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Arthritis Rheum. Author manuscript; available in PMC Jul 1, 2012.
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PMCID: PMC3128188
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Atherosclerosis in Systemic Sclerosis- A Systematic Review and Meta Analysis

Karen Au, MD,1 Manjit K. Singh, MD,1 Vijay Bodukam, MD,1 Sangmee Bae, MD,1 Paul Maranian, MS,1 Rikke Ogawa, MLIS,2 Brennan Spiegel, MD, MSHS,3 Maureen McMahon, MD, MS,1 Bevra Hahn, MD,1 and Dinesh Khanna, MD, MS1

Abstract

Purpose

Systemic sclerosis (SSc) is characterized by calcification, vasculopathy, and endothelial wall damage, all of which can increase the risk for atherosclerosis and cardiovascular disease. Our objective was to perform a systematic review and meta-analysis to determine if atherosclerosis is increased in patients with SSc compared to healthy individuals.

Methods

We performed a systematic search of studies published in PubMed and the Cochrane database up to May 2010, and reviewed recently-published abstracts. Two reviewers independently screened articles to identify studies comparing rates of atherosclerosis in SSc patients vs. healthy controls using one of the following modalities: angiography, doppler ultrasound to assess plaque and carotid intima-medial thickness (CIMT), computer tomography, magnetic resonance imaging, flow mediated dilation (FMD), ankle-brachial index, or autopsy findings. For CIMT and FMD, we computed a pooled estimate of the summary mean difference (MD) and explored predictors of CIMT using random-effects meta-regression.

Results

Of 3,156 articles initially identified, 33 were selected for the systematic review. Meta-analysis included 14 CIMT and 7 FMD studies. Compared to healthy controls, SSc patients had higher prevalence of coronary atherosclerosis, peripheral vascular disease, and cerebrovascular calcification. Meta-analysis showed SSc subjects had increased CIMT [MD 0.11mm (95% CI 0.05, 0.17), P=0.0006] and lower FMD [MD -3.07% (95%CI -5.44, -0.69), P=0.01]. There was marked heterogeneity between the studies, namely from variations in disease duration and difference in mean/median age between SSc and control groups.

Conclusion

Patients with SSc have increased atherosclerosis compared to healthy controls. Further studies should elucidate the mechanism of this increased risk.

Introduction

Atherosclerosis is the hallmark of cardiovascular disease and the leading cause of mortality in the world(1). Much of the mortality attributed to cardiovascular disease comes from myocardial infarctions and strokes. The association between autoimmune diseases and atherosclerosis is well described in many connective tissue diseases such as systemic lupus erythematosus and rheumatoid arthritis(2, 3), and lead to increased cardiovascular morbidity and mortality(2, 3). Mechanisms by which atherosclerosis is promoted in connective tissue diseases remain unknown, but is believed to be secondary to chronic inflammation(4, 5), altered lipid profiles and function (6, 7), autoantibodies(8), and endothelial dysfunction (9).

Systemic sclerosis (SSc) is a multi-system autoimmune disease characterized by vasculopathy and organ fibrosis. Vasculopathy is triggered by endothelial damage, which occurs early in SSc. Although the detrimental effects of SSc on the small arteries and capillaries are well-known(10), increasing evidence shows that atherosclerosis is also present in SSc and may be increased compared to healthy individuals. A recent meta-analysis of carotid intima-medial thickness (CIMT) in rheumatic diseases found that atherosclerosis was increased in patients with rheumatic diseases compared to controls. This study also included a small number of studies with SSc subset in their analysis(11). In addition, flow mediated dilation (FMD) is also a surrogate marker for atherosclerosis(12). We sought to perform a systematic review of studies that compared atherosclerosis in SSc to controls and perform a meta-analysis to assess the prevalence of atherosclerosis in SSc vs. healthy controls using CIMT and FMD. We hypothesized that patients with SSc will have a greater prevalence of atherosclerosis in SSc compared to healthy controls.

Methods

Literature search

Structured Search Strategy

In concert with an expert librarian (R.O.), we searched PubMed and Cochrane Central Register of Controlled Trials (CENTRAL) to find all articles on scleroderma and macrovascular diseases. CENTRAL includes references from PubMed, EMBASE and Cochrane Review Groups' specialized registers of controlled trials and hand search results. While there is a specific Medical Subject Heading (MeSH) term for vascular disease, a broad search strategy was used to gather all articles related to the subject and included articles on related diseases of interest and diagnostic techniques for those conditions. MeSH terms for scleroderma and vascular disease were identified by the librarian and reviewed by the authors. Related text words were added to the search to retrieve articles not yet indexed with MeSH (Appendix 1). Articles referring to Animal only studies and non-English language articles were excluded from the group. The search was conducted on 5/5/10, and retrieved 3,155 citations from PubMed and 129 citations from CENTRAL. We also searched the 1st Scleroderma World Congress abstracts from 2010, and the American College of Rheumatology and European League against Rheumatism abstracts (2007–2009).

Selection of Instruments and Creation of Item Library

Under the direction of the two PIs (KA and DK), 3 investigators (MS, VB, and SB) reviewed the citations generated from the search of PubMed and CENTRAL. The review was divided into three stages: titles, abstracts, and manuscripts. The team reviewed the titles identified in PubMed and CENTRAL. Each generated title was assessed by two team members for relevancy, and was rejected if it fulfilled one of the following explicit exclusion criteria: (1) not written in English, (2) not concerned with human subjects, (3) not pertaining to SSc, (4) not pertaining to cerebrovascular or peripheral vascular or coronary vessels, (5) not pertaining to instruments or diagnostic tests, (6) not original research or review article, (7) pertaining to infant / children studies, (8) pertaining to genetic studies, or (9) pertaining to biomarkers (without any other diagnostic or imaging studies). If there were discordant assessments between reviewers, this was resolved during direct discussion between the two raters and, if there was uncertainty, included oversight by a third party arbiter (PIs) who reviewed and discussed the discordant titles. We were inclusive by accepting a title if there was uncertainty about how best to deliberate. After a review of the all 3,284 (PubMed and CENTRAL) titles, 3145 titles were excluded leaving 139 abstracts. We applied the same exclusion criteria (outlined above) to the abstracts, resulting in 80 of the abstracts being rejected. In addition, we searched through the references of review articles on the topic of atherosclerosis in SSc and hand-selected an additional 10 articles. A final total of 69 abstracts were selected for rigorous review, and manuscripts were rejected if they met any of the following exclusion criteria: (1) meeting abstract exclusion criteria, (2) no control subjects or non-healthy controls, (3) not pertaining to cerebrovascular or peripheral vascular or coronary vessels, and (4) SSc population as part of a connective tissue disease group. Review of the 1st Scleroderma World Congress abstracts, ACR and EULAR abstracts resulted in an additional 5 abstracts; 27 manuscripts and 5 abstracts were included in the systematic review. We calculated Newcastle-Ottawa score for each selected manuscript and abstract that assesses quality of the observational study(13). The Newcastle-Ottawa score was developed to assess the quality of non-randomized studies with its design, content and ease of use directed to the task of incorporating the quality assessments in the interpretation of meta-analytic results. The score ranges from 0–9 where higher score denotes better quality of the study.

Meta-analysis

We included 14 manuscripts with CIMT and 7 studies with FMD in the meta-analyses. We e-mailed individual corresponding authors if means or standard deviations (SD) were not presented in the published manuscripts or abstracts. We did not include manuscripts if the data were not presented as a mean (SD) for the SSc and the controls (N=2)(14, 15). In addition, if the authors presented mean (SD) scores for CIMT separately for limited and diffuse SSc, we calculated pooled estimates of the mean SD for the overall disease group.

We modeled CIMT and FMD as continuous variables with study-level effect sizes calculated as absolute mean differences. For completeness, pooled estimates of the summary mean difference were computed using both the inverse-variance weighted fixed-effects model and the DerSimonian and Laird random-effects model(16). Publication bias was assessed graphically using an inverse SE funnel plot. In interpreting the I2 statistic, which measures the proportion of total variation among the study estimates due to heterogeneity rather than sampling error, we considered values of 25%, 50%, and 75% to indicate low, moderate, and high variation, respectively(17). Factors influencing overall mean difference and heterogeneity were investigated using 1) a sensitivity analysis in which each study is removed, one-by-one, from the analysis, with estimates re-examined at each step, and 2) meta-regression using study characteristics as covariates in conjunction with the between-study variance (T2) of the random-effects model. We chose the following study characteristics for univariate meta-regression models: disease duration of SSc group, difference in proportion of female between disease and control groups, and difference in mean/median age between disease and control groups. We presented the information on the unadjusted beta coefficients, confidence intervals and P-values for the covariates from each univariate regression model, along with the T2 values and percent reduction in T2, i.e. reduction in variance after controlling for the covariate. STATA v.10 was used for summary mean difference estimates, meta-regression and sensitivity analyses, and figures were produced using RevMan software (version 5)(18).

Results

Description and Quality of Studies

From an original search result of 3,284 titles, we selected 27 manuscripts and 5 abstracts in the systematic review (Figure 1). Controls were matched by age in 24 studies and by gender in 22 studies. Most of the subjects in the studies were female (pooled estimate: 86.8% [95% CI: 85.1%, 88.3%]). The mean age (SD) of the SSc patients was 50.3 (11.6) years and 51.6 (13.2) years for controls subjects (P=NS). Most SSc subjects had limited SSc (pooled estimate 69.0% [95%CI: 65.7%, 72.1%]), and the mean (SD) duration of disease was 10.7 (7.0) years. Demographics of the subjects in the individual studies are shown in Table 1. The median (25–75%) Newcastle-Ottawa score for the studies was 7.0 (IQR 6.0–7.5).

Figure 1
Flowchart of selected articles.
Table 1
Baseline characteristics of the SSc patients and controls in individual studies

Evidence for atherosclerosis in SSc

In general, atherosclerosis was increased in patients with SSc compared with healthy controls (Table 2). We present results of the systematic review by the type of vessels involved—coronary, carotid, cerebrovascular, and peripheral vessels.

Table 2
Results of atherosclerosis studies in SSc compared to healthy controls

Coronary arteries

Three studies assessed coronary arteries in SSc in comparison to a non-SSc cohort (Table 2). Of these, one was an autopsy study(19), another looked for evidence of coronary artery disease based upon retrospective chart review(20), and the third evaluated for asymptomatic atherosclerosis(21). In the largest autopsy study to date, D'Angelo et al compared 58 patients with SSc to 58 age-, gender-, and ethnicity-matched controls and found significantly more atherosclerosis in the patients with SSc. Although presence of medium-vessel coronary atherosclerosis was similar (48% SSc vs. 43% controls), atherosclerotic lesions of small coronary arteries or arterioles occurred in 17% of SSc patients compared with only 2% of controls (P<0.01) (19). Causes of death were not identified in the study. In Youssef's retrospective chart review of 31 patients with limited SSc and 31 controls, the presence of coronary artery disease was identified in 12 (39%) of SSc subjects versus 7 (23%) of controls, RR 1.7 (0.8–3.7)(20). In a study of 17 SSc patients and 17 controls with no clinical history of cardiovascular disease, coronary atherosclerosis (as measured by coronary calcification), was found in 56.2% of SSc patients versus 18.8% of age-, sex-, and race-matched controls (P=0.01) (21). The mean (SD) coronary calcium score in subjects with SSc (126.6[251.0]) was also significantly greater than the controls (14.7[52.2]; P = 0.003).

Carotid Artery

Most studies assessed the carotid artery using ultrasonography. Sixteen studies assessed CIMT in SSc patients vs. controls (14, 15, 2235). Of these, 7 (44%) reported significantly greater CIMT scores in SSc vs. controls(15, 22, 2628, 33, 34). Fourteen of the 16 studies were included in the meta-analysis (reported later); 1 study was excluded due to lack of control data (15) and 1 was excluded because means were not reported (14). Three studies evaluated carotid plaque(10, 32, 36), and 2 of these (67%) reported a higher rate of carotid stenosis and plaque in SSc patients than in healthy controls (10, 36).

Cerebrovascular Vessels

Four studies assessed the prevalence of cerebrovascular atherosclerosis in SSc compared to controls. One study used chart review to evaluate the history of strokes or transient ischemic attacks (20), and 3 of the studies evaluated asymptomatic cerebrovascular atherosclerosis(3739). In 1 study, Youssef et al. did not find a difference in the prevalence of cerebrovascular disease between SSc patients and controls(20), but the total number of events was low in both groups (8 in SSc versus 6 in controls). Of 3 studies that evaluated asymptomatic cerebrovascular atherosclerosis, there was significantly higher incidence of atherosclerosis in SSc compared to controls. In a study of 37 asymptomatic SSc patients and 74 age- and sex-matched controls, the prevalence of intracerebral calcification per non-contrast CT scan was significantly higher in SSc (32.4% vs. 9.5%, P=0.006)(37). Two studies examined white matter hyperintensities in asymptomatic SSc patients and controls(38, 39). Both studies found that not only were SSc patients more likely to have these lesions on MRI, but also they tended to have more lesions compared to healthy controls.

Peripheral Arteries and other Major Vessels

One retrospective study evaluated the prevalence of peripheral vascular disease in SSc and found significantly higher peripheral vascular disease in SSc patients when compared to controls (58 vs. 10%) (20). Seven studies evaluated brachial flow-mediated dilation (FMD) in SSc compared with healthy controls (22, 27, 29, 31, 4042). Four (57%) of the 7 studies reported significantly lower brachial FMD in SSc patients vs. healthy controls (8% vs. 15%, P<0.0001) (22, 27, 29, 42), 1 study reported lower brachial FMD in SSc patients but did not provide a P-value (41), and 2 found no difference(31, 40). Four studies evaluated ankle brachial index (ABI) in SSc compared to healthy controls (10, 26, 28, 43) and 3 of these studies (75%) concluded that there were no differences in ABI between SSc and healthy controls(26, 28, 43). One study (25%) did find significantly higher rates of abnormal ABI amongst the SSc patients compared to healthy controls (17% vs. 0%) (10). Three studies evaluated asymptomatic atherosclerosis in specific vessels (renal(44), radial(45), and ulnar(46)), and 2 of the studies (67%) found that asymptomatic atherosclerosis was increased in SSc compared to controls(44, 46). Trostle et al. found significantly increased intimal thickening in medium and large renal vessels of diffuse SSc patients without a history of renal crisis when compared to controls(44). Stafford et al. found that ulnar artery diameter in SSc patients was significantly decreased compared to controls(46).

CIMT Measurements and Meta-Analysis

The location of the CIMT measurements and mode of ultrasonography used in each study is included in Appendix 2. CIMT was found to be significantly higher in SSc patients versus controls in 6 of 14 (42.9%) studies. The summary mean difference between SSc subjects and controls under the fixed-effects model was 0.13mm (95% CI: 0.12, 0.15), while the summary mean difference under the random-effects model was 0.11mm (95% CI: 0.05, 0.17), P=0.0006 (see Figure 2). A funnel plot did not show evidence of publication bias (Figure 3). The fixed-effect I2 was 91%, with a corresponding X2 statistic achieving a P of 0.00001. These results suggest significantly elevated heterogeneity between the studies. The high heterogeneity led us to explore if an individual study may have overtly influenced our summary mean difference. We removed each individual study and recalculated the summary mean difference. No single study influenced the estimated summary mean difference, which ranged from 0.09 to 0.11mm among sensitivity analyses (Appendix 3). We next conducted univariate meta-regression to assess the impact of individual variables on CIMT point estimation. In order to compare values of the between-study variance T2, the set of studies included in the meta-regression was restricted to those having complete data on all 3 variables (N=8 studies). Six studies were excluded as they lacked information on disease duration (N=5) or information on the proportion of females and age (N=3; 2 studies lacked both). The empty univariate model produced a T2 of .0073, and this value served as the reference level for comparison with the T2 values from the subsequent univariate models (Appendix 4). Adjusting for disease duration and difference in age decreased heterogeneity by 37% and 62%, respectively compared to empty univariate model.

Figure 2
Meta-analysis showing the summary mean difference in carotid intima-medial thickness (CIMT) between SSc and control subjects (random-effects model).
Figure 3
Funnel plot of inverse standard error of the mean difference in CIMT between SSc subjects and controls under fixed effects model for meta-analysis. Pooled fixed effect estimate and 95% confidence bands are provided.

Meta-analysis of FMD studies

Seven studies which evaluated brachial artery FMD were included in the meta-analysis. FMD was significantly lower in SSc compared to controls. The summary mean difference in FMD between SSc and controls under the random-effects model was −3.01% (95% CI −5.44, −0.69), P=0.01 (Figure 4). There was marked heterogeneity in the studies, I2 was 89%, with a corresponding X2 statistic achieving a P of 0.00001.

Figure 4
Meta-analysis showing the summary mean difference in flow mediated dilation (FMD) between SSc and control subjects (random-effects model).

Discussion

Atherosclerosis is an inflammatory disease with increased prevalence in connective tissue disorders such as systemic lupus erythematosus and rheumatoid arthritis(3, 47, 48). Although microvascular disease is well described in systemic sclerosis (SSc), there has been conflicting reports regarding the presence of macrovascular disease or atherosclerosis in SSc (49). Our systematic analysis and meta-analysis convincingly demonstrates that SSc is associated with an increased prevalence of atherosclerosis when compared to healthy controls.

We systematically reviewed the published literature to evaluate the relationship between SSc and atherosclerosis in the coronary, carotid, cerebrovascular, and peripheral vasculature, and found an increased prevalence of atherosclerosis in all vessels. The most robust data were available for carotid atherosclerosis identified by carotid ultrasonography, an accurate and reliable measurement of atherosclerosis(50). Ultrasound allows detection and measurement of the intima-media wall thickness (CIMT) and degree of plaque in the carotid arteries. Persons with asymptomatic carotid disease are at increased risk for coronary heart disease, strokes, and death(51). Although carotid IMT results were widely varied among the 16 studies, our meta-analysis found significantly higher CIMT in SSc compared to controls, demonstrating that atherosclerosis is increased in SSc. In addition, evidence for increased carotid plaque in SSc was noted in 2 of 3 studies. Our results are in agreement with Tyrrell and colleagues(11) who recently conducted a systematic review and meta-analysis using CIMT in rheumatic diseases and showed an increased prevalence of atherosclerosis compared to healthy controls. Tyrrell et al also included 6 studies for SSc in their meta-analysis and demonstrated a mean difference of 0.10mm (95% CI, 0.03 to 0.18) in CIMT between SSc and controls (personal correspondence). Our meta-analysis using 14 studies showed a summary mean difference of 0.11mm (0.05, 0.17) between SSc subjects and controls. The increased mean difference in CIMT in our study is similar to that of other groups with increased cardiovascular disease risk such as rheumatoid arthritis (0.09mm)(52), diabetes mellitus (0.13mm)(53), and familial hypercholesterolemia (0.12mm)(54).

We found a trend of increasing carotid IMT with an increase in SSc disease duration. Every 10 year increase in SSc disease duration was associated with an increase in carotid IMT of 0.16mm (P=0.06; Appendix 4). CIMT is associated in the general population with an increased risk in both stroke and myocardial infarction in longitudinal population-based studies (55, 56). A meta-analysis of longitudinal studies found that an increase of 0.10 mm in CIMT, age- and gender- adjusted relative risk for myocardial infarction was 1.15 (CI% 1.12–1.17) and relative risk for stroke was 1.18 (95% CI 1.16–1.21)(57). Therefore, SSc patients may have an increased risk of myocardial infarction and stroke compared to healthy controls, and longer disease duration of SSc may be associated with increased risk of atherosclerosis in SSc.

Cerebrovascular atherosclerosis also appears to be increased in SSc. Intracerebral calcification and white matter hyperintensities are independent risk factors for stroke and mortality (58). All studies that assessed intracerebral calcification or white matter hyperintensities in SSc showed an increased prevalence when compared to controls. Peripheral vascular atherosclerosis was more prevalent among SSc subjects than in controls. Studies showed increased atherosclerosis in renal vasculature and ulnar arteries of SSc subjects in comparison to controls.

Flow-mediated dilation (FMD) assesses endothelial dysfunction, a contributor to the pathogenesis of atherosclerosis. A low brachial FMD, in particular, is an independent predictor of cardiovascular risk(12). Most (71%) of FMD studies found significantly lower brachial FMD in SSc when compared to controls. Our meta-analysis of FMD studies demonstrated a significantly lower FMD in SSc when compared to controls with a mean difference of −3.01% (95% CI −5.44, −0.69). The decreased FMD in SSc patients compared to controls is consistent with other high risk populations such as familial hypercholesterolemia (−5.31%) and familial combined hyperlipidemia (−3.60%)(54). FMD correlates with cardiovascular risk and a meta-analysis involving 5,547 subjects found that higher FMD was protective against future cardiovascular events(59). For every 1% increase in FMD, the relative risk of cardiovascular events was 0.87 (95% CI 0.83–0.91). Therefore, lower FMD in SSc subjects may confer increased risk of cardiovascular events.

The etiology of atherosclerosis in SSc is unknown, but may be secondary to multiple factors including traditional cardiovascular risk factors, increased endothelial damage, and disease specific factors such as medications. The literature shows that both traditional and novel biomarkers of atherosclerotic risk, such as homocysteine(21), lipid profiles(60), and oxidized low-density lipoprotein (oxLDL) (61) are dysfunctional in SSc. Abnormally functioning piHDL has been associated with atherosclerosis in the general population and in subjects with SLE or RA(7, 62). In a pilot study performed by our group comparing 17 patients with SSc and 17 age, sex, and ethnicity-matched controls, five patients with SSc (29%) had detectable levels of piHDL compared with none of the controls(P=0.06) (21). The oxidation of LDL plays a key role in the pathogenesis of atherosclerosis, and oxLDL molecules are believed to be more inflammatory than native LDL(61). LDL of SSc patients may be more susceptible to oxidation when compared to patients with primary Raynaud's phenomenon and healthy controls(63) and higher levels of oxLDL antibodies are found in patients with SSc (64, 65).

Our study has many strengths. We performed a systematic review of the literature that expanded the number of identified studies compared to previous meta-analyses on this topic. Whereas the study by Tyrrell and colleagues identified 6 manuscript pertaining to atherosclerosis in SSc vs. controls(11), our search found 14 relevant CIMT studies. We also performed meta-analysis in FMD studies and assessed the prevalence of atherosclerosis in the cerebrovascular, coronary, and peripheral vasculature. In addition, we performed a meta-regression of the CIMT studies to explore reasons for marked heterogeneity. When we accounted for SSc disease duration and difference in average age between SSc and controls, this led to a significant decline in the heterogeneity by 37% and 62%, respectively. We included the technical aspects of ultrasonography (where probe is placed on the carotid artery segment, whether one or both sites are assessed, B- vs. M-mode) for assessment of CIMT in our meta-regression model. Tyrrell et al recently assessed this in their meta-analysis and showed no significant contribution of measurement issues to the underlying heterogeneity.

Our study is not without limitations. First, there is always a risk of publication bias. We formally assessed this using funnel plot and did not find any evidence of publication bias. Second, we could not conduct a multivariable meta-regression due to small number of studies. Although disease duration was associated with an increased risk of CIMT, we did not adjust for age and other variables (such as smoking) known to be associated with increased atherosclerosis. Third, many of the studies did not control for factors which may impact risk of atherosclerosis such as smoking history, disease activity, disease duration, or SSc disease subtype. This may have resulted in bias in the findings as risk factors such as smoking has been correlated with increased vascular complications in a recently published large SSc registry(66). Fourth, there were a higher percentage of limited vs. diffuse SSc subjects in the carotid and FMD studies. Selection of patients based upon SSc subtype within individual studies may have biased the results as subjects with limited disease are thought to have more vasculopathy and other vascular complications(67). Finally, we were unable to control for temporal trends that may have resulted in differences in ultrasound techniques in the studies or changes in SSc disease (such as patients living longer lives or a reduction in renal crisis) that may impact the rate of atherosclerosis found amongst SSc patients.

In conclusion, SSc is associated with an increased of atherosclerosis when compared to age- and sex-matched controls. Further research in the mechanism of increased risk of atherosclerosis in SSc is warranted.

Acknowledgments

We thank Christopher Denton, M.D., PhD, M.E. Hettema, M.D., Ph.D., Pascal Tyrrell, Ph.D., and Serena Vettori, M.D.for sharing their data.

Dr. Karen Au was supported by American College of Rheumatology (Physician Scientist Development Award) and the Scleroderma Foundation. Dr. Dinesh Khanna was supported by a National Institutes of Health Award (NIAMS K23 AR053858-04).

Appendix 1

Search strategy: (“Scleroderma, Systemic”[Mesh] OR “scleroderma”[text word] OR “CREST syndrome”[text word] OR SSc[text word] OR “systemic sclerosis”[text word]) AND (“Vascular Diseases”[Mesh] OR “vascular disease”[text word] OR “vascular diseases”[text word] OR “coronary artery disease”[text word] OR “coronary artery diseases”[text word] OR “cardiovascular disease”[text word] OR “cardiovascular diseases”[text word] OR “peripheral vascular disease”[text word] OR “peripheral vascular diseases”[text word] OR “carotid ultrasound”[text word] OR “carotid ultrasounds”[text word] OR “carotid ultrasonography”[text word] OR “carotid imaging”[text word] OR “carotid doppler”[text word] OR IMT[text word] OR “intimal medial thickness”[text word] OR “coronary calcium score”[text word] OR angiograph*[text word] OR angiogram*[text word] OR “ankle brachial index”[text word] OR ABI[text word] OR plaque*[text word] OR “raynauds disease”[text word] OR “raynaud disease”[text word] OR “raynaud's disease”[text word] OR “raynauds phenomenon”[text word] OR “raynaud phenomenon”[text word] OR “raynaud's phenomenon”[text word]) AND English[lang] NOT (“animals”[MeSH] NOT “humans”[MeSH])

Appendix 2

Carotid studies for meta-analysis

StudyUltrasound modeSegmentsIMT measurement
Bartoli 2007 (26)B-modebifurcation of CCAfar wall, bilateral
Bartoli 2007 (25)NAbifurcation of CCAfar wall, bilateral
Cheng 2003(22)B- and M-modeCCAfar wall, left or right
Hettema 2008(29)B-modeCCAfar wall, left side
Kaloudi 2007(27)NAbifurcation of CCAfar wall, bilateral
Kumar 2010(32)NACCANA
Kawasaki 2005(24)NACCAposterior wall, right side
Lekakis 1998(21)B-modeCCAfar wall, bilateral
Nordin 2009(31)B-modeNANA
Roustit 2008(30)B-modeCCAbilateral
Szucs 2007(28)NACCAfar wall, bilateral
Tsifetaki 2010(33)B-modeCCAfar wall
Vettori 2010(34)NACCAfar wall, bilateral
Zakopoulos 2003(23)NACCA or ICAfar wall, bilateral

Appendix 3

Meta-analysis sensitivity analysis – reports summary mean difference estimate when each study is omitted

Study omittedCoef.95% CI
Bartoli 2007 (27)0.11(0.04, 0.17)
Bartoli 2007 (26)0.11(0.04, 0.17)
Cheng 2003(23)0.12(0.06, 0.18)
Hettema 2008(30)0.11(0.05, 0.18)
Kaloudi 2007(28)0.10(0.04, 0.17)
Kumar 2010(33)0.10(0.05, 0.15)
Kawasaki 2005(25)0.12(0.06, 0.18)
Lekakis 1998(22)0.10(0.04, 0.16)
Nordin 2009(32)0.13(0.07, 0.18)
Roustit 2008(31)0.12(0.06, 0.18)
Szucs 2007(29)0.11(0.05, 0.18)
Tsifetaki 2010(34)0.11(0.04, 0.17)
Vettori 2010(35)0.12(0.06, 0.18)
Zakopoulos 2003(24)0.11(0.05, 0.18)

Combined0.11(0.05, 0.17)

Appendix 4

Univariate meta-regression analysis for CIMT

Nβ coefficient (95% CI) [p-value]T2%(ΔT2)
Intercept only80.124 (0.057, 0.191 [<.001]0.0073Reference
Disease duration80.016 (−0.001, 0.033 [0.062]0.0046−37.0
Difference in female%80.345 (−0.884, 1.574 [0.582]0.0067−8.2
Difference in mean/median age80.022 (0.001, 0.044 [0.041]0.0028−61.6

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