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Psoriasis as the Marker of Underlying Systemic Disease

A. S. Kourosh, BS1; A. Miner, BS1; A. Menter, MD1,2
1The University of Texas Southwestern Medical School, Dallas, TX, USA
2Division of Dermatology, Baylor University Medical Center, Dallas TX, USA

ABSTRACT

Psoriasis is associated with comorbidities that include metabolic syndrome and increased cardiovascular risk. These conditions share etiologic features and health consequences that directly correlate with the severity of psoriatic disease. This disease, in both its skin and joint manifestations, may represent a relevant healthcare issue as an indicator of a broader, underlying disorder of systemic inflammation, and warrants more comprehensive study and multidisciplinary collaboration on its pathophysiology, epidemiology, and treatment in relation to its comorbid conditions.

Key Words: Psoriasis, metabolic syndrome, cardiovascular risk, myocardial infarction, comorbidities, hyperlipidemia, type 2 diabetes mellitus

While heart disease remains a quiet killer, ignored for years by those at risk, psoriasis is a highly visible disease. Its impact on social interaction and quality of life can prompt earlier physician consultation. Psoriasis patients are frequently obese, and unknowingly at greater risk than the general population for myocardial infarction (MI), metabolic syndrome and other comorbidities.1-4

Patients who are obese, and those who have severe psoriasis, often share a common psychological experience.5 However, beyond the social stigma, populations affected by psoriasis and/or obesity can similarly manifest insulin resistance, an aberrant lipid profile, and an increased cardiovascular risk.4,6 A growing body of research suggests that these diseases may in fact share an etiologic link, which may permit them to join atherosclerosis, autoimmune disease, and other comorbid conditions as facets of a larger systemic disorder of inflammation.4

As a common Th1 mediated disease affecting 1%-3% of the world’s population, psoriasis may serve as an external indicator of underlying immune and metabolic dysregulation.4 A recent population-based study showed an increased risk of death at a younger age in patients with severe psoriasis.7 Additionally, studies involving mice appear to support the role of obesity in Th1 mediated pathology where adipocytes are shown to secrete both hormones and cytokines. Of particular importance is the ability of adipocytes to secrete the proinflammatory cytokine tumor necrosis factor-á (TNF-á), as its overproduction is an important feature in the pathophysiology of psoriasis.8 Further exploration of the biologic markers and systemic comorbidities of psoriasis, and their genetic influences, could aid in identifying patients who may be at higher risk for systemic disease, including cardiovascular risk, thus ensuring that they receive timely diagnosis and care.

Discussion of Statistics

Individually, the features of metabolic syndrome may be associated with increased cardiovascular events. Taken in combination, this risk may be synergistically increased. Metabolic syndrome is generally defined by the presence of or treatment for at least three of the following five criteria: hypertension, insulin resistance, decreased high-density lipoprotein, hypertriglyceridemia, and central obesity. (Table 1)

In a cross-sectional study of psoriasis patients, the body mass index (BMI) was calculated for each participant at 18 years of age and was, for most, normal (BMI < 25). Subsequently, however, 78% of the patients in this group went on to become overweight or obese.10 A recent review of hospitalized patients from Germany (controlled for age, smoking, alcohol consumption, and gender) found that metabolic syndrome was more likely to be found in psoriasis patients vs. controls (odds ratio [OR]=5.29; 95% confidence interval [CI], 2.78-12.8).

The same report demonstrated that psoriasis is associated with type II diabetes mellitus (OR=2.48; 95% CI, 1.70-3.61) and coronary heart disease (OR=1.77; 95% CI, 1.07-2.93).10 Thus, recognized sequelae of the metabolic syndrome are more prevalent in patients with psoriasis. A case-control study from Italy similarly demonstrated in its outpatient psoriasis population that more than 30% of patients had metabolic syndrome, compared with 20.6% of dermatologic controls over the age of 40 years (OR=1.65; 95% CI, 1.16-2.35). While the presence of three of the five components of metabolic syndrome was more common in the psoriasis population, abdominal obesity and hypertriglyceridemia were additionally more common as individual factors among the psoriasis patients.2

A historical cohort study in Sweden comparing cardiovascular mortality in patients hospitalized for psoriasis vs. outpatient controls found that inpatient psoriatics had a 50% greater risk of cardiovascular death.11 This risk increased as the number of hospital admissions increased, and mortality was higher for those admitted at younger ages. Last year, a prospective, population-based cohort study conducted in the UK showed that psoriatic disease may confer an independent risk of MI, with the greatest relative risk residing in young patients with severe disease.1 The cohort was adjusted for hypertension, hyperlipidemia, diabetes, history of MI, age, sex, smoking, and BMI.

Pathophysiology

The nature of coronary artery disease as a chronic inflammatory condition is apparent in the histology of an atherosclerotic plaque.

Abnormality Out-of-Range Values
Abdominal obesity Waist circumference
>102cm (>40in) males
>88cm (>35in) females
Impaired glucose regulation Fasting glucose >5.55mmol/L
Hypertriglyceridemia Triglycerides >1.69mmol/L
Low HDL-C < 1.03mmol/L males
< 1.29mmol/L females
Hypertension >130/85mmHg either systolic or diastolic
Low HDL-C < 1.03mmol/L males
< 1.29mmol/L females
Table 1: Metabolic Syndrome Criteria NCEP ATP III (3 or more)
HDL-C = High-density lipoprotein cholesterol
From: Statistical Fact Sheet of the American Heart Association
At its core are CD4+ cells and macrophages that potentiate plaque formation.12 Its sites of rupture contain higher concentrations of these activated immune cells, as well as the inflammatory cytokines and proteolytic enzymes that weaken the cap and render it unstable.12 Its local environment comprises the same cytokine milieu of TNF-á, IL-6, IL-8, and IL-17, as that found in the gut of a patient with Crohn’s disease, in a psoriatic plaque, or in an arthritic joint, and its rupture is triggered by the same factors of infection and emotional stress that cause flares in these diseases. It resembles the pathology of a T-cell mediated disease.

Thus, the concern that psoriasis and rheumatoid arthritis patients face a higher risk of premature cardiovascular mortality than others of the same age and background may be explained by the fact that the cell-mediated immune dysregulation associated with heart disease is already markedly elevated at baseline in patients with T-cell mediated diseases.1,3,13-15

Recent studies implicate IL-17, which is released by a subset of memory T-helper cells (Th17 cells) that are stimulated by IL-23, as a mechanistic link between T-cell activation and inflammation.16,17 In contrast to normal skin, IL-17 is expressed in psoriatic skin lesions, and is known to induce the key psoriatic cytokines of TNFá, and IL-1, IL-6, and IL-8, among a cascade of inflammatory mediators. Its key role in driving epidermal activation in psoriatic plaques is evidenced by the mechanism of certain therapies. A recent clinical trial involving etanercept demonstrated the importance of the early inhibitory effects of this immunomodulator on Th17 cells, in addition to those on Th1 cellular products and effector molecules which were reduced later in disease resolution.18 IL-17 is also found in the inflamed joints of patients with rheumatoid arthritis and Lyme disease, as well as foci in inflammatory bowel disease, multiple sclerosis, collagen induced arthritis, experimental autoimmune encephalomyelitis, organ transplant rejection and ischemic stroke.16,17,19 Notably, IL-17 is also seen at higher levels, along with IL6, IL-8, and C-reactive protein, in the plasma of patients who have suffered unstable angina and acute MI.16

Theoretically, almost any cell could be a target, since the IL-17 receptor is ubiquitously expressed by activating an inflammatory response via a nuclear factor-êB associated pathway.16 Thus, the inflammatory reaction seen in a psoriatic plaque may be a microcosm for what is simultaneously propagating in the joints, gut, vasculature or other sites, which further exposes the underlying systemic nature of psoriasis. This has perhaps already been observed, not only in psoriatic arthritis, where a cutaneous disease progresses to include the joints as well, but also in the clustering of psoriasis with other autoimmune diseases such as Crohn’s disease, systemic lupus erythematosus, multiple sclerosis, and diabetes mellitus types 1 and 2. The epidemiologic association of psoriasis and psoriatic arthritis with Crohn’s disease, in particular, may arise from a genetic kinship, as both have been associated with the same organic cation gene transporter haplotype, and the PSORS8 locus of psoriasis overlaps with a Crohn’s disease locus (CARD15) on the long arm of chromosome 16. Of intense research interest at present is the possibility that psoriasis and obesity may share common genetic alleles.20-22

More broadly, certain single nucleotide polymorphisms in the promoter regions of TNF-á and IL-6 have been linked with greater relative production of these cytokines in some individuals, rendering them more sensitive in their response to the same inflammatory stimuli, whether infectious or intrinsic, than carriers of other variants.21,23,24 This allelic predisposition to higher levels of both cytokines has been seen with increased risk of coronary heart disease, particularly in the setting of type 2 diabetes and obesity, which are features of metabolic syndrome.21,23-25

The role of obesity in this picture of inflammation and heart disease emerges in the concept that adipose tissue can function not only as an endocrine organ, but also as a component of the immune system. Since adipocytes express toll receptors that are involved in the innate immune response, these cells can directly react to foreign pathogens via the release of inflammatory cytokines, such as macrophages, which are derived from the same mesothelial origin.26 This group of adipocytokines, or ‘adipokines’, includes adiponectin, leptin, resistin, and plasminogen activator inhibitor type 1 (PAI-1), as well as known key mediators of psoriatic lesions, such as IL-6 and TNF-á.

These two cytokines also induce insulin resistance, dyslipidemia, endothelial production of monocyte adhesion molecules, and subsequent adherence of monocytes, illustrating how adipocytes contribute to the formation of foam cells. Thus, adipocytes are not simply “dormant” cells “bulking up” the abdomen; rather, they act as an increased cellular store, as found in obese patients, that may amplify the processes, which breed both psoriatic and atherosclerotic plaques.4

Additionally, both cytokines promote thrombosis. TNF-á raises levels of PAI-1, which inhibit tissue plasminogen activator, causing impaired fibrinolysis and uninhibited clot formation, while IL-6 promotes hepatic release of fibrinogen and C-reactive protein (CRP), and augments a procoagulant effect on platelets.15,23,27,28 Circulating markers of inflammation, such as CRP and erythrocyte sedimentation rate have demonstrated value as adjunct predictors to the established risk factors for coronary artery disease and heart failure, respectively.29 In addition to traditional factors such as infection or autoimmune vasculopathies, for which their elevations are monitored, both markers are found to be elevated at baseline, not only in psoriasis patients, but also in those who are obese.30 Secretion of IL-6 and TNF-á by adipocytes may contribute to these elevated levels of CRP, which further portrays obesity as a condition of chronic inflammation connected with both psoriasis and heart disease.30,31

Future Considerations

Since the first study on susceptibility of psoriasis and genetic loci, much has been uncovered regarding the polymorphisms and human leukocyte antigen (HLA) associations of chronic diseases.32 Greater attention is necessary to understand their underlying genetic relationships and how these give rise to the epidemiologic clustering of many inflammatory and metabolic diseases, with an eye toward gene therapy. Also, since chronic disease morbidities are often difficult to distinguish from the long-term side-effects of their systemic therapies, the effects of medications such as methotrexate and biological agents on metabolic syndrome and cardiovascular risks must be assessed in patients with psoriatic disease, including the full spectrum of skin and joint involvement.

Most chronic diseases are managed by primary care doctors. Psoriatic disease is an exception, in that specialists, i.e., dermatologists and rheumatologists, often diagnose and manage this chronic disease with its now known systemic implications. With the evidence indicating that a higher incidence of obesity (BMI >30) occurs in these patients, and that joint disease usually appears 8–10 years post-onset of skin disease, it is critical for dermatologists to identify at-risk patients and initiate an interdisciplinary approach to the screening and management of their comorbidities.

References

  1. Gelfand JM, Neimann AL, Shin DB, et al. Risk of myocardial infarction in patients with psoriasis. JAMA 296(14):1735-41 (2006 Oct 11).
  2. Gisondi P, Tessari G, Conti A, et al. Prevalence of metabolic syndrome in patients with psoriasis: a hospital-based case-control study. Br J Dermatol 157(1):68-73 (2007 Jul).
  3. Henseler T, Christophers E. Disease concomitance in psoriasis. J Am Acad Dermatol 32(6):982-6 (1995 Jun).
  4. Sterry W, Strober BE, Menter A. Obesity in psoriasis: the metabolic, clinical and therapeutic implications. Report of an interdisciplinary conference and review. Br J Dermatol 157(4):649-55 (2007 Oct).
  5. Mease PJ, Menter MA. Quality-of-life issues in psoriasis and psoriatic arthritis: outcome measures and therapies from a dermatological perspective. J Am Acad Dermatol 54(4):685-704 (2006 Apr).
  6. Kremers HM, McEvoy MT, Dann FJ, et al. Heart disease in psoriasis. J Am Acad Dermatol 57(2):347-54 (2007 Aug).
  7. Gelfand JM, Troxel AB, Lewis JD, et al. The risk of mortality in patients with psoriasis. Arch Dermatol 143(12):1493-9 (2007 Dec).
  8. Weisberg SP, McCann D, Desai M, et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112(12):1796-808 (2003 Dec).
  9. Herron MD, Hinckley M, Hoffman MS, et al. Impact of obesity and smoking on psoriasis presentation and management. Arch Dermatol 141(12):1527-34 (2005 Dec).
  10. Sommer DM, Jenisch S, Suchan M, et al. Increased prevalence of the metabolic syndrome in patients with moderate to severe psoriasis. Arch Dermatol Res 298(7):321-8 (2006 Dec).
  11. Mallbris L, Akre O, Granath F, et al. Increased risk for cardiovascular mortality in psoriasis inpatients but not in outpatients. Eur J Epidemiol 19(3):225-30 (2004).
  12. Stary HC, Chandler AB, Dinsmore RE, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 92(5):1355-74 (1995 Sep 1).
  13. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352(16):1685-95 (2005 Apr 21).
  14. Reynoso-von Drateln C, Martínez-Abundis E, Balcázar-Muñoz BR, et al. Lipid profile, insulin secretion, and insulin sensitivity in psoriasis. J Am Acad Dermatol 48(6):882-5 (2003 Jun).
  15. Sattar N, McCarey DW, Capell H, et al. Explaining how “high-grade” systemic inflammation accelerates vascular risk in rheumatoid arthritis. Circulation 108(24):2957-63 (2003 Dec 16).
  16. Hashmi S, Zeng QT. Role of interleukin-17 and interleukin-17-induced cytokines interleukin-6 and interleukin-8 in unstable coronary artery disease. Coron Artery Dis 17(8):699-706 (2006 Dec).
  17. Iwakura Y, Ishigame H. The IL-23/IL-17 axis in inflammation. J Clin Invest 116(5):1218-22 (2006 May).
  18. Zaba LC, Cardinale I, Gilleaudeau P, et al. Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J Exp Med 204(13):3183-94 (2007 December 24).
  19. Teunissen MB, Koomen CW, de Waal Malefyt R, et al. Interleukin-17 and interferon-gamma synergize in the enhancement of proinflammatory cytokine production by human keratinocytes. J Invest Dermatol 111(4):645-9 (1998 Oct).
  20. Bernstein CN, Wajda A, Blanchard JF. The clustering of other chronic inflammatory diseases in inflammatory bowel disease: a population-based study. Gastroenterology 129(3):827-36 (2005 Sep).
  21. Bennermo M, Held C, Stemme S, et al. Genetic predisposition of the interleukin-6 response to inflammation: implications for a variety of major diseases? Clin Chem 50(11):2136-40 (2004 Nov).
  22. Ho P, Bruce IN, Silman A, et al. Evidence for common genetic control in pathways of inflammation for Crohn’s disease and psoriatic arthritis. Arthritis Rheum 52(11):3596-602 (2005 Nov).
  23. Sbarsi I, Falcone C, Boiocchi C, et al. Inflammation and atherosclerosis: the role of TNF and TNF receptors polymorphisms in coronary artery disease. Int J Immunopathol Pharmacol 20(1):145-54 (2007 Jan-Mar).

In this issue:

  1. Psoriasis as the Marker of Underlying Systemic Disease
  2. Novel Agents for Intractable Itch
  3. Update on Drugs and Drug News - February 2008