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Introduction
Psoriasis is a chronic inflammatory skin disease characterized by an increase in the speed of hematopoiesis that causes hyperplasia of the epidermis, clinically resulting in the formation of indurated erythematous squamous plaques1. Psoriasis vulgaris is far from being a disease with an exclusive impact on the skin, it is a systemic disease that seriously affects the general condition of the individual and can lead to serious complications, even leading to the death of the patient2. The causes of the disease are unknown, although its pathogenesis includes genetic and immunological aspects, and is also associated with different external factors that can exacerbate psoriasis, such as psychological stress, changes in environmental climate, infectious diseases, medications, physiological states such as pregnancy, among others3. The prevalence of the disease varies according to the geographical area, although it is accepted that the global prevalence is approximately 2%4; In Mexico, it is estimated that the prevalence is in line with that referred to worldwide.
Psoriasis predisposes to the development of cardiovascular disease (CVD) (25% increase in relative risk), with a relationship directly proportional to the severity of the disease5. The risk increases if the patient has other comorbidities associated with CVD such as obesity, dyslipidemia, hypertension, diabetes mellitus, and metabolic syndrome4. Chronic and persistent inflammation (PCI), which involves proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interferon γ (IFN-γ), interleukin (IL)-6, IL-8, IL-12, IL-17A, and IL-18, is a common factor in these diseases, including psoriasis6. This PCI directly contributes to the development of endothelial dysfunction, favoring atherosclerosis and CVD7.
The CVDs that increase in prevalence in patients with psoriasis are mainly acute myocardial infarction and ischemic heart disease, in addition to thromboembolic disease and cerebrovascular events8. This makes it necessary to routinely review the cardiovascular health status of the patient with psoriasis and determine the strategy to be followed, which includes modifications in the patient's lifestyle, treatment of comorbidities, and control of PCI associated with psoriasis.
The development of biological therapy has considerably changed the evolution of psoriasis. Recently, it has been suggested that this therapy can effectively reduce cardiovascular risk9. This review will discuss the most recent studies suggesting a protective effect of biologic therapies on CVD risk in patients with psoriasis.
Material and methods
A narrative review, through searching PubMed, EMBASE, MEDLINE, and Web of Science up to January 2023, was conducted to identify all studies documenting the use of biologic therapy in patients with psoriasis and evaluating cardiovascular risk modification.
The following search terms were used alone or in combination with the Boolean operators "AND," "OR:" "Psoriasis," "Biological therapy," "cardiovascular risk," "therapy" and "proinflammatory cytokines." We did not apply any temporal (except for the date of closure of the search), study design, or language restrictions. We focused on full-text articles but considered abstracts if relevant (Fig. 1).
Results and discussion
The psoriasis-atherosclerosis-CVD (PAC) triad
The common factor that the components of the PAC triad have is PCI, a factor that also contributes to the development of other comorbidities such as metabolic syndrome, obesity, dyslipidemia, and diabetes mellitus4. This PCI is one of the triggers of psoriasis in genetically predisposed individuals; as part of the natural history of the disease, psoriasis can contribute to the development of endothelial dysfunction and atherosclerosis, directly influencing the appearance of CVD, which can manifest itself in less than a decade of development of psoriasis, a process that is part of the so-called "psoriatic march"10 (Fig. 2).
Figure 2 Sequence of pathophysiological events of the PAC triad that begins with genetic predisposition and the development of persistent chronic inflammation that favors the appearance of psoriasis and that, through the elevation of proinflammatory cytokines, contributes to the development of endothelial dysfunction, atherosclerosis, and increased cardio-cerebrovascular risk. It is suggested that the intervention of biologic therapy in the selective control of key cytokines such as tumor necrosis factor, IL-23, and IL-17, involved in the pathogenesis of the PAC triad, could decrease the risk of the aforementioned outcome. IL: interleukin; PAC: psoriasis-atherosclerosis-cardiovascular disease.
Although endothelial dysfunction can be associated with different diseases such as hypertension, diabetes, insulin resistance, and dyslipidemia, in the case of patients with psoriasis, this dysfunction occurs even in the absence of such comorbidities, with psoriasis being an independent risk factor for CVD, 9 however, it is clear that the presence of these comorbidities substantially increases the risk of CVD, leading to a fatal outcome11.
It has been observed that the life expectancy of patients with severe psoriasis is 6 years shorter than in healthy subjects; in addition, the risk of acute myocardial infarction and cerebral vascular disease is higher in patients with severe psoriasis than in those with mild-to-moderate form12.
In an effort to reduce the risk of CVD in patients with psoriasis, Garshick and Berger13, using an algorithm that determined the risk of CVD in patients with psoriasis, proposed that if the patient was at high risk of CVD, statins should be considered, but not for low-risk patients, where only CVD risk factors had to be identified and controlled.
Insulin resistance and elevated leptin levels in patients with psoriasis are associated with an increased risk of CVD due to endothelial dysfunction, and this risk increases in direct proportion to the severity of psoriasis. It is imperative to implement more rigorous control measures to address this issue. These factors have the potential to promote atherosclerosis by directly influencing immune responses in vascular tissue. Consequently, this can lead to PCI and a harmful cycle that may ultimately result in CVD and an increased risk of mortality14. Other factors involved in the outcome of the PAC triad are dyslipidemia (oxidized low-density lipoprotein that is highly atherogenic, alterations in the reverse transport of high-density lipoprotein cholesterol, and hypertriglyceridemia)15 and the increase in the density of epicardial adipose tissue that promotes coronary heart disease,16 representing risk factors for CVD and consequently increasing the risk of death if not identified and controlled in time.
PCI, the common denominator of the PAC triad, is directly mediated by proinflammatory cytokines such as TNF-α, IL-23, and IL-17A, the latter through the IL-17 receptor that stimulates the production of granulocyte colony-stimulating factor and IL-6, causing vascular damage that contributes to atherosclerosis and CVD. Therefore, it is suggested that treatment aimed at blocking these cytokines could be beneficial not only for the control of psoriasis but also of atherosclerosis and the development of CVD17.
Effect of biologic therapy on PCI/PAC
Table 1 summarizes the main studies evaluating the effect of biologic therapy on the development of CVD in patients with psoriasis.
Table 1 Main studies evaluating the effect of biologic therapy on the development of cardiovascular disease in patients with psoriasis
| Author Reference | Country/year | Drug | Patients | Relative risk (95% CI) |
|---|---|---|---|---|
| Abaubara et al.25 | U.S.A./2010 | TNFi | 12,224 | 0.68 (0.5-0.94) |
| Wu et al.26 | U.S.A./2012 | TNFi | 1,673 | 0.56 (0.37-0.83) |
| Ahlehoff et al.27 | Denmark/2013 | TNFi | 693 | 0.42 (0.13-1.31) |
| Wu et al.28 | U.S.A./2013 | TNFi | 976 | 0.61 (0.41-0.91) |
| Ahlehoff et al.29 | Denmark/2015 | TNFi | 959 | 0.46 (0.22-0.98) |
| Shaaban and Al-Mutairi30 | Kuwait/2016 | TNFi | 1058 | 4.88 (2.5-7.2)* |
| Wu et al.31 | U.S.A./2018 | TNFi | 11,410 | 0.77 (0.60-0.99) |
| Wu et al.32 | U.S.A./2017 | TNFi | 9148 | 0.55 (0.45-0.67) |
| Rungapiromnan et al.33 | U.K./2016 | TNFi | 5205 | OR 0.67 (0.10-4.63) |
| Ryan et al.34 | U.S.A./2011 | TNFi | 1078 | −0.0005 (−0.01-0.009)** |
| Ahlehoff et al.29 | Denmark/2015 | IL-12/23i | 178 | 1.52 (0.47-4.94) |
| Rungapiromnan et al.33 | U.K./2016 | IL-12/23i | 2310 | OR 4.48 (0.24-84.77) |
| Ryan 34 | U.S.A./2011 | IL-12/23i | 771 | 0.012 (0.001-0.026)** |
| Reich et al.42 | U.K./2011 | IL-12/23i | 1582 | 0.44 (0.27-0.67) |
| Tzellos et al.43 | Germany/2012 | IL-12/23i | 3179 | OR 4.23 (1.07-16.75) |
| Poizeau et al.44 | France/2020 | IL-12/23i | 9290 | OR 4.17 (1.19-14.59) |
| Papp et al.45 | U.S.A./2013 | IL-12/23i | 3117 | IR (45 mg) 0.56/100 SY IR (90 mg) 0.36/100 SY |
| Gordon et al.46 | U.S.A./2012 | IL-12/23i | 981 | Exposure-adjusted rate: 1.06/100SY, (0.43-2.18). |
| Rungapiromnan et al.33 | U.K./2016 | IL-17i | 2549 | OR 1.00 (0.09-11.09) |
| Gottlieb et al.49 | U.S.A./2022 | IL-17i | 8819 | IR 0.4/100 PY (no increase over time) |
| Van De Kerkhof et al.50 | The Netherlands/2016 | IL-17i | 3430 | IR: 0.42/100 SY (300 mg dose) IR: 0.35/100 SY (150 mg dose) |
*Incidence rate of myocardial infarction per 1000 person-years (95% CI).
**Risk difference, events per person-year (95% CI). OR: odds ratio; IR: incidence rate; SY: subject-year of exposure; PY: per year; CI: confidence interval; TNF: tumor necrosis factor; IL: interleukin.
It has been suggested that PCI in psoriasis contributes to the atherosclerotic process and that modification of the former may contribute to reducing atherosclerosis and consequently the risk of CVD. The different treatments available for the management of psoriasis in different degrees of severity such as topical therapy, phototherapy, and systemic immunosuppressants can largely control the disease, some of them can even increase the already high cardiovascular risk in patients with the disease. Some exceptions are obvious, such as the effect of methotrexate that can decrease cardiovascular risk18.
Studies evaluating the protective effect of biological therapy on CVD are scarce in patients with psoriasis, although not in other diseases, and expectations for control of cardiovascular comorbidity have increased markedly, as they reduce the likelihood that patients with psoriasis will develop CVD, although their role in vascular damage processes remains controversial. Probably due to the inconsistency of clinical data on its efficacy against increased cardiovascular risk18. At present, biologic drugs included in the therapeutic regimen for psoriasis target three main targets: TNF, IL-12/IL-23, and IL-17.
A recent study found that suppression of some proinflammatory cytokines could reduce the risk of CVD, as has been observed with inhibition of IL-1β and subsequent reduction of CVD recurrence19. In addition to this effect, biologic therapy may reduce coronary inflammation; therefore, biologic therapy predominantly targeting TNF-α, IL-23, and IL-17 may influence PCI and thus lessen the impact of the PAC triad in psoriasis patients20. In the case of IL-17 inhibitors such as secukinumab, ixekizumab, and brodalumab, the first two blocking IL-17A, while the third blocks the IL-17 receptor21, could also impact the activation of neutrophils, crucial for psoriasis and PCI, in addition to the fact that these cells interact with the damaged endothelium and contribute to the development of atherosclerosis and CVD22.
Recent studies, including two meta-analyses, suggest that treatment with anti-TNF-α reduces the risk of CVD and acute myocardial infarction23-34. The cardioprotective effect of some biological therapies, mainly anti-TNF, has been observed in patients with other auto-inflammatory diseases such as rheumatoid arthritis, where it improved endothelial function and reduced the risk of CVD by 70%35. Among the most commonly used TNF anti-TNFs in the management of psoriasis is adalimumab, which effectively reduces PCI, although with a variable impact on vascular inflammation and endothelial dysfunction36.
Recent systematic reviews did not show a significant effect of TNF inhibitors on subclinical indicators of atherosclerosis in psoriasis or other chronic inflammatory diseases (including indicators of arterial stiffness, carotid intima-media thickness, endothelial dysfunction measured as forearm blood flow-mediated dilation, and aortic vascular inflammation)37,38, however, this could occur by different routes such as remission of the primary disease or reduction of the prothrombotic tendency37.
On the other hand, IL-23, a proinflammatory cytokine that induces the differentiation of Th17 and Th22 cells, is a key player in the pathogenesis of psoriasis, and its blockade is effective in the control of psoriasis and psoriatic arthritis39. We carry out this blockade in clinical practice with four drugs, including ustekinumab (the most commonly used), guselkumab, tildrakizumab, and risankizumab, the first inhibiting both IL-23 and IL-12, while the last three are selective toward IL-2340. IL-23 has been linked to the development of atherosclerosis, and its elevated serum levels are predictors of mortality in patients with CVD41.
IL-23 also mediates the production of granulocyte-macrophage colony-stimulating factor which promotes the development of atherosclerosis and increases oxidative stress that contributes to the PAC triad41. There is still little evidence on the cardioprotective effect of anti-IL2342-46, so more studies are needed in this regard.
IL-17 inhibitors have shown efficacy in the treatment of psoriasis, being comparable in their effect and even more effective than anti-TNF and anti-IL-2347. The cardioprotective effect of antiIL-17A has been documented in previous studies6,48-50. Considering the inhibition of the proatherogenic, proinflammatory, pro-oxidant, and prothrombotic effects of IL-17,48 however, more studies are needed to evaluate the impact of biological therapy on atherosclerosis, since previous studies have proposed that IL-17 could even have a protective effect against atherosclerosis and that its serum levels do not correlate with carotid intimal thickness18.
Regarding the effect of antiIL-17A on vascular dysfunction, the results are contradictory; a previous study with secukinumab showed that the addition of the biologic did not modify endothelial function in the first 12 weeks of use in patients with psoriasis and vascular dysfunction, but later until 52 weeks51. While in another recent study, it was observed that the addition of anti-IL-17 therapy reduced the thickness of non-calcified plaque in patients with psoriasis, improving endothelial function52.
Conclusion
Psoriasis is a systemic disease that increases the risk of CVD, and this increases in direct proportion to the severity of psoriasis. Therefore, biological therapies are an option to block proinflammatory signaling pathways common in these diseases. Biological therapies in their different modalities could reduce the risk of developing CVD, however, the available information is not entirely conclusive, so more studies are needed to define the real role of these drugs in CVD, mainly in patients with severe forms of psoriasis.
