Rheumatic disease and carotid intima-media thickness a systematic review and meta-analysis

Clinical and Population Studies Rheumatic Disease and Carotid Intima-Media Thickness A Systematic Review and Meta-Analysis Pascal N. Tyrrell, Joseph Beyene, Brian M. Feldman, Brian W. McCrindle, Earl D. Silverman, Timothy J. Bradley Objective—To perform a systematic review and meta-analysis to examine whether rheumatic disease is associated with an increased carotid intima-media thickness (CIMT; increasingly used as a surrogate marker for atherosclerosis) when compared with healthy control subjects. Methods and Results—A prespecified search strategy was used to identify relevant studies in the MEDLINE and EMBASE databases (January 1, 1986 to December 31, 2008). Methodological quality was assessed using the Newcastle-Ottawa score for observational studies. A total of 68 controlled comparisons from 60 different studies were reviewed: 25 (37%) on rheumatoid arthritis, 24 (35%) on systemic lupus erythematosus, 6 (9%) on systemic sclerosis, and 13 (19%) on other rheumatic diseases. Random-effects meta-regression analysis was performed. The estimated summary effect size between control and study subject CIMT measurement comparisons, with preexisting cardiovascular disease excluded, was 0.64 (95% CI, 0.46 to 0.82). This represented an overall absolute mean difference of 0.06 mm (95% CI, 0.05 to 0.06 mm). Preexisting cardiovascular disease, rheumatic disease type, and disease duration contributed to heterogeneity. Conclusion—Accelerated atherosclerosis is a common complication of autoimmune rheumatic diseases, with early changes seen even in pediatric patients. CIMT was significantly increased in rheumatic disease populations. Future studies need to use a standardized protocol to ensure clinically meaningful results when measuring CIMT as a surrogate for premature atherosclerosis. (Arterioscler Thromb Vasc Biol. 2010;30:1014-1026.) Key Words: rheumatic disease 䡲 carotid intima media thickness 䡲 atherosclerosis

B

eginning in the early 1970s, accelerated atherosclerosis leading to premature cardiovascular disease (CVD) began to be recognized as a significant cause of morbidity and mortality in autoimmune diseases and in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in particular.1–3 This was initially believed to be due to traditional risk factors for atherosclerosis and the use of certain drugs, specifically corticosteroids. However, more recently, it has been shown that traditional risk factors alone cannot explain the extent of observed premature atherosclerosis and that the chronic inflammation seen in patients with autoimmune diseases is an important contributing factor.4 It has also been demonstrated that the atherosclerotic process starts in childhood5,6 and that chronic inflammation, as demonstrated by an elevated C-reactive protein level, leads to early CVD.7 The results of a recent systematic review8 showed that RA is associated with a 60% increase in the risk of CVD-related death. Furthermore, a recent comparative study9 between RA

and diabetes mellitus suggested that preclinical atherosclerosis appears to be of equal frequency and severity, and that CVD risk factors in those with RA may need to be targeted as aggressively as in patients with diabetes. The identification of subclinical atherosclerosis before cardiovascular or cerebrovascular events is needed to allow the clinician to design preventive therapy.

See accompanying article on page 892 Noninvasive surrogate markers of early atherosclerosis have been developed to allow the early detection of atherosclerosis before overt disease. High-resolution ultrasonographic measurement of the carotid intima-media thickness (CIMT) is one such method. Multiple studies have shown that changes in CIMT can be used as a surrogate end point for determining the success of interventions to decrease the risk of CVD. A recent systematic review and meta-analysis10 has shown that CIMT can be used as a predictor of future vascular

Received on: October 5, 2009; final version accepted on: January 15, 2010. From the Division of Rheumatology (P.N.T., B.M.F., E.D.S.), The Hospital for Sick Children, Toronto, Ontario, Canada; the Child Health Evaluative Sciences Program (J.B., B.M.F., B.W.M.), The Hospital for Sick Children, Toronto, Ontario, Canada; the Departments of Health Policy, Management and Evaluation (J.B., B.M.F., B.W.M.), University of Toronto, Toronto, Ontario, Canada; the Dalla Lana School of Public Health (J.B., B.M.F.), University of Toronto, Toronto, Ontario, Canada; the Department of Pediatrics (B.M.F., B.W.M., E.D.S., T.J.B.), University of Toronto, Toronto, Ontario, Canada; the Division of Cardiology (B.W.M., T.J.B.), The Hospital for Sick Children, Toronto, Ontario, Canada; and the Department of Immunology (E.D.S.), University of Toronto, Toronto, Ontario, Canada. Correspondence to Earl Silverman, MD, FRCPC, Division of Rheumatology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8. E-mail [email protected] © 2010 American Heart Association, Inc. Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org

DOI: 10.1161/ATVBAHA.109.198424

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Rheumatic Disease and Carotid Intima-Media Thickness

events in otherwise healthy individuals. In particular, it was shown that for an absolute CIMT difference of 0.1 mm, the future risk of myocardial infarction increases by 10% to 15%, and the stroke risk increases by 13% to 18%. The aims of this systematic review and meta-analysis were as follows: (1) to examine whether rheumatic diseases are associated with an increased CIMT when compared with healthy control subjects and (2) to provide summary estimates for the effect size for all populations together and then stratified by preexisting CVD and rheumatic disease type.

Methods Search Strategy A prespecified search strategy was used to identify when CIMT first appeared in the literature, including relevant studies in the MEDLINE (January 1, 1986 to December 31, 2008) and EMBASE (January 1986 to December 2008) databases. The keywords for the searches were as follows: carotid intima-media thickness; flowmediated dilatation and pulse wave velocity and myocardial infarction; stroke; cardiovascular disease; carotid artery disease; and death and rheumatic disease. Variants for all keywords were used to increase the number of studies returned by the search. Flowmediated dilatation and pulse wave velocity were included as keywords in the search because these 2 modalities are often used along with CIMT in study protocols; this helped to minimize the chances of missing a relevant article. The references in the identified or related articles were then manually reviewed in the search for other relevant citations. All resulting articles were then screened for CIMT measures and the inclusion of healthy control groups.

Inclusion Criteria The inclusion criteria were as follows: (1) cohort or cross-sectional studies with data on both patients diagnosed as having a rheumatic disease and healthy age- and sex-matched controls and (2) use of high-resolution ultrasonography to measure CIMT. All subjects diagnosed as having rheumatic diseases needed to fulfill the standard accepted diagnostic criteria, and healthy controls needed to be clearly described to be included in our analysis. Final inclusion of the studies was determined by both reviewers independently (P.N.T. and T.J.B.). If a study was reported in more than 1 publication, we considered all publications for data abstraction; however, only 1 report was included in our study. If a given publication included several groups of patients, the study yielded a corresponding number of comparisons in our database. The 6 publications that were not available in English were assessed, and data were extracted with the help of a translator. In 5 publications that did not contain all the information necessary for meta-analysis and/or quality assessment, missing information was requested directly from the authors.

Data Extraction The quality of the studies was assessed and scored by 2 of us (P.N.T. and T.J.B.) using the Newcastle-Ottawa quality assessment scale (NOS) for observational studies. From each study, the following data items were extracted: study design, recruitment and number of patients, rheumatic disease studied, disease duration, inclusion or exclusion of patients with preexisting CVD, sex and age distribution, mean and SD CIMT, and ultrasonographic method, including type (B or M mode), location of measurements (common carotid artery [CCA], bifurcation carotid artery, or internal carotid artery; right or left side; and near or far wall), inclusion or exclusion of plaque in CIMT measurement, interrater and/or intrarater variation, and blinding. In case of uncertainty, issues were resolved by consensus with 1 of us (E.D.S.).

Statistical Analysis The effect size for each study was calculated using the standardized mean difference, Cohen’s D11: CD⫽m[e]⫺m[c]/SD[pooled] with

1015

SD[pooled]⫽SQRT(((n[e]⫺1)*SD[e] 2 ⫹(n[c]⫺1)*SD[c] 2 )/(N)) with e⫽exposed and c⫽control. These estimates and 95% CIs were illustrated with a Forest plot and graphed by disease type. Pooled estimates were calculated using a fixed-effects model (to test and assess the level of heterogeneity) and a random-effects model12 to obtain an average effect size and to study heterogeneity. Heterogeneity was tested with the ␹2 heterogeneity statistic Q and quantified using I2, which is a measure that describes the percentage of total variation across comparisons that is the result of heterogeneity rather than chance.13 We considered I2 values of 25%, 50%, and 75% to indicate low, moderate, and high variation, respectively.14 Metaregression was performed modeling the following independent variables: age, sex (female to male ratio), disease duration, NOS score, disease type (RA, SLE, systemic sclerosis [SSc], and other rheumatic disease), exclusion or nonexclusion of plaque in the CIMT measurement, and exclusion or nonexclusion of subjects diagnosed as having preexisting CVD. This last parameter was tested in a multivariable model adjusting for age, sex ratio, and disease duration. Continuous variables were centered to their respective group mean before being entered into meta-regression analysis. Heterogeneity was then further assessed by between-study variance (␶2), obtained from a mixed-effects model with fixed covariate effects and random study effects. Publication bias was assessed graphically using an inverse SE funnel plot and graphed by disease type. Pooled estimates, meta-regression, and other statistical analyses were performed using commercially available software (SAS 9.2; SAS Institute Inc, Cary, NC). Plots were obtained using MIX version 1.7.15

Results Studies and Subjects The search was performed in December 2008 and yielded 1030 articles (Figure 1). Of the original 1030 articles reviewed, 271 were duplicates. A total of 679 articles were excluded for the following reasons: (1) the study did not include patients with a clearly defined rheumatic disease, (2) the study did not include CIMT measurements, or (3) the study did not include a control group. The remaining 80 articles were retrieved for detailed analysis. Six articles did not contain a comparable healthy control group, 11 contained studies based on previously published data, and 5 had missing data. Of the latter group, only 2 sets of authors responded to our request for information; therefore, the 3 other articles (with missing data) were excluded. Sixty studies were available for assessment, comprising 68 comparisons and 6854 subjects (3761 cases and 3093 controls).16 –75 Translation was required for 8 articles: 1 German,31 3 Italian,30,35,52 2 Polish,25,44 1 Spanish,69 and 1 Russian.61 Five articles were submitted to review for arbitration by 1 of us (E.D.S.). The median age of the study subjects was 45 years (range, 11 to 79 years), with most subjects being female (median, 89%; range, 39% to 100%). Most comparisons (80%) clearly indicated matching of cases and controls by sex and age by design; the remainder showed no significant difference between study groups. Of 68 comparisons, 11 received a minimum of 5 of 9 possible stars (median, 7; range, 5 to 9) of the Newcastle-Ottawa quality assessment scale. Thirty-two comparisons had a score of 8 of higher. The 68 comparisons were divided as follows: 25 (37%) RA, 24 (35%) SLE, 6 (9%) SSc, and 13 (19%) other rheumatic diseases (including 1 ankylosing spondylitis, 1 Behc¸et disease, 1 connective tissue disorder, 2 familial Mediterranean fever, 1 giant cell arteritis, 4 primary antiphospholipid syndrome, 1 psoriatic arthritis, 1 Sjogren syndrome, and 1 Wegener granulomatosis). Only 3

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Arterioscler Thromb Vasc Biol

May 2010

Figure 1. Flowchart of selected articles.

comparisons included children (2 pediatric SLE and 1 juvenile idiopathic arthritis).18,61,67 Forty-one comparisons (60%) did not specify exclusion of subjects with preexisting CVD, and 27 comparisons (40%) excluded subjects with preexisting CVD (Table 1).

CIMT Measurements Of the 68 comparisons, 52 (76%) measured CIMT using B-mode ultrasonography and 4 (6%) measured CIMT using M-mode ultrasonography; the remaining comparisons did not specify the mode. Fourteen comparisons (21%) clearly specified that they avoided areas of thickening as the result of atheromatous plaques in the CIMT measurement, 19 (28%) indicated that it was possible that their measurements included areas of plaque, and 35 (51%) did not specify. The location of the measurements (ie, segments: CCA, bifurcation carotid artery, or internal carotid artery; far or near wall; or right or left side), measurements used for the summary CIMT value, and reproducibility (number of observers, blinding, and interrater-intrarater reliability) are also included in Table 1. In 40 (59%) of the 68 comparisons, the study authors reported a statistically significant greater mean CIMT in patients compared with healthy controls, including 17 (41%) of the 41 comparisons with CVD included and 23 (85%) of the 27 comparisons with CVD excluded. When considering the presence of plaques, 29 (66%) of the 44 comparisons that reported the prevalence of plaques found a significant difference between patients and controls. No agreement between the 2 methods (CIMT measure versus plaque prevalence) was found (␬⫽⫺0.045).

A summary estimate of the absolute mean difference in CIMT between case and control groups was calculated using a fixed-effects model (overall mean difference, 0.042 mm; 95% CI, 0.037 to 0.048 mm) and a random-effects model (overall summary estimate, 0.061 mm; 95% CI, 0.045 to 0.076). To estimate the strength and significance of the relationship of the difference in CIMT, the effect size for all comparisons (Cohen’s D) was calculated and graphically represented in a forest plot by disease type, ordered by author with meta-analysis weight included (Figure 2). The estimated summary effect size calculated by a fixed-effect model was 0.36 (95% CI, 0.31 to 0.41). The overall estimated summary effect size calculated by a random-effect model was 0.47 (95% CI, 0.34 to 0.60) (Table 2). No significant difference between disease types (type 3 test probability value, 0.51) was observed. The summary estimate for SSc comparisons was the largest: 0.58 (95% CI, 0.15 to 1.00). This was followed by RA (0.56; 95% CI, 0.36 to 0.76), other rheumatic disease (0.47; 95% CI, 0.19 to 0.75), and SLE (0.35; 95% CI, 0.14 to 0.55).

Assessment of Heterogeneity and Confounding To assess publication bias, a funnel plot was produced, with comparisons sorted by the inverse SE of the calculated effect size. A slightly positively skewed distribution with larger samples showing smaller effect sizes was observed similarly for all disease types (Figure 3). To further assess this bias, we used the trim-and-fill procedure, which resulted in an adjusted fixed-effects summary estimate for all comparisons

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Tyrrell et al Table 1.

Rheumatic Disease and Carotid Intima-Media Thickness

1017

Characteristics of Abstracted Studies Cases

Population Ankylosing spondylitis

Source

No. (%) of Females

Controls

Age, Mean⫾SD or Median (Range)

No. (%) of Females

Age, Mean⫾SD or Median (Range)

Disease Duration, y

NOS

Sari, 2006

54 (46)

37⫾11

31 (48)

35⫾9

12.4

8

Keser, 2005

114 (40)

38.15⫾9.44

77 (40)

37.20⫾7.87

10.1

9

Connective tissue disorders

Dropinski, 2003

74 (85)

34⫾9

75 (83)

35.0⫾5.5

NA

6

Familial Mediterranean fever

Akdogan, 2006

43 (42)

27.5⫾7.2

29 (52)

29.2⫾6.5

NA

7

Sari, 2007

61 (51)

31.5 (18–54)

31 (48)

31 (22–58)

16.0

8

Gonzalez-Juanatey, 2007

40 (63)

78.6⫾6.5

40 (63)

78.8⫾7.2

NA

8

Pietrewicz, 2007

40 (50)

11 (4–16)

23 (48)

12 (3–17)

NA

8

Bowser, 2008

20 (95)

16.90⫾2.27

20 (95)

16.70⫾2.07

3.3

7

Falaschi, 2000

26 (81)

17.1 (6.2–25.4)

26 (81)

17.1 (6.2–25.4)

5.5

8

4.0

7

Behçet disease

Familial Mediterranean Giant cell arteritis Juvenile idiopathic arthritis Pediatric SLE

Primary antiphospholipid syndrome

Psoriatic arthritis RA

Ames, 2005

20 (65)

35⫾12

20 (65)

34⫾12

Der, 2007

44 (57)

52⫾15

36 (56)

50⫾11

NA

5

NA

7

Roch, 2004

20 (80)

44⫾16

24 (88)

43⫾9

Vlachoyiannopoulos, 2003

33 (100)

33.9⫾7.4

33 (100)

33.3⫾7.9

7.4

6

Gonzalez-Juanatey, 2007

59 (47)

48.8⫾12.4

59 (47)

48.8⫾12.0

7.8

8

Abu-Shakra, 2005

57 (82)

52.1⫾14.6

59 (85)

51.6⫾15.6

12.8

7

Alkaabi, 2003

40 (50)

56 (37–77)

40 (50)

55 (36–73)

15.0

8

Bocci, 2005

32 (88)

50⫾7

28 (86)

48⫾8

11.0

8

Carotti, 2007

40 (68)

59.9⫾11.9

40 (63)

54.2⫾12.3

10.5

7

Ciftci, 2008

30 (27)

43.67⫾9.05

52 (27)

45.33⫾5.36

9.5

8

Coaccioli, 2007

38 (84)

51.70⫾4.40

30 (53)

58.50⫾4.60

12.4

8

Cuomo, 2004

48 (73)

55 (26–69)

22 (73)

50 (28–66)

8.7

9

Daza, 2007

55 (100)

43.64⫾8.39

20 (100)

40.70⫾6.04

11.5

8

102 (88)

59.7 (40–81)

NA

8

⬍1

Del Rincon, 2003

204 (89)

59.6 (40–83)

Georgiadis, 2008

40 (75)

53.10⫾13.40

45 (67)

52.20⫾11.70

Gonzalez-Juanatey, 2003

47 (77)

59.2⫾12.5

47 (74)

60.5⫾12.5

9

15.5

9

8.0

8

Grover, 2006

57 (91)

41.52⫾7.53

45 (89)

39.71⫾6.60

Hannawi, 2007

40 (68)

53 (22–78)

40 (68)

53 (21–80)

Kerekes, 2008

52 (77)

51.20⫾12.30

40 (78)

50.30⫾10.10

10.5

7

Kumeda, 2002

138 (88)

55.0⫾10.7

94 (90)

52.1⫾14.5

NA

9

⬍1

7

Pahor, 2006

70 (100)

42.0⫾5.5

40 (100)

41.7⫾5.4

9.6

Park, 2002

53 (100)

55.0⫾3.2

53 (100)

54.9⫾2.9

4.2

7 8

Pereira, 2008

71 (90)

48.90⫾12.30

53 (87)

45.40⫾9.40

4.1

9

Roman, 2005

80 (99)

45⫾12

105 (95)

47⫾8

NA

7

Roman, 2006

98 (98)

48⫾13

98 (98)

47⫾13

12.3

8

Surdacki, 2007

30 (83)

47⫾12

20 (85)

45⫾10

5.1

9

Vlachoyiannopoulos, 2003

33 (100)

35.4⫾8.5

33 (100)

33.3⫾7.9

6.8

6

Wada, 2005

50 (92)

60.5⫾12.2

30 (93)

60.4⫾12.9

12.4

8

Wallberg Jonsson, 2001

39 (77)

51.6 (38–65)

39 (77)

51.6 (37–65)

21.0

7

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Table 1.

Continued

Manifest CVD Excluded

Segments

Plaques Excluded

Yes

CCA

No

Yes

CCA

Yes

No

CCA, BIF, ICA, or combined

NA

Yes

CCA

Yes

CCA or ICA

May 2010

Type of Ultrasonography

IMT Definition

No. of Readers (Blinded, Yes or No)

NA

Both sides

1 (Yes)

NA

B mode

Far wall and both sides

1 (Yes)

Pearson r⫽0.82

NA

Far wall

NA

NA

NA

NA

Far wall and both sides

NA

NA

NA

NA

Far wall and both sides

1 (Yes)

␬⫽0.81, averaged CCA of IMT

Reproducibility

No

CCA

NA

B mode

Right side only

1 (Yes)

ICC⫽0.86

Yes

CCA

No

B mode

NA

NA

NA

No

CCA

No

B mode

Far wall

1 (Yes)

ICC⫽0.83, coefficient of variation⫽2%(9.9.8)

Yes

CCA

No

B mode

Far wall and both sides

1 (Yes)

Coefficient of variability⫽4.23 ⫾1.69%

No

CCA, BIF, ICA, or separate

No

NA

Far wall and both sides

1 (No)

Coefficient of variation⫽3–4%

No

CCA

NA

NA

Far wall and both sides

NA

NA

No

CCA

No

B mode

NA

NA

NA

No

NA

NA

B mode

Far wall and both sides

NA

Coefficient of variation⫽10.4%

Yes

CCA

NA

B mode

Right side only

1 (Yes)

0.98 correlation coefficient for

No

CCA

NA

B mode

Far wall and both sides

1 (Yes)

CVF interrater⫽8.3%, CV intrarater⫽5.7%

Yes

CCA

NA

B mode

Far wall and both sides

1 (No)

NA

Yes

CCA, BIF, or ICA

No

B mode

NA

NA

NA

No

CCA

Yes

B mode

Far wall

NA

NA

Yes

CCA or BIF

Yes

NA

Far wall and right side only

1 (Yes)

Coefficient of variation⫽1.4%

Yes

CCA, ICA, or ECA

No

NA

Far wall and both sides

2 (Yes)

NA

Yes

CCA

No

B mode

Far wall

1 (Yes)

NA

Yes

CCA

NA

B mode

Far wall, right side only

2 (Yes)

ICC⫽0.94

No

CCA, ICA, or combined

NA

B mode

Near and far wall

1 (Yes)

Intrarater ICC⫽0.99, interrater ICC⫽0.94

Yes

CCA

NA

B mode

Far wall

1 (Yes)

NA

Yes

CCA

NA

B mode

Far wall, right side only

2 (Yes)

ICC⫽0.99

Yes

BIF

NA

B mode

Far wall, both sides

1 (Yes)

NA

No

CCA

Yes

B mode

Far wall, both sides

1 (No)

Coefficient of variation⫽5%

Yes

CCA

No

B mode

Far wall, both sides

1 (No)

NA

Yes

CCA

Yes

B mode

Far wall, both sides

1 (Yes)

Coefficient of variation⫽2.8%

No

CCA

Yes

B mode

Both sides

1 (Yes)

NA

Yes

CCA

NA

B mode

Far wall, both sides

1 (Yes)

ICC⫽0.98

Yes

CCA or BIF

NA

B mode

Both sides

1 (Yes)

NA

No

CCA

Yes

M mode

Far wall, both sides

1 (No)

NA

No

CCA

Yes

M mode

Far wall, both sides

1 (Yes)

NA

Yes

CCA

Yes

B mode

Near and far wall

1 (Yes)

Relative SD: intrarater, 4.9%; interrater, 6.4% Coefficient of variation⫽10.4%

No

NA

NA

B mode

Far wall, both sides

NA

Yes

CCA

Yes

B mode

Both sides

1 (Yes)

NA

No

CCA

NA

B mode

Far wall, right side only

1 (No)

NA (Continued)

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Tyrrell et al Table 1.

Rheumatic Disease and Carotid Intima-Media Thickness

1019

Continued Cases

Source

No. (%) of Females

Sjogren syndrome

Vaudo, 2005

SLE

Bhatt, 2006 De Leeuw, 2006

Population

Controls

Age, Mean⫾SD or Median (Range)

No. (%) of Females

Age, Mean⫾SD or Median (Range)

Disease Duration, y

NOS

37 (100)

48⫾14

50 (94)

31.60⫾10.05

35 (100)

51⫾16

7.3

7

50 (94)

31.30⫾9.78

4.4

72 (88)

7

41⫾12

36 (92)

41⫾12

8.7

6 7

De Leeuw, 2007

55 (85)

43⫾12

55 (85)

43⫾13

12.1

Estevez Del Toro, 2008

51 (90)

37.9 (11.0)

51 (90)

37.8 (11.9)

10.1

7

Fischer, 2006

103 (87)

44.5 (19–76)

30 (80)

42.9 (20–74)

NA

5

Jackson, 2006

32 (100)

47.5⫾9.4

33 (100)

48⫾10

13.0

7

Jimenez, 2005

70 (97)

40.2⫾11.4

40 (100)

42.2⫾11.2

11.6

7

Lopez, 2006

30 (90)

31⫾9

27 (100)

31⫾7

10.0

8

Nomura, 1999

100 (91)

40 (16–69)

66 (100)

40 (19–62)

6.5

5

39⫾15

24 (88)

43⫾9

NA

7

Roch, 2004

12 (100)

Roman, 2003

197 (94)

44⫾13

197 (94)

44⫾12

12.1

8

Roman, 2005

101 (95)

45⫾13

105 (95)

47⫾8

NA

7

Sato, 2007

25 (100)

56.8⫾7.2

22 (100)

57.9⫾7.0

21.2

7

Svenungsson, 2001

26 (100)

52.2⫾8.2

26 (100)

52.3⫾8.2

18.5

8

Svenungsson, 2001

26 (100)

52.2⫾8.2

26 (100)

52.3⫾8.2

18.5

8

Thompson, 2008

217 (100)

45.1⫾10.3

104 (100)

44.3⫾6.8

10.5

8

Wolak, 2004

51 (96)

40.5⫾14.0

47 (96)

41.1⫾14.0

8.7

7

SLE/ anticardiolipin negative

Vlachoyiannopoulos, 2003

33 (100)

32.8⫾8.1

33 (100)

33.3⫾7.9

6.6

6

SLE/ anticardiolipin positive

Vlachoyiannopoulos, 2003

33 (100)

33.1⫾7.6

33 (100)

33.3⫾7.9

6.7

6

Belizna, 2008

58 (62)

29.1⫾10.0

58 (72)

28.1⫾10.0

NA

8

Jimenez, 2005

25 (100)

38.6⫾11.4

40 (100)

42.2⫾11.2

11.6

7

Roch, 2004

14 (93)

43⫾16

24 (88)

43⫾9

NA

7

SLE/secondary antiphospholipid syndrome

SSc

Wegener granulomatosis

Bartoli, 2007

53 (89)

60.40⫾10.68

53 (75)

56.30⫾10.23

9.4

8

Hettema, 2008

49 (84)

55.4⫾11.6

32 (91)

50.9⫾10.1

6.0

7

Lekakis, 1998

12 (100)

49⫾14

12 (100)

49⫾14

13.1

8

Roustit, 2008

42 (90)

51⫾13

33 (91)

52⫾14

5.0

8

Szucs, 2007

29 (86)

51.8⫾10.0

29 (79)

49.3⫾9.6

9.4

7

Zakopoulos, 2003

40 (88)

51.49⫾12.70

45 (87)

48.02⫾12.70

NA

5

Nienhuis, 2007

28 (39)

49⫾9

28 (39)

50⫾9

7.6

6

BIF indicates; CCA, common carotid artery; CVD, cardiovascular disease; ICA, internal carotid artery; ICC, intraclass correlation coefficient; IMT, intima-media thickness; NA, not available; NOS, nitric-oxide synthase; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SSc, systemic sclerosis; WTS.

that remained statistically significant and clinically relevant, with an effect size of 0.13 (95% CI, 0.08 to 0.17). The degree of inconsistency in the comparison results was tested using the Q statistic and measured using I2. A significant Q statistic of 225 (P⬍0.001) and a high level of variation with an I2 of 84% (95%CI, 81% to 87%) were found for the overall fixed model (all comparisons). After finding such a high degree of heterogeneity, we progressed to a random-effects model to further define this heterogeneity. Inconsistency in the comparison results was estimated by ␶2 from the random-effects model. A significant level of heterogeneity was found for the crude model (␶2⫽0.22; 95% CI, 0.15 to 0.35) and was used as the reference level for further modeling (Table 2). To explore possible sources of heterogeneity, we first investigated age,

sex ratio, disease duration, and NOS score independently as possible contributors to between-study variance. None of these 4 variables was found to remain significant in the model. However, disease duration was found to reduce heterogeneity by 22% compared with the crude model. Age, sex ratio, and NOS score barely reduced heterogeneity (range, 1% to 3%). We then considered the methodological factors that could be contributing to heterogeneity. Considering the coronary segment where the IMT was measured, a sensitivity analysis of the 41 comparisons that measured the CIMT in the CCA segment exclusively (ie, excluding the 27 comparisons that did not clearly indicate the measured segment or that included multiple measured segments) resulted in a small increase in

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Table 1.

Continued

Manifest CVD Excluded

Segments

Plaques Excluded

May 2010

Type of Ultrasonography

IMT Definition

No. of Readers (Blinded, Yes or No)

Reproducibility NA

No

CCA, BIF, ICA, or combined

NA

NA

Far wall, both sides

2 (Yes)

Yes

CCA

Yes

B mode

Far wall, both sides

NA

NA

No

NA

NA

B mode or WTS

Far wall, left side only

NA

NA

No

NA

No

B mode

NA

NA

NA

No

CCA, BIF, or ICA

NA

B mode

NA

1 (Yes)

NA

No

NA

No

B mode

NA

NA

NA

No

CCA

Yes

B mode

Both sides

NA

ICC⫽0.92 (95% CI, 0.84–1.00)

No

CCA, BIF, or ICA

NA

NA

Both sides

1 (No)

NA

Yes

CCA or ICA

NA

B mode

Far wall, both sides

1 (Yes)

NA

No

CCA

NA

B mode

Far Wall, right side only

1 (No)

NA

No

CCA

No

NA

NA

NA

NA

No

CCA, ICA, or ECA

NA

M mode

Both sides

1 (Yes)

NA

No

CCA

No

M mode

Far Wall, both sides

1 (No)

NA

No

CCA

NA

NA

Far Wall, both sides

NA

NA

No

NA

NA

B mode

NA

NA

NA

Yes

NA

NA

B mode

NA

NA

NA

No

CCA, BIF, or ICA

NA

B mode

NA

2 (Yes)

ICC intrarater, ⱖ0.90; interrater⫽0.87

No

CCA

NA

B mode

Far wall, both sides

1 (Yes)

Coefficient of variation interrater, 8.30%; intrarater, 5.7%

No

NA

NA

B mode

Far wall, both sides

NA

Coefficient of variation ⫽10.4%

No

NA

NA

B mode

Far wall, both sides

NA

Coefficient of variation⫽10.4%

No

CCA, BIF, or ICA

NA

B mode

Both sides

1 (Yes)

NA

No

CCA, BIF, or ICA

NA

NA

Both sides

1 (No)

NA

No

CCA

No

B mode

NA

NA

NA

No

CCA or BIF

NA

B mode

Far wall, both sides

NA

NA

No

CCA

NA

B mode

Far wall, left side only

1 (Yes)

NA NA

No

CCA

No

B mode

Far wall, both sides

2 (Yes)

Yes

CCA

Yes

B mode

Both sides

NA

NA

Yes

CCA

No

B mode

Far wall, both sides

NA

NA

No

CCA or ICA

No

B mode

Far wall, both sides

1 (No)

NA

No

CCA

No

B mode

Far wall, left side only

NA

NA

the summary estimate of effect size (2%) and no change in residual heterogeneity (data not shown). Considering the ultrasonographic imaging mode used, a sensitivity analysis of the 52 comparisons that specifically used B-mode ultrasonography (excluding the 4 comparisons that used M-mode ultrasonography and the 12 comparisons that did not clearly indicate the method used) resulted in a small increase in summary effect size (6%) but a 14% reduction in residual heterogeneity (data not shown). Considering that the 23 comparisons that clearly indicated areas of plaque were excluded from the CIMT measurement relative to the 45 comparisons that did not, the summary effect size was no different in the model (0.43 versus 0.55; P⫽0.39) and there

was little change in residual heterogeneity (Table 2). Finally, considering the 27 comparisons with preexisting CVD excluded relative to the 41 comparisons not excluded, the summary effect size was increased by 91% (0.65 versus 0.34; P⫽0.01), with an 11% reduction in residual heterogeneity (Table 2). When stratifying preexisting CVD excluded by disease type, the 27 comparisons were as follows: 16 of 25 were RA, 4 of 24 were SLE, 2 of 6 were SSc, and 5 of 13 were other rheumatic disease. The ratios between disease types differed significantly (P⫽0.009). When considering both factors (preexisting CVD excluded and disease type) in the model together, preexisting CVD excluded remained significant (P⫽0.03) and disease type did not (P⫽0.89).

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Figure 2. Meta-analysis showing the effect size (Cohen’s D) of the difference in CIMT between patients with rheumatic disease and control subjects. Plots are separated into major rheumatic disease populations: RA, SLE, SSc, and other rheumatic disease. The random-effects weight (percentage) of each included comparison is listed to the right of each plot.

Residual heterogeneity was reduced by 16% (data not shown). We then considered a multivariable model that included preexisting CVD excluded as the factor of interest and adjusted for age, sex ratio, and disease duration (Table 2). The difference between summary estimates with preexisting CVD excluded versus not remained significant (0.64 versus 0.27; P⫽0.004); residual heterogeneity was reduced by 43%. To obtain an absolute mean difference representative of the studies included in our analysis, we performed a fixed-effect meta-analysis of the mean difference of comparisons, with preexisting CVD excluded, and obtained a summary estimate of 0.06 mm (95% CI, 0.05 to 0.06 mm). This absolute difference suggests that the effect of rheumatic disease on

CIMT with preexisting CVD excluded can be estimated to be a 7- to 8-year increase in age when assuming a linear relationship between age and CIMT thickening (where with every 10-year increase, a thickening of 0.079 mm can be expected).76 When the analysis was performed with only comparisons that excluded pre-existing CVD, the resulting summary estimates were markedly increased. When considering pediatric populations who, because of the young age of the subjects, are inherently excluding preexisting CVD, the effect sizes were large and similar for both studied diseases: two pediatric SLE studies, 0.73 (95% CI, 0.17 to 1.30)18 and 0.66 (95% CI, 0.03 to 1.30)67 and one study of juvenile idiopathic arthritis, 0.74 (95% CI, 0.19 to 1.30).61

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Table 2.

Meta-Regression Analysis Summary of the 68 Comparisons

Risk Factor

May 2010

␤ Coefficient (95% CI) 关P value兴

Mean Effect Size (95% CI)

␶2 (95% CI) 关P Value兴

⌬␶2 (%)

0.47 (0.34 to 0.60) 关⬍0.001兴

0.47 (0.34 to 0.60)

0.22 (0.15 to 0.35) 关⬍0.001兴

Reference

Univariable Models Intercept only Plus age

⫺0.006 (⫺0.017 to 0.005) 关0.32兴

0.22 (0.15 to 0.34) 关⬍0.001兴

Plus sex

⫺0.409 (⫺1.124 to 0.306) 关0.26兴

0.21 (0.15 to 0.34) 关⬍0.001兴

⫺3

Plus disease duration (n⫽56)

⫺0.012 (⫺0.041 to 0.017) 关0.42兴

0.17 (0.11 to 0.30) 关⬍0.001兴

⫺22

0.067 (⫺0.056 to 0.190) 关0.28兴

0.22 (0.15 to 0.34) 关⬍0.001兴

⫺2

Plus NOS, quality score

⫺2

Plus disease type RA

⫺0.022 (⫺0.491 to 0.448) 关0.93兴

0.56 (0.36 to 0.76)

0.21 (0.14 to 0.34) 关⬍0.001兴

SLE

⫺0.300 (⫺0.702 to 0.243) 关0.34兴

0.35 (0.14 to 0.55)

NA

Other rheumatic

⫺0.104 (⫺0.614 to 0.405) 关0.69兴

0.47 (0.19 to 0.75)

NA

0.58 (0.15 to 1.00)

NA

SSc

Reference

⫺4

Plus area of plaque Excluded from the measure

⫺0.026 (⫺0.329 to 0.151) 关0.87兴

0.45 (0.18 to 0.72)

0.22 (0.15 to 0.35) 关⬍0.001兴

Reference

0.47 (0.33 to 0.62)

NA

⫺0.314 (⫺0.557 to ⫺0.071) 关0.01兴

0.65 (0.47 to 0.85)

0.19 (0.13 to 0.31) 关⬍0.001兴

Reference

0.34 (0.19 to 0.50)

NA

Included in the measure

0

Plus preexisting CVD Excluded from the study Not excluded from the study

⫺11

Multivariable Model (n⫽56) Plus preexisting CVD Excluded from the study

⫺0.371 (⫺0.620 to ⫺0.122) 关0.004兴

0.64 (0.46 to 0.82)

0.13 (0.08 to 0.24) 关⬍0.001兴

Not excluded in the study

Reference

0.27 (0.11 to 0.42)

NA

0.009 (⫺0.003 to 0.022, 0.144)

NA

NA

NA

Plus age Plus sex Plus disease duration

⫺43

0.201 (⫺0.517 to 0.919, 0.583)

NA

NA

NA

-0.016 (⫺0.041 to 0.017, 0.261)

NA

NA

NA

CVD indicates cardiovascular disease; NA, not available; NOS, nitric-oxide synthase; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SSc, systemic sclerosis.

Discussion In this article, we reviewed data from 68 comparisons of populations with rheumatic disease populations versus controls, including 6864 subjects who had CIMT measurements reported. Although CIMT is a known strong predictor of cardiovascular events in the general population,10 and has been predominantly reported in the literature on patients with rheumatic diseases, it has been suggested that detection of carotid plaques by ultrasonography is a more reliable predictor of cardiovascular events.77 We observed in 59% of the 68 reviewed comparisons that the study authors reported a statistically significant greater mean CIMT in patients with rheumatic diseases compared with healthy controls and a similarly increased prevalence of plaques in 66% of the 44 reviewed comparisons that reported the presence of carotid plaque. Interestingly, no agreement between the 2 methods was observed; however, this likely reflects the considerable differences in methodological approach to inclusion or exclusion of plaques in the CIMT measurement between different study authors. Furthermore, because each rheumatic disease may differ in the amount and type of inflammation, active inflammatory plaques could be fewer but potentially larger and/or more destructive. In this case, patients would potentially have an increased CIMT but fewer plaques. Significant heterogeneity existed between comparisons; therefore, a random-effects analysis was chosen to best model

and explore sources of this heterogeneity. The best metaregression analysis model of the effect size between the CIMT of patients with rheumatic diseases compared with healthy controls adjusted for age, sex ratio, and disease duration. Patients with preexisting CVD were excluded. The resulting significant summary effect size estimate of 0.64 (95% CI, 0.46 to 0.82) represented an overall mean difference of 0.055 mm (95% CI, 0.048 to 0.063 mm). The effect of rheumatic disease on CIMT when excluding preexisting CVD can be estimated to be a 7- to 8-year increase in age. When considering the effect of including subjects with preexisting CVD, 59% of reviewed comparisons reported a greater mean CIMT in patients with rheumatic diseases; this occurred in 85% of comparisons with CVD excluded and in only 41% of comparisons with CVD included. This was similarly reflected in our random-effects model, with an increase in effect size and a decrease in heterogeneity for the comparisons with CVD excluded. This would suggest that the inclusion of subjects with preexisting CVD might significantly confound the interpretation of the independent effect of rheumatic diseases on CIMT. Although there are too few pediatric comparisons for any conclusive results, this would be consistent with the generally larger effect sizes seen in the 3 pediatric comparisons included, with the lowest possible risk for premature atherosclerosis being the result of Framingham risk factors.5

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Figure 3. Funnel plot of the effect size (Cohen’s D) of the difference in CIMT between patients with rheumatic disease and control subjects by inverse SE. Lines represent the meta-analysis summary estimate and the 95% CI. Plots are separated into major rheumatic disease populations: RA, SLE, SSc, and other rheumatic disease.

The 3 most frequently included rheumatic diseases (ie, RA, SLE, and SSc) had different overall effect sizes. However, these were not as significantly different as the betweencomparison variability, which was high. Also, the number of comparisons per group differed substantially. However, the multiple rheumatic diseases included did contribute to heterogeneity overall. This may be due to the effect of chronic inflammation not being uniform across the rheumatic diseases and subgroups included and the potential for overlap in the diagnostic criteria of some of the rheumatic diseases included. Also, there are many possible reasons to expect differences4 between disease types because each disease has a different amount and/or type of chronic inflammation, which has been shown to be an important factor leading to premature atherosclerosis. Although all 3 diseases may involve blood vessel inflammation, the type and degree of inflammation differ among the disease. Given that SSc, unlike RA or SLE, always involves some degree of vascular involvement, it may not be surprising that it had 1 of the largest effect sizes. Finally, although the estimate for SLE was the smallest, this may have been confounded again by the fact that too few comparisons excluded subjects with preexisting CVD compared with the other diseases. Other possible sources of variability include carotid ultrasonographic methods. Comparisons differed by carotid segment investigated; whether both sides or a single side was measured; whether the far wall, the near wall, or both walls were measured; whether the final result was expressed as a

mean or a maximal IMT; and which ultrasonographic imaging mode was used (B versus M mode). Reproducibility also has improved steadily since the initial development of the techniques, but it is infrequently reported (34% of comparisons in this review). We only considered comparisons that included healthy age- and sex-matched controls, and most measured the CCA segment and calculated the mean CIMT with a minimum of 3 measures. However, although it is beyond the scope of this review to assess differences between ultrasonographic measurement techniques, it is of interest that most of these technical considerations made little difference and only B- versus M-mode ultrasonography contributed to the observed heterogeneity of the model. We support the suggestion by others10,78,79 of the need to use a standardized protocol for future studies to ensure clinically meaningful results. Measuring the CIMT in areas of thickening as the result of atheromatous plaques is of definite concern. Although our analysis showed little difference in the summary effect size between healthy and rheumatic disease populations when plaque was included or excluded in the measure, the absolute CIMT measures were somewhat inflated when areas of plaques were potentially included. In future studies, this again stresses the need for a standardized protocol and approach to distinguishing early atherosclerotic plaque formation from thickening of IMT. This systematic review and meta-analysis clearly demonstrated that there was a significant increase in CIMT in

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May 2010

rheumatic disease populations compared with age- and sexmatched healthy controls. However, some limitations are apparent. First, the choice of “healthy controls” as the comparator group comes with challenges that need to be considered. Most healthy controls were volunteers and were generally not described with the same rigor as the cases. This can be problematic when the study design has as its purpose to elicit differences between these groups. Population controls have also served as the comparator group, especially for studying the effects of plaque, and should be considered as a viable alternative. Second, some publication bias was present. This bias is often accentuated when the disease of interest is relatively rare (often the case in rheumatic diseases) because studies in these situations often have a small sample size, with increased variability leading to insignificant comparisons that ultimately remain unpublished.80,81 With the large potential sources of heterogeneity that existed between comparisons, sampling bias could become a factor if the reason for the heterogeneity (rheumatic disease population, exclusion of preexisting CVD, or disease duration) could influence the authors’ decision on how to report (ie, mean or maximal IMT) the results. We are not overly concerned with this potential problem because most comparisons reported a mean CIMT or both. Finally, although most studies were assessed to be of acceptable quality, it was the comparability of the methodological considerations (ie, independent blind assessment) that mostly affected the NOS score. As previously suggested, a standardized method would lead to less variation and, therefore, better summary effect size estimates. In conclusion, CIMT was significantly increased in rheumatic disease populations compared with age- and sexmatched healthy populations in our systematic review and meta-analysis of 68 comparisons. The type of rheumatic disease, preexisting atherogenic risk factors, and disease duration were important in considering the utility of CIMT as a surrogate for premature atherosclerosis. Because cardiovascular events are rare in children, CIMT measurements may be particularly useful in younger populations as an end point for epidemiological and treatment studies.

Acknowledgments We thank Tyla Holmes and Cheri Nichol, librarians at The Hospital for Sick Children, for their assistance in preparing and performing the database searches; Brian Kim and Sunita Sidhu for their help in data collection, validation, and management; Drs Roman Jurˇencˇa´k, Andrea Mazˇa´rova´, and Susanne Benseler for the translation of articles not available in English; and Drs Abu-Shakra, MD, Kotsis, MD, and Yavuz, MD for responding to our request for further information.

Sources of Funding This study was supported in part by grants from the Heart and Stroke Foundation of Ontario (Drs Silverman, MD, Bradley, MD, Beyene, PhD). Mr Tyrrell was supported by a doctoral award from the Heart and Stroke Foundation of Canada; Dr Beyene, PhD is supported by the Canadian Institutes of Health Research and Natural Sciences and Engineering Research Council of Canada for his work in statistical methods; and Dr Feldman, MD holds the Canada Research Chair in Childhood Arthritis.

Disclosures None.

References 1. Cobb S, Anderson F, Bauer W. Length of life and cause of death in rheumatoid arthritis. N Engl J Med. 1953;249:553–556. 2. Urowitz MB, Bookman AA, Koehler BE, Gordon DA, Smythe HA, Ogryzlo MA. The bimodal mortality pattern of systemic lupus erythematosus. Am J Med. 1976;60:221–225. 3. Hesselstrand R, Scheja A, Akesson A. Mortality and causes of death in a Swedish series of systemic sclerosis patients. Ann Rheum Dis. 1998;57: 682– 686. 4. Shoenfeld Y, Gerli R, Doria A, Matsuura E, Cerinic MM, Ronda N, Jara LJ, Abu-Shakra M, Meroni PL, Sherer Y. Accelerated atherosclerosis in autoimmune rheumatic diseases. Circulation. 2005;112:3337–3347. 5. Berenson GS, Srinivasan SR, Bao W, Newman WP III, Tracy RE, Wattigney WA. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults: the Bogalusa Heart Study. N Engl J Med. 1998;338:1650 –1656. 6. Kavey RE, Allada V, Daniels SR, Hayman LL, McCrindle BW, Newburger JW, Parekh RS, Steinberger J; American Heart Association Expert Panel on Population and Prevention Science; American Heart Association Council on Cardiovascular Disease in the Young; American Heart Association Council on Epidemiology and Prevention; American Heart Association Council on Nutrition, Physical Activity and Metabolism; American Heart Association Council on High Blood Pressure Research; American Heart Association Council on Cardiovascular Nursing; American Heart Association Council on the Kidney in Heart Disease; Interdisciplinary Working Group on Quality of Care and Outcomes Research. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation. 2006;114:2710 –2738. 7. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340:115–126. 8. Meune C, Touze´ E, Trinquart L, Allanore Y. Trends in cardiovascular mortality in patients with rheumatoid arthritis over 50 years: a systematic review and meta-analysis of cohort studies. Rheumatology (Oxford). 2009;48:1309 –1313. 9. Stamatelopoulos KS, Kitas GD, Papamichael CM, Chryssohoou E, Kyrkou K, Georgiopoulos G, Protogerou A, Panoulas VF, Sandoo A, Tentolouris N, Mavrikakis M, Sfikakis PP. Atherosclerosis in rheumatoid arthritis versus diabetes: a comparative study. Arterioscler Thromb Vasc Biol. 2009;29:1702–1708. 10. Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation. 2007;115:459 – 467. 11. Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Hillsdale, NJ: Lawrence W. Erlbaum; 1988. 12. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188. 13. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539 –1558. 14. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–560. 15. Bax L, Yu LM, Ikeda N, Tsuruta H, Moons KG. Development and validation of MIX: comprehensive free software for meta-analysis of causal research data. BMC Med Res Methodol. 2006;6:50. 16. Lekakis J, Mavrikakis M, Papamichael C, Papazoglou S, Economou O, Scotiniotis I, Stamatelopoulos K, Vemmos C, Stamatelopoulos S, Moulopoulos S. Short-term estrogen administration improves abnormal endothelial function in women with systemic sclerosis and Raynaud’s phenomenon. Am Heart J. 1998;136:905–912. 17. Nomura K, Yamano S, Ikeda Y, Yamada H, Fujimoto T, Minami S, Fukui R, Takaoka M, Yamamoto Y, Dohi K. Asymptomatic cerebrovascular lesions detected by magnetic resonance imaging in patients with systemic lupus erythematosus lacking a history of neuropsychiatric events. Intern Med. 1999;38:785–795.

Downloaded from http://atvb.ahajournals.org/ by guest on June 19, 2016

Tyrrell et al

Rheumatic Disease and Carotid Intima-Media Thickness

18. Falaschi F, Ravelli A, Martignoni A, Migliavacca D, Sartori M, Pistorio A, Perani G, Martini A. Nephrotic-range proteinuria, the major risk factor for early atherosclerosis in juvenile-onset systemic lupus erythematosus. Arthritis Rheum. 2000;43:1405–1409. 19. Svenungsson E, Jensen-Urstad K, Heimburger M, Silveira A, Hamsten A, De Faire U, Witztum JL, Frostegard J. Risk factors for cardiovascular disease in systemic lupus erythematosus. Circulation. 2001;104: 1887–1893. 20. Wallberg Jonsson S, Backman C, Johnson O, Karp K, Lundstrom E, Sundqvist KG, Rantapaa Dahlqvist S. Increased prevalence of atherosclerosis in patients with medium term rheumatoid arthritis. J Rheumatol. 2001;28:2597–2602. 21. Kumeda Y, Inaba M, Goto H, Nagata M, Henmi Y, Furumitsu Y, Ishimura E, Inui K, Yutani Y, Miki T, Shoji T, Nishizawa Y. Increased thickness of the arterial intima-media detected by ultrasonography in patients with rheumatoid arthritis. Arthritis Rheum. 2002;46:1489 –1497. 22. Park YB, Ahn CW, Choi HK, Lee SH, In BH, Lee HC, Nam CM, Lee SK. Atherosclerosis in rheumatoid arthritis: morphologic evidence obtained by carotid ultrasound. Arthritis Rheum. 2002;46:1714 –1719. 23. Alkaabi JK, Ho M, Levison R, Pullar T, Belch JJF. Rheumatoid arthritis and macrovascular disease. Rheumatology. 2003;42:292–297. 24. Del Rincon I, Williams K, Stern MP, Freeman GL, O’Leary DH, Escalantel A. Association between carotid atherosclerosis and markers of inflammation in rheumatoid arthritis patients and healthy subjects. Arthritis Rheum. 2003;48:1833–1840. 25. Dropin´ski J, Szczeklik W, Wegrzyn W. Increased carotid artery intima-media thickness as an indicator of the onset of atherosclerosis in patients with connective tissue systemic diseases [in English, Polish]. Kardiol Pol. 2003;59:475– 483. 26. Gonzalez-Juanatey C, Llorca J, Testa A, Revuelta J, Garcia-Porrua C, Gonzalez-Gay MA. Increased prevalence of severe subclinical atherosclerotic findings in long-term treated rheumatoid arthritis patients without clinically evident atherosclerotic disease. Medicine. 2003;82: 407– 413. 27. Roman MJ, Shanker BA, Davis A, Lockshin MD, Sammaritano L, Simantov R, Crow MK, Schwartz JE, Paget SA, Devereux RB, Salmon JE. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med. 2003;349:2399 –2406. 28. Vlachoyiannopoulos PG, Kanellopoulos PG, Ioannidis JPA, Tektonidou MG, Mastorakou I, Moutsopoulos HM. Atherosclerosis in premenopausal women with antiphospholipid syndrome and systemic lupus erythematosus: a controlled study. Rheumatology. 2003;42:645– 651. 29. Zakopoulos NA, Kotsis V, Gialafos EJ, Papamichael CM, Pitiriga V, Mitsibounas DN, Mavrikakis ME. Systemic sclerosis is not associated with clinical or ambulatory blood pressure. Clin Exp Rheum. 2003;21: 199 –204. 30. Cuomo G, Di Micco P, Niglio A, La Montagna G, Valentini G. Atherosclerosis and rheumatoid arthritis: relationships between intima-media thickness of the common carotid arteries and disease activity and disability [in Italian]. Reumatismo. 2004;56:242–246. 31. Roch B, Kopprasch S, Pietzsch J, Schroder HE. Oxidatively modified lipoproteins and their antibodies in patients with antiphospholipid syndrome and systemic lupus erythematosus [in German]. Z Rheumatol. 2004;63:331–337. 32. Wolak T, Todosoui E, Szendro G, Bolotin A, Jonathan BS, Flusser D, Buskila D, Sukenik S, Abu-Shakra M. Duplex study of the carotid and femoral arteries of patients with systemic lupus erythematosus: a controlled study. J Rheumatol. 2004;31:909 –914. 33. Abu-Shakra M, Polychuck I, Szendro G, Bolotin A, Jonathan BS, Flusser D, Buskila D, Sukenik S. Duplex study of the carotid and femoral arteries of patients with rheumatoid arthritis: a controlled study. Semin Arthritis Rheum. 2005;35:18 –23. 34. Ames PR, Margarita A, Sokoll KB, Weston M, Brancaccio V. Premature atherosclerosis in primary antiphospholipid syndrome: preliminary data. Ann Rheum Dis. 2005;64:315–317. 35. Bocci EB, Marchesi S, Delle Monache F, Vaudo G, Giordano A, Alunni FR, Angrisani C, Mannarino E, Shoenfeld Y, Gerli R. Subclinical atherosclerosis in young patients with rheumatoid arthritis and low disease activity [in Italian]. Reumatismo. 2005;57:16 –21. 36. Jimenez S, Garcia-Criado MA, Tassies D, Reverter JC, Cervera R, Gilabert MR, Zambon D, Ros E, Bru C, Font J. Preclinical vascular disease in systemic lupus erythematosus and primary antiphospholipid syndrome. Rheumatology. 2005;44:756 –761.

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37. Keser G, Aksu K, Tamsel S, Ozmen M, Kitapcioglu G, Kabaroglu C, Killi R, Bayindir O, Doganavsargil E. Increased thickness of the carotid artery intima-media assessed by ultrasonography in Behcet’s disease. Clin Exp Rheum. 2005;23:S71–S76. 38. Roman MJ, Devereux RB, Schwartz JE, Lockshin MD, Paget SA, Davis A, Crow MK, Sammaritano L, Levine DM, Shankar BA, Moeller E, Salmon JE. Arterial stiffness in chronic inflammatory diseases. Hypertension. 2005;46: 194–199. 39. Vaudo G, Bocci EB, Shoenfeld Y, Schillaci G, Wu R, Del Papa N, Vitali C, Delle Monache F, Marchesi S, Mannarino E, Gerli R. Precocious intima-media thickening in patients with primary Sjogren’s syndrome. Arthritis Rheum. 2005;52:3890 –3897. 40. Wada Y, Kuroda T, Murasawa A, Tanabe N, Nakano M, Gejyo F. Autoantibodies against oxidized low-density lipoprotein (LDL) and carotid atherosclerosis in patients with rheumatoid arthritis. Clin Exp Rheum. 2005;23:482– 486. 41. Akdogan A, Calguneri M, Yavuz B, Arslan EB, Kalyoncu U, Sahiner L, Karadag O, Ertenli I, Kiraz S, Aytemir K, Akata D, Tokgozoglu L, Oto A. Are familial Mediterranean fever (FMF) patients at increased risk for atherosclerosis? impaired endothelial function and increased intima media thickness are found in FMF. J Am Col Card. 2006;48:2351–2353. 42. Bhatt SP, Handa R, Gulati GS, Sharma S, Pandey RM, Aggarwal P, Ramakrishnan L, Shankar S. Atherosclerosis in Asian Indians with systemic lupus erythematosus. Scand J Rheumatol. 2006;35:128 –132. 43. De Leeuw K, Freire B, Smit AJ, Bootsma H, Kallenberg CG, Bijl M. Traditional and non-traditional risk factors contribute to the development of accelerated atherosclerosis in patients with systemic lupus erythematosus. Lupus. 2006;15:675– 682. 44. Fischer K, Brzosko M, Walecka A, Ostanek L, Sawicki M. Antiendothelial cell antibodies as a risk factor of atherosclerosis in systemic lupus erythematosus [in Polish]. Ann Acad Med Stetin. 2006;52(suppl 2):95–99. 45. Grover S, Sinha RP, Singh U, Tewari S, Aggarwal A, Misra R. Subclinical atherosclerosis in rheumatoid arthritis in India. J Rheumatol. 2006;33:244 –247. 46. Jackson M, Ahmad Y, Bruce IN, Coupes B, Brenchley PE. Activation of transforming growth factor-␤1 and early atherosclerosis in systemic lupus erythematosus. Arthritis Res Ther. 2006;8:R81. 47. Lopez LR, Salazar-Paramo M, Palafox-Sanchez C, Hurley BL, Matsuura E, Garcia–De La Torre I. Oxidized low-density lipoprotein and ␤2-glycoprotein I in patients with systemic lupus erythematosus and increased carotid intima-media thickness: implications in autoimmune-mediated atherosclerosis. Lupus. 2006;15:80 – 86. 48. Pahor A, Hojs R, Holc I, Ambrozic A, Cucnik S, Kveder T, Rozman B. Antiphospholipid antibodies as a possible risk factor for atherosclerosis in patients with rheumatoid arthritis. Immunobiology. 2006;211:689 – 694. 49. Roman MJ, Moeller E, Davis A, Paget SA, Crow MK, Lockshin MD, Sammaritano L, Devereux RB, Schwartz JE, Levine DM, Salmon JE. Preclinical carotid atherosclerosis in patients with rheumatoid arthritis. Ann Intern Med. 2006;144:249 –256. 50. Sari I, Okan T, Akar S, Cece H, Altay C, Secil M, Birlik M, Onen F, Akkoc N. Impaired endothelial function in patients with ankylosing spondylitis. Rheumatology. 2006;45:283–286. 51. Bartoli F, Angotti C, Fatini C, Conforti ML, Guiducci S, Blagojevic J, Melchiorre D, Fiori G, Generini S, Damjanov N, Rednic S, Pignone A, Castellani S, Abbate R, Cerinic MM. Angiotensin-converting enzyme I/D polymorphism and macrovascular disease in systemic sclerosis. Rheumatology. 2007;46:772–775. 52. Carotti M, Salaffi F, Mangiacotti M, Cerioni A, Giuseppetti GM, Grassi W. Atherosclerosis in rheumatoid arthritis: the role of high-resolution B mode ultrasound in the measurement of the arterial intima-media thickness [in Italian]. Reumatismo. 2007;59:38 – 49. 53. Coaccioli S, Capito` G, Valentini M, Pinoca F, Landucci P, Fatati G, Puxeddu A. Intima-media thickness of common carotid as cardiovascular risk factor in rheumatoid arthritis and metabolic disorders. Clin Ter. 2007;158:505–508. 54. Daza L, Aguirre M, Jimenez M, Herrera R, Bollain JJ. Common carotid intima-media thickness and von Willebrand factor serum levels in rheumatoid arthritis female patients without cardiovascular risk factors. Clin Rheum. 2007;26:533–537. 55. de Leeuw K, Graaff R, de Vries R, Dullaart RP, Smit AJ, Kallenberg CG, Bijl M. Accumulation of advanced glycation endproducts in patients with systemic lupus erythematosus. Rheumatology (Oxford). 2007;46: 1551–1556. 56. Der H, Kerekes G, Veres K, Szodoray P, Toth J, Lakos G, Szegedi G, Soltesz P. Impaired endothelial function and increased carotid

Downloaded from http://atvb.ahajournals.org/ by guest on June 19, 2016

1026

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

Arterioscler Thromb Vasc Biol

May 2010

intima-media thickness in association with elevated von Willebrand antigen level in primary antiphospholipid syndrome. Lupus. 2007;16: 497–503. Gonzalez-Juanatey C, Llorca J, Amigo-Diaz E, Dierssen T, Martin J, Gonzalez-Gay MA. High prevalence of subclinical atherosclerosis in psoriatic arthritis patients without clinically evident cardiovascular disease or classic atherosclerosis risk factors. Arthritis Rheum. 2007;57: 1074 –1080. Gonzalez-Juanatey C, Lopez-Diaz MJ, Martin J, Llorca J, Gonzalez-Gay MA. Atherosclerosis in patients with biopsy-proven giant cell arteritis. Arthritis Rheum. 2007;57:1481–1486. Hannawi S, Haluska B, Marwick TH, Thomas R. Atherosclerotic disease is increased in recent-onset rheumatoid arthritis: a critical role for inflammation. Arthritis Res Ther. 2007;9:R116. Nienhuis HL, de Leeuw K, Smit AJ, Bijzet J, Stegeman CA, Kallenberg CG, Bijl M. Enhanced endothelium-dependent microvascular responses in patients with Wegener’s granulomatosis. J Rheumatol. 2007;34: 1875–1881. Pietrewicz E, Urban M. Early atherosclerosis changes in children with juvenile idiopathic arthritis [in Polish]. Pol Merkur Lekarski. 2007;22: 211–214. Sari I, Karaoglu O, Can G, Akar S, Gulcu A, Birlik M, Akkoc N, Tunca M, Goktay Y, Onen F. Early ultrasonographic markers of atherosclerosis in patients with familial Mediterranean fever. Clin Rheumatol. 2007;26: 1467–1473. Sato H, Miida T, Wada Y, Maruyama M, Murakami S, Hasegawa H, Kuroda T, Narita I, Nakano M, Gejyo F. Atherosclerosis is accelerated in patients with long-term well-controlled systemic lupus erythematosus (SLE). Clin Chim Acta. 2007;385:35– 42. Surdacki A, Martens-Lobenhoffer J, Wloch A, Marewicz E, Rakowski T, Wieczorek-Surdacka E, Dubiel JS, Pryjma J, Bode-Boger SM. Elevated plasma asymmetric dimethyl-L-arginine levels are linked to endothelial progenitor cell depletion and carotid atherosclerosis in rheumatoid arthritis. Arthritis Rheum. 2007;56:809 – 819. Szucs G, Timar O, Szekanecz Z, Der H, Kerekes G, Szamosi S, Shoenfeld Y, Szegedi G, Soltesz P. Endothelial dysfunction precedes atherosclerosis in systemic sclerosis: relevance for prevention of vascular complications. Rheumatology. 2007;46:759 –762. Belizna CC, Richard V, Primard E, Kerleau JM, Cailleux N, Louvel JP, Marie I, Hamidou M, Thuillez C, Levesque H. Early atheroma in primary and secondary antiphospholipid syndrome: an intrinsic finding. Semin Arthritis Rheum. 2008;37:373–380. Bowser CS, Kumar S, Salciccioli L, Kutlin A, Lazar J, Rahim I, Suss A, Kohlhoff S, Hammerschlag MR, Moallem HJ. Absence of Chlamydia pneumoniae and signs of atherosclerotic cardiovascular disease in adolescents with systemic lupus erythematosus. Pediatr Cardiol. 2008;29: 545–551. Ciftci O, Yilmaz S, Topcu S, Caliskan M, Gullu H, Erdogan D, Pamuk BO, Yildirir A, Muderrisoglu H. Impaired coronary microvascular function and increased intima-media thickness in rheumatoid arthritis. Atherosclerosis. 2008;198:332–337. Estevez Del Toro M, Capote AC, Jorge RAB, Paneque RJ, Castro JH. Prevalence of atherosclerotic vascular disease in Cuban patients with

70.

71.

72.

73.

74.

75.

76.

77. 78.

79.

80. 81.

systemic lupus erythematosus [in Spanish]. Reumatol Clin. 2008;4: 13–18. Georgiadis AN, Voulgari PV, Argyropoulou MI, Alamanos Y, Elisaf M, Tselepis AD, Drosos AA. Early treatment reduces the cardiovascular risk factors in newly diagnosed rheumatoid arthritis patients. Semin Arthritis Rheum. 2008;38:13–19. Hettema ME, Zhang D, de Leeuw K, Stienstra Y, Smit AJ, Kallenberg CG, Bootsma H. Early atherosclerosis in systemic sclerosis and its relation to disease or traditional risk factors. Arthritis Res Ther. 2008; 10:R49. Kerekes G, Szekanecz Z, Der H, Sandor Z, Lakos G, Muszbek L, Csipo I, Sipka S, Seres I, Paragh G, Kappelmayer J, Szomjak E, Veres K, Szegedi G, Shoenfeld Y, Soltesz P. Endothelial dysfunction and atherosclerosis in rheumatoid arthritis: a multiparametric analysis using imaging techniques and laboratory markers of inflammation and autoimmunity. J Rheumatol. 2008;35:398 – 406. Pereira I, Laurindo I, Burlingame R, Anjos L, Viana V, Leon E, Vendramini M, Borba E. Auto-antibodies do not influence development of atherosclerotic plaques in rheumatoid arthritis. Joint Bone Spine. 2008; 75:416 – 421. Roustit M, Simmons GH, Baguet JP, Carpentier P, Cracowski JL. Discrepancy between simultaneous digital skin microvascular and brachial artery macrovascular post-occlusive hyperemia in systemic sclerosis. J Rheumatol. 2008;35:1576 –1583. Thompson T, Sutton-Tyrrell K, Wildman RP, Kao A, Fitzgerald SG, Shook B, Tracy RP, Kuller LH, Brockwell S, Manzi S. Progression of carotid intima-media thickness and plaque in women with systemic lupus erythematosus. Arthritis Rheum. 2008;58:835– 842. Bots ML, Hofman A, Grobbee DE. Increased common carotid intima-media thickness: adaptive response or a reflection of atherosclerosis? findings from the Rotterdam Study. Stroke. 1997;28:2442–2447. Salmon JE, Roman MJ. Subclinical atherosclerosis in rheumatoid arthritis and systemic lupus erythematosus. Am J Med. 2008;121:S3–S8. Urbina EM, Williams RV, Alpert BS, Collins RT, Daniels SR, Hayman L, Jacobson M, Mahoney L, Mietus-Snyder M, Rocchini A, Steinberger J, McCrindle B; American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee of the Council on Cardiovascular Disease in the Young. Noninvasive assessment of subclinical atherosclerosis in children and adolescents: recommendations for standard assessment for clinical research: a scientific statement from the American Heart Association. Hypertension. 2009;54:919 –950. Touboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P, Bornstein N, Csiba L, Desvarieux M, Ebrahim S, Fatar M, Hernandez Hernandez R, Jaff M, Kownator S, Prati P, Rundek T, Sitzer M, Schminke U, Tardif JC, Taylor A, Vicaut E, Woo KS, Zannad F, Zureik M. Mannheim carotid intima-media thickness consensus (2004 –2006): an update on behalf of the Advisory Board of the III and IV Watching the Risk Symposium, 13th and 15th European Stroke Conferences, Mannheim, Germany, 2004, and Brussels, Belgium, 2006. Cerebrovasc Dis. 2007;23:75– 80. Schork MA. Publication bias and meta analysis. J Hypertens. 2003;21: 243–245. Behera M, Kumar A, Soares HP, Sokol L, Djulbegovic B. Evidence-based medicine for rare diseases: implications for data interpretation and clinical trial design. Cancer Control. 2007;14:160 –166.

Downloaded from http://atvb.ahajournals.org/ by guest on June 19, 2016

Rheumatic Disease and Carotid Intima-Media Thickness: A Systematic Review and Meta-Analysis Pascal N. Tyrrell, Joseph Beyene, Brian M. Feldman, Brian W. McCrindle, Earl D. Silverman and Timothy J. Bradley Arterioscler Thromb Vasc Biol. 2010;30:1014-1026; originally published online February 11, 2010; doi: 10.1161/ATVBAHA.109.198424 Arteriosclerosis, Thrombosis, and Vascular Biology is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2010 American Heart Association, Inc. All rights reserved. Print ISSN: 1079-5642. Online ISSN: 1524-4636

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