Experts on psoriasis convened with authorities from other medical specialties to discuss the recently described association between psoriasis, obesity and subsequent cardiovascular comorbidity. Similar to other diseases of increased systemic inflammation, psoriasis has been linked to a heightened risk of myocardial infarction, especially in the more severely affected, younger patients. However, unlike in other inflammatory diseases – such as rheumatoid arthritis – more severely affected patients with psoriasis are much more likely to be obese. Importantly, the pathophysiology of both psoriasis and obesity shows many shared cytokines that are known to contribute to features of the metabolic syndrome, such as hypertension, dyslipidaemia and insulin resistance. The strong association between psoriasis and obesity potentially makes psoriasis an important healthcare issue that requires an update in its standard of care. This meeting reviewed the evidence‐based literature and addressed how, moving forward, dermatologists and other specialists may redefine the magnitude of health risk associated with more severe psoriasis and its comorbidities, while clarifying both the epidemiology and pathophysiology of the association with obesity.

Psoriasis is a physically and psychologically disabling disease. In addition, patients with severe psoriasis are frequently obese. Contrary to common belief, the ‘obesity of psoriasis’ may reflect a common pathophysiology and not simply a sedentary behaviour deriving from the social ‘stigma’ of a disfiguring cutaneous condition. Importantly, both psoriasis and obesity independently confer cardiovascular risk and thus when present in the same patient may augment mortality risk. The International Psoriasis Council convened a conference in Rhodes, Greece on 3 October 2006 in conjunction with the European Academy of Dermatology and Venereology to evaluate these possibilities from an evidence‐based perspective. Psoriasis experts from dermatology and other fields of medicine – including cardiology, hepatology, pharmacology and rheumatology – presented data relating psoriatic pathophysiology and clinical outcomes to those of more recognized diseases in which comorbid risk has been established. Indeed, the participants raised the possibility that both psoriasis and obesity when presenting simultaneously may derive from an underlying inflammatory state nurturing significant comorbidity, providing recognition of psoriasis as possibly an integral part of a greater systemic disease.

Psoriasis and a link to obesity The developed world is increasingly overweight or obese.1 Dr Nick Finer observed that we live in an ‘obesogenic environment’, created by a combination of our genes, decreased physical activity, and an overconsumption of inexpensive, energy‐dense food. Regardless of aetiology, obesity confers a mortality risk, with life expectancy inversely related to an individual’s degree of adiposity, and independent of other negative health influences such as smoking. The body mass index (BMI: weight in kilograms divided by the square of the height in metres) is a surrogate measure of obesity, as higher values of BMI correlate with a greater percentage of body fat. However, Dr Finer related that the BMI tells an incomplete story about a person’s health risk, as it does not consider fitness level, muscle mass, bone structure, sex and ethnicity. More relevant are both the degree of intra‐abdominal fat (visceral adiposity) and a correlative increased waist circumference, parameters that independently confer an augmented risk of type 2 diabetes mellitus, hypertension, sleep apnoea, heart disease, myocardial infarction, stroke and some cancers and, ultimately, reduced life expectancy.1, 2 Henseler and Christophers in 1995 observed a correlation between psoriasis and obesity.3 More recently, large clinical trials evaluating biological agents for moderate to severe psoriasis reported that subjects were much heavier than the population norm.4, 5 This was substantiated by Dr Frank Dann, who showed that 46% of 3700 subjects with moderate to severe psoriasis in studies evaluating etanercept were obese (BMI ≥ 30 kg m−2). By comparison, 31% of all adults in the U.S.A. are classified as obese.2 Furthermore, Andrew Miner’s review of phase II and III clinical studies on biological agents involving more than 10 000 patients with moderate‐severe psoriasis showed that the average BMI of the enrolled subjects was 30·6 kg m−2. Dr Luigi Naldi (Italy) and Gerald Krueger (UT, U.S.A.) further drew links between obesity and psoriasis. In the former, Dr Naldi demonstrated that the risk of psoriasis was directly related to elevated BMI.6 In the latter, a large cohort of patients with psoriasis had a mean BMI that significantly exceeded that of the general Utah population. Additionally, obese patients from this latter cohort were more likely to have severe psoriasis, i.e. ≥ 20% body surface area. Confirming these analyses, a more broadly representational and controlled cross‐sectional study of patients with psoriasis in the U.K. underscores that patients with psoriasis are more likely to be obese than nonpsoriatic controls, and that obesity is more prevalent in patients with severe vs. mild psoriasis.7 Finally, using a retrospective patient‐reported assessment of body image, the Utah study suggested that in individual patients obesity usually follows – not precedes – psoriasis, implying that psoriatic inflammation contributes to the obese state.8 Nevertheless, the distinct possibility remains that psoriasis and obesity are not reciprocally or unidirectionally causal, and instead may derive from a common underlying pathophysiology.

The metabolic syndrome, inflammation and comorbidity Intra‐abdominal obesity is directly linked to the metabolic syndrome, a state of chronic systemic inflammation requiring at least three of the following five pathophysiological states: abdominal obesity, impaired glucose regulation, hypertriglyceridaemia, reduced high‐density lipoprotein and hypertension.9 This syndrome affects approximately 25% of the U.S. population, 10% in France and 20% in Australia, and markedly increases cardiovascular mortality.10 Additionally – with or without the metabolic syndrome – elevations in BMI and waist circumference are strongly correlated with increased risk for coronary heart disease.2 Many studies have shown that individual features of the metabolic syndrome are enriched in the population with psoriasis.3, 6, 7, 11-13 Intra‐abdominal fat is not merely an inert mass but a vigorous endocrine organ capable of secreting multiple bioactive proteins – or adipocytokines – promoting inflammation and affecting glucose metabolism and vascular endothelial biology. Primary adipocytokines include interleukin (IL)‐6, tumour necrosis factor (TNF)‐α, adiponectin and plasminogen activator inhibitor type 1 (PAI‐1), each of which plays multiple roles in inflammation, metabolism and endothelial cell function regulation. Importantly, visceral adiposity is associated with an elevation of TNF‐α, IL‐6 and PAI‐1. Serum TNF‐α level increases with increasing BMI, induces insulin resistance, and causes endothelial cells to produce adhesion molecules with the subsequent adherence of monocytes. TNF‐α also induces an increase in free fatty acids (FFA) which further increases insulin resistance. These processes play an important role in the early stages of atherosclerosis. IL‐6 likewise may induce insulin resistance, increase endothelial adhesion molecules, promote the hepatic release of both fibrinogen and C‐reactive protein (CRP), and augment the procoagulant effects on platelets, all sequelae that promote atherosclerosis. Finally, TNF‐α also increases the levels of PAI‐1. PAI‐1 inhibits the activity of tissue‐type plasminogen activator, an anticlotting factor. Therefore, elevated PAI‐1 results in impaired fibrinolysis and uninhibited clotting.2, 14, 15 Adiponectin works in opposition to both TNF‐α and IL‐6. Plasma adiponectin levels are negatively correlated with the BMI and waist‐to‐hip ratio and, importantly, are positively correlated with weight loss. Adiponectin reduces TNF‐α production, monocyte cell adhesion, macrophage phagocytic activity and transformation of macrophages to foam cells. Adiponectin also increases insulin sensitivity and may be directly involved in the repair of damaged vasculature. In fact, the detrimental sequelae of visceral adiposity ultimately may derive from a state of ‘hypoadiponectaemia’,2, 15 as high levels of plasma adiponectin confer a lower risk of myocardial infarction in men.16 How, then, is obesity pathophysiologically linked to psoriasis? Drs Dann and Finer both highlighted that psoriasis and obesity share similar mediators of inflammation – such as TNF‐α and IL‐6 – and that the engines of adipocytic and psoriatic inflammation – the adipocyte and macrophage, respectively – both derive from a common mesothelial origin. Importantly, psoriasis, like obesity, is associated with high systemic and local (skin and joint) levels of TNF‐α.17-19 This suggests that obesity may potentiate some of the TNF‐α‐ and IL‐6‐driven inflammation seen in psoriasis, additionally leading to impaired glucose regulation, dyslipidaemia, endothelial dysfunction, hypertension and a heightening of the inherent cardiovascular risk of cutaneous psoriatic inflammation (to be discussed later).

An immunological relationship between psoriasis and adipose tissue How might increased adiposity and psoriasis be linked immunologically? Dr Britta Siegmund discussed adipose tissue as an organ of immunity. Lymph nodes often are surrounded by fatty tissue, and both the skin and the gut are organs proximally located to large depots of fat. Thus, there may be a noncoincidental close proximity of adipocytes to tissues (lymph nodes, skin and the gut) regularly exposed to foreign pathogens (such as bacteria or viruses). From this perspective adipocytes potentially are a component of innate immunity. Indeed, adipocytes bear toll‐like receptors that allow an immediate response to foreign pathogens and release a variety of immunoregulatory cytokines – such as IL‐6 and TNF‐α– that are highly relevant to psoriatic pathophysiology.20 Interestingly, this process is dependent on leptin, an adipocytokine known for its regulation of satiety and body weight and ability to regulate both innate and acquired immunity.21, 22 Dr Siegmund emphasized that leptin is a stimulator of T cells, and that in mouse models leptin deficiency negates autoimmune pathophysiology, suggesting a potential link between adipose tissue and psoriatic inflammation and, hence, improving our understanding of the observed association between obesity and psoriasis. Psoriatic skin inflammation and its neighbouring fat potentially could allow each tissue to induce a ‘hyperproliferative state’ of the other.

Nonalcoholic fatty liver disease in patients with psoriasis Does the increased prevalence of obesity influence the known increased risk of liver pathology in patients with psoriasis? Dr Guru Aithal discussed primary nonalcoholic fatty liver disease (NAFLD), a condition prevalent in obese patients without exposure to an obvious proximate cause (e.g. drugs and viral hepatitis). Obese patients have high levels of circulating FFA with resultant insulin resistance leading to possible NAFLD. Patients with NAFLD display liver pathology ranging from steatosis, steatohepatitis (or nonalcoholic steatohepatitis, NASH), fibrosis, and even cirrhosis. NAFLD, more common in men under the age of 50 years and independently associated with features of the metabolic syndrome,23 may be asymptomatic, or associated with fatigue and vague abdominal symptoms. Liver function tests may be normal, and are regarded as insensitive measures of the presence of either NAFLD or NASH. No epidemiological studies exist evaluating the prevalence of NAFLD in patients with psoriasis. Case reports do, however, document their coexistence.24, 25 Patients with psoriasis and NAFLD (and, specifically, NASH) are at an increased risk for methotrexate‐induced hepatotoxicity, methotrexate being a common therapy for psoriasis.26 Further, methotrexate‐induced liver toxicity histologically closely resembles NASH. In fact, patients with psoriasis with risk factors for NASH (obesity and diabetes, primarily) display liver fibrosis at a lower cumulative methotrexate dose than do patients without risk factors, and methotrexate probably aggravates pre‐existing NASH.26 Patients with psoriasis show an increased likelihood of developing methotrexate‐induced hepatotoxicity.27 Thus, methotrexate treatment guidelines for psoriasis and rheumatoid arthritis differ with regard for the need for liver biopsy, required after a cumulative dose of methotrexate 1·5 g in the psoriasis population.28, 29 From this vantage point, obesity – in addition to alcohol excess – may represent an inherent feature of patients with psoriasis that increases hepatotoxic risk during methotrexate therapy. Dr Aithal also described data that indicate that the presence of NAFLD may lead to vascular endothelial dysfunction, thus providing an explanation for the observation that patients with NAFLD and, specifically, NASH have an increased likelihood of developing cardiovascular disease.30 Taken together, psoriasis, obesity and NAFLD may be manifestations of a shared pathophysiology that in certain individuals contributes to increased cardiovascular risk.

Inflammatory disease and cardiovascular risk Rheumatoid arthritis increases cardiovascular mortality independent of other risk factors for coronary artery disease such as smoking, diabetes, obesity, cholesterol level and age.31-34 Chronic inflammation is the culprit. The greater the inflammatory burden – as measured by the number of inflamed joints – the greater the atherosclerotic effects. Thus, more severe disease correlates with an increased risk of premature cardiovascular mortality.14 Sites of inflammation in rheumatoid arthritis elaborate multiple cytokines such as TNF‐α, IL‐1 and IL‐6. As described above, these cytokines induce insulin resistance and dyslipidaemia, cause endothelial dysfunction, and create a prothrombotic milieu. Additionally, specific T‐cell subsets of the rheumatoid inflammation gain entry into the circulation and incorporate into the atherosclerotic plaques. Finally, patients with rheumatoid arthritis are less able to repair damaged endothelium. Repair of disrupted vascular endothelium significantly relies upon circulating (as opposed to resident) bone‐marrow‐derived endothelial progenitor cells to ‘patch up’ the damaged vascular wall. Circulating endothelial progenitor cells are relatively deficient in persons with high cardiovascular risk, such as those who smoke, have higher low‐density lipoprotein‐cholesterol, diabetes, or who have a family history of coronary artery disease.35, 36 Similarly, patients with active rheumatoid arthritis also display a relative dearth of these circulating cells.37 The level of circulating endothelial progenitor cells in patients with psoriasis is unknown. Dr Jonathan Barker substantiated the concept that, similar to rheumatoid arthritis, psoriasis is a disease of systemic inflammation with associated cardiovascular risk factors and increased mortality.3, 7, 12, 38-42 Dr Alexa Kimball presented a retrospective analysis of two large Centocor databases of patients with immune‐mediated inflammatory disorders, and revealed that patients with psoriasis had an elevated odds ratio of having well‐known cardiovascular risk factors such as atherosclerosis, hypertension and type 2 diabetes. Drs Ulrich Mrowietz and Damiano Abeni described similar scenarios in Germany and Italy, respectively. Dr Wolf‐Henning Boehncke in his paper showed an increased prevalence and severity of coronary artery calcification in a small cohort of German patients with psoriasis when compared with a group of matched nonpsoriasis patients.43 Dr Joel Gelfand was the first to establish that psoriasis is a risk factor for cardiovascular mortality independent of the other cardiovascular risk factors shown to be more prevalent in the psoriatic population. Dr Gelfand performed a controlled analysis of the British General Practice Research Database (a repository of medical information for 8 million persons representative of the U.K. population) and showed that patients with severe psoriasis had a higher relative risk of myocardial infarction that varied with age, with younger patients at the greatest risk.11 Finally, patients with severe rheumatoid arthritis have lower than normal BMI, and, interestingly, BMI is inversely associated with mortality.44 Therefore, adiposity may contribute little to the inflammatory burden in patients with rheumatoid arthritis. In contrast, as described earlier, patients with severe psoriasis have a higher BMI that is directly related to the risk of cardiovascular mortality.6-8, 11 From this perspective, a strict analogy between rheumatoid arthritis and psoriasis cannot be drawn, and individual studies of these diseases may draw conclusions irrelevant to the other.

Future directions: a call to action Overwhelmingly, the data presented at this meeting support the linkage of psoriasis to both obesity and increased comorbid risk. Further, psoriasis probably functions independently as a risk factor for myocardial infarction. But many questions still remain. We would like to propose that future investigations address the following important areas: 1 Prospective analyses of broadly representative psoriatic populations with well‐matched control populations must examine the chronology of psoriasis‐associated obesity and the metabolic syndrome. In essence, what comes first? Does obesity appear concurrently with or after the onset of psoriasis? Further, in patients with psoriasis, is BMI (or intra‐abdominal fat) directly related to the subsequent appearance of dyslipidaemia, insulin resistance, endothelial dysfunction, and, ultimately, cardiovascular mortality? Finally, do different psoriatic genotypes or phenotypes (i.e. plaque, pustular or palmoplantar) and varying severity of disease confer different risk for obesity and comorbidity? 2 Correlation does not equate with causation. Psoriasis and obesity (or the metabolic syndrome) must be mechanistically, and not solely epidemiologically, demonstrated as inter‐related and perhaps mutually potentiating. Future investigations should examine not only the absolute levels of adipocytokines but also how the endocrine/immunological functions of adipose tissue directly interact with the pathophysiology of psoriasis. For example, what are the direct effects of either adiponectin or leptin on psoriatic skin? Does the location of the adipocytes – either intra‐abdominal or subcutaneous – relate to the pattern and effects of the released adipocytokines? Is it possible that adipose tissue acting as an organ of immunity is a primary regulator of psoriasis‐related inflammation, or vice versa? 3 The effects of various systemic therapies for psoriasis, including traditional and biological agents, on comorbidity need to be prospectively measured. For example, a 4‐week course of etanercept 25 mg twice weekly in obese patients with type 2 diabetes significantly reduces systemic inflammatory markers such as CRP and IL‐6, but has no effect on vascular or metabolic insulin sensitivity.45 In patients with the metabolic syndrome a 4‐week course of etanercept 50 mg once weekly lowers CRP and fibrinogen and elevates adiponectin levels when compared with the effects on a matched group of patients receiving a placebo, with no effects noted on insulin sensitivity and on either BMI or waist‐to‐hip ratio.46 In contrast, multiple studies in rheumatoid arthritis have shown that TNF‐α inhibition generally is effective in improving vascular function47, 48 and insulin resistance,49 with varying effects on lipid profiles.47, 50-52 Given the diametrically different BMI/severity of disease relationship between rheumatoid arthritis and psoriasis, the effects of therapy on lipid profiles in psoriasis may differ from the effects in rheumatoid arthritis. Regardless, methotrexate (especially when given with folate supplementation) has been shown to lower cardiovascular risk in patients with both psoriasis and rheumatoid arthritis,53 and was shown in a prospective study to produce a dramatic reduction in the incidence of cardiovascular death in a rheumatoid arthritis cohort.54 TNF‐α inhibition also lowers the incidence of a first cardiovascular event in a select population of patients with rheumatoid arthritis.55 Cardiovascular outcomes in patients with treated psoriasis must be measured, as well as effects on obesity, vascular function, dyslipidaemia, hypertension and insulin resistance. Data will allow us to conclude whether the long‐term health benefits significantly outweigh the risks of systemic antipsoriatic therapies, including methotrexate. 4 The effects of obesity on therapy should be evaluated. Are heavier patients with psoriasis more difficult to treat solely due to pharmacokinetic considerations? Dr Atholl Johnston, describing the effects of adipose tissue on drug therapy, showed how adipose tissue can dramatically alter the volume of drug distribution, and thus limit efficacy. Most systemic therapies for psoriasis are administered on a fixed‐dose basis, and therefore may be inadequately dosed for heavier patients. Should all psoriasis therapy, therefore, be ‘BMI‐based’? From another perspective, are there also correlatively increased levels of inflammatory cytokines in the obese patient that make anticytokine therapy (such as TNF‐α inhibition) more difficult to implement, i.e. requiring higher doses? 5 Do direct interventions regarding weight loss, smoking and alcohol reduction and better lipid, glucose and blood pressure control positively affect psoriasis severity? 6 Future prospective psoriasis studies and registries, at a minimum, should capture weight and/or abdominal circumference, height, comprehensive metabolic laboratory measurements, fasting lipids, and blood pressure measurements, so that potential relationships between cardiac risk factors and effective therapy can be established. Is improvement in psoriasis reflected by a change in these measurements? 7 Biomarkers of psoriatic inflammation must be identified. For example, as shown in a general population of men,16 is adiponectin level in patients with psoriasis inversely related to risk of myocardial infarction? Prospective studies should examine if and how the absolute burdens of TNF‐α and IL‐6 relate to psoriasis severity, adiposity and cardiovascular risk. Are already established inflammatory markers, such as CRP, relevant to psoriasis and its associations with other comorbid conditions? More precise markers of inflammation and predictors of future risk of morbidity and mortality must be uncovered so that high‐risk psoriasis populations can be identified and more aggressively managed. Are nonaggressive topical therapies likely to be sufficient for a patient with psoriasis with a specific inflammatory profile? 8 Future studies should examine for the presence of psoriatic arthritis, now known to affect between 10% and 40% of patients with psoriasis.56 The findings of these studies should stratify the results based on the presence or absence of joint disease or, more specifically, enthesopathy. Does psoriatic arthritis affect cardiovascular risk, increase comorbidity, and induce features of the metabolic syndrome (such as intra‐abdominal fat) beyond the effects of psoriasis alone? Dr Alice Gottlieb noted in her presentation that the synovial fluid of patients with psoriatic arthritis has levels of TNF‐α and IL‐6 that are lower than the synovial levels in patients with rheumatoid arthritis. Does this imply that psoriatic arthritis is less inflammatory and thus less ‘risk conferring’ than rheumatoid arthritis? Are patients with minimal psoriasis but with significant levels of psoriatic arthritis at a lower or higher risk for future comorbidity? 9 Studies on circulating vascular endothelial progenitor cells should be evaluated in psoriasis populations. Does psoriasis, like rheumatoid arthritis, affect the ability to repair damaged endothelium directly? 10 Studies on the genetics of psoriasis should include examination of mutations in genes known to regulate adipose tissue, obesity, and other facets of the metabolic syndrome. 11 Dermatologists will better accomplish the diverse range of research studies discussed above with assistance from colleagues in endocrinology, genetics, cardiology, vascular biology, hepatology, pharmacology and rheumatology. Such collaboration may contribute to psoriasis being accepted as an important healthcare policy issue. In conclusion, the emerging data strongly suggest that psoriasis, a disease with a worldwide incidence of approximately 2%, is associated with obesity and significant systemic inflammation. Therefore, especially in its more severe presentations, psoriasis may represent a relevant healthcare issue. Psoriasis warrants a more comprehensive, prospective and multidisciplinary investigative approach, better to clarify the nature of its comorbidities both epidemiologically and mechanistically. Current guidelines of care for psoriasis may require a significant update.

Acknowledgments Unrestricted funding for the conference was provided by Amgen Inc., Merck Serono SA and Wyeth. These companies had no influence on the meeting content, the choice of participants, or in the construction of this paper. Participants in the conference ‘Obesity in Psoriasis: Metabolic, Clinical, and Therapeutic Implications’ presented by the International Psoriasis Council and held in Rhodes, Greece, 3 October 2006 were (in alphabetical order): Damiano Abeni, MD, Guru Padur Aithal, MD, Jonathan Barker, MD, Wolf‐Henning Boehncke, MD, Frank Dann, MD, Nick Finer, MD, Joel Gelfand, MD, Alice Gottlieb, MD, PhD, Atholl Johnston, MSc, PhD, Alexa Kimball, MD, Gerry Krueger, MD, Alan Menter, MD, Andrew Miner, BSc, Ulrich Mrowietz, MD, Luigi Naldi, MD, Britta Siegmund, MD, Wolfram Sterry, MD and Bruce Strober, MD, PhD.