Epidemiology of Inflammatory Disorders and Cardiovascular Disease

Inflammation is a common underlying component of many chronic rheumatologic inflammatory joint disorders (IJD), such as rheumatoid arthritis, systemic lupus erythematosus (SLE), and psoriasis. It is also a key mediator in the progression of atherosclerosis and resultant cardiovascular disease (CVD) due to rupture of vulnerable plaques, which could account for the higher incidence of CVD and overall worse for patients with IJD.^1-3 Accordingly, the increased prevalence of CVD among individuals with chronic IJD has long been recognized.

Among patients with rheumatoid arthritis, the risk of myocardial infarction is estimated to be equivalent to patients with diabetes and/or an individual who is 10 years older without rheumatoid arthritis.^4-6 A meta-analysis incorporating data from 111,758 patients also demonstrated that patients with rheumatoid arthritis had a 50% higher risk for CVD death with a standardized mortality rate of 1.5 (95% CI 1.39- 1.61).⁷ Patients with systemic lupus erythematosus (SLE) and psoriasis also have a similarly increased risk of CVD.^8,9

Rheumatoid arthritis is typically considered the most common IJD with an estimated prevalence of approximately 1,000 per 100,000, or 1.3 million US adults, with a prevalence two times greater in women than in men.¹⁰ However, data from the 2010 National Health and Nutrition Education Survey (NHANES) showed a prevalence of 3.2% or 7.2 million US adults with self-reported psoriasis.¹¹ SLE has an estimated prevalence of approximately 54 per 100,000 among US adults, but is more prevalent among women with an estimated prevalence of 100 per 100,000.10 While there is shared pathophysiology among the IJD, the majority of data on CVD risk is derived from patients with rheumatoid arthritis and SLE, which is the focus of this review.

Evaluating CVD Risk for Patients with Inflammatory Disorders

Patients with IJD commonly have traditional CVD risk factors such as hypertension, dyslipidemia, insulin resistance, and obesity. They are also more likely to have a lower level of physical activity secondary to joint pain inherent in IJD. Dyslipidemia is estimated to affect up to two thirds of patients with rheumatoid arthritis and lipid levels are directly impacted by disease activity.¹² Despite this, less than half of Medicare patients with rheumatoid arthritis are screened for lipid abnormalities and the majority of rheumatoid arthritis patients with an indication for lipid-lowering therapy are untreated.^13,14

Two aspects of the relationship between dyslipidemia and CVD risk are contrary and inverse in patients with RA and referred to as the "Lipid Paradox." The first observation is that patients who are untreated and/or have high disease activity generally have decreased levels of LDL-C, HDL-C, triglycerides, and total cholesterol.¹⁵ These lower lipid levels are believed to be secondary to increased inflammation and lead to functional pro-atherogenic changes such as a decreased cholesterol efflux capacity of HDL-C.^16,17 The second divergent observation is that treatment with anti-inflammatory medication, such as methotrexate or TNF-α inhibitors is associated with an increase and normalization in lipid levels, but an overall reduction in atherogenic lipid burden as demonstrated by a decrease in the total cholesterol to HDL-C ratio.¹⁸ Accordingly, CVD risk prediction with lipid levels measured when the patient has a stable and low disease activity level can be expected to produce a more accurate CVD risk estimate, while lower lipid levels measured during high disease activity may contribute to underestimation of an individual's CVD risk.¹²

Among the anti-inflammatory medications, biologics have the greatest effect on reducing the atherogenic lipid burden and a meta-analysis of 25 studies showed that patients taking tofacitinib 5 mg twice daily had an observed increase of 13 mg/dL for HDL- C and 11 mg/dL of LDL-C with slightly higher increases for those taking 10 mg twice daily.¹⁹ Therefore, the net change in lipid levels with anti-inflammatory treatment should be monitored, although whether the magnitude of change is associated with improved CVD outcomes is not known.²⁰

CVD risk assessment in patients with IJD is challenging for a number of reasons including the interaction of lipids with anti-inflammatory IJD treatments, the increased risk for CVD in IJD patients, the lack of variables accounting for IJD disease severity (e.g., number of disease flare-ups) in CVD risk prediction models for the general public, and because established CVD risk prediction tools are based on a lower observed CVD in the general populations. This is especially significant for women, who are the majority of IJD patients. Established CVD risk prediction models such as the Framingham Risk Score, ACC/AHA Pooled Cohort Equation, and Systematic Coronary Risk Evaluation score (SCORE) have been shown to underestimate risk in patients with IJD.^21-23

The European League Against Rheumatism (EULAR) recommends using a multiplication factor of 1.5 in order to correct for the underestimation of CVD risk in patients with rheumatoid arthritis, but not for other IJD due to a lack of evidence regarding the magnitude of the multiplicative factor in these disease states.²⁰ However, it is estimated that less than 15% of patients are reclassified to a high or very high risk even after using the multiplication factor.^24,25 Accordingly, while patients with increased disease severity are at a higher risk for CVD, the 2017 EULAR guidelines no longer mandate the use of rheumatoid arthritis-specific criteria for this multiplication factor due to evidence supporting an increased CVD risk in patients who are in the early stages of the disease.

Efforts to adapt and recalibrate traditional risk scores have not yielded a clinically significant improvement in risk prediction.²¹ Other efforts to improve CVD risk prediction have focused on incorporating nontraditional CVD risk factors such as disease duration, disease severity, and anti-inflammatory medication use.²² This approach resulted in a statistically significant improvement, but its comparison to commonly-used risk models was limited due to the use of categorical risk factor variables. In addition, the improvements in CVD risk prediction for both efforts were predominantly in non-event cases, downward classification of intermediate risk patients, and less so for upward classification of high-risk patients.^21,22

Non-Traditional Risk Factors and Imaging for Risk Stratification

While disease duration is not strongly associated with CVD, other non-traditional risk factors can be considered as part of the clinician and patient risk discussion.^{22, 26} In a cohort of 44,418 rheumatoid arthritis patients, high-sensitivity C-reactive protein (hsCRP) levels >10 mg/L and erythrocyte sedimentation rate values >42 mm/h were associated with a greater than two-fold increased risk for myocardial infarction among patients with rheumatoid arthritis.²⁷ The cumulative burden of inflammatory disease should also be considered as the number of rheumatoid arthritis flares and overall severity of functional impairment have been significantly associated with an increased risk for CVD.²⁸ Other non-traditional IJD risk factors, including a positive anti-nuclear antibody or positive rheumatoid factor, have also been shown to have an approximately 25% increased risk for CVD.²⁹

Moderate disease activity has also been associated with a 4.5-fold increased risk for high risk plaque morphology on cardiac CT angiography.³⁰ Furthermore, patients in remission from rheumatoid arthritis and with a reduced inflammatory state may have a similar CVD risk as those without rheumatoid arthritis.²⁸ Accordingly, in a meta-analysis of 66,334 individuals, treatment with low dose methotrexate was associated with a 21% lower risk for CVD.³¹ This observation in patients with rheumatoid arthritis formed the basis for the National Institutes of Health-sponsored Coronary Inflammation Reduction Trial (CIRT) that is targeting patients who have coronary artery disease with diabetes or metabolic syndrome and typically have higher than average levels of inflammation.

A number of studies have shown that increased carotid intima media thickness and carotid plaques are associated with a higher CVD risk factor burden and higher CVD risk score for patients with rheumatoid arthritis, but fewer studies have examined its use for improving CVD risk prediction.^24,32 In a study of 105 patients followed for a mean of 12 years, CVD risk did not differ based on carotid intima media thickness, but patients with bilateral carotid artery plaques had approximately a four-fold greater CVD event rate than individuals with unilateral or no carotid plaques.³³ In a separate study of 104 patients with rheumatoid arthritis who had both carotid ultrasound and coronary artery calcium (CAC) scanning, 58% of patients with CAC = 0 had carotid artery plaque, while all of the patients with CAC >100 had carotid plaques.³² This suggests that carotid ultrasonography may potentially detect atherosclerotic disease at an earlier stage, but this study did not correlate these imaging findings to CVD events.

However, CAC is a superior predictor of CVD risk compared to cIMT in the general population and significantly improves risk prediction beyond traditional risk scores; this suggests that CAC may also be of value in the setting of IJD.³⁴ Furthermore, only 41% of rheumatoid arthritis patients with CAC ≥ 300 or ≥75th percentile CAC were correctly classified as high risk by the 2013 ACC/AHA Pooled Cohort Equation.³⁵ Patients with IJD have higher levels of CAC compared to patients without IJD even with similar LDL-C levels and similar total cholesterol to HDL-C ratios.^36,37 In an analysis from the Multi-Ethnic Study of Atherosclerosis (MESA), it was observed that the difference in CAC scores between patients with and without rheumatoid arthritis was greatest for the youngest age category of 45-54 years with rheumatoid arthritis patients having 149% higher mean CAC score (97 vs. 39).³⁸ However, further research is needed to determine if CAC improves CVD risk prediction specifically in patients with IJD.

Given that a higher burden of atherosclerotic plaque inflammation with increased risk of vulnerable plaque rupture may be the mechanism of CV events in patients with IJD, there is emerging interest in imaging plaques and arterial inflammation with FDG-PET as a tool for risk stratification. However, though promising, this technique is not established as superior to other modalities of imaging or even superior to clinical risk scores for the purpose of risk stratification.^39,40

Indications for Statin Therapy Among Patients with Inflammatory Disorders

Empiric statin therapy should be strongly considered for patients with IJD given that their risk for CVD is generally equivalent to individuals with diabetes, currently one of the four statin treatment groups recommended in the 2013 ACC/AHA guidelines, and the lack of an IJD specific risk score that has demonstrated an improvement over the systematic underestimation of risk with established risk scores. Consideration should also be given to starting statin therapy earlier rather than later for patients with IJD given that there appears to be a greater difference in subclinical atherosclerosis for younger rather than older individuals.³⁸ This is especially relevant if they have other high-risk features such as poorly controlled IJD severity. Even in the absence of classical dyslipidemia, statins should be considered given their beneficial effects in reducing CVD events down to very low LDL-C levels and the possibility of pleiotropic effects among IJD patients such as a reduction in plaque inflammation and improvement in endothelial dysfunction.⁴¹

An analysis of 528,654 new users of statin therapy showed that high-intensity statin therapy is associated with a 23% reduction in the incidence of rheumatoid arthritis compared to low-intensity statin therapy.⁴² In addition to lipid lowering, statins have also been shown to reduce the severity of IJD.⁴³ In a propensity score analysis of 2,943 individuals with rheumatoid arthritis and using at least one disease-modifying antirheumatic drug (DMARD) agent, statin therapy was associated with a 21% reduction in all-cause mortality over a mean follow-up of 4.5 years compared to individuals with rheumatoid arthritis not on statin therapy.⁴⁴ Conversely, an analysis of 4,102 incident statin users who subsequently discontinued statin therapy for ≥3 months showed a 67% increase in the risk of myocardial infarction.⁴⁵

The Trial of Atorvastatin for the Primary Prevention of Cardiovascular Event Patients with Rheumatoid Arthritis (TRACE RA) included patients 50 years and older or with greater than 10 years of rheumatoid arthritis duration who were without known atherosclerotic disease, diabetes, or myopathy and not on statin therapy.⁴⁶ Patients were randomized to atorvastatin 40 mg/day and 2,986 patients were enrolled, but the trial was stopped early at 2.5 years due to a lower-than-expected event rate of 0.8% (expected 1.7%). Overall, the atorvastatin group had 24 CVD events and a net reduction in LDL-C of 36 mg/dL compared to 36 events in the placebo group with a hazard ratio of 0.66 (85% CI 0.40-1.11) for the primary composite CVD endpoint. While the results were not statistically significant due to early stoppage of the trial, the 34% reduction in CVD risk is in accordance with what would be expected based on the Cholesterol Treatment Trialists (CTT) Collaboration meta-analysis given that the primary composite endpoint for TRACE RA was more inclusive than that of the CTT meta-analysis.⁴⁷

Clinicians may consider potential interactions of lipid lowering and anti-inflammatory therapies. In a study of 12 patients, tocilizumab seemed to reduce the mean effect ratio of simvastatin by as much as 61% after five weeks of tocilizumab infusion, suggesting that lipid levels should be reevaluated after the initiation of new anti-inflammatory treatments for IJD.⁴⁸ Reduced rituximab efficacy was observed in patients with hematologic malignancies in some preclinical studies, but follow-up studies showed no significant effect.^49-53 However, overall, statin therapy appears similarly efficacious in the reduction of LDL-C for patients with and without rheumatoid arthritis, with minimal side effects and/or interactions for patients actively being treated for IJD.^43,54-58

Consideration of Non-Statin Lipid-Lowering Therapy

There is limited evidence for the use of non-statin therapy among patients with IJD. However, the effectiveness of simvastatin 20 mg/day and ezetimibe 10 mg/day were evaluated in a double blinded crossover trial of 20 patients with active rheumatoid arthritis and a hsCRP of >6 mg/L.⁵⁹ Both simvastatin and ezetimibe showed significant reductions in LDL-C, hsCRP, and disease severity. Therefore, given efficacy for lipid-lowering it is reasonable to consider the addition of ezetimibe 10 mg/day in addition to statin therapy for IJD individuals with a high CVD risk who are similar to individuals included in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT).⁶⁰ Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are new class of lipid-lowering medications that can reduce LDL-C levels by >50% on top of statin therapy and have recently been shown to reduce CVD events.⁶¹ PCSK9 inhibitors have not yet specifically been studied in patients with IJD, although DMARD agents were not considered an exclusion criteria in early trials, and, as such, these agents could be considered for IJD patients with a LDL-C ≥70mg/dL at high risk for recurrent CVD.

In summary, patients with IJD have an increased risk for CVD that is comparable to patients with diabetes, and this increased CVD risk is present even at the early stages of disease. However, commonly used risk prediction equations significantly underestimate the CVD risk for patients with IJD, which is in part due to the Lipid Paradox. Accordingly, noninvasive imaging with CAC (or possibly carotid ultrasound in younger patients) should be considered to improve risk prediction. Treatment of the underlying IJD and control of disease activity can significantly reduce an individual's CVD risk. In addition, empiric statin therapy should be strongly considered for patients with IJD especially if they have other high-risk features such as poorly controlled disease activity. Further IJD research to determine the best method for CVD risk reclassification and a follow-up to the TRACE RA trial to confirm the efficacy of statin therapy in patients with IJD are significant gaps in the current literature that need to be answered.

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Keywords: Antibodies, Monoclonal, Humanized, Antirheumatic Agents, Arteritis, Arthralgia, Arthritis, Rheumatoid, Atherosclerosis, Blood Sedimentation, Carotid Intima-Media Thickness, Carotid Stenosis, Cholesterol, Angiography, Coronary Artery Disease, Diabetes Mellitus, Dyslipidemias, Hematologic Neoplasms, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertension, Inflammation, Insulin Resistance, Lipids, Lupus Erythematosus, Systemic, Metabolic Syndrome, Methotrexate, Myocardial Infarction, Obesity, Piperidines, Plaque, Atherosclerotic, Primary Prevention, Psoriasis, Pyrimidines, Pyrroles, Rheumatic Diseases, Rheumatoid Factor, Risk Assessment, Risk Factors, Simvastatin, Subtilisins, Triglycerides, Tumor Necrosis Factor-alpha

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