Can treatment of the skin rescue the heart?
Article first published online: 12 NOV 2012
© 2012 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine
Volume 273, Issue 2, pages 186–188, February 2013
How to Cite
Ståhle, M. (2013), Can treatment of the skin rescue the heart?. Journal of Internal Medicine, 273: 186–188. doi: 10.1111/joim.12008
- Issue published online: 19 JAN 2013
- Article first published online: 12 NOV 2012
- Accepted manuscript online: 19 OCT 2012 12:58AM EST
During the past decade, an important association between psoriasis and cardiovascular disease (CVD) has emerged. Since the initial report by Mallbris et al. in 2004 , the association has been confirmed by others [2, 3]. To date, the link between these conditions is based primarily on epidemiological data and the underlying pathophysiology is only poorly understood.
Psoriasis is a common (3%) immune-mediated disease in which the skin is the main target organ. Although the ultimate cause of psoriasis remains elusive, the genetic background and the inflammatory pathways mediating the skin pathology are being established. Psoriasis is characterized by T helper (Th)1/17/22-driven inflammation which is initiated and sustained by an array of skin dendritic cells, culminating in the production of associated cytokines such as tumour necrosis factor-α (TNF-α), interferon-γ, interleukin (IL)-17 and IL-22. In addition, resident cells, primarily keratinocytes, are important players that respond to signals from T cells and dendritic cells and secrete proinflammatory cytokines, chemokines and growth factors . The validity of this conceptual model is strongly supported by the impressive clinical efficacy of novel therapies targeting key mediators in these pathways, such as antibodies against TNF-α and p40 (subunit shared by IL-12 and IL-23) as well as IL-17 and IL-22 (currently in development).
What is the basis for the link between psoriatic inflammation in skin and the development of CVD? Psoriasis and CVD are complex diseases involving environmental factors in addition to immunological and metabolic pathways controlled by the genetic backbone. Thus, many factors may contribute to cardiovascular morbidity in psoriasis such as shared genetic background, lifestyle factors, inflammation and metabolic dysfunction. The hereditary component of psoriasis is strong, and many psoriasis-susceptibility genes have been identified and replicated in large genome-wide studies [5-7]. The majority are immune system–regulatory genes with the main gene HLA-C estimated to contribute approximately 50% of the genetic load. Amongst other associated genes are key components of inflammatory pathways such as IL-23R, IL23A and IL-12B, which further underlines the rationale for targeting these molecules in psoriasis treatment. However, the precise role of these genes in disease pathogenesis, in particular HLA-C, remains to be clarified. It should also be noted that psoriasis is by no means a homogenous disease, and the hereditary background is expected to vary considerably amongst phenotypes. Genetic studies with stratification for different phenotypes have recently begun and are expected to contribute additional risk genes and a more thorough understanding of disease variation. Recent genome-wide association studies have identified more than 20 loci for CVD  but with no obvious overlap with known psoriasis-susceptibility loci. Thus, there does not appear to be a common genetic predisposition towards both psoriasis and CVD. However, genetic contribution to disease is complex, and findings from noncoding RNA genetic and epigenetic studies may reveal novel interactions.
Psoriasis is associated with a plethora of traditional risk factors for CVD, such as obesity, dyslipidaemia, hypertension and diabetes [9, 10]. Of particular interest is the contribution of obesity to psoriasis. The results of several studies have shown that obesity is linked to a higher risk of psoriasis and to a more severe disease course. Moreover, the findings of case studies suggest that weight loss may improve psoriasis symptoms. It is interesting that individuals with psoriasis have a higher body mass index than matched healthy controls already at disease onset, even amongst those with clinically mild disease , implying that the tendency to gain weight may be a part of the psoriasis phenotype. It is possible that the parallel capacity to efficiently store energy and to mount an exaggerated innate immune response (as in psoriasis) is a part of a genetic survival mechanism favoured during evolution. Current research on adipose tissue biology has greatly advanced our understanding of the role of obesity in human disease. Adipose tissue is now recognized as an active endocrine organ with inflammatory cells and adipocytes secreting an array of hormones and proinflammatory cytokines . Thus, it is likely that an excess fat load may fuel inflammation in psoriasis.
Is the underlying metabolic imbalance in psoriasis responsible for the increased CVD risk detected in epidemiological studies or is the metabolic dysfunction additional to an independent risk conferred by psoriasis per se, as has been argued ? The answer remains debatable, but so far most findings indicate that the high CVD risk is restricted to the subset of patients with moderate to severe disease, estimated to comprise approximately 20% of the psoriasis population and does not involve the majority of psoriasis patients with mild disease. The systemic inflammatory burden is considerable in severe psoriasis. Likewise, inflammation is considered to be an important aspect of atherosclerosis and thromboembolic disease, which have a Th1/Th17 signature and thus overlap with the inflammatory profile of psoriasis [13, 14].
If systemic inflammation is the major cause of the CVD risk in psoriasis, it would be logical to attempt to control inflammation in addition to treating psoriasis. Data regarding how effective psoriasis therapy may influence CVD comorbidity are so far limited and somewhat conflicting. Methotrexate, which is the most widely used systemic therapy in psoriasis, was shown to lower CVD events in patients with psoriasis as well as in those with rheumatoid arthritis (RA) . Encouraging data also indicate that treatment with TNF-α antagonists may reduce CVD morbidity in RA [16-18].
The first biological agents were introduced in 2004 for the treatment of psoriasis, and so far, most data on treatment effects have been derived from clinical trials. A recent meta-analysis including 22 randomized controlled trials of anti-IL-12/23 (p40) and anti-TNF-α agents for the treatment of psoriasis (excluding psoriatic arthritis) failed to show a difference in CVD events compared with placebo with either drug . A main aim of the analysis was to validate a potentially negative impact of the two anti-IL-12/23 drugs (ustekinumab and briakinumab) on CVD. Briakinumab increased major CVD events in a placebo-controlled phase III trial and has subsequently been withdrawn, whereas ustekinumab targeting the same p40 subunit had the same effect on CVD events as placebo. IL-12 and IL-23 are thought to promote atherosclerosis and blocking these cytokines and downstream pathways should theoretically reduce CVD events; however, this seems to be contradictory to the findings with briakinumab. Considering the rapid development of new drugs targeting these pathways, there is a need for a full understanding of the role of these cytokines in vascular biology and inflammation.
Meta-analysis may be a powerful instrument to detect rare events, but clinical trials do not reflect the use of drugs postmarketing. Therefore, studies such as that reported by Ahlehoff et al. in this issue of the Journal of Internal Medicine  on the effects (and side effects) in the real-life clinical situation are critical to fully determine the therapeutic profiles of novel drugs. In this nationwide study, the authors compared CVD events between patients with psoriasis receiving biological drugs and those treated with other systemic therapies. They reported a significantly lower incidence of CVD events in the group treated with biological agents (anti-p40 and anti-TNF-α), followed by those treated with methotrexate, compared with patients receiving other systemic therapies. Three-year data were presented, and an important strength of the study is the completeness of follow-up of patients receiving biological therapies, as recording in the national psoriasis registry (DERMBIO) is mandatory for all prescriptions of these drugs in Denmark. By using the unique personal identifier, information could be linked to other registries such as the National Registry of Medicinal Pharmacy to capture data on other therapies. Regardless, the results will not enable firm conclusions as to whether biological agents are indeed cardioprotective in psoriasis because basic demographic characteristics differed substantially between groups. Patients receiving biological therapies were younger, received fewer cardiovascular therapeutic agents and were more likely to be male. Also, information about traditional CVD risk factors (e.g. obesity, hypertension, smoking, blood lipids), which are important confounders, was not available. Nevertheless, the results are promising; although a more detailed analysis may have enabled potential differences between individuals with good clinical response and those with insufficient antipsoriatic response to be compared.
Clinical follow-up of real-life usage of biological and other novel drugs is vital, and registries such as DERMBIO have the potential to contribute important information. Even though the data presented may not be conclusive with regard to whether effective antipsoriatic treatment can protect against CVD events in severe psoriasis, this study has provided a firm foundation for more detailed and long-term future studies.
Conflict of interest statement
No conflict of interest was declared.
- 14Increased Th17 cell frequency concomitant with decreased Foxp3+ Treg cell frequency in the peripheral circulation of patients with carotid artery plaques. J Mol Cell Biol 2012; doi 10.1007//s00011-012-0510-2. [Epub ahead of print]., , .
- 20cardiovascular event rates in patients with severe psoriasis treated with systemic anti-inflammatory drugs: a Danish real-world cohort study. J Intern Med 2012; doi: 10.1111/j.1365-2796.2012.02593.x. [Epub ahead of print]., , et al.