Psoriasis and Metabolic Comorbidities: The Importance of Well-Designed Prospective Studies

Psoriasis is a chronic inflammatory skin disease affecting 2–3% of the population, and that is now recognized to be associated with other diseases. The more common comorbidities include anxiety/depression disorders. Although suspected for many years, recent large epidemiological studies have confirmed that psoriasis and psoriatic arthritis are also associated with metabolic diseases including obesity, dyslipidemia and diabetes [1–5]. Moreover, an increased mortality from cardiovascular diseases has been documented in patients with severe psoriasis, and psoriasis may confer an independent risk of myocardial infarction especially in young patients [6–8]. Young patients (aged 20–40 years) with psoriasis have indeed a 2- to 3-fold increase in manifesting myocardial infarction compared to nonpsoriatic controls [7]. Major factors that can contribute to this unfavorable cardiovascular risk profile include cigarette smoking, obesity, physical inactivity, hyperhomocysteinemia and psychological stress that have a higher prevalence among patients with psoriasis [6–9]. Patients with psoriasis have also an increased prevalence of metabolic syndrome compared to nonpsoriatic dermatological patients [10]. The metabolic syndrome is a cluster of risk factors, which include central obesity, atherogenic dyslipidemia, hypertension and glucose intolerance, and is a strong predictor of cardiovascular diseases, diabetes and stroke [11, 12]. The metabolic syndrome takes into account the fat distribution, with central or abdominal obesity more relevant than peripheral or subcutaneous obesity. The importance of the metabolic syndrome is that it may confer a cardiovascular risk higher than the single components. In addition, the metabolic syndrome also increases the risk of all cause and colon cancer mortality. Interestingly enough, its prevalence does not correlate with psoriasis severity [10].The directionality of the association between metabolic comorbidities and psoriasis is not known. The results of a case-control study published in this issue of Dermatology suggest that psoriasis comes before some of these comorbidities [13]. In particular, the study shows that psoriasis patients when they were first ever diagnosed of having psoriasis did not have an increased prevalence of hyperlipidemia, diabetes, hypertension or any other medical conditions. In contrast, a higher proportion of psoriatic patients were overweight or obese when they were first diagnosed to be affected with psoriasis. This observation is in contrast with that of other studies showing that patients with psoriasis at their disease onset do not have an increased prevalence of obesity [14, 15]. One such study also reports that serum lipid abnormalities precede the onset of psoriasis [15]. We found that the psoriasis patients with metabolic syndrome had disease onset at an earlier age and a longer disease duration compared to psoriasis patients without metabolic syndrome [10], suggesting that psoriasis duration is a risk factor for metabolic syndrome. The major problem with all these studies is that they are retrospective. Prospective research with well-designed longitudinal studies is urgently needed to precisely assess whether metabolic disorders are risk factors for psoriasis and whether psoriasis favors atherosclerosis, and to accurately estimate the increased cardiovascular risk in psoriasis [16].It is likely that some common genetic background predisposes to both psoriasis and psoriatic arthritis as well as to obesity and metabolic diseases. Psoriasis is associated with depression, altered eating habits, physical inactivity and alcohol consumption, all of which favor weight gain. On the other hand, abdominal obesity is a proinflammatory state with the visceral adipose tissue being a rich source of inflammatory mediators known as adipocytokines. These include adiponectin, leptin, resistin and visfatin, which may provide an important link between obesity, insulin resistance and related inflammatory disorders. Other products of adipose tissue that have been characterized include TNF-α, IL-6 and MCP-1 [17]. These products have well-established roles in the pathogenesis of psoriasis and at the interface between the immune and metabolic systems. In line with this hypothesis is the evidence that obesity is a risk factor for other inflammatory diseases such as atherosclerosis and asthma. The relationship between chronic inflammatory disorders, metabolic deterioration, cardiovascular risk factors (e.g. insulin resistance) and accelerated atherosclerosis is well known for rheumatoid arthritis and systemic lupus erythematosus [18, 19], and may well apply for psoriasis, where skin and/or joint inflammation, obesity and metabolic alterations may establish vicious circles or reciprocal deterioration.The association of psoriasis with metabolic disorders has many relevant practical implications. First, we should be aware that cyclosporin, retinoids and methotrexate can negatively affect metabolic comorbidities, such as dyslipidemia, glucose intolerance, hypertension and hyperhomocysteinemia [20]. Biologicals are apparently not associated with these side effects. However, a recent retrospective study showed that anti-TNF-α therapy (infliximab and etanercept) is associated with a significant weight gain after 6 months compared to methotrexate [21]. In particular, about one fourth of patients under anti-TNF-α gained 4–10 kg body weight, suggesting caution in the use of these drugs in overweight or obese patients and a careful follow-up with diet advice for the others. Another important point is that dermatologists should be prepared to accurately screen patients for comorbidities and be actively involved in the treatment of comorbidities, especially obesity. Apart from markedly improving quality of life and being of the utmost importance in the global management of patients, reduction of body weight may render patients more responsive to antipsoriatic drugs, a hypothesis currently tested in our clinic.In conclusion, psoriasis and psoriatic arthritis have implications far beyond the skin or the joints. Research aimed at understanding the biological bases of the associations with metabolic comorbidities and how to fit this information in the management of patients is an important challenge for the very near future.