Examining the Link: Systemic Manifestations Associated with Psoriasis

Discussions with patients about the comorbidities of psoriasis should emphasize the impact of associated diseases in order to improve overall health and quality of life.

Psoriasis is traditionally known as a chronic inflammatory skin disease that is estimated to affect approximately 2% of the adult population in the United States.1 Psoriasis affects individuals of all ages and ethnicities, with peak incidence in the second and fifth decades of life. Psoriasis may be mild and limited to one area of the body or more severe and generalized.1 The underlying cause of psoriasis remains a complex mixture of genetic and environmental factors.2,3

Beyond its association with psoriatic arthritis, psoriasis has become increasingly recognized for its relationship with other medical conditions like heart disease, metabolic disorder and inflammatory bowel disease.4-7 People with severe psoriasis tend to have a higher likelihood of such comorbidities and an increased risk of mortality as well.8 Some clinicians believe effectively treating psoriasis can have a positive impact on these comorbidities, but there is still not enough evidence to support — or even refute — this claim. Overall, it is important that dermatologists not only educate their patients about the varied systemic effects associated with psoriasis, but also that more studies are conducted to measure the effect of systemic therapies indicated for psoriasis on these comorbidities.9

Psoriatic Arthritis

Psoriatic arthritis (PsA) is considered the most common extra-cutaneous manifestation of psoriasis.10 Depending on the study, PsA is found to occur in 4% to 42% of patients with psoriasis.11-13 In the majority of cases, symptoms and signs of PsA develop several years after the appearance of psoriatic skin lesions, which typically facilitates the diagnosis.13 However, there are different clinical and radiographic criteria for the diagnosis of PsA, which makes the true prevalence of this disorder unknown and leads to challenges in interpreting the most effective therapies for PsA.14-16

The serological presence of rheumatoid factor helps differentiate PsA from rheumatoid arthritis (RA). Other clinical features that differ between PsA and RA include the tendency of PsA to occur equally in males and females compared to RA, which occurs predominately in females. PsA more often involves the distal joints and can present with all joints in one digit affected, compared to RA, which has a higher likelihood of affecting the same joint bilaterally.17

Considering 20% of patients with PsA are estimated to suffer from debilitating and destructive disease, the continued evaluation of therapies for PsA is important.18 Methotrexate, anti-TNF-α therapy or a combination are often considered the standard of care for moderate-to-severe PsA.19 However, there is a lack of randomized, double-blind clinical trials that evaluate the effectiveness of methotrexate alone or in combination with anti-TNF-α therapy for PsA.19

Cardiovascular Disease

Risk factors for cardiovascular disease, such as age, hypertension, obesity, smoking and genetics, are often found in patients with psoriasis.20 There is significant evidence that patients with psoriasis have a higher rate of cardiovascular disease.4,21-24 Systemic inflammation has been known to be associated with the progression of atherosclerosis.25 The chronic inflammatory nature of psoriasis may be a major underlying factor that contributes to this increased risk of cardiovascular disease. Indeed, one study found an increased rate of coronary artery calcification (CAC) in patients with psoriasis.26 In another study,32 patients with psoriasis were matched with control patients. After non-contrast–enhanced spiral computerized tomography was performed, 59.14% of patients with psoriasis were found to have CAC compared to 28.1% of controls (P=0.015). The CAC severity score was also significantly higher (P=0.019) in patients with psoriasis.26 Another study of 3,236 patients with psoriasis and 2,500 controls found a higher rate of ischemic heart disease, cerebrovascular disease and peripheral vascular disease in patients with the skin disease.22

The evaluation of a patient’s cardiovascular health before and after systemic treatments has not been well studied. One retrospective cohort study found patients treated with methotrexate for psoriasis or RA had a decreased risk of cardiovascular disease. Lower doses of methotrexate as well as concomitant use of folic acid led to a further reduction in cardiovascular disease.27 One study showed cardiovascular events are decreased in patients with rheumatoid arthritis who are treated with anti-TNF-α therapy.28 A recent review of randomized controlled trials found that patients with psoriasis treated with anti-TNF-α therapy had a lower incidence of cardiovascular events compared to psoriasis patients treated with placebo (1 out of 3,858 patients compared to 1 out of 1,812 patients, respectively).29 More prospective studies are needed to evaluate the potential long-term effect of systemic therapies for psoriasis on cardiovascular disease.

Metabolic Syndrome

Several studies demonstrate a link between psoriasis and metabolic syndrome.30,31 In 1999, the World Health Organization characterized “metabolic syndrome” as a combination of obesity, dyslipidemia, glucose intolerance and elevated blood pressure.32 According to the new International Diabetes Federation definition, a person must have the following characteristics to have the diagnosis of metabolic syndrome: Central obesity (defined by a certain waist circumference specific to ethnicity) as well as any two of the following five criteria: elevated triglyceride level; low HDL cholesterol level; elevated blood pressure; elevated fasting plasma glucose; or previous diagnosis of type 2 diabetes.33

Central obesity is considered a predisposing risk factor for metabolic syndrome, with the increased intra-abdominal fat acting as an “endocrine organ” leading to increased levels of adipocytokines and insulin resistance.34,35 Some of the more common cytokines produced in adipose tissue include adiponectin, leptin, Il-6 and TNF-α.36 A negative association between obesity and serum adiponectin has been found.37 Studies have also shown that the production of adiponectin is decreased by other adipocytokines like TNF-α and IL-6.38

Several studies provide evidence that psoriasis is linked to obesity.39-41 In one study, the Psoriasis Area and Severity Index (PASI) score had a positive correlation with the Body Mass Index of patients.42 Patients with psoriasis are also more likely to be overweight or obese.43 In a case control study of 560 patients, obesity was determined to be a predisposing factor for the development of psoriasis.44 Obesity also has a negative impact on the efficacy of systemic treatments for psoriasis.45

Studies have shown that adiponectin levels are decreased in patients with psoriasis compared to controls46,47 and negatively correlated with the PASI score.46 Treatment with anti-TNF-α therapy as well as phototherapy has led to increased levels of adiponectin.48

Due to its strong association with obesity, some characterize non-alcoholic fatty liver disease (NAFLD) as metabolic syndrome of the liver. NAFLD can present as mild to severe steatosis with inflammation and fibrosis.49 In one study, 138 patients with psoriasis and 260 matched controls were enrolled, with abdominal ultrasound used to diagnosis NAFLD. NAFLD was found to affect 47% of patients with psoriasis compared to 28% of controls. Patients with psoriasis who had been diagnosed with NAFLD were also more likely to have metabolic syndrome, increased serum C-reactive protein and more severe psoriasis.50

Psychiatric Disorders

Depression is a common comorbidity associated with psoriasis, with approximately 15% of psoriatic patients reporting the disease.51 Patients with a more severe form of depression have also been found to have a higher percentage of body surface area affected by psoriasis.52 Patients with psoriasis also have a higher rate of suicidal ideations.53 One study found patients with moderate-to severe psoriasis not only had a higher rate of depression compared to the control group, but an increased prevalence of anxiety, bipolar disorder and delirium as well.54 Future studies are needed to evaluate the effect biologic therapies have on co-existing psychiatric disorders.

Inflammatory Bowel Disease

Crohn’s disease and ulcerative colitis are common chronic inflammatory diseases of the gastrointestinal system. The pathogenesis of these two conditions, which together comprise inflammatory bowel disease (IBD), is still not clearly defined.55 However, anti-TNF-α therapy points to a similar immunologic pathogenesis.10 In a Canadian review of more than 8,072 cases of IBD, patients with either Crohn’s disease or ulcerative colitis were found to have a higher rate of psoriasis compared to controls.56 Although the risk of developing ulcerative colitis increases with psoriasis, it is not as robust as the risk for Crohn’s disease,10 which is approximately seven times more common in patients with psoriasis compared to healthy individuals.57 Both forms of IBD and psoriasis share the same genetic susceptibility locus 6p21, which includes the IBD3 locus for Crohn’s disease and ulcerative colitis and the PSORS1 locus for psoriasis.58,59

Lymphoma

The dysregulation of the immune system in psoriasis has been postulated as a predisposing factor for lymphoma. Studies examining this possibility both support and refute the claim.60,61 One study enrolled 153,197 patients with psoriasis and 765,950 controls and showed an increased rate of lymphoma, specifically Hodgkin’s lymphoma and cutaneous T-cell lymphoma, in patients with psoriasis.62  

Ocular Disease

There are a variety of eye complications associated with psoriasis. Unfortunately, such ocular issues are often neglected in clinical practice and in the scientific literature.63 Eye disease in patients with psoriasis occur more often in males and typically after the appearance of skin lesions.64 Blepharitis involves chronic inflammation of the eyelids and is one of the more common eye problems associated with psoriasis.65 Another common ocular finding is anterior uveitis, which has been reported to occur in 7% to 20% of patients with psoriasis.66 There are currently no guidelines for eye examinations for patients with psoriasis, but yearly ophthalmic evaluations would likely benefit patients with severe disease.63

Conclusion

For many years, psoriasis was viewed solely as a skin condition that primarily affected a person’s quality of life.10 Now, there is growing evidence about the different systemic manifestations associated with psoriasis, which collectively causes not only an increase in morbidity but also mortality.8,67 In one cohort study, 3,603 patients with severe psoriasis were compared to 14,330 patients with no history of the skin disease. Mortality in patients with severe psoriasis was increased and included deaths from cardiovascular disease, malignancies, chronic respiratory disease, diabetes, dementia, infection and kidney disease.68 There is some evidence that systemic treatments for psoriasis, such as anti-TNF-alpha therapy, improve comorbidities, specifically cardiovascular disease. There is also evidence in the literature that systemic treatments like methotrexate and cyclosporine lead to an increased occurrence of malignancies. Overall, there is not enough clinical data evaluating the effects of biological treatments on the various comorbidities of psoriasis.29 Patients should be educated about the health-related conditions associated with psoriasis in order to improve overall quality of life and reduce healthcare costs.9

Dr. Haddican is with the Department of Dermatology at Mount Sinai School of Medicine in New York, NY.

Dr. Goldenberg is Assistant Professor of Dermatology and Pathology and Medical Director of the Dermatology Faculty Practice at Mount Sinai School of Medicine in New York, NY.

Disclosure: Dr. Haddican has no conflicts to disclose. Dr. Goldenberg is a speaker for Abbott Laboratories and Leo Pharma and an investigator for GSK and Leo Pharma.