LABORATORIO DE URGENCIAS

Psoriasis and Atherosclerotic CV Disease

Risk Factor or Risk Marker?

Michael Garshick,MD,MS; Brittany Weber,MD,PhD; Joel M. Gelfand,MD,MSCE

(Division of Cardiology, Department of Medicine and Dermatology, New York University School of Medicine, New York+ Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital,Harvard Medical School, Boston, Massachusetts+Department of Dermatology and Department of Biostatistics, Epidemiology, and Informatics,University of Pennsylvania Perelman School of Medicine, Philadelphia)

JAMA Cardiol. Published online September, 2024. /  doi:10.1001/jamacardio.2024.2868

Psoriasis, an immune-mediated inflammatory disease, primarily involves the skin and joints and
is common, impacting almost 8 million adults in the US.¹ 
Psoriasis can occur at any age, but incidence initially spikes in young adulthood and gradually increases in the following decades.¹ 
Psoriasis has emerged as one of the best-studied immune-mediated inflammatory diseases with respect to major cardiovascular (CV) events.
A meta-analysis of 75 studies encompassing 500 000 patients with psoriasis observed CV disease as approximately 50% higher when compared to those without psoriasis.¹ 
Psoriasis is also associated with numerous cardiometabolic comorbidities.¹ 
Large-scale epidemiological studies, carefully controlled CV imaging studies suggest psoriasis is associated with CV disease independent of traditional CV risk factors and in a dose-response manner.¹
Within this context, Ramessur et al² conducted a 2-sample mendelian randomization study using variants from a large psoriasis genome-wide association study meta-analysis to investigate the relationship between genetic predictors of psoriasis and atherosclerotic cardiovascular disease (ASCVD). They found that while genetic predictors of psoriasis were not associated with enhanced ASCVD risk, genetic predictors of ASCVD, including coronary artery disease (CAD; odds ratio [OR], 1.07; 95% CI, 1.04-1.10) and stroke (OR, 1.22; 95% CI, 1.05-1.41), were associated with psoriasis. Genetic predictors of ASCVD were specifically associated with psoriasis and not other immune-mediated diseases examined, including asthma, multiple sclerosis, rheumatoid arthritis, atopic dermatitis, and inflammatory bowel disease.
Their results are consistent with another mendelian randomization investigation describing shared systemic inflammatory pathways and a causal relationship of genetic predictors of CAD driving psoriasis but not of genetic predictors of psoriasis promoting CAD.³ 
However, despite a strong statistical association of genetic susceptibility loci with psoriasis, the overall predictive value of these loci may be low given the modest association of these loci with psoriasis and the relatively low prevalence of psoriasis in the general population.⁴ In other words, only a small proportion of the patients with the genetic instrument studied actually have psoriasis, and even fewer will have moderate to severe psoriatic disease, in which the most clinically significant associations between psoriasis and ASCVD are observed.
Regardless, there is now a series of mendelian randomization studies on psoriasis, which provide new insights into this complex relationship. For example, in contrast to Ramessur et al, 2 other mendelian randomization studies have observed a causal relationship between genetic predictors of psoriasis and ASCVD.^5,6 
Additional studies provide further insights. Mendelian randomization and observational data suggest elevated triglycerides are a causal risk factor for psoriasis,⁷ and patients with a genetic predisposition to lower PCSK9 exhibit a lower risk of psoriasis.⁸ 
An updated conceptual framework of the relationship between psoriasis and CAD is emerging, which may be bidirectional and includes substantial overlap between the pathologic mechanisms observed in both psoriasis and CV disease. The findings from Ramessur et al highlight that these processes may be unique to psoriasis and not seen in other immune-mediated diseases that were examined. Inflammasome signaling, interleukin 6 (IL-6)–, and IL-8–driven pathways are elevated in psoriatic skin lesions and circulate systemically.¹ In psoriatic lesional skin, preferentially (when compared to nonpsoriasis) platelet clumping and characteristic lipidomic signatures are found.^9,10 Systemically, patients with psoriasis have greater oxidized and modified lipid particles, reduced high-density lipoprotein efflux, and platelet activation.^9,10 All these processes, while enriched in ASCVD, are also enriched in psoriasis and may be important mediators of the relationship between psoriasis and ASCVD.

It is provocative to think that atherosclerosis may cause psoriasis, yet it is still unclear whether targeting atherosclerosis reduces psoriasis risk.¹ Targeting biological pathways that are implicated in ASCVD and associated with psoriasis prevalence and severity, such as IL-6, are not effective in the treatment of psoriasis. However, statins, a cornerstone treatment for atherosclerosis, may improve psoriasis severity in small clinical trials.¹¹ Similarly, it is of critical importance to determine if psoriasis treatments can treat atherosclerosis and prevent CV events.
Randomized clinical trials of tumor necrosis factor inhibitors in psoriasis reduced IL-6 but failed to reduce other surrogates of CV risk (ie, vascular aortic inflammation).¹² The most commonly used biologics in psoriatic disease today, anti–IL-17 and anti–IL-23 biologics, have not been tested in large-scale trials in ASCVD. This question is becoming increasingly important as patients, clinicians, payers, and other stakeholders want to know if treating psoriasis reduces CV risk.
Additionally, not all immunotherapies may impact CV risk equally, such as JAK inhibitors, which are effective in psoriatic disease but increase thrombotic risk, especially compared to tumor necrosis factor inhibitors.¹
Ultimately, the findings from Ramessur et al further emphasize that psoriasis is a risk marker for ASCVD. In a young patient, the subclinical CV disease potentiating psoriasis may not be clinically evident, but the psoriasis is.
In line with American College of Cardiology/American Heart Association guidelines recommendations, those with psoriasis (a “risk enhancer”) should be aggressively screened and treated for traditional CV risk factors. However, this is rarely done.
In a study of almost 3000 patients with psoriasis who entered a biologic clinical trial, only 8% had optimal CV risk factor control.¹⁰ 
In a survey study of 100 patients with psoriasis, less than one-third were aware of the connection between psoriasis and CV disease and were provided recommendations to undergo CV risk screening.¹³ Awareness of this association is needed at both the health care professional and the patient level. The growing field of cardio-rheumatology is one example of an initiative to enhance this awareness.¹⁴
Recognizing the clinical need and psoriasis as a risk marker for both ASCVD and dyslipidemia, an ongoing clinical trial is using clinical care coordinators and decision support systems layered within dermatologist clinics to help guide conversations upon ASCVD risk and, when appropriate, statin initiation.¹⁵ With the recognition of the association across many autoimmune diseases and CV manifestations (regardless of directionality) combined with recent and ongoing clinical trials targeting inflammation in CV disease, it is an exciting time in the world of cardio-inflammation.
In the meantime, the solid epidemiologic evidence of a relationship between psoriasis and CV disease, combined with studies such as those by Ramessur et al, highlight the need for physicians, at a minimum, to take a more aggressive approach to identifying and treating early atherosclerosis in psoriasis.

REFERENCES

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