012;71(12):1980–1983. 15. Chu SY , Chen YJ, Liu CJ, Tseng WC, Lin MW , Hwang CY, et al. Increased risk of acute myocardial infarction in systemic sclerosis: a nationwide population-based study. Am J Med 2013:126(11):982–988. 16. 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(8):1099-104. 17. Man A, Zhu Y, Zhang Y, Dubreuil M, Rho YH, Peloquin C, et al. The risk of cardiovascular disease in systemic sclerosis: a population-based cohort study. Ann Rheum Dis. 2013;72(7):1188-93. 18. Zöller B, Li X, Sundquist J, Sundquist K. Risk of subsequent ischemic and hemorrhagic stroke in patients hospitalized for immune-mediated diseases: a nationwide follow-up study from Sweden. BMC Neurol. 2012;12:41. 19. Chiang CH, Liu CJ, Huang CC, Chan WL, Huang PH, Chen TJ, et al. Systemic sclerosis and risk of ischaemic stroke: a nationwide cohort study. Rheumatology (Oxford). 2013;52(1):161-5. 20. 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(9):603-5. 21. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trial 1986;7(3):17788.
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22. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in metaanalyses. BMJ 2003;327(7414):557-60. 23. Nordin A, Jensen-Urstad K, Björnådal L, Pettersson S, Larsson A, Svenungsson E. Ischemic arterial events and atherosclerosis in patients with systemic sclerosis: a population-based case-control study. Arthritis Res Ther. 2013 Aug 14;15(4):R87. 24. Yurkovich M, Choi H, Agha M, Hemmati I, Sayre E, Shojania K, et al. The risk of cerebrovascular accidents in systemic sclerosis. Presented at the Canadian Rheumatology
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Association Annual Scientific Meeting, February 26-March 1, 2014 , Whistler, British Columbia. [Abstract no. 189]. 25. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352(16):1685–95. 26. Khurma V, Meyer C, Park GS, McMahon M, Lin J, Singh RR, et al. A pilot study of subclinical coronary atherosclerosis in systemic sclerosis: coronary artery calcification in cases and controls. Arthritis Rheum 2008;59:591-7. 27. Tsifetaki N, Georgiadis AN, Alamanos Y, Fanis S, Argyropoulou MI, Drosos AA. Subclinical atherosclerosis in scleroderma patients. Scan J Rheumatol 2010;39:326-9. 28. Heron E, Hernigou A, Chatellier G, Fornes P, Emmerich J, Fiessinger JN. Intracerebral calcification in systemic sclerosis. Stroke 1999;30:2183-5. 29. Xu J, Lupu F, Esmon CT. Inflammation, innate immunity and blood coagulation. Hamostaseologie 2010;30(1):5-6, 8-9. 30. Lipinski S, Bremer L, Lammers T, Thieme F, Schreiber S, Rosenstiel P. Coagulation and inflammation. Molecular insights and diagnostic implications. Hamostaseologie. 2011;31(2):94-102, 31. Esmon CT. The interactions between inflammation and coagulation. Br J Haematol 2005;131(4):417-30. 32. Ungprasert P, Srivali N, Wijarnpreecha K, Thongprayoon C, Cheungpasitporn W, Knight EL. Is the incidence of malignancy increased in patients with sarcoidosis? A systematic review and meta-analysis. Respirology. 2014;19(7):993-8.
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Figure legend Figure 1: Outline of our search methodology
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Figure 2: Forest plot of the included studies
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Figure 3: Funnel plot of the included studies
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Table1: Main characteristics of studies included in the meta-analysis Man et al. [17]
Zoller et al. [18]
Chiang et al. [19]
Yurkovich et al. [24]
Country
United Kingdom
Sweden
Taiwan
Canada
Study design
Retrospective cohort
Retrospective cohort
Retrospective cohort
Retrospective cohort
Year
2012
2012
2013
2014
Cases
All patients who were newly diagnosed with SSc between 1986 2011. Cases were identified by using The Health Improvement Network database which included 7.3 million patients across the United Kingdom. Cases with previous diagnosis of stroke were excluded.
All hospitalized patient with a diagnosis of SSc (without previous or co-existing ischemic stroke) between 1987 -2008. Cases were identified from the Swedish national registry.
All patients who were newly diagnosed with SSc between 1995 2006. Cases were identified by using The National Health Insurance Network database which provided comprehensive health care for all citizens of Taiwan. Cases with previous diagnosis of stroke were excluded.
All patients who were newly diagnosed with SSc between 1996 -2010. Cases were identified by using the comprehensive provincial medical services plan database.
Diagnosis of SSc
Diagnostic code from the registry.
Diagnostic code from the registry.
Diagnostic code from the registry.
Diagnostic code from the registry.
Controls
Sex, age and month/year of cohort entrymatched subjects randomly selected from same database.
Swedish age- and sex-specific general population incidence rates for ischemic stroke were used as the comparator for the calculation of standardized incidence ratio.
Sex and agematched subjects randomly selected from same database.
Sex and agematched subjects randomly selected from same database.
Diagnosis of ischemic stroke
Diagnostic code from the registry.
Diagnostic code from the registry.
Diagnostic code from the registry.
Diagnostic code from the registry.
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Follow up
Until the stroke, death, emigration from the system or September 30, 2011.
Until hospitalization for stroke, death, emigration from the system or December 31, 2008.
Until the stroke, death, or December 31, 2006.
NA
Mean age of cases, Y
58.7
NA
49.4
56.3
Female, %
85.8
77.1
76.0
83.0
Number of cases
865
1,758
1,238
1,236
Number of control
8,643
NA
12,380
12,360
Average range 5.2 of follow up, Y
NA
4.7
NA
Confounder adjusted
Age, sex, time of cohort entry, comorbidities, NSAIDs and steroid use.
Age, socioeconomic status, region of residence, obesity, HTN, diabetes, atrial fibrillation, heart failure and coronary heart disease.
Age, sex and comorbidities.
Age, sex, comorbidities and medications.
Quality assessment (NewcastleOttawa scale)
Selection: 4 stars Comparability: 2 stars Outcome: 3 stars
Selection: 4 stars Comparability: 1 star Outcome: 3 stars
Selection: 4 stars Comparability: 2 stars Outcome: 3 stars
Selection: 3 stars Comparability: 2 stars Outcome: 3 stars
SSc indicates systemic sclerosis; NA, not available; HTN, hypertension; NSAIDs, nonsteroidal anti-inflammatory drugs
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Risk of Ischemic Stroke in Patients with Systemic Sclerosis: A Systematic Review and Meta-analysis Patompong Ungprasert, Anawin Sanguankeo, Sikarin Upala Doi: 10.3109/14397595.2015.1056931 Abstract
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Background: Several chronic inflammatory disorders, such as rheumatoid arthritis and idiopathic inflammatory myositis, have been shown to increase risk of ischemic stroke but the data on systemic sclerosis (SSc) remains unclear. Methods: We conducted a systematic review and meta-analysis of observational studies that reported odds ratio, relative risk, hazard ratio or standardized incidence ratio comparing risk of ischemic stroke in patients with SSc versus non-SSc participants. Pooled risk ratio and 95% confidence intervals were calculated using a randomeffect, generic inverse variance method of DerSimonian and Laird. Results: Four retrospective cohort studies were identified and included in our data analysis. We found a statistically significant elevated ischemic stroke risk in patients with SSc with a pooled risk ratio of 1.68 (95% CI, 1.26 to 2.24). The statistical heterogeneity was moderate with an I2 of 69%. Conclusions: Our study demonstrated a statistically significant increased ischemic stroke risk among patients with SSc.
© 2015 Informa UK, Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
IMOR_A_1056931_Coverpage.indd 1
29-05-2015 15:34:22
Original Article
Risk of Ischemic Stroke in Patients with Systemic Sclerosis: A Systematic Review and Meta-analysis
Patompong Ungprasert1,2, Anawin Sanguankeo3, Sikarin Upala3 1
Division of rheumatology, Mayo Clinic, Rochester, MN, USA, 2Department of Internal
Medicine, Faculty of medicine Siriraj hospital, Mahidol University, Bangkok, Thailand, 3
Department of Preventive and Social Medicine, Faculty of medicine Siriraj hospital,
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Mahidol University, Bangkok, Thailand
Correspondence: Patompong Ungprasert, Division of rheumatology, Mayo Clinic, Rochester, MN, USA. E-mail: [email protected] Abstract Background: Several chronic inflammatory disorders, such as rheumatoid arthritis and idiopathic inflammatory myositis, have been shown to increase risk of ischemic stroke but the data on systemic sclerosis (SSc) remains unclear. Methods: We conducted a systematic review and meta-analysis of observational studies that reported odds ratio, relative risk, hazard ratio or standardized incidence ratio comparing risk of ischemic stroke in patients with SSc versus non-SSc participants. Pooled risk ratio and 95% confidence intervals were calculated using a random-effect, generic inverse variance method of DerSimonian and Laird. Results: Four retrospective cohort studies were identified and included in our data analysis. We found a statistically significant elevated ischemic stroke risk in patients with SSc with a pooled risk ratio of 1.68 (95% CI, 1.26 to 2.24). The statistical heterogeneity was moderate with an I2 of 69%. Conclusions: Our study demonstrated a statistically significant increased ischemic stroke risk among patients with SSc.
Keywords: Meta-analysis, Stroke, Systemic Sclerosis, Epidemiology, Inflammation
MORH-D-15-00166 Received: Mar-09-15; Accepted: May-26-15
1
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Introduction Over the past few decades, several large epidemiological studies have demonstrated an increased incidence of cardiovascular disease among patient with chronic inflammatory disorders, such as rheumatoid arthritis, idiopathic inflammatory myositis, vasculitis, systemic lupus erythematosus and autoimmune liver diseases [1-6]. Premature atherosclerosis from chronic inflammation appears to be the cornerstone of these excessive cardiovascular complications [7-9]. Systemic sclerosis (SSc) is another autoimmune connective disease characterized by diffuse fibrosis of the skin and internal organs. Its incidence varies from 0.6 per million person-year to 122 per million person-year [10]. SSc is subcategorized into diffuse and limited form, based on the extent of skin involvement. The pathogenesis of this disorder is complex and not well-understood. Microvascular abnormality is one of the hallmarks of its pathology which is linked to the clinical presentations of Raynaud’s phenomenon, periungual capillary changes, gastric antral vascular ectasia and scleroderma renal sclerosis [11]. Though not originally regarded as a clinical feature of SSc, macrovascular complication has been increasingly recognized in this group of patients as a possible link between coronary artery disease (CAD) and this autoimmune disorder has been suggested in several case reports [12, 13]. Subsequent epidemiological studies and a meta-analysis have confirmed this association with an overall 82% excess risk compared with sex and agedmatch controls [14-16]. Ischemic stroke is another major atherosclerotic macrovascular disease that shares a similar pathogenesis to CAD. Patients with SSc might be at an increased risk of ischemic stroke as well. Nonetheless, the data remains inconclusive as previous epidemiological studies yielded inconsistent results [17-19]. Thus, to further investigate this possible association, we conducted a systematic review and meta-analysis of observational studies that compared the ischemic stroke risk in patients with SSc versus non-SSc participants. Methods Search strategy Two investigators (P.U. and A.S.) independently searched published studies indexed in MEDLINE and EMBASE from inception to February 2015 using the terms for systemic sclerosis combined with the terms for ischemic stroke. Detailed search strategy is available in Supplementary data. References of selected retrieved articles were also manually searched. Inclusion criteria The inclusion criteria were as follows: (1) Population-based, case-control or cohort studies published as original study or abstract to evaluate the risk of incident ischemic stroke in patients with SSc, (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) or enough data to calculated this ratios were provided (3) participants without SSc were used as the reference group in cohort study and participants without ischemic stroke were used as the reference group in case-control study. Study eligibility was independently determined by the two investigators noted above. Any differences in decision were resolved by consensus with the third investigator. The quality of each study was also independently assessed by each investigator using Newcastle-Ottawa quality assessment scale [20]. 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, number of case and control, control selection, characteristics of included participants, method used to diagnose SSc and ischemic stroke, average duration of follow up, confounders and adjusted effect estimates with 95% CI. This data extraction was performed by all three investigators. Any discrepancy in data extraction was also resolved by consensus. Statistical analysis Review Manager (RevMan) 5.3 software from the Cochrane Collaboration was used for the statistical analysis. Point estimates and corresponding standard errors were extracted from individual studies and were combined by the generic inverse variance method of DerSimonian and Laird [21]. We used a random-effect model rather than a fixed-effect
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model, in light of the high likelihood of between study variance. Cochran’s Q test was used to determine the study’s statistical heterogeneity. This statistic is complemented with the I2 statistic, which quantifies the proportion of total variation across studies that is due to true heterogeneity rather than chance. A value of I2 of 0% to 25% represents insignificant heterogeneity, 26% to 50% low heterogeneity, 51% to 75% moderate heterogeneity, and > 75% high heterogeneity [22]. Results Our search strategy yielded 209 potentially relevant articles (78 from Medline and 131 articles from EMBASE). After exclusion of 75 duplicated articles, 134 articles underwent title and abstract review. 124 articles were excluded as they clearly did not fulfill our inclusion criteria on the basis of type of article, study design, study population or outcome of interest, leaving nine articles for full-length article review and one conference abstract for detailed review. Five studies were excluded because they reported only subclinical atherosclerotic diseases while a study was excluded as it reported prevalence, not incidence, of ischemic stroke in patients with SSc [23]. Four studies, all of which were retrospective cohorts, with 5,097 patients with SSc met our inclusion criteria and were included in the data analysis [17-19, 24]. The search methodology and literature review process are outlined in Figure 1. The detailed characteristics and Newcastle-Ottawa scale of the included studies are illustrated in Table 1. We found a statistically significantly elevated risk of ischemic stroke in patients with SSc versus control with the pooled risk ratio of 1.68 (95% CI, 1.26 to 2.24). The statistical heterogeneity was moderate with an I2 of 69%. Figure 2 demonstrates the forest plot of the included studies. Sensitivity analysis To further explore the statistical heterogeneity, we performed a sensitivity analysis by excluding the study by Zoller et al. [18] as this study was the only study that included only hospitalized patients, which could potentially lead to a selection of only severe cases. This sensitivity analysis considerably reduced the I2 to 51% without significantly altering the pooled risk ratio (RR 1.88; 95% CI, 1.43 to 2.48). Evaluation for publication bias Funnel plot (Figure 3) was used for the evaluation for publication bias. The plot was asymmetric, suggesting that publication bias in favor of positive studies might be present. Discussions Our meta-analysis demonstrated a significant association between systemic sclerosis and ischemic stroke with an overall 1.68-fold (95% CI 1.26 to 2.24) increased risk compared with non-SSc participants. The increased risk of ischemic stroke was consistently seen across all studies, with the exception of Zoller et al. in which the increased risk was numerically evaluated but not statistically significant. [18]. Why patients with SSc have an increased risk of cerebrovascular events is not wellunderstood. Premature atherosclerosis related to chronic inflammation is the widelyaccepted hypothesis as the deleterious effects of inflammatory mediators and oxidative stress on endothelial function have been extensively documented [7-9, 25]. In fact, increased atherosclerotic burden in patients with SSc has been demonstrated in several studies [26-28]. In addition, chronic inflammation related to autoimmune disorder is known to cause a hypercoagulable state as inflammatory cytokines have been shown to promote the coagulation cascade, inhibit the anticoagulation pathway and impair the fibrinolytic process [29-31]. These factors, in conjunction with the vasculopathy of SSc, may serve as the fundamental pathophysiology of the development of ischemic stroke. Even though the included studies were of high quality, there are some limitations and, therefore, our results should be interpreted with caution. First, all of the included studies were medical registry-based studies. Thus, coding inaccuracies and incompleteness for both SSc and ischemic stroke may have been present. Second, we could not evaluate the risk of each subtypes of SSc (i.e., diffuse and limited SSc) as the primary studies did not provide data for each subgroup. Third, statistical heterogeneity was present in this meta-analysis, though the I2 square considerably decreased after excluding the study with potential selection bias [18]. Fourth, as previously discussed, publication bias in favor of positive studies might be present. Fifth, this is a meta-analysis of observational studies which, at best, can demonstrate only an association, not causality. Therefore, we cannot be certain that SSc
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itself or other potential confounders were responsible for the increased risk. Furthermore, detection bias might have been present in these studies as the patients in SSc cohort, because of their chronic illness, were exposed to more medical examinations and investigations and, thus, more likelihood of stroke detection [32]. In conclusion, our meta-analysis demonstrated a statistically significant increased ischemic stroke risk among patients with SSc with 68% excess risk. Physicians should be aware of this association and a strategy to control other traditional cardiovascular risk factors should be employed as a part of standard of care for these patients. Disclosure None
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coronary heart disease and cardiovascular risk factors in a national cross-sectional cohort study of systemic sclerosis. Ann Rheum Dis 2012;71(12):1980–1983. 15. Chu SY , Chen YJ, Liu CJ, Tseng WC, Lin MW , Hwang CY, et al. Increased risk of acute myocardial infarction in systemic sclerosis: a nationwide population-based study. Am J Med 2013:126(11):982–988. 16. 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(8):1099-104. 17. Man A, Zhu Y, Zhang Y, Dubreuil M, Rho YH, Peloquin C, et al. The risk of cardiovascular disease in systemic sclerosis: a population-based cohort study. Ann Rheum Dis. 2013;72(7):1188-93. 18. Zöller B, Li X, Sundquist J, Sundquist K. Risk of subsequent ischemic and hemorrhagic stroke in patients hospitalized for immune-mediated diseases: a nationwide follow-up study from Sweden. BMC Neurol. 2012;12:41. 19. Chiang CH, Liu CJ, Huang CC, Chan WL, Huang PH, Chen TJ, et al. Systemic sclerosis and risk of ischaemic stroke: a nationwide cohort study. Rheumatology (Oxford). 2013;52(1):161-5. 20. 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(9):603-5. 21. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trial 1986;7(3):17788.
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22. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in metaanalyses. BMJ 2003;327(7414):557-60. 23. Nordin A, Jensen-Urstad K, Björnådal L, Pettersson S, Larsson A, Svenungsson E. Ischemic arterial events and atherosclerosis in patients with systemic sclerosis: a population-based case-control study. Arthritis Res Ther. 2013 Aug 14;15(4):R87. 24. Yurkovich M, Choi H, Agha M, Hemmati I, Sayre E, Shojania K, et al. The risk of cerebrovascular accidents in systemic sclerosis. Presented at the Canadian Rheumatology
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Figure legend Figure 1: Outline of our search methodology
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Figure 2: Forest plot of the included studies
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Figure 3: Funnel plot of the included studies
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Table1: Main characteristics of studies included in the meta-analysis Man et al. [17]
Zoller et al. [18]
Chiang et al. [19]
Yurkovich et al. [24]
Country
United Kingdom
Sweden
Taiwan
Canada
Study design
Retrospective cohort
Retrospective cohort
Retrospective cohort
Retrospective cohort
Year
2012
2012
2013
2014
Cases
All patients who were newly diagnosed with SSc between 1986 2011. Cases were identified by using The Health Improvement Network database which included 7.3 million patients across the United Kingdom. Cases with previous diagnosis of stroke were excluded.
All hospitalized patient with a diagnosis of SSc (without previous or co-existing ischemic stroke) between 1987 -2008. Cases were identified from the Swedish national registry.
All patients who were newly diagnosed with SSc between 1995 2006. Cases were identified by using The National Health Insurance Network database which provided comprehensive health care for all citizens of Taiwan. Cases with previous diagnosis of stroke were excluded.
All patients who were newly diagnosed with SSc between 1996 -2010. Cases were identified by using the comprehensive provincial medical services plan database.
Diagnosis of SSc
Diagnostic code from the registry.
Diagnostic code from the registry.
Diagnostic code from the registry.
Diagnostic code from the registry.
Controls
Sex, age and month/year of cohort entrymatched subjects randomly selected from same database.
Swedish age- and sex-specific general population incidence rates for ischemic stroke were used as the comparator for the calculation of standardized incidence ratio.
Sex and agematched subjects randomly selected from same database.
Sex and agematched subjects randomly selected from same database.
Diagnosis of ischemic stroke
Diagnostic code from the registry.
Diagnostic code from the registry.
Diagnostic code from the registry.
Diagnostic code from the registry.
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Follow up
Until the stroke, death, emigration from the system or September 30, 2011.
Until hospitalization for stroke, death, emigration from the system or December 31, 2008.
Until the stroke, death, or December 31, 2006.
NA
Mean age of cases, Y
58.7
NA
49.4
56.3
Female, %
85.8
77.1
76.0
83.0
Number of cases
865
1,758
1,238
1,236
Number of control
8,643
NA
12,380
12,360
Average range 5.2 of follow up, Y
NA
4.7
NA
Confounder adjusted
Age, sex, time of cohort entry, comorbidities, NSAIDs and steroid use.
Age, socioeconomic status, region of residence, obesity, HTN, diabetes, atrial fibrillation, heart failure and coronary heart disease.
Age, sex and comorbidities.
Age, sex, comorbidities and medications.
Quality assessment (NewcastleOttawa scale)
Selection: 4 stars Comparability: 2 stars Outcome: 3 stars
Selection: 4 stars Comparability: 1 star Outcome: 3 stars
Selection: 4 stars Comparability: 2 stars Outcome: 3 stars
Selection: 3 stars Comparability: 2 stars Outcome: 3 stars
SSc indicates systemic sclerosis; NA, not available; HTN, hypertension; NSAIDs, nonsteroidal anti-inflammatory drugs
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