Psoriasis Inflammation and Systemic Co Morbidities

Psoriasis is the most prevalent immune-mediated skin disease affecting 2-4% of the world's population. Severe psoriasis is a disabling disease affecting the physical and emotional well being of patients, and its effect on quality of life is similar to that seen with other major medical diseases such as diabetes, rheumatoid arthritis, and cancer. Psoriasis is a prototypical Th-1 and Th-17 inflammatory disease, which demonstrates a complex interplay between innate and adaptive immunity. Although the etiology of psoriasis in still not completely elucidated, on the basis of existing knowledge, it is obvious that psoriasis is a complex trait involving genetic, metabolic and immune mechanisms as well as environmental factors. Moreover, it is increasingly being recognized that psoriasis is not merely a skin disease but is probably associated with other co-morbidities such as psoriatic arthritis, Crohn's disease, the metabolic syndrome and CVD. Some of these co-morbidities often become clinically apparent years after the onset of psoriasis and are frequently found in patients with severe disease. Furthermore, recently, studies based on large cohorts of psoriasis patients showed that severe psoriasis was association with increased mortality and CVD was found to be the most common cause of death. The metabolic syndrome The metabolic syndrome is a combination of diabetes mellitus type II (or insulin resistance), hypertension, central obesity, and combined hyperlipidemia (elevated LDL; decreased HDL; elevated triglycerides). The prevalence of the metabolic syndrome in the USA is estimated to be up to 15% of the population. Obesity, which is a central feature in the metabolic syndrome, has been termed the modern "epidemic" of the western world. The metabolic syndrome components are associated with increased risk for CVD, which is still the leading cause of death in the western world. Interestingly, inflammation was also implicated in the pathophysiology of the metabolic syndrome. Th-1 and Th-17 cells and cytokines as well as other adipocyte-derived-cytokines adipokines and hormones were identified. Excess numbers of psoriatics are obese, interestingly, the average weight of patients in recent phase 3 studies was around 90Kg. Mechanistic links between psoriasis and its co-morbidities Low-grade inflammation possibly mediated by TNF is suspected to be the biological plausibility explaining the associations discovered in the epidemiological studies linking between psoriasis and its co-morbidities and especially the metabolic syndrome. Progress in understanding the immunology of these apparently diverse diseases has discovered common physiological pathways. Clearly many different tissues and organs have a common blood supply and can be exposed to increased levels of inflammatory cytokines, chemokines and other mediators through the systemic circulation. The "obesity of psoriasis" is thought to be a key link to the metabolic syndrome as well as to CVD. In the past, the only known adipose tissue functions were energy storing and free fatty acids production. However, a dramatic increase of research on the role of adipose tissue has led to the current view that adipose tissue is an active endocrine organ with many secretory products including adipokines and other cytokines. Moreover now it is also being recognized as a part of the innate immune system. Adipocytokines play important roles in the pathogenesis of insulin resistance and associated metabolic complications such as dyslipidemia, hypertension, and premature heart disease. TNF is a major mediator of disrupted insulin receptor signaling. Preventing co-morbidities In view of the chronic nature of the inflammation in psoriasis and the lingering process of metabolic syndrome and CVD development, the most important question is whether effective, long-term control of psoriasis could prevent, reverse, or attenuate these co-morbitides.

Why is this trial important? At present, we do not know how "deep" psoriasis goes as an inflammatory disease.

Inflammatory cells (macrophages) are increased in skin lesions of psoriasis, going as deep as the deep dermis/adipose tissue interface. Macrophages are postulated to be cells increased in adipose tissue that, in conditions of obesity, produce excess TNF and thus directly cause disrupted insulin receptor signaling in adipocytes. The extension of inflammation in skin lesions could well continue into the fat, with common inflammatory circuits then driving both skin disease and obesity/metabolic syndrome that is so common in psoriasis patients.

However, for the purposes of this study, we consider that the adipose tissue in skin is a functional compartment that is distinct from the epidermis and dermis and that production of adipokines and other mediators in the fat compartment can drive not only the metabolic derangements, but also influence the systemic risk of cardiovascular disease. We believe that treatment of inflammation in the primary site of this disease, epidermis and dermis of skin lesions could have corresponding effects on inflammation in other "co-morbid" tissues.

Adipose tissue underlying psoriasis plaques is the most accessible tissue to direct analysis for a reduction in co-morbidity pathophysiology. Interestingly, psoriasis lesion show altered expression of leptin receptors in the "skin" component18 but no studies have been done to compare "skin" vs. adipose tissue. We want to use powerful, high density, arrays and functional imaging studies to assess the degree of inflammation and associated metabolic derangement in fat tissue and then determine the extent to which a reduction in inflammatory circuits in the skin affects the core pathology in fat tissue. Associated biomarker and functional assessments of the cardiovascular tree will provide critical information on whether associated cardiovascular dysfunction can be reversed by treating inflammation in the primary site. If this study is successful, it will not only extend information on the pathophysiology of psoriasis and disease-specific co-morbid risks, but it will also provide guidance on whether long-term effective treatment of inflammation could improve long-term tissue outcomes deeper than the skin. Some of the studies we propose are "firsts" for the study of psoriasis and stand to create new research approaches for psoriasis and other diseases that have similar inflammatory and co-morbid risks. Preliminary Studies Studies in rheumatoid arthritis (RA) patients, another chronic inflammatory disease associated with increased risk for CVD, showed that response to methotrexate treatment is associated with reduction in CVD events and mortality. Biologic treatments for psoriasis, e.g. anti TNF-α (etanercept) or anti p-40 (ustekinumab), have also been shown to reduce C reactive protein (CRP) in short-term trials. A key hypothesis to this study is that the classical TNF pathway (TNF,IL-1,IL-6,IL-8 then the NF kappa B immediate genes) contributes directly to the metabolic alterations in psoriatic patients and that this pathway could also drive systemic inflammation. CRP is produced in the liver in response to IL-6. Many other inflammatory mediators associated with increased CVD risk are made at excess levels in psoriasis lesions and may well contribute to the systemic inflammation burden through release into the circulation. We have used gene arrays and RT-PCR to follow systemic modulation of these CVD related inflammatory molecules in previous studies and will extend this analysis to adipose tissue in this study. However, the question whether long-term effective management of psoriasis can alter the pathophysiology of its comorbid conditions has not been investigated yet.