Cardiovascular Disease Prevention in Individuals with Underlying Chronic Inflammatory Disease

Abstract

Purpose of Review:

Patients with chronic inflammatory disease have an increased risk of cardiovascular disease. This article reviews the current evidence of cardiovascular prevention in three common systemic inflammatory disorders (SID): psoriasis, rheumatoid arthritis and systemic lupus erythematosus.

Recent Findings:

General population CV risk assessment tools currently underestimate CV risk and disease-specific risk assessment tools are an area of active investigation. A disease-specific CV risk estimator has not been shown to more accurately predict risk compared with the current guidelines. RA-specific risk estimators have been shown to better predict CV risk in some cohorts and not others. SLE-specific scores have also been proposed and require further validation, whereas psoriasis is an open area of active investigation. The current role of universal prevention treatment with statin therapy in patients with SID remains unclear. Aggressive risk factor modification and control of disease activity are important interventions to reduce CV risk.

Summary:

A comprehensive approach that includes cardiovascular risk factor modification, control of systemic inflammation, and increased patient and physician awareness is needed in cardiovascular prevention of chronic inflammation. Clinical trials are currently underway to test whether disease-specific anti-inflammatory therapies will reduce CV risk.

Introduction:

Cardiovascular disease (CVD) is a leading cause of mortality and morbidity among patients with chronic inflammatory conditions (1–4). This review will focus on 3 common systemic inflammatory diseases (SID) with the majority of current data on CVD: psoriasis, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). At least 2% of people in United States and worldwide have one of these 3 chronic inflammatory diseases, which often affect multiple organ systems. These chronic inflammatory diseases are often driven by “autoimmunity” and “autoinflammatory” responses, meaning the body’s immune system attacks itself. Classically speaking, autoimmunity is driven by the adaptive immune system, which includes both T and B cell immunity. Autoinflammatory is often a term used to describe inflammation driven by the innate immune system, although overlap and interplay exists between these responses. Psoriasis is an autoinflammatory disorder of the skin associated with red, itchy, scaly patches. It can result in elevated systemic inflammation and in up to 30% of patients, will also involve joints, termed psoriatic arthritis. RA is a chronic autoimmune inflammatory disease manifesting primarily as joint inflammation most commonly in the hands and feet. SLE is an autoimmune condition associated with inflammation in multiple organ systems, including skin, joints, kidney, brain, heart, and lung. Both RA and SLE predominantly affect women. Gaps in our current knowledge of CVD in these populations include not only the specific role of inflammation but whether current preventive measures in the general population, such as statins, have a similar efficacy in patients with systemic inflammatory disease. Given the complex interplay between inflammation and traditional CVD risk factors in each disease, recommendations for CV screening and prevention will likely need to be tailored to each specific disease including the optimal timing and frequency of screening. In this review, we will discuss the current cardiovascular risk assessment tools and highlight modification of risk factors, particularly dyslipidemia and the role of statin therapy. Lastly, we will end with the emerging role of cardio-rheumatology and how multi-disciplinary care models can enable us to better understand and treat the elevated cardiovascular risk in patients with these conditions.

Current Cardiovascular Risk Assessment:

It is well known that current CV risk estimators underestimate CV risk in patients with SID. This has been most studied in RA where CV risk calculators underestimate risk by at least 2-fold in women. There have been multiple RA-specific scores created that incorporate inflammation, disease activity, RA specific factors, and a generic multiplication factor of 1.5 to the standard CV risk estimates; however, these prediction scores have been shown to improve CV risk in some but not all cohorts (5–8). A more recent SLE specific CV risk score has been developed that incorporated SLE-specific factors in addition to the traditional CV risk factors but requires external validation (9). No disease specific scores for psoriasis have currently been published to our knowledge. A recent systematic review assessed all CV prediction models in SID in 11 studies that met the inclusion criteria found that most underestimated CV risk in SID patients, and some could overestimate (10*).

The ACC/AHA has acknowledged the well-known fact that our current risk estimators underestimate the true CV risk by the addition of chronic inflammatory conditions (psoriasis, SLE, RA, and HIV) as “risk enhancers” (11**). Further risk discussion with the patient about initiation of statin therapy is now recommended when individuals in a borderline or intermediate risk category, i.e ASCVD score ranges from 5–20%, have evidence of a risk enhancer. Although the recognition of SID as risk enhancers is a beneficial approach to promote a discussion with the patient, this strategy may still fail to capture the at-risk younger patient population. Younger patients routinely fall in the low-risk category since age is a dominant component of the ASCVD risk score. In fact, in recent work we have investigated the relationship between SID and all-cause mortality among patients in the YOUNG-MI registry, a retrospective cohort that includes patients who experienced a first myocardial infarction (MI) at age 50 years or younger. In this study, 53/2097 individuals had evidence of SID, and were more likely to be female and have hypertension. Over a median follow-up of 11.2 years, patients with SID experienced an increased risk of all-cause mortality compared with both the full cohort and a matched cohort based on age, gender an CV risk factors. Compared to the general population, patients with SID had similar ASCVD risk scores at the time of the MI and would not have been eligible for primary prevention statin therapy (12*). These findings highlight the importance of better recognition and prevention of coronary artery disease in young patients with SID.

Cardiometabolic Risk Factor Modification:

The key elements in the prevention of CV risk in patients with SID include aggressive management of traditional risk factors and targeted therapy to reduce inflammation and achieve effect disease control.

Hypertension

The prevalence of hypertension (HTN) in patients with SID is increased for some conditions such as psoriasis compared with the general population (13, 14), whereas in RA and SLE some studies indicating a higher prevalence but not others (15–17). The etiology is likely complex, including both the interplay of chronic systemic inflammation, physical inactivity, and medications. A recent study examined the prevalence of resistant hypertension (RHTN), which is associated with a high risk of CAD, stroke and all-cause mortality in the general population, in SLE compared with matched controls and found a higher prevalence of RHTN. Furthermore, RHTN was associated with older age, black race, male sex and baseline creatinine as well as high mortality in SLE patients (18*).

Corticosteroids and NSAIDs have been associated with higher incidence of hypertension (19, 20). In addition, traditional disease modifying anti-rheumatic drugs (DMARDS) such as leflunomide and cyclosporine can result in elevations in blood pressure (21, 22). However, the current biologic DMARDs, including anti-TNF therapy, do not appear to result in an increase in blood pressure (23*). Conversely, some studies have even reported beneficial effects on reducing systolic blood pressure likely as a result of reducing inflammation and controlling disease activity.

There are currently no disease-specific guidelines to the treatment of hypertension in patients with SID. Whether there are specific therapies that would be more beneficial than other classes in each individual disease is not known. For instance, in SLE the initiation of an ACE-I or ARB may be the best first-line agent but outside of the renal-specific guidelines for lupus nephritis, this has not been studied (24). Several case reports have associated use of beta-blockers with an increased risk of psoriasis flare; however, this association was not observed in large analyses (25). Thus, the interplay between the pathophysiology of hypertension among patients with SID remains a gap in our current knowledge and the physician-patient awareness of hypertension is essential. For now, physicians should aggressively manage and treat blood pressure.

Smoking

Smoking is an established and modifiable risk factor for atherosclerosis (26). Smoking is also a risk factor for psoriasis, RA and SLE. Smoking has been associated with a reduced risk of psoriatic arthritis among patients with psoriasis, referred to as the “smoking paradox” (27*); however, until this is better understood physician’s should aggressively seek smoking cessation in these patients. In RA, there is a known gene-environment interaction, whereby individuals who are cigarette smokers carrying genetic risk factors for RA have significant higher risk for seropositive RA compared to non-smokers (28). In SLE, smoking is associated with higher positivity of dsDNA, generally a marker associated with more severe SLE (29).

Obesity, Insulin Resistance, and Diabetes Mellitus:

Patients with systemic inflammatory disease commonly have traditional risk factors and this includes obesity, insulin resistance and obesity. They are also more likely to have a lower level of physical activity in disorders that involve joint pain and destruction. Long term use of corticosteroids can further increase the risk of insulin resistance and obesity. In psoriasis, there is a notable link between obesity as previous studies have demonstrated that obesity is associated with a higher incidence and severity of psoriasis and that patients with a genetically higher BMI have an increased odds of developing psoriasis (30). Anti-inflammatory treatment may also be affected by obesity; for instance, anti-TNF agents in psoriasis have been shown to be less effective in obese patient compared to the non-obese (31, 32*). Similar to obesity, there is a clear association between psoriasis and increased risk of diabetes mellitus. A meta-analysis that included 42 observational studies estimated the risk for type 2 DM to be increased 1.76-fold in patients with psoriasis and psoriatic arthritis. Data from a population-based twin study supports a possible genetic correlation that could account for the strong association of psoriasis with type 2 DM and obesity (33, 34). However, each SID is mechanistically different and it is not clear that similar associations are present across these conditions. For example, contrary to psoriasis previous epidemiologic studies had yielded inconsistent results between the relationship between type 2 DM and RA with risk estimates that suggest a modest increase or no increase. A recent study examined this question by examining the risk of type 2 DM in patients with RA compared to 4 different non-RA populations. Adjusting for potential confounders, RA was associated with a lower incidence of type 2 DM (RA vs HTN, HR 0.65 [95% CI 0.60–0.71], RA vs osteoarthritis, HR 0.75 [95% CI 0.69–0.81], and RA vs psoriatic arthritis, HR 0.76 [95% CI 0.67–0.86] which suggests that despite the increased risk of CVD in RA, RA itself does not result in an increased risk of type 2 DM (35). This could be secondary to the widespread use of biologic DMARDs in these patients which have been shown to reduce the risk of DM when compared to more conventional DMARDs (36).

Despite these advances, there remains a paucity of data in all three diseases and mechanistic studies are much needed to understand the relationship between obesity, insulin resistance, inflammation (37) and the role of immunosuppressant therapy for the development of disease-specific screening and management strategies. Until then, aggressive lifestyle counseling through diet and physical activity should be emphasized and monitored in all patients with SID.

Dyslipidemia

Dyslipidemia is a complex issue in patients with SID. The “lipid paradox”, which has been mostly described in RA patients, refers to the observation that low levels of low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) during high levels of inflammation have similar risk to those with the highest LDL-C and TC levels (38, 39). Furthermore, this relationship is dynamic, a reduction in inflammation in RA is associated with increased levels of LDL-C and is not specific to a particular class of DMARDS (40*–42). A reduction of inflammation is also associated with improved anti-atherogenic capacity of high-density lipoprotein cholesterol (HDL-C) measured by high density lipoprotein cholesterol efflux capacity (CEC). A study measuring the association of lipid changes with subclinical biomarkers of cardiovascular injury found that RA patients with enhanced inflammation had an increase in detectable hs-cTnT levels while a reduction in LDL-C was observed, a change typically associated with reduced CV risk. In contrast, RA patients experiencing a decrease in inflammation showed an increase in LDL-C without a change in circulating hs-cTnT levels (43*). These results highlight the importance of the future exploration of biomarkers for CV risk prediction and risk stratification in RA. While the lipid paradox is likely not unique to RA, it has not been firmly established in other SIDs. From a practical consideration, cardiologists should be aware of this and ideally screen lipid profiles when the inflammatory condition is either under good control or has been stabilized. It is also important to check the lipid profiles following new DMARDs given the possible impact of different therapies on lipid profiles. Increases in lipids are a known side effect of anti-IL-6 monoclonal antibody therapy (tocilizumab) and JAK inhibitor therapy. For patients on tocilizumab, the manufacturer recommends checking a lipid panel 4–8 weeks after initiation, and every 6 months thereafter. For tofacitinib, a JAK inhibitor, routine lipid screening is recommended 4–8 weeks after initiation; LDL-C levels are reported to maximize at 6 weeks (44).

The increase in lipids in the context of changes in inflammation may not necessarily associate with an increase in CV risk. A recent randomized, open-label, parallel-group trial examined CV outcomes in patients with active RA who had an inadequate response to conventional DMARDs and who had at least 1 cardiovascular (CV) risk factor that were randomly assigned to tocilizumab or etanercept. The mean follow-up was 3.2 years and was powered to exclude a relative hazard ration of 1.8 or higher in the tocilizumab group. Despite higher mean lipid values in the tocilizumab patients, there were no differences in time to occurrence of first MACE (45*). The JAK inhibitors, can increase lipid levels although long term data on MACE and CV event was lacking (46, 47). Preliminary results from a safety clinical trial of tofacitinib compared to TNFi has resulted in FDA warnings including an increased risk of venous thromboembolism and death with the higher doses as well as increased risk of serious heart-related problems and malignancy in both doses of tofacitinib compared to TNFi-treated RA patients (48**).

The role of primary prevention statin treatment is still not firmly established in patients with SID and leads to significant underuse of statins even in patients who fulfill general population thresholds for statin treatment (49). There may also be a concern of statin-induced myositis or intolerance given the involvement of myositis in different systemic inflammatory diseases (50). In 2019, the only randomized control trial of primary prevention of cardiovascular events in patients with RA was published, known as the TRACE RA study. This study included 2986 patients who were 50 years and older, with at least 10 years of RA disease duration, and without known atherosclerotic disease or DM. Patients were randomized to atorvastatin 40mg/daily or placebo. Unfortunately, the trial was stopped early at 2.5 years due to a lower-than-expected event rate. While the study showed a reduced risk of CV events, the association was non-significant and thus could not support guidelines for widespread statin use in RA (51**). No primary prevention trials with hard CV outcomes have been published in patients with psoriasis or SLE. We believe that a discussion of statin initiation should be addressed in every patient with SID and if the benefits outweigh the risk, therapy should be initiated until we have further guidance on risk assessment and stratification. In cases where the decision is unclear, imaging for underlying coronary atherosclerosis using CAC testing may be helpful (11, 52**, 53).

Role of Preventive Cardiology:

As highlighted above, cardiovascular disease risk assessment in patients with SID is complex. Based on our current understanding, key take home points are that disease activity should be controlled, lifestyle modifications encouraged, CV risk factors addressed, and that diligence is needed to limit or avoid deleterious medications, such as NSAID therapy and long-term glucocorticoid use. A blossoming area of cardiology is the concept of a Cardio-Rheumatology collaborative clinic model under prevention cardiology (Figure). Given the complex needs of these patients and the known increased CVD risk of SID, a multi-disciplinary model with preventive cardiology, rheumatology/dermatology, and primary care will facilitate an unmet need in CV prevention in this population.

Figure:

Cardio-Rheumatology: ABCDE for Cardiovascular Risk Prevention in Systemic Inflammatory Disease

Until we have large prospective studies in patients with SID, it is reasonable to consider patients with SID as moderate or high-risk patients and apply appropriative preventative measures, including lipid-lowering therapies, blood pressure control, tobacco cessation, physical activity, and dietary modifications. The effectiveness of each of these therapies has not been established in SID as it has in the general population; however, it reasonable to assume these preventive therapies will provide benefit to reduce the overall CV risk. When necessary, such as in the younger SID population, patient reluctance, or the risk/benefit ratio is less clear, further risk stratification using imaging may be considered (e.g, coronary artery calcium or coronary CT angiography (CCTA) for atherosclerotic plaque assessment and cardiovascular PET for microvascular function). The integration of a care model with both cardio-rheumatology imbedded within routine rheumatologic care will allow a patient-centered approach with risk counseling and individualization of therapy. Control of disease activity in patient with SID can significantly reduce CVD risk and a multi-disciplinary approach with clear communication would provide a model to individualize therapy and provide timely, efficient, coordinated patient care. Current models of integrated cardio-rheumatology are rare but do exist at few centers although we hope that in the future more cardio-rheumatology clinics will be developed and enhanced education to fellows-in-training will be developed to reduce the barriers in addressing CV risk prevention in this unique population (54*, 55).

Conclusion and Future Directions:

Future directions should focus on investigating the role of reducing inflammation in patients with SID and whether this will improve cardiovascular outcomes. One challenge has been sample size and length of follow-up time. Due to these challenges, novel cardiac imaging based studies using techniques such as cardiac PET and coronary CCTA, which offer biomarkers which are directly linked to CV outcomes, could provide useful mechanistic insights linking the biology of dysregulated immunity and inflammation among patients with SID with cardiovascular disease (56**), here are current early ongoing mechanistic studies that incorporate the use of CV imaging as a surrogate endpoint and we eagerly await results from these studies (NCT02374021, NCT02714881, NCT04271540).

Lastly, as our understanding of the precise immune perturbation and immunopathology improve and the role of more targeted therapy for each individual disease evolves, it will be important to explore the mechanistic relationship between specific immune pathways and CV risk within each disease. Ultimately, we may even be able to apply this knowledge to the general population as we begin to disentangle the complex relationship between inflammation and atherosclerosis.

KEY POINTS.

• Systemic Inflammatory Diseases are associated with increased CV Risk

• Current CV risk guidelines underestimate CV risk and better disease-specific tools are needed

• Whether all patients with SID would benefit from statin therapy is not clear

• An integrated multidisciplinary approach with aggressive modification and treatment of cardiometabolic risk factors is needed

• Evidence-based disease specific treatments that reduce CV risk in SID patients has yet to be defined and is an active area of ongoing research