Gastroenterology & Hepatology

April 2024 - Volume 20, Issue 4

Cardiovascular Comorbidities and Inflammatory Bowel Disease: Causes and Consequences

Preetika Sinh, MD
Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin 

Raymond K. Cross, MD, MS
Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Maryland

Corresponding author:
Dr Preetika Sinh
8701 Watertown Plank Road
Medical College of Wisconsin
Milwaukee, WI 53226
Tel: (414) 955-6858
Fax: (414) 955-0037

Abstract: Patients with inflammatory bowel disease (IBD) have an increased risk of cardiovascular disease (CVD) such as myocardial infarction and stroke. CVD in patients with IBD might occur in those with younger age and active disease, which are not traditional risk factors of CVD. Atherosclerotic CVD (ASCVD) and IBD are both proinflammatory conditions, and the underlying chronic inflammation might drive ASCVD risk. Decreasing inflammation might reduce this risk; however, data are limited. IBD medications can increase or decrease ASCVD risk. There are no specific guidelines or modalities to assess ASCVD in IBD. Early detection and risk stratification strategies have been established in other chronic inflammatory disorders. This article discusses causes of CVD in IBD and strategies to modify the consequences. 

Cardiovascular disease (CVD) is the leading cause of mortality in the United States.1 Increased risk of CVD such as myocardial infarction (MI) and stroke as well as CVD mortality are well established in chronic inflammatory disorders (CIDs) such as rheumatoid arthritis (RA), psoriasis, and lupus, and early risk stratification and strategies to minimize this risk are recommended.2 Several studies have demonstrated an increased risk of CVD in patients with inflammatory bowel disease (IBD), which affects approximately 3 million Americans and 6.8 million people worldwide.3-5 Currently, there are no guidelines to risk stratify CVD in patients with IBD. CVD, in particular atherosclerotic CVD (ASCVD), in IBD does not correlate well with traditional risk factors of ASCVD such as advanced age, obesity, and hyperlipidemia.6-8 Nontraditional risk factors such as younger age, female sex, and IBD activity have been associated with ASCVD events.6,7,9,10 IBD and atherosclerosis are both proinflammatory conditions with common independent underlying mechanisms of immune, endothelial, and platelet dysfunction in genetically predisposed individuals. Understanding the link between the 2 processes will help risk stratify IBD patients with respect to their heart disease and help providers select the most appropriate treatment strategy. Current data are limited, and in-depth information regarding mechanisms and factors that influence CVD in IBD remains a major knowledge gap.11-14 There are also limited data regarding the role of medications in reducing CVD risk. This article aims to enhance understanding of CVD in patients with IBD by classifying it as ischemic (ASCVD) or nonischemic (Table 1); discusses epidemiologic data related to risk factors and mechanisms of CVD in IBD (Table 2); and examines assessment tools, medication data, and proposed strategies to modify this risk (Table 3). Review of these aspects and identifying knowledge gaps will likely help alter the consequences of CVD in patients with IBD.

Causes of Cardiovascular Disease in Inflammatory Bowel Disease 

To better understand the risk and common mechanisms, this article categorizes CVD in IBD into venous or arterial disorders and focuses on the latter (Table 1). Arterial CVD can be further classified as (1) ischemic CVD or ASCVD such as coronary artery disease, cerebrovascular disease (stroke), peripheral arterial disease (PAD), and mesenteric ischemia; and (2) nonischemic CVD such as arrhythmias, pericarditis, nonischemic cardiomyopathies, and valvular heart disease. Heart failure (HF) can be ischemic from ASCVD or nonischemic from cardiomyopathies or congenital causes. Epidemiologic data, risk factors, and possible mechanistic links are examined in the following sections. 

Ischemic or Atherosclerotic Cardiovascular Disease 

Epidemiologic Data  ASCVD or ischemic CVD is related to atherosclerotic plaque burden in the arterial vasculature and is often referred to with the term major atherosclerotic cardiovascular event (MACE). The classical definition of MACE comprises nonfatal MI, nonfatal stroke, cardiac revascularization (percutaneous cardiovascular stent or coronary artery bypass graft), and cardiovascular mortality. There is a 2-fold increased risk of MACE in patients with IBD.3,6,15,16 The increased prevalence of ASCVD is now well recognized in IBD patients.6,15,17-21 However, in patients with IBD, the role of traditional risk factors of ASCVD such as hypertension, hyperlipidemia, obesity, and smoking needs further investigation.22,23 Multiple population-based cohort and case-control studies across different regions of the world have shown a higher prevalence of ASCVD in younger and female IBD patients without higher rates of obesity or hyperlipidemia.3,7,10,24-26 Lee and colleagues showed higher prevalence of premature (<55 years; odds ratio [OR], 1.14; 95% CI, 1.08-1.21) and extremely premature (<40 years; OR, 1.82; 95% CI, 1.52-2.17) ASCVD in IBD patients compared with non-IBD patients in a US veteran population.7 Our recent analysis of a large cohort of US veterans showed that IBD was an independent risk factor for MI in 63,155 IBD patients compared with 252,595 non-IBD patients (adjusted hazard ratio [aHR], 1.23; 95% CI, 1.11-1.36). When stratified by age, incidence of MACE was significantly higher in patients with IBD vs controls less than 40 years of age (0.49% vs 0.40%; P=.03).27 Aggarwal and colleagues retrospectively studied 131 IBD patients at a single center with coronary artery disease diagnosed by coronary angiogram, which is a gold standard for atherosclerosis assessment. Compared with 524 controls, IBD patients were younger, had lower prevalence of active smoking, and had lower body mass index.24 Hence, nontraditional risk factors of IBD activity might contribute to the process of atherosclerosis. 

Although there is more consistent information about ASCVD risk in IBD patients, the outcomes of MI and mortality in patients with IBD during hospitalization are unclear. CVD complications contribute to increased length of stay and cost of hospitalization, especially in older patients, but the risk of CVD mortality is debatable.3,21,28 Several retrospective national administrative database cohort studies have shown contrary results, and significant heterogeneity has been reported in meta-analy­ses.17,19,29-32 Population-based cohort studies have the advantage of analyzing a large number of patients; however, reporting of events is based on diagnosis codes that have potential for error, and the studies lack information on biologic medications that may influence outcomes. Many studies assess CVD events during the short period of hospital admission and do not assess re­admissions.17,18 The impact of IBD on CVD mortality needs to be further investigated. 

Patients with IBD, especially those who are younger, are also at increased risk of PAD and mesenteric ischemia.17,26,33 In a French cohort study, IBD patients had an increased risk of PAD (standardized incidence ratio, 1.27; 95% CI, 1.17-1.37) that was most significant in those with Crohn’s disease who were less than 35 years old.26 

Atherosclerotic Cardiovascular Disease Is Associated With Inflammatory Bowel Disease Activity  An important aspect to consider is that ASCVD has been associated with disease activity in patients with IBD.9,28,34,35 Assessing disease activity from large retrospective cohort studies has its limitations. Objective assessment of
disease activity with serum or stool biomarkers (fecal calprotectin) and endoscopy is not available in most studies.3,36 However, a consistent pattern that has emerged over the years is that disease flare, as assessed by surrogate markers of active inflammation (such as corticosteroid use, time since diagnosis, and hospital admissions for IBD), is associated with increased incidence of ASCVD.9,26,28,35 A recent study from UK Biobank reported a 19% higher risk of acute arterial events, defined as coronary, cerebral, and peripheral arterial events, in IBD patients (aHR, 1.19; 95% CI, 1.08-1.31), which was most pronounced in younger patients (39% higher risk in men <55 years of age and women <65 years of age) compared with non-IBD patients. High-sensitivity C-reactive protein (hsCRP) (aHR, 1.53; 95% CI, 1.15-2.03) and disease severity as assessed by IBD-related hospitalizations and surgeries (aHR, 5.4; 95% CI, 4.03-7.22) were independent risk factors. HsCRP in this study was assessed at 1 time point, but IBD was associated with increased acute arterial events even after adjusting for hsCRP, suggesting that chronic inflammation plays a role in long-term outcomes. The median follow-up duration was 15 years in this study.34 Aarestrup and colleagues assessed ASCVD risk profiles in a Danish cohort and reported that patients with IBD had slightly lower cholesterol but a higher level of inflammatory markers (hsCRP and fibrinogen) when assessed at random time points during the disease course of the patients.22 Decreasing the inflammatory burden may decrease ASCVD risk; however, it would be important to determine which medical therapy can decrease ASCVD risk independent of its role in controlling inflammation. 

Mechanism of Atherosclerotic Cardiovascular Disease in Inflammatory Bowel Disease  Atherosclerosis and IBD have a similar mechanism in which individuals with genetic predisposition develop immune, platelet, and endothelial dysfunction leading to chronic inflammation. The underlying chronic inflammatory process likely drives ASCVD in patients with IBD. Chronic inflammation in the gut can lead to systemic and extraintestinal manifestations (EIMs) of IBD such as arthropathy in the joints and uveitis in the eyes. Inflammation in the vascular bed can lead to atherosclerosis, MI, and stroke.14 

It is now widely accepted that the underlying mechanism of atherosclerosis involves both innate and adaptive immune responses with platelet and endothelial dysfunction in genetically susceptible hosts, similar to IBD.37 Various biomarkers of altered immune response (oxidized low-density lipoprotein, fibrinogen, nuclear factor [NF]-κB, interferon-γ, tumor necrosis factor [TNF]α) and endothelial dysfunction (CD40/CD40 ligand, endothelial precursor cells, matrix metallopeptidase, vascular cell adhesion molecule 1, intercellular adhesion molecule 1, P-selectin) have been studied and are associated with CVD events.38 Inflammatory markers that are elevated in IBD such as CRP, interleukin (IL)-6, IL-1, IL-8, and TNFα have been shown to be predictive of future CVD events.39 In addition, certain genetic factors such as common polymorphisms in nucleotide-binding oligomerization domain-containing protein 2/caspase recruitment domain-containing protein (NOD2/CARD15) have been independently reported in the pathophysiology of both atherosclerosis and IBD.40 Some cytokine inhibitors, such as the IL-6 inhibitor tocilizumab, the TNF inhibitor adalimumab, and the IL-1 receptor–blocking agent anakinra (which also blocks IL-1α and IL-1β), have been studied in CVD drug trials in the general population and showed reduction in inflammatory markers such as CRP and modest benefit with respect to CVD outcomes.41 The landmark CANTOS trial, published in 2017, showed promising results with a significant decrease in CVD events with the use of an IL-1β monoclonal antibody.42 The take-home message was that it decreased CVD endpoints of MI and nonfatal stroke, irrespective of reduction in lipids, and this was evident in the subgroup of patients who showed significant reduction in IL-6.43 However, the cost of the drug and higher incidence of fatal infections among the treatment group raise concerns about its clinical use. 

Even though certain biomarkers such as IL-6, TNFα, and CRP are increased in both atherosclerosis and IBD, further investigation is needed to obtain a deeper understanding of the underlying mechanism to formulate specific treatment targets that address both inflammatory pathways.

Nonischemic Heart Disease


Epidemiologic Data   Atrial fibrillation (AF) is the most common arrhythmia in patients with IBD. A meta-analy­sis by Zuin and colleagues reported a 2-fold increased risk of AF in IBD patients (OR, 2.26; 95% CI, 2.11-2.41). However, owing to the small numbers and significant heterogenicity in the 2 cohorts and 1 cross-sectional study included in the meta-analysis, further investigation is needed to determine the risk of AF in patients with IBD.25 Kristensen and colleagues reported that the risk of AF and stroke was higher in IBD patients during flares and periods of disease activity, and this risk was not seen during periods of remission.44 The prevalence of cardiac conduction disorders such as bradycardia in ulcerative colitis (UC) appears to be low.45 The risk of other arrhythmias in patients with IBD has not been studied.

Mechanism  Chronic inflammation has been implicated in the mechanism of AF.46 Certain biomarkers such as IL-6 and CRP are common to the pathogenesis of both disease processes. Fibrogenesis, enhanced automaticity, atrial dilatation, and conduction defects have been implicated as possible mechanisms in other CIDs.47 Can and colleagues performed a cross-sectional study in 79 IBD patients and found a significant delay in atrial conduction time (ACT) in IBD patients compared with controls. ACT is a risk factor for severe AF.48 Conduction abnormalities such as increased P-wave dispersion, electromechanical delays, and QTc dispersion have been reported in adult and pediatric patients with IBD. These abnormalities predispose to atrial and ventricular arrhythmias.49-52 

Further studies are needed to better define the baseline risk of arrhythmias in patients with IBD and its relationship to disease activity to develop appropriate tools for early detection and treatment of arrhythmias in these patients. 

Pericarditis and Myocarditis

Epidemiologic Data  Pericarditis and myocarditis have been reported in patients with IBD53-56 and may manifest as the presenting sign or even precede the diagnosis of IBD.57,58 More commonly, they have been reported as adverse events of medications such as mesalamine, with some case reports of pericarditis induced by infliximab or thiopurine.55,59-63 

Mechanism  Autoantigens have been implicated as a trigger for myocarditis, but complete understanding of the underlying mechanism remains unclear.64 Acknowledging that myocarditis or pericarditis can be an EIM or complication of medical treatment of IBD will assist in early diagnosis and appropriate treatment. Collaborative efforts with a cardiologist and discontinuing or holding the possible inciting medication should be considered for timely management. 

Heart Failure 

Epidemiologic Data  HF can be caused by ischemic heart disease or nonischemic causes such as cardiomyopathies and congenital heart diseases. Patients with IBD have a 2-fold increased risk of HF, which is associated with periods of disease activity.15,65 HF in IBD patients is associated with worse IBD and clinical outcomes.66 

Mechanism  Inflammation can be both a cause and consequence of HF and plays a central role in disease pathogenesis and progression.67 This has been well studied in the general population, including several clinical trials exploring inflammatory pathways as a target for HF treatment.67 The role of the gut is of particular interest in HF due to 2 mechanisms. The first involves the release of endotoxins from the gut such as lipopolysaccharides during HF. The circulating endotoxins lead to activation of the NLRP3 inflammasome with subsequent maturation of proinflammatory cytokines (such as NF-κB, TNFα, IL-1β, IL-6, and IL-18), negative cardiac inotropic effects, fibrosis, and systolic and diastolic dysfunction.67 Endotoxins released from the gut are elevated during episodes of decompensated HF and decreased after successful treatment of decompensation, supporting the role of the gut in the inflammatory process.68 Second, HF is also associated with dysbiosis of the gut microbiome with low bacterial diversity.69 Altering gut dysbiosis with dietary modifications and probiotics is being looked into as a therapeutic target for HF.70

Understanding the underlying mechanism of HF in patients with IBD is of particular importance due to its interplay with IBD medications such as corticosteroids and anti-TNF drugs.

Consequences of Cardiovascular Disease in Inflammatory Bowel Disease 

The following sections will review modalities to assess CVD in IBD, current recommendations for CVD risk assessment in IBD and other CIDs, and the role of medications in CVD. Review of these aspects and identifying knowledge gaps will help identify areas of research that will alter the consequences of CVD in patients with IBD. 

Modalities to Assess Cardiovascular Disease Risk in Inflammatory Bowel Disease 

Although there are data that CVD risk is increased in IBD, there is limited information regarding modalities to assess this risk.11 Only a few prospective studies have shown evidence of early signs of atherosclerosis in patients with IBD as measured by markers of subclinical atherosclerosis and vascular dysfunction.71-73 

Clinical risk calculators such as the American College of Cardiology/American Heart Association (ACC/AHA) 10-year ASCVD risk calculator, Framingham Risk Score calculator, Reynolds Risk Score (RRS), and Systematic Coronary Risk Evaluation (SCORE2) are based on traditional risk factors for ASCVD. Most clinical scores do not take into account nontraditional risk factors such as disease activity and serologic markers that contribute to increased ASCVD risk in CIDs.74,75 RRS is a risk prediction algorithm that has been used in the RA population owing to its inclusion of hsCRP, which is a marker of inflammation.76 ASCVD or other risk prediction scores have not been validated in patients with IBD. 

Modalities to assess ASCVD and vascular function can be broadly classified into those evaluating structural markers of atherosclerosis and those assessing endothelial or vascular dysfunction.11 Structural imaging to assess for plaque burden and coronary artery calcium deposition by computed tomography (CT) angiogram or noncontrast CT has not been widely studied in patients with IBD.77 However, even preceding calcium or plaque deposition, chronic inflammation can lead to endothelial dysfunction as seen in patients with RA.2 Endothelial dysfunction is an imbalance between vasodilating and vasoconstricting substances produced by endothelial cells. Endothelial dysfunction is characterized by upregulation of cellular adhesion molecules, compromised barrier function, increased leukocyte diapedesis, and increased vascular smooth muscle tone. These phenomena are related to impaired production of vasodilator substances such as nitric oxide as well as increased production of vasoconstrictor substances, including endothelin, which initiate a prothrombotic state.39 Endothelial dysfunction is present in both IBD and atherosclerosis and is a precursor for CVD events.39

Arterial stiffness, which is a measure of endothelial function, is impaired in patients with IBD and can be assessed by pulse wave velocity. Endothelial or vascular dysfunction can also be classified as macrovascular or microvascular. Macrovascular (large vessel) dysfunction can be assessed by flow-mediated dilatation and carotid intima thickness via ultrasound and dysfunction in the microvasculature (small vessels) by EndoPAT.11 However, the studies that have used these modalities in patients with IBD are small and lack long-term follow-up. 

In addition, laser Doppler with microdialysis has been used to assess small vessel endothelial dysfunction in vivo.78 This technique has not yet been studied in patients with IBD and might help in the understanding of how medications may alter vascular function in real time at a mechanistic level. 

Currently, the only modalities available in the clinical setting to assess atherosclerosis are CT angiogram and noncontrast CT for the coronary artery calcium score. Even these have not been validated in IBD to determine whether they detect ASCVD or preclinical atherosclerosis appropriately, especially in younger patients with short-term disease. The assessment and treatment of ASCVD risk with clinical risk calculators in the primary care setting is suboptimal.79 Hence, there remains a need to investigate ways to risk stratify ASCVD in IBD patients with methods that incorporate inflammation. 

Recommendations for Assessment of Atherosclerotic Cardiovascular Disease in Chronic Inflammatory Disorders 

The 2019 update of the ACC/AHA guidelines on primary prevention of CVD identifies CIDs such as psoriasis, RA, lupus, and HIV/AIDS as risk-enhancing factors.80 Per ACC/AHA guidelines, all adults should undergo ASCVD risk assessment by using an ASCVD risk score calculator that incorporates traditional risk factors. In patients with borderline risk (5% to <7.5% 10-year ASCVD risk) or intermediate risk (>7.5% to <20% 10-year ASCVD risk), risk-enhancing factors such as CIDs should be used to guide clinical decision-making for primary prevention strategies such as statin therapy. IBD is not incorporated in the 2019 ACC/AHA guidelines. However, guidelines published by the European Society of Cardiology in 2019 recognized IBD, along with other proinflammatory conditions such as cancer treatment, RA, and systemic lupus erythematosus (SLE), as needing more intensive risk screening, counseling, and management.81 

There are well-established guidelines for the assessment of ASCVD in other CIDs such as RA, psoriasis, ankylosing spondylitis, and SLE per the European Alliance of Associations for Rheumatology (EULAR).2,82 The key take-home point from these recommendations is that all patients with RA, ankylosing spondylitis, or psoriatic arthritis should be screened for ASCVD risk using SCORE2 at least once every 5 years so that lifestyle advice and CVD preventive treatment can be initiated when indicated.83 A multiplication factor of 1.5 is recommended in RA patients to incorporate the role of the chronic inflammatory process. Aggressive management of disease activity, as well as avoiding and minimizing use of nonsteroidal anti-inflammatory drugs and corticosteroids, is recommended. The 2017 EULAR update was notable for being the first time to include the recommendation for screening of asymptomatic atherosclerotic plaque by carotid ultrasound in RA patients because the plaque reclassifies a considerable proportion of patients with RA into a more appropriate CVD risk group, which might change the indication to start statin therapy.84 European consensus on EIMs in IBD established CVD as an EIM; however, there is a lack of specific recommendations to risk stratify patients with IBD.85

Cardiovascular Disease Risk and Inflammatory Bowel Disease Medications 

IBD can be treated with various medications that can be broadly classified into (1) aminosalicylates/mesalamines, (2) corticosteroids, (3) immunomodulators, (4) biologics, and (5) small molecules. The following sections highlight CVD risk associated with medications of interest in current IBD management such as corticosteroids, anti-TNF drugs, Janus kinase (JAK) inhibitors, IL-12/IL-23 inhibitors, and sphingosine-1 phosphate (S1P) receptor modulators.11,86,87 

Corticosteroids  Corticosteroid use has been associated with increased risk of HF and ASCVD in the general population.67,88 Minimizing corticosteroid use and transitioning to corticosteroid-sparing medications are recommended in CIDs to reduce CVD risk.82 In SLE patients, a dose-dependent relationship was noted with an increase in long-term side effects when taking a daily dose of more than 10 mg for longer than 6 months.89 Corticosteroids have a detrimental effect on the cardiometabolic profile and cause weight gain, fluid retention, and increases in blood glucose and blood pressure. These require close monitoring, adjustment of the corticosteroid dose, and initiation of hypoglycemic and/or antihypertensive therapy if appropriate.90,91 Corticosteroids are frequently used to treat IBD flare. Lewis and colleagues assessed side effects of long-term corticosteroid use (>3 g or equivalent dose over a 12-month period). Long-term corticosteroid use was associated with increased mortality, compared with use of anti-TNF drugs, mainly related to MACE.92 

Interpretation of short-term effects of corticosteroids in IBD through epidemiologic studies can be difficult. The detrimental effect of corticosteroids in IBD can be confounded by the fact that they are often used during active disease, which has been shown to be associated with ASCVD events. In addition, corticosteroid use is often utilized as a surrogate marker for disease activity in large retrospective cohort studies. Hence, the short-term effects of corticosteroids on ASCVD in patients with IBD may be best assessed by prospective studies. Yarur and colleagues did not find corticosteroids to be associated with increased risk of ASCVD in patients with IBD in a single-center retrospective case-control study.6 

Anti–Tumor Necrosis Factor Medications  TNF inhibition emerged as a potential therapeutic target for HF after preclinical data suggested harmful effects of TNF signaling in HF and improvement in left ventricle ejection fraction with TNF blockage.67 Two large trials of anti-TNF therapy in the general population, RENEWAL and RENAISSANCE, did not show improvement in clinical outcomes.93 The ATTACH trial found that high-dose infliximab (10 mg/kg) was associated with an increased risk of all-cause death and HF hospitalization.94 Hence, use of anti-TNF agents is contraindicated in severe HF patients (New York Heart Association [NYHA] class III and IV). Of note, 10 mg/kg is not the usual dose in patients with IBD, and no detrimental effects were noted at standard dosing. A paradoxical effect at high dosage of anti-TNF therapy may be related to inhibition of NF-κB signaling. NF-κB is activated by TNF and, contrary to TNF, is cardioprotective. Hence, it is possible that the beneficial effects of NF-κB were lost by excessive suppression of TNFα.67 

Anti-TNF drugs, however, have not been associated with worsening of HF in the RA population.95 Several studies have shown a beneficial effect of anti-TNF agents in RA and psoriasis patients, especially if the disease is controlled in the first 6 months.89,96,97 Data in IBD are limited, but several studies indicate the beneficial effect of anti-TNF drugs in reducing CVD risk and mortality.92,98,99 Kirchgesner and colleagues reported decreased risk of acute arterial events in a French IBD cohort exposed to anti-TNF drugs (HR, 0.79; 95% CI, 0.66-0.95) but not to thiopurines (HR, 0.54; 95% CI, 0.82-1.05).98 Analysis of US Medicare and Medicaid data showed significant mortality benefit in Crohn’s disease patients treated with anti-TNF drugs compared with patients who were treated with prolonged courses of corticosteroids (21.4 vs 30.1 per 1000 person-years; OR, 0.78; 95% CI, 0.65-0.93).92 A prospective study assessing subclinical atherosclerosis by pulse wave velocity showed that anti-TNF use was associated with reduction in arterial stiffness to a level comparable to that of controls after 4 years of treatment.100 Anti-TNF agents have been associated with dyslipidemia in case reports.101 Although anti-TNF agents show promise in reducing CVD risks, studies are needed to assess their effect on lipid patterns and HF in patients with IBD. In addition, whether the protective effect is due to control of disease activity or a mechanistic effect regardless of control of disease activity needs to be investigated. 

Interleukin-12/Interleukin-23 Antagonists  IL-12 and IL-23 inhibition in mouse models has been shown to be protective against atherosclerosis.67,102 However, an increased risk of MACE was seen with the IL-12/IL-23 inhibitor briakinumab, which led to study discontinuation in 2011.103 The IL-12/IL-23 inhibitor ustekinumab (Stelara, Janssen) is now available for Crohn’s disease and UC patients. Ustekinumab was not associated with an increased risk of MACE in psoriasis or psoriatic arthritis, and current data in IBD patients have not shown any signals of increased CVD risk.104,105 Cardioprotective effects of ustekinumab, including improvements in left ventricular and vascular function, were seen in a small clinical trial of psoriasis patients.106 Risankizumab (Skyrizi, AbbVie), an IL-23 inhibitor, has no safety concerns regarding MACE in clinical trials for IBD or other CIDs.107 Long-term data in IBD are awaited. Given the molecular mechanism of cardioprotection, its effectiveness for reducing CVD risk would be worth exploring.

Janus Kinase Inhibitors  Tofacitinib (Xeljanz, Pfizer) is a pan-JAK inhibitor and the first oral small molecule approved for UC. Subsequently, the JAK1-selective inhibitor upadacitinib (Rinvoq, AbbVie) was approved for UC and Crohn’s disease, and the JAK1-selective inhibitor filgotinib is being studied in patients with IBD. 

JAK inhibitors are currently indicated as second-line agents in UC and Crohn’s disease owing to safety concerns regarding thromboembolism, MACE, and malignancy. In 2019, the US Food and Drug Administration (FDA) reviewed initial results of the postmarketing Oral Rheumatoid Arthritis Trial (ORAL) Surveillance, which randomized RA patients 50 years and older on methotrexate with at least 1 CVD risk factor into 3 groups (tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, or anti-TNF therapy [adalimumab or etanercept]).108 An increased risk of MACE (HR, 1.33; 95% CI, 0.91-1.94) was found in patients on tofacitinib. This was most pronounced in patients older than 65 years and smokers. Subsequent post hoc analysis of ORAL Surveillance published in January 2023 showed an increased risk of MACE in the group that had prior history of ASCVD.109 

In patients with IBD, data from more than 7 years of follow-up of randomized controlled trials (RCTs) have not shown any adverse signals for MACE with JAK inhibitors.110 Pooled analysis from RCTs of tofacitinib in UC found 8 CVD events in 1124 patients. Five of the 7 patients with MACE had multiple CVD risk factors at baseline with intermediate to high ASCVD risk as calculated by the ACC/AHA 10-year risk calculator.111,112 One patient had an aortic dissection that resulted in death, but that was not considered to be related to the drug. It is notable that the total incidence of MACE in RCTs of tofacitinib over a 7-year period in IBD was low (0.7%; 0.26/100 patient-years; 95% CI, 0.11-0.54). This is similar to pooled data from RCTs in the RA population with 9.5 years of follow-up (incidence rate, 0.4; 95% CI, 0.3-0.5).113 

Several studies have investigated the risk of MACE with tofacitinib in real-world settings and have not found it increased, although most studies had a small number of patients.87,114 Kochar and colleagues reported a 2% risk of MACE (HR, 2.5; 95% CI, 0.37-6.18) in 305 patients receiving tofacitinib in a study from a large US claims database; this was not significantly different from patients receiving anti-TNF therapy.115 

In clinical trials of upadacitinib in UC, there was 1 MACE in the placebo group and none in the treatment group with 52 weeks of follow-up.116 One MACE was reported at 30-month follow-up in a clinical trial of upadacitinib for Crohn’s disease in a patient who had multiple CVD risk factors.117 RCTs of filgotinib in patients with IBD have reported few cerebrovascular events, but long-term data are awaited.118 Data on upadacitinib and filgotinib from RCTs in RA, psoriasis, and atopic dermatitis reported infrequent MACEs, and the exposure-­adjusted incidence rates remained stable over time.119-123 Real-world data of patients with IBD are still awaited for upadacitinib and filgotinib, and whether selective JAK inhibition confers protection against CVD adverse effects remains to be determined.

Two meta-analyses, comprising a total of 20 RCTs across all CIDs (including IBD), showed no significant increased risks in mortality, MACE, and venous thromboembolism with use of selective (upadacitinib and filgotinib) and nonselective (tofacitinib and baricitinib) JAK inhibitors.124,125

There are a few other aspects to consider regarding JAK inhibitors and cardiovascular risk. First, even though ORAL Surveillance reported an increased risk of MACE in patients with RA, the absolute incidence of MACE is low and was not statistically significant in RCTs and real-world studies across multiple CIDs, including IBD. Second, most patients who had MACE had known CVD risks or prior ASCVD, which appears to be a more important factor than the drug. Hence, JAK inhibitors should be used with caution in older patients with multiple CVD risk factors. 

Lipid alterations have been reported with tofacitinib in IBD trials, especially with higher doses. These are reversible, and the long-term implications in patients with IBD are still to be investigated.111 In the RA population, review of data from RCTs found that hypertension, age, and total cholesterol to high-density lipoprotein cholesterol (HDL-C) ratio were associated with risk of MACE. Increase in HDL-C and decrease in total cholesterol over a 24-week period were associated with lower future MACE risk.126 

A recently published international consensus statement regarding venous and arterial thromboembolism in patients with IBD recommended use of strategies to establish and control traditional ASCVD risk factors and IBD activity to improve CVD outcomes in patients with IBD. Tofacitinib was not considered to be a risk factor for MACE in IBD.16 However, intermediate or high baseline ASCVD risk appears to be associated with MACE in patients treated with tofacitinib.112 Both the FDA and European Medicines Agency have issued guidelines regarding small molecules (JAK inhibitors and S1P receptor modulators) in IBD treatment recommending the use of JAK inhibitors as second-line agents and with caution in patients with baseline risk of ASCVD.127,128

Sphingosine-1 Phosphate Receptor Modulators  The S1P molecule binds to S1P receptors in different cell types. Their highest density is on leukocytes, and S1P receptor modulators prevent trafficking of lymphocytes from the spleen and lymph nodes into the systemic circulation leading to decrease in inflammation.129 S1P receptors have 5 subtypes (1-5), and 3 (1-3) are present ubiquitously, including in the CVD system possibly leading to arteriovenous block and transient bradycardia.130 Three S1P receptor modulators have been studied in IBD (ozanimod [Zeposia, Bristol Myers Squibb], etrasimod [Velsipity, Pfizer], and amiselimod), and ozanimod (S1P1/5 receptor modulator) and etrasimod have been approved for use in UC. Ozanimod is contraindicated in patients who have experienced MI, unstable angina, cerebrovascular accident, or NYHA class III or IV HF in the 6 months prior to initiation of therapy and patients with significant conduction abnormalities (Mobitz type II second-degree or third-degree atrioventricular block, sick sinus syndrome, or sinoatrial block) unless the patient has a functioning pacemaker. Given cardiac considerations, it is recommended that patients obtain a baseline electrocardiogram to screen for any conduction abnormalities. Follow-up cardiac monitoring is not recommended. Pooled data from RCTs in UC and multiple sclerosis did not show increased risk of MACE, and the incidence of bradycardia was low (mean decrease in heart rate by 0.7 beats per minute from baseline) and primarily in the induction period (within the first 5 hours and returned to baseline after 6 hours).131 Ozanimod is not associated with increased risk of MACE, QTc prolongation, or clinically significant bradycardia.


Patients with IBD are at increased risk of ASCVD events such as MI and stroke. Traditional risk factors such as obesity, hyperlipidemia, and advanced age may not completely explain the higher risk of ASCVD in the IBD population. Disease activity and chronic inflammation appear to drive the risk. Modalities to assess ASCVD in IBD are needed to appropriately risk stratify patients so that early intervention and risk modification strategies can be implemented. Anti-TNF medications may decrease ASCVD risk; however, it is unclear whether this is due to underlying mechanisms of the drugs or due to control of inflammation. Corticosteroids increase ASCVD risk, and small molecules such as tofacitinib, upadacitinib, and ozanimod must be used with caution in patients with prior ASCVD risk factors or conduction defects of the heart. Patients with IBD should be assessed for baseline ASCVD risk; however, whether ASCVD clinical risk scores or imaging modalities appropriately risk stratify CVD in IBD needs further investigation. Table 3 lists our recommendations for CVD risk assessment in patients with IBD. 


Dr Sinh has no relevant conflicts of interest to disclose. Dr Cross has participated in consulting and advisory boards for AbbVie, Adiso, BMS, Fresenius Kabi, Fzata, Janssen, Magellan Health, Pfizer, Pharmacosmos, Samsung Bioepis, Sebela, and Takeda. He has a research grant with Janssen. He is also the Scientific Co-Director of the CorEvitas registry and is a member of the executive committee for the IBD Education Group. 


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