Association Between the Systemic Treatment of Psoriasis and Cardiovascular Risk

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Association Between the Systemic Treatment of Psoriasis and Cardiovascular Risk

Psoriasis, a chronic inflammatory disease affecting approximately 2% of the global population, is characterized by dysregulated interactions between innate and adaptive immune systems. Beyond its dermatological manifestations, psoriasis is increasingly recognized as a systemic condition associated with elevated cardiovascular risks. Patients with psoriasis exhibit a higher incidence of cardiovascular diseases (CVDs), which represent the leading cause of morbidity and mortality in this population. The systemic inflammatory state in psoriasis drives endothelial dysfunction, atherosclerosis, and metabolic disturbances, contributing to adverse cardiovascular outcomes. This article examines the impact of systemic psoriasis therapies on cardiovascular risk, focusing on major adverse cardiovascular events (MACE), atherosclerotic burden, and cardiovascular risk factors.

Systemic Psoriasis Therapies and Major Adverse Cardiovascular Events (MACE)

Psoriasis is an independent risk factor for CVDs, with disease severity and duration correlating with increased MACE risk—a composite endpoint of myocardial infarction (MI), cerebrovascular accident, or cardiovascular death. While mild psoriasis confers a relatively low cardiovascular risk, moderate-to-severe disease significantly elevates this risk. The long-term cardiovascular effects of systemic psoriasis treatments remain a critical area of investigation.

Tumor Necrosis Factor-Alpha (TNF-α) Inhibitors and Methotrexate (MTX)
TNF-α inhibitors and MTX demonstrate the most robust evidence for cardioprotective effects. TNF-α inhibitors reduce inflammatory mediators such as IL-6, CCL20, and CXCL10, which are implicated in both psoriasis and CVD pathogenesis. Studies suggest that TNF-α inhibitors lower MACE risk, particularly in treatment responders, possibly due to attenuated systemic inflammation. MTX, a conventional immunosuppressant, also shows cardiovascular benefits, though its mechanism may differ from biologics. Comparative studies between TNF-α inhibitors and MTX yield conflicting results: two studies favor TNF-α inhibitors for superior cardioprotection, while others report equivalent effects.

Interleukin (IL)-12/23 and IL-17 Inhibitors
Ustekinumab, an IL-12/23 inhibitor, initially raised concerns due to signals of increased MACE in early trials. However, subsequent long-term studies found no elevated risk, with some suggesting potential cardiovascular benefits. In contrast, briakinumab, another IL-12/23 inhibitor, was discontinued in 2011 after five trials linked it to higher MACE rates. IL-17 inhibitors (secukinumab, ixekizumab) and IL-23 inhibitors (guselkumab, tildrakizumab, risankizumab) show neutral or favorable cardiovascular profiles. Preclinical models indicate that IL-17 inhibition improves endothelial function, reduces circulating neutrophils, and prolongs thrombosis clotting times, hinting at potential cardioprotective mechanisms.

Janus Kinase (JAK) Inhibitors
Tofacitinib, a JAK inhibitor, is associated with low MACE incidence in psoriasis patients. Its cardioprotective effects may stem from reduced oxidized LDL-mediated cytotoxicity and improved endothelial viability. Tofacitinib also modulates cardiovascular risk factors, such as lipid profiles, without altering atherogenic ratios (total cholesterol:HDL, LDL:HDL).

Cyclosporine A (CsA) and Acitretin
CsA, a calcineurin inhibitor, exacerbates cardiovascular risk by inducing hypertension, dyslipidemia, and myocardial oxidative stress. Acitretin, a retinoid, has no significant impact on MACE but contributes to dyslipidemia, further complicating cardiovascular risk management.

Impact of Systemic Therapies on Atherosclerotic Burden

Psoriasis accelerates atherosclerosis through chronic inflammation, endothelial dysfunction, and vascular remodeling. Systemic treatments variably influence arterial plaque burden and vascular inflammation.

Coronary and Carotid Artery Disease
Biologic therapies, including TNF-α inhibitors and IL-17/IL-23 inhibitors, reduce non-calcified coronary plaque burden—a key predictor of acute coronary events. TNF-α inhibitors exhibit dual effects on carotid intima-media thickness (IMT): they decrease IMT in patients without baseline calcified plaques but may promote arterial remodeling in those with established atherosclerosis. Tofacitinib consistently reduces carotid IMT, while IL-17/IL-23 inhibitors demonstrate neutral effects on IMT in most studies. One trial noted IMT reduction with ustekinumab and MTX, suggesting that targeting specific inflammatory pathways may benefit vascular health.

Vascular Inflammation Imaging
18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) reveals that biologic therapies reduce vascular inflammation, as measured by the fat attenuation index (FAI). This effect is consistent across TNF-α, IL-12/23, and IL-17 inhibitors. Ustekinumab significantly decreases systemic and vascular inflammation on 18F-FDG PET/CT, though other studies report no changes with TNF-α inhibitors or secukinumab. These discrepancies may reflect differences in patient populations, treatment durations, or imaging protocols.

Modulation of Cardiovascular Risk Factors

Systemic psoriasis therapies differentially influence cardiovascular risk factors, including obesity, diabetes, dyslipidemia, hypertension, and systemic inflammation.

Obesity and Metabolic Syndrome
Obesity exacerbates psoriasis severity and diminishes treatment response. TNF-α inhibitors are associated with weight gain and elevated BMI, whereas IL-12/23 inhibitors, IL-17 inhibitors, and apremilast promote weight loss. Concurrent MTX use mitigates TNF-α inhibitor-induced weight gain, highlighting the importance of combination therapy in obese patients.

Diabetes Mellitus
Psoriasis patients exhibit higher rates of insulin resistance and hyperglycemia. Apremilast improves glucose metabolism, while CsA increases diabetes risk. TNF-α inhibitors and ustekinumab enhance insulin sensitivity, though their effects on HbA1c and fasting glucose remain inconsistent. Notably, concomitant use of TNF-α inhibitors with sulfonylureas or insulin may precipitate hypoglycemia, necessitating careful glucose monitoring.

Dyslipidemia
CsA and acitretin exacerbate dyslipidemia, elevating total cholesterol, LDL, and triglycerides. TNF-α inhibitors have mixed effects on lipid profiles, while IL-17/IL-23 inhibitors and MTX exert neutral influences. Tofacitinib increases total cholesterol, LDL, and HDL in a dose-dependent manner but maintains stable atherogenic ratios, suggesting a neutral net effect on lipid-related cardiovascular risk.

Hypertension
CsA dose-dependently increases blood pressure, elevating risks of stroke, MI, and heart failure. Other systemic therapies, including biologics and JAK inhibitors, show no significant impact on blood pressure. CsA-induced hypertension is reversible upon discontinuation, underscoring the need for alternative agents in hypertensive patients.

Systemic Inflammation and C-Reactive Protein (CRP)
Elevated CRP, a marker of systemic inflammation and cardiovascular risk, is reduced by TNF-α inhibitors, ustekinumab, ixekizumab, and tofacitinib. Secukinumab does not lower CRP, and higher baseline CRP levels correlate with reduced efficacy of etanercept and ustekinumab but not secukinumab. This suggests that CRP may serve as a predictive biomarker for treatment response in certain therapies.

Clinical Implications and Therapeutic Considerations

The selection of systemic psoriasis therapies must account for individual cardiovascular risk profiles. Key recommendations include:

  1. High MACE Risk or Established Atherosclerosis: Prioritize TNF-α inhibitors or MTX, which have the strongest evidence for reducing cardiovascular events. IL-17/IL-23 inhibitors are suitable alternatives, particularly for patients with coronary microcirculatory dysfunction.
  2. Dyslipidemia: Avoid CsA and acitretin; consider IL-17/IL-23 inhibitors or apremilast.
  3. Hypertension: Contraindicate CsA; prefer biologics or JAK inhibitors.
  4. Obesity: Opt for IL-12/23 inhibitors, IL-17 inhibitors, or apremilast to avoid TNF-α inhibitor-associated weight gain.
  5. Diabetes: Use apremilast or TNF-α inhibitors with caution regarding hypoglycemia risk.

Conclusion

Systemic psoriasis therapies exhibit heterogeneous effects on cardiovascular risk, necessitating personalized treatment strategies. TNF-α inhibitors and MTX remain cornerstone therapies for patients with high cardiovascular risk, while IL-17/IL-23 inhibitors offer promising alternatives with favorable metabolic profiles. Ongoing research is needed to elucidate long-term cardiovascular outcomes and optimize therapeutic algorithms for this vulnerable population.

doi.org/10.1097/CM9.0000000000001249

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