Patients with vs without psoriatic arthritis (PsA) have markedly elevated risks to their cardiometabolic health. More than half of patients with PsA have at least 1 comorbidity (Figure 1).1 Patients with PsA are estimated to be 46% more likely to be diagnosed with a cardiovascular disease (CVD) than the general population, with a higher rate of hospitalization related to CVD as well.2 Moreover, patients with PsA have a higher prevalence of obesity, diabetes mellitus, hypertension, and hypertriglyceridemia than those with rheumatoid arthritis3,4 and psoriasis without joint involvement.5
Cardiometabolic differences in patients with PsA also carry implications for treatment outcomes. Patients with both PsA and obesity receiving treatment with tumor necrosis factor α (TNF-α) inhibitors were markedly less likely to achieve minimal disease activity (MDA; hazard ratio, 4.90) and to sustain MDA 2 years later.6
However, small-scale studies suggest that clinicians may not find opportunities to assess risk comprehensively in patients with PsA.7
“Awareness is key,” says Brittany Weber, MD, PhD, associate physician in cardiovascular medicine and cardiovascular imaging at Brigham and Women’s Hospital in Boston, Massachusetts. “A patient with psoriatic disease should understand that [they are] at an elevated risk of heart disease. We believe that is due to a combination of the standard cardiovascular risk factors that affect the [general] population as well as the ongoing inflammation observed in PsA. The most common cardiac complication would be atherosclerosis, which can lead to a heart attack; but we also have some smaller scale data that patients with psoriasis may have higher rates of heart failure as well.”8
Ongoing translational research in cardio-rheumatology, leveraging advanced cardiovascular imaging and immunology assays, has begun to elucidate risk factors, uncover new disease markers, and determine treatment options and their mechanisms. Many of the newest insights are derived from investigations in psoriasis; however, the pathologic mechanisms that increase cardiometabolic risks in PsA may be similar.
Dr Weber, who specializes in cardio-rheumatology and the cardiovascular risks for systemic inflammatory disease, points to the role of coronary microvascular disease as an example of the elevated cardiometabolic risks for patients with inflammatory disorders, such as PsA.9 In microvascular dysfunction, the smaller coronary vessels fail to dilate sufficiently to meet oxygen demand in the myocardium, possibly due to loss of normal endothelial cell function. These changes appear to be more prevalent and severe in high-cardiovascular-risk patients with than those without PsA and other inflammatory disorders, and may affect myocardial perfusion in the absence of coronary artery stenosis or obstruction. These findings suggest that cardiovascular risk assessment in patients with psoriasis and PsA should account for both decreases in coronary artery flow reserve and potential loss of microvascular reserve.
Increased platelet activation is another vascular disease mechanisms now receiving attention, particularly as it corresponds to psoriasis disease severity.10 Platelet RNA sequencing has revealed upregulated interferon expression and cyclooxygenase-1 (COX-1) signaling, indicating that endothelial cells are most likely exposed to excess interferon-mediated inflammation; in turn, this is likely aggravated further by the presence of interleukin (IL)-17A typical in psoriatic disease.
Traditional diagnostic studies and markers of coronary artery disease may not fully capture the excess cardiometabolic risk in PsA. For example, patients with psoriatic disease exhibit distinctive patterns of elevation of circulating lipids and lipid oxidation. The associated inflammatory and immune responses are accentuated in diabetes, obesity, and metabolic syndrome. However, detection of these lipid and physiologic markers currently requires specialized staining, mass spectrometry, and other molecule-specific assays. Hence the extent and characteristics of dyslipidemia in these patients may not be evident via standard clinical diagnostics. Similarly, quantification of myocardial flow reserve and evaluation of coronary microvascular dysfunction require positron emission tomography (PET)-based imaging methods that are not routinely available in many clinics.
Dr Weber suggests that “all patients should have a lipid panel, body mass index (BMI) calculation, A1c, and blood pressure measured. Some patients may benefit from a [coronary artery] calcium score12 to identify the presence and degree of atherosclerosis. These measures should be re-evaluated over time: just as psoriatic disease is not static, neither are these cardiometabolic conditions.”
“I think it is also important to have good working relationships between rheumatology and cardiology, and a referral strategy to a cardiologist as well. The rheumatologist also could consider referring to cardio-rheumatology — or if cardio-rheumatology is not available, then to a preventive cardiologist.”
Aggressive lifestyle interventions remain an important step for managing cardiometabolic risk in patients with PsA, noted Dr Weber, particularly if a traditional cardiovascular risk factor is identified (eg, high blood pressure, high cholesterol). ”Pharmacological interventions may be appropriate. However, future work is needed as we do not know how effective our traditional pharmacological strategies, such as statins (and aspirin when appropriate), are to reduce risk are in this patient population. While small clinical trials have suggested benefit of these therapies10,13 clinical trials in this area are [much]needed.”
As with mechanistic understanding and risk stratification, recent evidence regarding the effect of PsA medications on cardiometabolic variables result from investigations in patients with psoriasis.11= Results of clinical trials are often mixed; for example, small studies suggest methotrexate may have cardioprotective effects in PsA.14 Liver toxicity of methotrexate remains a particular concern in patients already at metabolic risk, such as those with diabetes.
By contrast, nonsteroidal anti-inflammatory drugs (NSAIDs), other than aspirin, are weakly associated with increased cardiovascular risk, including hypertension. Of these, naproxen may be safer compared with diclofenac and ibuprofen, which may have higher cardiovascular risks. Corticosteroids, commonly used as a first-line treatment for inflammatory joint diseases, are associated with a dose- and duration-dependent increase in CVD risk, as well as dysglycemia.15 Non-biologic apremilast, a small-molecule phosphodiesterase-4 (PDE4) inhibitor, may reduce A1c, without an impact on glucose intolerance that may be related to the role of PDE4-expressing cells in the pancreas.16
A number of biologic medications have more consistently exhibited the potential to reduce cardiovascular risk in addition to controlling psoriatic disease. In an observational study with a 1-year follow-up of 238 patients with severe psoriasis, TNF-α, IL-17-, and IL-23-inhibitors reduced coronary noncalcified plaque burden during treatment by 6%.17 The TNF inhibitors, such as etanercept, may also lower risk for type 2 diabetes and multiple components of metabolic syndrome; however, they are contraindicated in patients with congestive heart failure, and appear less effective in patients with obesity and PsA.
Fewer studies on cardiovascular outcomes have been conducted with newer biologics such as IL-17 inhibitors, and with biologics such as TNF-α antagonists, small studies have produced conflicting results. Nonhuman studies on IL-17 blockers suggest an antiatherogenic role, but other studies have shown either a beneficial or neutral role of these agents in vascular protection. In addition, outcomes of psoriatic disease vary between neutral and beneficial based on BMI.
Studies of IL-12/23 inhibitors have produced divergent results. A pooled safety analysis of clinical trials of briakinumab for severe psoriasis has indicated a worsened risk for major adverse cardiovascular events, as well as malignancy and infections.18 On the other hand, a small phase 4 trial of ustekinumab appeared to lower aortic vascular inflammation transiently, with more sustained (at 52 weeks) improvement in biomarkers of inflammation.19 Evidence for IL-23p19 blockers, such as guselkumab and risankizumab, is only beginning to emerge, and real-world studies with long-term follow-up are currently lacking for this drug class.
Recent evidence has cautioned the use of Janus kinase (JAK) inhibitors for PsA. Tofacitinib has been approved for PsA; however a US Food and Drug Administration (FDA)-mandated safety trial indicated increased risk for serious adverse cardiovascular events, including heart attack, stroke, and thromboembolism. The FDA currently requires a warning for JAK inhibitors including tofacitinib.20 Population-based cohort studies suggest that bariatric surgery in patients with obesity decreases risk of developing both psoriasis and PsA; but no clinical trial evidence is available to date.21
While it, therefore, remains unclear what medications to treat psoriatic disease may also confer cardiometabolic protection, Dr Weber reiterated that patients with PsA need to be informed about the associated cardiometabolic risks to empower them to minimize their risk for serious adverse cardiovascular events.
“I’ll say it again: awareness is the key. Too often I’ll meet a patient during a clinical trial we’re running, and they’ll tell me they had no idea they were at a higher risk with psoriatic disease. Recognition and modification early on is the best way we can prevent these future events from occurring,” she noted.
Brittany Weber, MD, PhD, is associate physician in cardiovascular medicine and cardiovascular imaging at Brigham and Women’s Hospital in Boston, Massachusetts.
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