Carotid Intima-Media Thickness in Patients With Inflammatory Bowel Disease

Abstract

We systematically reviewed the available data on carotid intima-media thickness (cIMT) in patients with inflammatory bowel diseases (IBDs) without history of cardiovascular disease (CVD) and its associated factors. A total of 6 studies met the inclusion criteria including 217 patients with Crohn's disease (CD) and 85 with ulcerative colitis (UC). Two studies included only patients with CD. The prevalence of traditional CVD risk factors and the inflammatory burden (IBD duration and activity) varied greatly among patients and studies. Factors that correlated with cIMT were age, male gender, body mass index, arterial hypertension, as well as cholesterol and homocysteine levels. The current data on cIMT in patients with IBD are inconclusive. This is probably due to small number of patients, population heterogeneity with regard to inflammatory burden and smoking habits, and lack of strict matching with controls. In order to elucidate any potential association between IBD and CVD risk, larger prospective studies are required.

Keywords

inflammatory bowel diseases atherosclerosis cardiovascular disease carotid intima-media thickness

Introduction

Atherogenesis is an inflammatory process leading to formation of atheromatous plaques and eventually cardiovascular disease (CVD).¹ Increased serum levels of low-density lipoprotein cholesterol (LDL-C), hypertension, diabetes mellitus (DM), and smoking (to mention reversible CVD risk factors only) result in endothelial dysfunction. This subsequently leads to macrophage and T-cell accumulation and release of chemokines, adhesion molecules, and proinflammatory cytokines.² C-reactive protein (CRP), an acute-phase reactant and inflammatory marker, is implicated in arterial wall inflammation and its levels are associated with CVD risk.^3,4 In addition, increased levels of proinflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), have been demonstrated in patients with acute coronary syndromes⁵ underlying the role of inflammation, not only in atherogenesis, but also in plaque rupture and thrombus formation, leading to acute CVD events.⁶

Chronic systemic inflammation is probably an independent risk factor for CVD events in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), 2 conditions characterized by chronic relapsing inflammation. The incidence of CVD events is increased in these conditions, but this cannot be justified by traditional CVD risk factors.⁷ Coronary artery disease (CAD) is responsible for 35% to 50% of mortality in RA.⁸ Early atherosclerosis has been demonstrated in patients with SLE and has been associated with disease duration and severity.⁹ Proinflammatory cytokines having adverse effects on the liver, adipose tissue, striated muscles, and endothelium may induce various proatherogenic changes such as alterations in lipid concentrations, mainly decreased high-density lipoprotein cholesterol (HDL-C) levels, hyperhomocysteinemia, oxidative stress, insulin resistance, and endothelial dysfunction.⁸ In the context of chronic systemic inflammation, these changes may predispose to primary atherosclerosis.¹⁰

Chronic inflammation is a feature of inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC).¹¹ These conditions are most often diagnosed at young age, and their natural history is usually characterized by a relapsing course.^11,12 There are multiple extraintestinal manifestations with thromboembolic (TE) events being the main vascular complication.¹² The incidence of TE events in IBD is as high as 6.5%, that is, 3-fold the incidence in the general population.¹³ Venous thrombosis is more common than arterial, mainly involving the deep veins of the lower limbs.¹⁴ Arterial thrombosis is more common in the mesenteric vasculature.¹⁵ In addition, microthrombosis in the intestinal microcirculation is believed to play a pathogenetic role in intestinal inflammation in IBD.¹⁶ However, the effect of systemic inflammation and prothrombotic state, both related to IBD, on coronary or carotid atherosclerosis has not been extensively investigated.

Early changes in the arterial wall, which precede atherosclerosis, have been detected in patients with IBD.^17
–19 Plaque formation is the result of long-standing changes in the arterial wall, which can be detected before becoming clinically evident. An accurate method to study the structure of the arterial wall is high-resolution B-mode ultrasonography of the carotids, by which carotid intima-media thickness (cIMT) can be measured.²⁰ An initial stage in atherogenesis is smooth muscle cell hyperplasia in the arterial wall, leading to increased cIMT. cIMT is associated with CVD risk factors as well with the risk of CVD events.^21,22 Thus, it is widely used in clinical trials as a surrogate marker of atherosclerosis and a marker of response to therapeutic interventions aiming to ameliorate CVD risk factors.²³

The aim of this study was to systematically review all the available data on cIMT in patients with IBD without history of CVD in order to determine the presence of early changes in the arterial wall that may reflect increased CVD risk compared to healthy individuals as well as factors that may correlate with cIMT.

Search Strategy and Selection Criteria

A PubMed/Medline search was performed using the following MeSH terms “inflammatory bowel diseases,” “ulcerative colitis,” “Crohn’s disease,” and “carotid intima-media thickness.” The bibliography of the retrieved articles was manually searched for relevant references.

Original articles published in English as full-length articles were selected if they fulfilled the following criteria: (1) included adult (age ≥18 years) patients with IBD; (2) included patients without history of CVD; (3) cIMT was measured using B-mode ultrasonography; and (4) there was a control group of healthy individuals.

Literature search and data extraction were performed by 2 independent authors. Standardized forms were used for data extraction. The concordance of the data extracted was assessed and discrepancies were resolved by 2 reviewers during a joint meeting with all the authors.

Studies and Patient Characteristics

The literature search yielded 7 articles and the manual search of their references 1 additional article. There was 1 duplicate publication²⁴ and 1 article that reported cIMT measurement in pediatric patients with IBD,²⁵ which were excluded. The remaining 6 full-length articles were reviewed^{17
–19,26
–28}; all 6 articles met the inclusion criteria.

In total, there were 302 patients with IBD, 217 with CD and 85 with UC. Two studies included only patients with CD.^19,26 The mean age ranged from 31.5 ± 7.2 to 42.4 ± 12.8 years. Most studies included patients younger than 60 years, with 3 studies including patients younger than 45 years.^17,18,26 There were 161 men and 141 women.

The IBD Characteristics

The mean disease duration was 4.2 ± 0.8 to 10.9 years (standard deviation not always reported; range 0.5-38 years). In 1 article, the disease duration was not reported.¹⁹ The extent of the involved intestine was reported only in 2 studies.^17,26 There were discrepancies in the assessment and reporting of disease activity, with different studies using different scores and reporting either the mean value of the score or the proportion of patients in remission. Three studies used Crohn's Disease Activity Index for CD,^26
–28 with mean scores ranging from 62.3 ± 26.3 to 180 ± 139, and 1 study used the Harvey Bradshaw Index (HBI; mean value 2.7 ± 4.8).¹⁹ For UC disease activity, the Mayo score (mean value 3.5 ± 3.5)²⁸ and the Truelove-Witt's criteria (mean value 2.8 ± 2.3)²⁷ were used in 2 studies, respectively. In 1 study, the score used to assess disease activity was not reported,¹⁸ and another study provided no information about disease activity.¹⁷ Two studies reported the proportion of patients in remission, which was 80%¹⁷ and 45% (HBI < 4),¹⁹ respectively, although in the former remission was not defined.

The wide range of disease activity is also reflected by serum inflammatory markers as these were evident from CRP and erythrocyte sedimentation rate (ESR) levels. Five studies measured high sensitivity CRP, with mean levels ranging from 5.2 ± 5.2 to 21 ± 59.7 mg/dL and 1 study measured CRP levels.¹⁸ Mean ESR ranged from 23.5 ± 16.3 to 44 ± 26 mm/h. The ESR was not reported in 2 studies.^19,26

With regard to medical treatment, 34 patients received infliximab, 63 immunomodulators, 158 aminosalicylates, and 67 corticosteroids, at the time of the evaluation. In 1 article, no reference was made to treatment.¹⁹ In particular, the proportion of patients treated with infliximab in the different studies varied from 0% to 32.7%.

Patient and disease characteristics are summarized in Table 1.

Table 1.

Patient Characteristics in the 6 Studies That Evaluated Carotid Intima-Media Thickness (cIMT) in Patients With IBD.

Author	Year	Number	Age, Years	M/F	CD/UC	Disease Duration, Years	Disease Activity	Disease Extent	IFX/IMM/5ASA/STER	CRP/hsCRP, mg/L	ESR, mm/h
Papa¹⁸	2005	52	34 ± 10.2 (<45)	34/18	34/18	7.2 ± 4.6 (CD) 8.3 ± 5.2 (UC)	Not reported	Not reported	17/16/24/14	CRP: 22 ± 25 (CD) 19 ± 21 (UC)	44 ± 26 (CD) 41 ± 23 (UC)
Maharshak²⁸	2007	61	36 ± 11 (18-60)	28/33	45/16	8.74 ±8.5 (0.5-38)	CDAI: 165 ± 121 Mayo score: 3.5 ± 3.5	Not reported	0/17/38/14	hsCRP: 5.2 ± 5.23	23.5 ± 16.3
van Leuven¹⁹	2007	60	42.4 ± 12.8	27/33	60/0	Not reported	Harvey Bradshaw Index: 2.7 ± 4.8 48 (80%) with HBI < 4 (remission)	Not reported	Not reported	hsCRP: 21 ± 59.7	Not reported
Dagli¹⁷	2010	40	39.4 ± 11 (18-45)	23/17	8/32	4.2 ± 0.8 (1-20)	26 (65%) in remission	14 left colon 10 rectum 8 pancolitis 6 small intestine 2 ileocecal region	1/7/39/7	hsCRP: 13 ± 21.3	32 ± 21
Broide²⁶	2011	50	31.46 ± 7.23 (18-45)	28/22	50/0	10.9 (0.5-24)	CDAI: 180 ± 139	19 small bowel 6 large bowel 24 both	15/19/30/27	hsCRP: 14.6 ± 25.8	Not reported
Kayahan²⁷	2012	39	34.4 ± 9.8	21/18	20/19	5 ± 3.6	CDAI: 62.3 ± 26.3 Truelove-Witt criteria: 2.8 ± 2.3	Not reported	1/4/27/5	hsCRP: 7.8 ± 6.05	25.5 ± 16.8

Abbreviations: IBD, inflammatory bowel diseases; M, male; F, female; CD, Crohn's disease; UC, ulcerative colitis; IFX, infliximab; IMM, immunomodulators; 5-ASA, 5-aminosalicylate; STER, steroids; CRP, C-reactive protein; hsCRP, high sensitivity C-reactive protein; ESR, erythrocyte sedimentation rate; CDAI, Crohn's Disease Activity Index.

The CVD Risk Factors

Established CVD risk factors, including DM, dyslipidemia, arterial hypertension, obesity, and smoking, were assessed in the majority of studies. However, there were discrepancies in the definition of both dyslipidemia and hypertension among studies, and in some cases these definitions were not in agreement with current consensus statements. Only 1 patient with DM was included in the study.²⁸

Mean total cholesterol levels were 139 ± 25 to 182 ± 42.9 mg/dL in 3 studies.^17
–19 One study reported the proportion (36%) of patients with total cholesterol >200 mg/dL.²⁸ Three studies excluded patients with total cholesterol >220 mg/dL^17,18,26 and one >260 mg/dL.²⁷ The HDL-C levels were 41 ± 14 to 59.2 ± 18.6 mg/dL.^17
–19,26 One study reported the proportion (13%) of patients with HDL-C <40 mg/dL,²⁸ and another did not include HDL-C levels.²⁷ Mean LDL-C levels were 78.6 ± 28.8 to 119.1 ± 32.9 mg/dL in 4 studies.^17
–19,26 In 2 studies, LDL-C levels were not reported,^27,28 but in the former no patient with LDL-C >160 mg/dL was included. Mean triglyceride levels ranged from 81.5 ± 54.9 to 137.3 ± 70.9 mg/dL in 4 studies.^17
–19,26 In 3 of these studies, patients with triglyceride levels >180 mg/dL were excluded.^17,18,26 Two articles did not report triglyceride levels.^27,28

Three studies excluded patients with blood pressure >150/90 mm Hg,^17,18,26 and one > 140/90 mm Hg.²⁷ In 1 study, 8% of the patients had blood pressure >140/90 mm Hg,²⁸ and another 8.3% of the patients had hypertension¹⁹; however, a definition for hypertension was not provided.

Mean body mass index (BMI) was 22.57 ± 4.07 to 24.6 ± 4.8 kg/m². In 1 study, the mean BMI was not reported.²⁷

With regard to smoking, 2 studies excluded current smokers,^17,18 but in the latter study 23% of the patients were exsmokers. The proportion of smokers in 3 studies was 12.8% to 31%.^18,19,27,28 One study did not report the number of smokers.²⁶

The CVD risk factors for patients included in the 6 studies are shown in Table 2.

Table 2.

Traditional CVD Risk Factors in Patients With IBD.

Authors	Glucose, mg/dL	Total Cholesterol	HDL-C	LDL-C	Triglycerides	Systolic BP, mm Hg	Diastolic BP, mm Hg	BMI, kg/m²	Smokers
Papa¹⁸	None with DM	CD: 139 ± 25 mg/dL UC: 142 ± 30 mg/dL None with cholesterol >220 mg/dL	CD: 41 ± 14 mg/dL UC: 43 ± 18 mg/dL	CD: 82 ± 30 mg/dL UC: 84 ± 35 mg/dL	CD: 110± 49 mg/dL UC: 114 ± 54 mg/dL None with triglycerides >180 mg/dL	CD: 116.6 ± 20.5 UC: 115.9 ± 22.7 None with BP >150/90	CD: 70.1 ± 12 UC: 69.7 ± 10.5	CD: 22.8 ± 2.7 UC: 23.9 ± 3.2	Ex: 12 (23%)
Maharshak²⁸	1 (1.6%) with DM	22 (36%) with cholesterol >200 mg/dL	8 (13%) with HDL <40 mg/dL	Not reported	Not reported	118 ± 14 5 (8%) with BP >140/90	74 ± 9	23.1 ± 3.8	19 (31%)
van Leuven¹⁹	None with DM	4.54 ± 1.12 mmol/L (175.6 ± 43.3 mg/dL)	1.53 ± 0.48 mmol/L (59.2 ± 18.6 mg/dL)	2.59 ± 0.96 mmol/L (100.2 ± 37.1 mg/dL)	0.92 ± 0.62 mmol/L (81.5 ± 54.9 mg/dL)	5 (8.3%) with hypertension	Not reported	24.4 ± 3.9	13 (21.7%)
Dagli¹⁷	96 ± 17 None with DM	4.71 ± 1.11 mmol/L (182 ± 42.9 mg/dL) None with cholesterol >5.6 mmol/L or 216.6 mg/dL	1.19 ± 0.23 mmol/L (46 ± 8.9 mg/dL)	3.08 ± 0.85 mmol/L (119.1 ± 32.9 mg/dL)	1.55 ± 0.8 mmol/L (137.3 ± 70.9 mg/dL) None with triglycerides >2 mmol/L or 177 mg/dL	130.3 ± 9.5 None with BP >150/90	73.6 ± 5.7	24.6 ± 4.8	0
Broide²⁶	88.7 ± 12 None with DM	None with cholesterol >220 mg/dL	54.1 ± 17 mg/dL	78.6 ± 28.8 mg/dL	113.9 ± 69.2 mg/dL None with triglycerides >180 mg/dL	None with BP >150/90	Not reported	22.57 ± 4.07	Not reported
Kayahan²⁷	None with DM	None with cholesterol >260 mg/dL	Not reported	None with LDL >160 mg/dL	Not reported	None with BP >140/90	Not reported		5 (12.8%)

Abbreviations: CVD, cardiovascular disease; IBD, inflammatory bowel disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; BP, blood pressure; BMI, body mass index; DM, diabetes mellitus; CD, Crohn's disease; UC, ulcerative colitis.

Control Group

All 6 studies were prospective case–control studies. However, only 1 study included controls that were matched for age, gender, BMI, and smoking status.²⁸ In addition, the frequency of DM, hypercholesterolemia, low HDL-C, hypertension, and family history of CAD were similar in the study group and the control group, but physical activity was decreased in patients with IBD.²⁸ In the remaining 5 studies, there was no matching between patients with IBD and controls. However, there were no significant differences in age, gender, BMI, cholesterol levels, and smoking habits between the 2 groups, and the frequency of DM and hypertension was similar. In 1 study, HDL-C and LDL-C levels were lower in patients with IBD,²⁶ and in another patients with CD had lower BMI compared to controls.²⁷ There were no differences in ethnicity.

Characteristics of the control groups are summarized in Table 3.

Table 3.

Characteristics of the Control Groups.

Author	Number of Controls	Controls’ Characteristics
Papa¹⁸	20	Similar age, gender, BMI, cholesterol levels, BP, and smoking habits None with DM
Maharshak²⁸	61	Matched for age (±2 years), gender, BMI (±2 kg/m²), and smoking habits Similar frequency of DM, hypercholesterolemia, low HDL-C, hypertension, and family history of CAD Decreased physical activity in patients
van Leuven¹⁹	122	Similar age, gender, BMI, cholesterol levels, and smoking habits Similar frequency of hypertension None with DM
Dagli¹⁷	40	Similar age, gender, BMI, cholesterol levels, BP None with DM Nonsmokers
Broide²⁶	25	Similar age, gender, BMI, and smoking habits None with DM Lower LDL-C and HDL-C in patients
Kayahan²⁷	31	Similar age, gender, and smoking habits None with DM, hypertension, or hyperlipidemia Lower BMI in patients with CD

Abbreviations: BMI, body mass index; BP, blood pressure; DM, diabetes mellitus; HDL-C, high-density lipoprotein cholesterol; CAD, coronary artery disease; LDL-C, low-density lipoprotein cholesterol; CD, Crohn's disease.

Carotid IMT

The cIMT was evaluated with high resolution B-mode ultrasonography, using 7-,^18,28 7.5-,^17,27 or 10-MHz²⁶ linear array transducer. Measurements were obtained from both common carotid arteries, at least at 3 recording sites on the posterior wall, proximal to the carotid artery bifurcation, and were, subsequently, averaged. In 1 study, recordings were also obtained from the lower part of the common carotid artery.²⁷ One article did not provide a detailed description of the methodology used for cIMT measurement.¹⁹

Mean cIMT in patients with IBD was 0.52 ± 0.08 to 0.74 ± 0.08 mm.^17,18,27,28 In the 2 studies that included only patients with CD,^19,26 and in 1 study that reported cIMT in patients with CD separately,²⁷ mean cIMT was 0.494 ± 0.04 to 0.71 ± 0.17 mm. In the only study that reported cIMT in patients with UC separately, mean cIMT was 0.55 ± 0.1 mm.²⁷ Two studies found significantly higher cIMT in patients with IBD compared to controls (0.63 ± 0.15 vs 0.53 ± 0.08 mm, P = .008¹⁸; 0.74 ± 0.08 vs 0.7 ± 0.05 mm, P = .01¹⁷) and 1 study in patients with CD (0.71 ± 0.17 vs 0.59 ± 0.14, P < .001¹⁹). In addition, 1 study found significantly higher cIMT in patients with UC compared to controls but without reporting cIMT values in these patients.¹⁸ The remaining 3 studies found no difference in mean cIMT values between patients with IBD or CD and controls.

Four studies failed to show any association of cIMT with disease duration or activity.^18,26
–28 In 1 study, patients in remission had higher mean cIMT compared to patients with active disease (0.73 ± 0.17 vs 0.62 ± 0.13 mm).¹⁹

The factors that correlated with cIMT were age,^18,26
–28 male gender,²⁸ hypertension,²⁸ BMI,²⁷ total cholesterol, and LDL-C levels²⁷ as well as homocysteine levels.¹⁸

The cIMT in patients with IBD and controls and factors associated with cIMT are shown in Table 4.

Table 4.

Carotid Intima-Media Thickness (cIMT) in Patients With IBD and Controls, and Factors Associated With cIMT.^a

Author	Year	cIMT-IBD, mm	cIMT-CD, mm	cIMT-UC, mm	cIMT-controls, mm	Association With Disease Duration, Extent, Activity	Factors Associated With IMT
Papa¹⁸	2005	0.63 ± 0.15 (P = .008)	Not reported	Not reported (P = .018 vs controls)	0.53 ± 0.08	No	Age Homocysteine
Maharshak²⁸	2007	0.66 ± 0.09	Not reported	Not reported	0.64 ± 0.07	No	Age Hypertension Male gender
van Leuven¹⁹	2007		0.71 ± 0.17 (P < .001)^b		0.59 ± 0.14	Remission-IMT: 0.73 ± 0.17 mm Active IBD-IMT: 0.62 ± 0.13 mm	Not reported
Dagli¹⁷	2010	0.74 ± 0.08 (P = .01)	Not reported	Not reported	0.7 ± 0.05	Not reported	None
Broide²⁶	2011		0.51 ± 0.1 (right CCA) 0.52 ± 0.1 (left CCA)^a		0.54 ± 0.07 (right CCA) 0.55 ± 0.07 (left CCA)	No	Age
Kayahan²⁷	2012	0.52 ± 0.08	0.494 ± 0.04	0.55 ± 0.1	0.516 ± 0.06	No	Age BMI Total and LDL cholesterol

Abbreviations: cIMT, carotid intima-media thickness; IBD, inflammatory bowel diseases; CD, Crohn’s disease; UC, ulcerative colitis; CCA, common carotid artery; LDL, low-density lipoprotein.

^aOnly patients with CD included.

Discussion

Of the 6 studies included in our systematic review, 2 reported increased cIMT in patients with IBD compared to controls^17,18; in 1 of these, the difference was more evident in patients with UC.¹⁸ One additional study showed increased cIMT in patients with CD.¹⁹ The remaining 3 studies found no difference in cIMT between patients with IBD and controls.

The CVD mortality does not seem to be increased in patients with IBD. A meta-analysis of 11 studies including more than 14 000 patients with mean follow-up between 5 and 19 years failed to show a difference in CVD mortality between patients with IBD and the general population.²⁹ Nevertheless, CVD mortality is a suboptimal surrogate of CVD incidence, mainly due to advances in the management of CVD that have significantly improved survival.

The incidence of CVD and/or CVD events has been assessed in retrospective cohorts of patients with IBD. The risk of CAD was greater in all but one study,^15,30

–33 with this increase being more prominent among women. The risk of CAD in a Danish cohort of about 29 000 patients with IBD was 1.6-fold increased, in particular in the first year after IBD diagnosis was established.³² The risk was lower in patients receiving 5-aminosalicylates (5-ASA) and higher in those requiring corticosteroids. A tendency toward lower risk was observed in those treated with biologic agents and/or immunomodulators and those who had undergone major intestinal surgery. Although these results may imply an association between the inflammatory burden in IBD and the risk of CAD, there are several important limitations, which also apply to the other cohort studies. The major limitation is related to the accuracy of CVD risk factor assessment, in particular the reporting of smoking habits. For example, in the latter study comorbidities were extracted from prescribed medications registered in a nationwide database, whereas there were no data on 2 major CVD risk factors, that is, smoking and BMI. Although BMI is usually low in patients with IBD, this is not the case with smoking, which may represent an important component of CVD risk in IBD, as discussed below. The second limitation is associated with the accuracy of the retrospective recording of CVD events. In the Danish cohort, a National Patient Register and corresponding International Classification of Diseases codes were used to identify CAD cases. However, other studies applied less accurate methods for data extraction, with 1 study³¹ using questionnaires mailed to patients, almost half of which did not reply. Another aspect of the problem is that increased rates of CVD may reflect the closer medical surveillance that patients with IBD receive, as suggested by the higher incidence of CAD in the first few months after IBD diagnosis in the Danish cohort.³² Therefore, although several studies demonstrate increased incidence of CVD in patients with IBD, their limitations do not allow a definitive conclusion.

With regard to early arterial lesions, as reflected by cIMT, in patients with IBD without CVD, the results of this review are contradictory and, thus, warrant a more comprehensive evaluation. Certain factors should be considered in order to evaluate the discrepancies. First, all 6 studies included small number of patients. Second, there was considerable heterogeneity with regard to inflammatory burden both within and among different studies. The inflammatory burden consists of several components, mainly disease duration, extent of intestinal involvement, and disease activity, that is, frequency and severity of flares. Patients with higher inflammatory burden, such as those with long-standing more active intestinal inflammation, would be expected to have more pronounced arterial lesions. Disease duration varied greatly (0.5-38 years) as did disease activity as reflected by the wide range of disease activity scores as well as CRP and ESR levels. It is possible that the inclusion of both patients with high- and low-inflammatory burden may compromise the ability to detect significant differences in cIMT compared to healthy individuals. Third, the introduction of highly potent drugs, such as infliximab, in the management of IBD has altered their natural history. Although patients treated with infliximab are usually those with more aggressive disease, infliximab is efficient in treating active disease and ameliorating the inflammatory burden.³⁴ In this context, the Danish IBD cohort found a trend toward decreased incidence of CAD in patients who received infliximab, but this was not significant.³² Furthermore, in a study that showed higher cIMT in patients with IBD, those treated with infliximab had a lower cIMT that did not differ from controls.¹⁸ Therefore, aggressive suppression of inflammation with biologic agents may decrease the risk of primary atherosclerosis. Unfortunately, the proportion of patients treated with infliximab varied considerably (from 0% to 33%) among studies included in this review. In addition, patients who received 5-ASA in the Danish cohort had lower risk of CAD, which can be partly attributed to a potential antiplatelet effect of these agents.³⁵ Thus, the wide use of 5-ASA for the treatment of IBD may further confound any association between IBD and CVD. Fourth, only 1 study included a well-matched for established CVD risk factors control group.²⁸ This study showed similar cIMT values in patients with IBD (n = 61) and controls (n = 61). However, these patients mainly had mild disease that might account for the results.³⁶ The remaining studies did not use matching, although the control groups were comparable with regard to most CVD risk factors. However, a constellation of different risk factors may account for different CVD risk; thus, comparisons between apparently similar groups may not be safe. Finally, patients with CD and UC may not represent a homogenous study population, as there are considerable differences in smoking habits. Smoking seems to have a beneficial effect on intestinal inflammation in UC, and its cessation has been associated with exacerbations of intestinal inflammation and increased risk of colectomy.³⁷ In contrast, in CD smoking may be associated with disease flares.³⁸ In a cohort of 820 patients with IBD, 52% of the patients with CD smoked initially, but about half of the active smokers stopped smoking after CD diagnosis.³⁹ In contrast, patients with UC were more likely to be nonsmokers or to have ceased smoking before UC diagnosis. After the diagnosis of UC, only 9% of these patients were active smokers. These differences in smoking rates may account for increased CVD risk in certain subgroups of patients with IBD.⁴⁰

A probable link between IBD and atherosclerosis can be supported by (1) the prevalence of established CVD risk factors, in particular smoking, in IBD subpopulations, (2) the alteration of known CVD risk factors as a result of systemic inflammation, and (3) a direct effect of systemic inflammation on the vascular endothelium. As discussed earlier, smoking rates in patients with IBD may not differ from general population, but in certain subgroups, such as patients with UC before diagnosis and patients with CD at diagnosis, smoking rates are high and may account for increased CVD risk. In addition, patients with IBD often have altered lipid profiles, increased homocysteine concentrations, and insulin resistance. Patients with IBD, in particular those with active disease, exhibit decreased apolipoprotein A-I, total and HDL-C levels, and increased triglyceride levels.⁴¹ Systemic inflammation has an impact on individual lipid components.⁴² In addition, HDL exhibits antioxidative, anti-inflammatory, and antithrombotic properties⁴³ that can become dysfunctional in the context of chronic inflammation.⁴⁴ The antioxidative effect of HDL particles seems to be impaired in patients with IBD.¹⁹ Insulin resistance, as reflected by increased insulin levels and Homeostasis Model of Assessment—Insulin Resistance, has been shown in patients with IBD, in the absence of DM or hyperglycemia.^17,45 Increased resistin levels, an adipokine that has been associated with insulin resistance and atherogenesis, may be responsible for insulin resistance in these patients.⁴⁶ Hyperhomocysteinemia has also been found in a significant proportion of patients with IBD⁴⁷; homocysteine can precipitate endothelial dysfunction and plays a role in atherogenesis.⁴⁸ These alterations may enhance CVD risk in patients with IBD. Finally, inflammatory molecules, such as the inflammatory cytokines IL-6 and TNF-α, and CRP, which are released due to intestinal inflammation, may be involved in endothelial dysfunction and primary arterial wall lesions. CRP is not only a surrogate of CVD and a predictor of CVD events, but it may also participate in arterial wall inflammation, promoting atherosclerosis.^49,50

Chronic systemic inflammation is an independent CVD risk factor, as is clearly indicated by the paradigm of rheumatologic disorders such as SLE, RA, and psoriasis.⁵¹ IBDs are also characterized by systemic inflammation with extraintestinal manifestations. Thus, it could be supported that IBD is associated with increased CVD risk that parallels rheumatologic diseases. However, patients with IBD exhibit some unique features such as smoking pattern, lower BMI, and dietary habits, which may alter this association. The Canadian Cardiovascular Society⁵² and the European Society of Cardiology/European Atherosclerosis Society guidelines⁵³ have included patients with SLE, RA, and psoriasis in the populations that should be screened for established CVD risk factors and treated according to their determined risk. If a link between IBD and atherosclerosis is proved, these patients should also receive comprehensive assessment and treatment of CVD risk factors.

In conclusion, systemic inflammation in IBD may represent a risk factor for atherosclerosis. A pathogenetic link between IBD and atherogenesis may exist. Several epidemiologic studies showed increased rates of CVD and/or CVD events in patients with IBD; however, methodological limitations make the interpretation of their results difficult. With regard to cIMT, this review demonstrates that current data are inconclusive. This is due to the small number of patients, the heterogeneity of the study populations with regard to inflammatory burden and smoking habits, and the lack of strict matching with controls. In order to elucidate a potential association between IBD and CVD risk, prospective studies with sufficient number of patients and long-term follow-up are needed. In addition, thorough assessment of traditional CVD risk factors, as well as patient stratification according to type of disease, inflammatory burden, and type of treatment is required. The confirmation of such an association will probably have important implications for the surveillance and treatment strategies in these patients. Risk factor modification with statins may even turn out to benefit IBD itself.^54,55

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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