Research Progress in Psoriatic Arthritis-Related Cardiovascular Damage
Psoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disease associated with psoriasis, primarily manifesting as peripheral arthritis, enthesitis, finger or toe inflammation, and spinal arthritis. The disease can develop at any age, with a peak incidence between 30 and 50 years, and shows no significant gender difference, although spinal involvement is more frequent in men. In China, the prevalence of PsA is approximately 1.23‰. About 75% of PsA patients develop a rash before the onset of arthritis, while 10% develop arthritis before the rash.
PsA is closely associated with various comorbidities, including obesity, metabolic syndrome, cardiovascular disease (CVD), cerebrovascular disease, and peripheral vascular disease. According to the European League Against Rheumatism (EULAR) recommendations for the management of PsA with pharmacological therapies, non-musculoskeletal manifestations such as skin, eyes, and gastrointestinal tract should be monitored during treatment. Additionally, complications like metabolic syndrome, CVD, or depression should be considered. This article summarizes recent literature on PsA-related cardiovascular damage to provide guidance for clinical practice.
PsA is a chronic recurrent inflammatory disease primarily mediated by T cells and other immune cells. Various effector cells and inflammatory mediators participate in the pathogenesis of PsA, including proinflammatory adipocytokines produced by adipocytes, such as resistin, leptin, and visfatin. Leptin, in addition to its inhibitory function on regulatory T cells, promotes the proliferation of CD4+ T cells and natural killer cells, increases neutrophil chemotaxis, and induces macrophages to produce tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-12. Consequently, TNF-α and IL-6 can inhibit adiponectin production by adipocytes, increasing the disease severity of cutaneous-only psoriasis (PsC). Increased TNF-α production also elevates serum leptin levels, promoting local inflammatory responses and enhancing PsC progression. Notably, both body mass index (BMI) and leptin levels are significantly higher in PsA patients than in PsC patients.
The close correlation between PsA and CVD is likely due to shared pathophysiological pathways. Elevated levels of C-reactive protein (CRP), IL-6, TNF-α, and other inflammatory mediators in CVD patients can affect vascular endothelial cells, leading to endothelial dysfunction and promoting the occurrence and progression of major vascular events. It remains unclear whether specific inflammatory cytokines are involved in the development of PsA-CVD. However, human cartilage glycoprotein-39 (YKL-40), a biomarker of endothelial dysfunction, is significantly increased in PsA patients. As a risk factor for CVD, metabolic syndrome is characterized by endothelial dysfunction. Since YKL-40 is associated with adiponectin and leptin, key adipokines in psoriasis pathogenesis, further studies are needed to determine whether increased YKL-40 levels indicate a higher risk for CVD in PsA patients.
Patients with psoriasis often exhibit lipid metabolism disorders. The prevalence of metabolic syndrome, hyperglycemia, hypertension, atherosclerosis, and abnormal lipid metabolism in psoriasis patients is significantly higher than in normal subjects, possibly related to obesity and increased production of adipokines, TNF-α, and other inflammatory factors. Analysis of single nucleotide polymorphisms in psoriasis, rheumatoid arthritis, and other immune diseases revealed multiple risk loci in high-density lipoprotein (HDL) and low-density lipoprotein genes, providing a molecular basis for elucidating the mechanisms underlying PsA complicated by dyslipidemia. However, current findings on the expression profile of blood lipid levels in PsA patients are inconsistent. HDL levels in PsA patients were lower than in healthy controls and increased after effective treatment.
Classical risk factors for CVD in PsA include hypertension, dyslipidemia, increased BMI, subclinical cardiovascular risk factors such as carotid intima-media thickness, and drug-related factors (non-steroidal anti-inflammatory drugs, glucocorticoids). Recent studies have found that CRP can serve as an important predictor of CVD in patients with inflammatory arthritis. In addition to classical cardiovascular risk factors, PsA disease activity and systemic inflammatory response have been identified as independent risk factors for cardiovascular events.
The main manifestations of PsA involving CVD include ascending aorta arteritis, aortic valve lesions, and conduction disorders, while pericarditis, cardiomyopathy, and mitral valve lesions are less common. The incidence rate and mortality of CVD increase with the extension of the disease course and its aggravation. Congestive heart failure, particularly left ventricular congestive heart failure, may occur when heart disease becomes severe. A prospective follow-up study of 648 PsA patients showed that the incidence rate of myocardial infarction was significantly higher than in healthy subjects.
Atherosclerosis begins with intimal involvement caused by the interaction of chronic mild inflammatory reactions and metabolic abnormalities in the vascular wall. Initially, the local migration of smooth muscle cells, macrophages, and T lymphocytes occurs in the intima, followed by lipid accumulation in macrophages and smooth muscle cells and extracellular matrix. Finally, fibrous tissue hyperplasia and calcification result in the thickening and hardening of the arterial wall. Compelling evidence indicates that immune dysregulations can directly lead to an increased incidence rate of atherosclerosis or subclinical atherosclerosis. The incidence of atherosclerosis in PsA patients is higher than in normal controls. Moreover, the higher coronary plaque burden in PsA patients is not associated with metabolic syndrome but is associated with the severity of the underlying disease.
Current treatments for PsA include non-steroidal anti-inflammatory drugs (NSAIDs), conventional disease-modifying anti-rheumatic drugs (cDMARDs), biological DMARDs (bDMARDs), and targeted synthetic DMARDs (tsDMARDs). NSAIDs can inhibit inflammatory reactions and relieve joint pain, swelling, and morning stiffness in PsA patients. Long-term and continuous use of NSAIDs reduces radiographic progression in patients with ankylosing spondylitis. Cyclooxygenase-2 inhibitors can reduce the side effects of NSAIDs on the gastrointestinal tract but may increase the incidence rate of cardiovascular events such as thrombosis, hypertension, and heart failure. However, other studies have reported that celecoxib does not increase the risk of cardiovascular events.
In clinical applications, cDMARDs include methotrexate, acitretin, and cyclosporin. Methotrexate can reduce the incidence of CVD, but its long-term use may lead to a higher risk of end-organ toxicity. Acitretin often causes hyperlipidemia, while cyclosporin can lead to hypertension, hyperlipidemia, and even myocardial damage through the production of reactive oxygen species. Therefore, more attention is needed to monitor the side effects of these drugs on the cardiovascular system.
Both bDMARDs and tsDMARDs provide new options for the treatment of PsA. Several studies have observed the effects of these new therapies on lipid metabolism disorder and cardiovascular events in PsA patients. Spanakis et al. compared the effect of infliximab on 60 patients with refractory rheumatism and found that HDL levels showed a long-term upward trend. Furthermore, anti-TNF-α therapy is beneficial in reducing the incidence rate of CVD in these patients. Recent studies show that the IL-12/23 inhibitor ustekinumab has potential effects on cardiac protection and does not increase the risk of serious cardiovascular adverse events, but further studies with longer-term follow-up are required to confirm this finding. Additionally, the IL-17A inhibitor secukinumab does not cause any significant changes in blood glucose, blood pressure, body mass index, and blood lipid in PsA patients after three years of treatment. Since systemic inflammation may affect cardiac metabolism and increase the risk of CVD in PsA patients during the natural course of the disease, the observed cardiac safety of secukinumab from clinical studies supports its application as a new treatment option for PsA patients with cardiac metabolic risk factors. A recent study evaluated the influence of treatment with JAK inhibitors on cardiovascular events, in which the incidences of deep vein thrombosis and pulmonary embolism were higher in the baricitinib treatment group than in the placebo group.
Patients with PsA often have metabolic diseases with an increased mortality rate after serious cardiovascular complications. Therefore, evaluating and controlling the cardiovascular risk of PsA patients remains a challenge in clinical management. Moreover, further clinical trials are needed to determine the therapeutic potentials of newly developed JAK and phosphodiesterase-4 inhibitors in the treatment of PsA patients with CVD.
doi.org/10.1097/CM9.0000000000001215
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