Psoriasis Inflammation and Systemic Co Morbidities
Condition: Psoriasis
MeSH terms: Psoriasis; Inflammation
Study type: Interventional

Summary: 
      Psoriasis is a chronic relapsing prevalent inflammatory 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. Lately, 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 cardio-vascular diseases (CVD). 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).
      As the literature linking psoriasis and the metabolic syndrome expands, also reports of an
      increased rate of CVD mortality in psoriasis patients accumulates. These data emphasize that
      metabolic dysregulations are the leading risk factors for occlusive vascular events and early
      death in patients with severe psoriasis. Progress in understanding the pathogenesis of these
      apparently diverse diseases has discovered that low-grade systemic inflammation might be the
      common physiological pathway that may provide the biological plausibility of the associations
      discovered in the epidemiological studies. Since some of these co-morbidities often become
      clinically apparent years after the onset of psoriasis we assume that controlling systemic
      inflammation might prevent or reverse some of these co-morbidities.

      Presently there is no study in psoriasis that shows that a "systemic" co-morbidity can be
      prevented or treated by reversing skin inflammation.
    

Detailed description: 
      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.
    

Intervention name(s): Etanercept
Intervention type(s): Drug
Intervention description(s): self-administered for 52 weeks
Other intervention name(s): Enbrel
Intervention MeSH terms: Etanercept
Intervention model: Single Group Assignment
Intervention model description: Participants will be screened and enrolled based on inclusion/exclusion criteria. Those enrolled will have intervention for 52 weeks and assessed for outcome measures along the way.
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Psoriasis; Co morbidities; Inflammation