Comorbid disease in psoriasis

INTRODUCTION — Although psoriasis is classically associated with the development of inflammatory plaques on the skin, increasing evidence supports the recognition of psoriasis as a multisystem chronic inflammatory disorder with multiple associated comorbidities. Examples of extracutaneous disorders that have been linked to psoriasis include:

●Psoriatic arthritis

●Obesity

●Metabolic syndrome

●Cardiovascular, cerebrovascular, and peripheral vascular disease

●Malignancy

●Autoimmune diseases

●Chronic kidney disease

●Nonalcoholic fatty liver disease

●Cardiac arrhythmia

●Chronic obstructive pulmonary disease

●Obstructive sleep apnea

●Bone disease

●Parkinsonism

●Psychosocial effects

●Psychiatric disorders

●Alcohol abuse

●Smoking

●Migraine

The relationship between psoriasis and other disease states will be reviewed here. The pathogenesis, diagnosis, and treatment of psoriasis are discussed separately. (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis" and "Guttate psoriasis" and "Treatment of psoriasis in adults".)

PSORIATIC ARTHRITIS — Psoriatic arthritis is an inflammatory seronegative spondyloarthropathy that occurs in association with psoriasis. Estimates of the proportion of patients with psoriasis who develop psoriatic arthritis range from 7 to 42 percent [1].

Psoriatic arthritis is characterized by stiffness, pain, swelling, and tenderness of the joints and their surrounding ligaments and tendons (dactylitis and enthesitis). The course of psoriatic arthritis is variable and unpredictable ranging from mild and nondestructive joint involvement to a severe, debilitating, erosive arthropathy.

In the majority of patients, cutaneous manifestations of psoriasis precede joint disease [2]. The severity of the skin disease usually does not correlate with the severity of arthritis. Psoriatic arthritis is discussed in greater detail separately. (See "Clinical manifestations and diagnosis of psoriatic arthritis" and "Psoriatic juvenile idiopathic arthritis: Pathogenesis, clinical manifestations, and diagnosis".)

OBESITY — Multiple studies have demonstrated an increased prevalence of obesity among patients with psoriasis [3-8]. Obesity is typically defined as a body mass index (BMI) ≥30 kg/m². (See "Obesity in adults: Prevalence, screening, and evaluation", section on 'Body mass index'.)

Evidence — The findings of a systematic review and meta-analysis of observational studies published between 1980 and 2012 support an increased prevalence of obesity in patients with psoriasis [8]. The pooled odds ratio [OR] for obesity for patients with psoriasis compared with a control group without psoriasis was 1.66 (95% CI 1.46-1.89). Additional support for a link between psoriasis and obesity stems from a review of more than 10,000 patients with moderate to severe psoriasis enrolled in clinical trials of biologic therapies [4]. The average BMI for patients in the trials reviewed was 30.6 kg/m².

Studies have also identified a correlation between obesity and the severity of psoriasis [3,5,9]. In the systematic review and meta-analysis described above, the risk for obesity was more pronounced in patients with severe psoriasis (pooled OR 2.23, 95% CI 1.63-3.05) than patients with mild psoriasis (pooled OR 1.46, 95% CI 1.17-1.82) [8]. In particular, a study of 4065 individuals with psoriasis and 40,650 controls that was included in the meta-analysis illustrated a progressive relationship between disease severity and obesity. Among patients with mild (≤2 percent body surface area [BSA]), moderate (3 to 10 percent BSA), and severe psoriasis (>10 percent BSA), the prevalence of obesity compared with controls increased by 14, 34, and 66 percent, respectively [9].

Children are not exempt from the increased risk for obesity observed in the setting of psoriasis. In an international cross-sectional study of 409 children with psoriasis, children with psoriasis were significantly more likely to be obese (BMI ≥95^th percentile) than controls (OR 4.29, 95% CI 1.96-9.39) [10]. Similar to the general population of patients with psoriasis, a correlation between disease severity and obesity was observed. Children with severe psoriasis had a greater increase in risk for obesity than children with mild disease (OR 4.92, 95% CI 2.20-10.99 versus 3.60, 95% CI 1.56-8.30).

Additional study is necessary to confirm findings of a systematic review and network meta-analysis that suggest an association between treatment with tumor necrosis factor (TNF) inhibitors and weight gain in patients with psoriasis [11].

Rationale — More than one factor may contribute to the association between obesity and psoriasis. Although the negative psychosocial impact of psoriasis was initially considered the sole reason for excess weight in patients with psoriasis [3], newer data suggest that obesity may increase risk for this disease. As an example, increased adiposity and weight gain were identified as strong risk factors for psoriasis in an analysis of data collected from almost 80,000 women in the Nurses' Health Study II [12]. Compared with women with a BMI of 21.0 to 22.9 kg/m² at age 18, the multivariate relative risk for the development of psoriasis for subjects with a BMI ≥30 kg/m² at the same age was 1.73 (95% CI, 1.24-2.41), and only 0.76 (95% CI, 0.65-0.90) for women with a BMI <21 kg/m². In addition, a retrospective study of 27 children with psoriasis and a BMI ≥85^th percentile found that 93 percent were overweight or obese prior to the onset of psoriasis [13].

A pathophysiologic explanation for the link between obesity and psoriasis has not been definitively established. Growing evidence supports the designation of psoriasis as a systemic inflammatory disease [14], and the status of obesity as a proinflammatory state may be a relevant factor. TNF-alpha, a major proinflammatory cytokine involved in the pathogenesis of psoriasis [15], is found at increased levels in obesity and is produced by adipose tissue [16]. Additional cytokines and bioactive products produced by adipose tissue (also known as adipokines or adipocytokines), such as interleukin (IL) 6, leptin, resistin, adiponectin, and others [17] might also stimulate psoriasis.

Implications — Data on the effects of weight loss on disease severity in psoriasis are limited. The first randomized trial designed to explore the effect of weight loss on the severity of psoriasis (n = 60) found a statistically nonsignificant trend towards greater improvement in psoriasis (as assessed by Psoriasis Area Severity Index [PASI] score) in patients with a BMI >27 kg/m² who were placed on a low-energy diet compared with a similar group of patients who continued to eat ordinary healthy foods [18]. The median baseline PASI score for all patients (5.4) correlated with mild to moderate psoriasis, and during the 16-week trial, patients allocated to the low-energy diet lost a mean of 15.8 kg compared with a mean loss of 0.4 kg in the control group. By study end, PASI scores were reduced by a mean of 2.3 in the low-energy diet group compared with only 0.3 in the control group. In addition, improvement in the Dermatology Quality of Life Index (a secondary outcome measure aimed at assessing the change in the impact of psoriasis on patient quality of life) was significantly greater in the low-energy diet group.

Improvement in psoriasis following gastric bypass surgery has been documented in case reports and a retrospective study [16,19-21]. The mechanism of this is unclear, but may be related to alterations in the production of proinflammatory and antiinflammatory adipokines, increased production of glucagon-like peptide-1 (GLP-1, a gut-derived hormone), or weight-loss related changes in cutaneous microflora that result in the elimination of an antigenic stimulant [16,22]. However, worsening of psoriasis has also been reported to occur after weight loss and weight loss surgery [23-25]. Further study is necessary to explore the effect of weight loss on psoriasis.

Obesity may impact the efficacy of some psoriasis treatments [26]. A cohort study of approximately 2400 patients receiving systemic therapy for psoriasis (including conventional and biologic agents) found that, compared with patients with a BMI of 20 to 24 kg/m², patients with a BMI ≥30 kg/m² were less likely to achieve 75 percent improvement in disease severity (odds ratio 0.62, 95% CI 0.49-0.79 at 16 weeks) regardless of the type of therapy [27]. In addition, in a randomized trial of 61 patients who were obese and had moderate to severe psoriasis, weight loss improved the response to cyclosporine (2.5 mg/kg per day) [28]. The weight-based dosing regimen for ustekinumab, a newer treatment option for psoriasis, is used to mitigate the reduction in drug efficacy observed when the standard dose is utilized in patients with obesity [26].

METABOLIC SYNDROME — Metabolic syndrome is a constellation of risk factors associated with increased risk for type 2 diabetes mellitus and cardiovascular disease. The criteria used to identify this syndrome vary. One of the most widely used definitions of the metabolic syndrome is derived from the National Cholesterol Education Adult Treatment Panel (NCEP ATP III). According to a 2005 update of the NCEP ATP III criteria, the presence of three or more of the following elements constitutes a diagnosis of metabolic syndrome [29]:

●Elevated waist circumference (men ≥102 cm, women ≥88 cm)

●Elevated blood pressure (≥130 mm Hg systolic or ≥85 mm Hg diastolic) or receiving drug treatment for elevated blood pressure

●Elevated fasting glucose (≥100 mg/dL) or receiving drug treatment for elevated blood glucose

●Elevated triglycerides (≥150 mg/dL) or receiving drug treatment for elevated triglycerides

●Reduced high density lipoprotein levels (<40 mg/dL in men and <50 mg/dL in women or individuals receiving drug treatment for low HDL cholesterol).

The metabolic syndrome is reviewed in greater detail separately. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)".)

Evidence — Multiple epidemiologic studies support an association between psoriasis and the metabolic syndrome or components of the metabolic syndrome [5,12,30-40]. A systematic review and meta-analysis of 14 observational studies that evaluated the association between psoriasis and metabolic syndrome in adults found that patients with psoriasis were more likely to have metabolic syndrome than individuals in the general population (odds ratio 1.42, 95% CI 1.28-1.65) [39].

Children may also be affected by the relationship between psoriasis and metabolic syndrome. Observational studies have found increased rates of components of the metabolic syndrome (hyperlipidemia, hypertension, and diabetes) in children with psoriasis [41,42].

Not all studies have supported an association between psoriasis and metabolic syndrome. A Korean study of 490 patients with psoriasis and 682 controls that was not included in the meta-analysis failed to find a statistically significant difference in the prevalence of metabolic syndrome between the two groups [43].

Rationale — In theory, both psoriasis and obesity may contribute to metabolic syndrome via the effects of proinflammatory cytokines and adipokines associated with these disorders on glucose regulation, lipid status, and endothelial function [17]. However, an exact mechanism for the interaction between psoriasis and metabolic syndrome remains uncertain.

Implications — Metabolic syndrome is well accepted as a risk factor for the development of type 2 diabetes and cardiovascular disease [29]. Thus, psoriasis may serve as a marker for increased risk for the morbidity and mortality associated with these diseases.

The effect of treatment of the metabolic syndrome on psoriasis is uncertain. The findings in a series of three patients with mild plaque-type psoriasis suggest a possible benefit [44]. In these patients, psoriasis improved by at least 50 percent following the institution of interventions to treat the metabolic syndrome, such as dietary changes, pharmacotherapy for hyperlipidemia and hyperglycemia, and weight loss. In addition, beneficial effects of psoriasis treatment on HDL composition and function were observed in a small uncontrolled study [45].

HYPERTENSION AND DIABETES — In addition to a relationship between psoriasis and elevated blood glucose and blood pressure in the context of metabolic syndrome as reviewed above, observational studies have detected independent relationships between psoriasis and hypertension and diabetes [5,31,46-49].

Evidence — An association between hypertension and psoriasis is supported by a systematic review and meta-analysis of 24 observational studies that found that hypertension was more prevalent in patients with psoriasis than in control populations (odds ratio [OR] 1.58, 95% CI 1.42-1.76) [50]. A systematic review and meta-analysis that evaluated observational study data on the risk for diabetes also found an elevated prevalence of diabetes in the psoriasis population (OR 1.59, 95% CI 1.38-1.83) [51]. A trend towards a stronger association between severe psoriasis and hypertension or diabetes than between mild psoriasis and hypertension or diabetes was observed in these studies.

Examples of individual studies that support a relationship between psoriasis and these diseases include:

●A Danish cross-sectional, population-based twin study that included over 33,000 twins found a significant association between psoriasis and type 2 diabetes (OR 1.53, 95% CI 1.03-2.27) and between psoriasis and increasing body mass index (OR 1.81, 95% CI 1.28-2.55 in individuals with a body mass index ≥35) [37].

●In a prospective cohort study of approximately 78,000 women in the Nurses' Health Study II (among which 1813 reported a diagnosis of psoriasis), women with psoriasis were more likely to develop diabetes or hypertension than women without psoriasis (multivariate relative risks 1.63, 95% CI 1.25-2.12 and 1.17, 95% CI 1.06-1.30, respectively) [31].

●A population-based cohort study of approximately 108,000 adults with psoriasis and 431,000 adults without psoriasis in the United Kingdom found that psoriasis was an independent risk factor for type 2 diabetes [47]. The study also found that patients with severe psoriasis and diabetes were more likely than controls with diabetes to receive systemic diabetic therapy (particularly oral hypoglycemic agents). The reason for this latter observation remains to be determined.

●A case-control study of 835 patients with both psoriasis and hypertension and 2418 matched controls with hypertension found that patients with psoriasis were more likely to require intensive treatment for hypertension than controls [46]. As an example, psoriasis patients were 16.5 times more likely than controls to require treatment with three antihypertensive agents (95% CI, 11.01-24.84). In addition, a separate population-based study of 1322 patients with psoriasis and 11,997 matched controls found a positive dose-response relationship between uncontrolled hypertension and psoriasis severity [52].

Rationale — The pathophysiologic mechanisms for the relationship between psoriasis and diabetes and psoriasis and hypertension are unclear. As postulated for metabolic syndrome, the chronic inflammatory state in psoriasis may be a significant contributing factor. Additional theories on the relationship between psoriasis and hypertension include effects related to angiotensin II production in visceral fat as well as the impact that increased reactive oxygen species and increased serum endothelin-1 may have on endothelial function in patients with psoriasis [46,53].

Implications — The consequences of hypertension and diabetes are reviewed in detail separately. (See "Overview of hypertension in adults", section on 'Complications of hypertension' and "Cardiovascular risks of hypertension" and "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Diabetes-related complications'.)

Psoriasis may be a marker of a modest increase in risk for vascular complications of diabetes. A retrospective cohort study of 6164 diabetics with psoriasis and 6164 matched diabetics without psoriasis found that diabetics with psoriasis were slightly more likely to develop microvascular complications (hazard ratio [HR] 1.14, 95% CI 1.06-1.23) and macrovascular complications (HR 1.13, 95% CI 1.05-1.22) of diabetes than diabetics without psoriasis [54]. Additional study is necessary to confirm these findings.

ATHEROSCLEROTIC DISEASE — Psoriasis is associated with increased risk for the development of atherosclerotic vascular disease including cardiovascular, cerebrovascular, and peripheral vascular disease.

Evidence — Most data on atherosclerosis in patients with psoriasis focus on cardiac disease. Several studies, including studies from North America, Europe, and China have detected an elevated risk for myocardial infarction (MI) in this population [7,55-58].

The seminal study that identified psoriasis as an independent risk factor for MI was a retrospective cohort study of more than 130,000 adults with psoriasis and over 550,000 controls in the United Kingdom [55]. The incidence of MI per 1000 person-years was 3.58 (95% CI 3.52-3.65) for control patients, 4.04 (95% CI 3.88-4.21) for patients with mild psoriasis (defined as not requiring systemic therapy), and 5.13 (95% CI 4.22-6.17) for patients with severe psoriasis (defined as requiring systemic therapy). The increase in risk for MI detected in patients with psoriasis remained even after adjusting for major cardiovascular risk factors, such as age, sex, smoking, prior MI, diabetes, hypertension, hyperlipidemia, and BMI. Younger patients exhibited the greatest increase in risk. For example, for a 30-year-old patient with mild or severe psoriasis, the adjusted relative risks (RR) for MI were 1.29 (95% CI 1.14-1.46) and 3.10 (95% CI 1.98-4.86), respectively. In contrast, for a 60-year old patient with mild or severe psoriasis, the respective adjusted RR assessments were 1.08 (95% CI 1.03-1.13) and 1.36 (95% CI 1.13-1.64).

In addition to cardiac disease, other manifestations of atherosclerotic disease, including stroke and peripheral vascular disease, occur at increased frequency in patients with psoriasis [56,58-62]. A meta-analysis of seven cohort studies that combined data on MI and stroke found an increased risk for these events in patients with psoriasis [59]. Examples of individual studies that support an increased risk for non-MI atherosclerotic events include:

●A population-based cohort study utilizing patient records from the United Kingdom found an increase in strokes among patients with severe psoriasis (defined as psoriasis treated with systemic therapy) and a very modest increase in strokes in patients with mild psoriasis (defined as psoriasis not requiring systemic therapy) [60]. The hazard ratios (HR) were 1.43 (95% CI 1.1-1.9) and 1.06 (95% CI 1.0-1.1), respectively.

●A United States study of 3236 patients with psoriasis and 2500 controls found an increased prevalence of ischemic vascular disease (odds ratio [OR] 1.78, 95% CI 1.51-2.11), cerebrovascular disease (OR 1.70, 95% CI 1.33-2.17), and peripheral vascular disease (OR 1.98, 95% CI 1.32-2.82) among patients with psoriasis [61]. Psoriasis was also a marker of increased risk for mortality (OR 1.86, 95% CI 1.56-2.21).

●A retrospective analysis of data from approximately 1600 patients with moderate to severe psoriasis who were enrolled in therapeutic trials found a 28 percent increase in risk for coronary heart disease and a 12 percent increase in risk for stroke among patients with psoriasis compared with the general population [56].

Of note, some authors have challenged the designation of psoriasis as a risk factor for cardiovascular disease [63-65]. In a Dutch cohort study of approximately 15,800 patients with psoriasis and 27,600 controls, the difference in risk for hospitalization due to ischemic heart disease was not statistically significant (1.10, 95% CI 0.99-1.23) [64].

An association between cardiovascular disease and psoriasis is detected most consistently among patients with severe psoriasis. A 2013 systematic review and meta-analysis in which classification as severe psoriasis was based upon surrogate markers (eg, requirement for systemic treatment or hospital admission) found support for an increased risk for MI, cardiovascular mortality, and stroke among patients with severe psoriasis [58]. In contrast to severe psoriasis, studies evaluating the relationship between milder psoriasis and cardiovascular disease have yielded less consistent findings [58,66]. Longer duration of disease may be an additional risk factor for adverse cardiovascular events [67].

Rationale — The rationale for a correlation between psoriasis and atherosclerotic disease is not well understood. Although the increased prevalence of risk factors for cardiovascular disease (obesity, hypertension, diabetes, hyperlipidemia, metabolic syndrome, and cigarette smoking) in the psoriatic population likely contributes to the elevated risk for atherosclerosis, the role of chronic inflammation in the pathogenesis of both disorders may also be a key factor [68].

Implications — Atherosclerotic disease is a major cause of morbidity and mortality, and psoriasis may portend an increased risk for death due to cardiovascular disease [58,69]. In a systematic review and meta-analysis that pooled the results of four studies, all-cause cardiovascular mortality was significantly greater in patients with severe psoriasis than in the general population (standardized mortality ratio 1.37 95% 1.17-1.60) [58]. A fifth study that reported a hazard ratio from multivariate analysis offered additional support; the cohort study of approximately 3600 patients in the United Kingdom with severe psoriasis (defined as psoriasis treated with systemic therapy) and 14,330 control patients without a history of psoriasis, found that patients with severe psoriasis were more likely than controls to die from cardiac or cerebrovascular disease (HR 1.57, 95% CI 1.26-1.96) [69].

Data are limited on the effects of systemic therapies for psoriasis on the risk for cardiovascular disease in individuals with psoriasis [70]. Treatment with methotrexate may be of benefit [71,72]. In a retrospective cohort study, treatment of psoriasis with methotrexate was associated with a reduced risk for cardiovascular disease, cerebrovascular disease, and atherosclerosis [71]. However, a separate retrospective study did not find a significant difference in rates of ischemic heart disease hospitalizations in patients taking methotrexate versus patients taking other nonbiologic antipsoriatic drugs [73].

Treatment with tumor necrosis factor (TNF)-alpha inhibitors also may reduce the risk of cardiovascular events [70,74]. A reduction in the risk for MI was detected in a retrospective study (n = 8845) that compared the rate of MI in patients who had received at least two consecutive months of treatment with a TNF-alpha inhibitor, patients who were treated with either oral agents or phototherapy, and patients who were treated with only topical therapy [75]. After adjustments for risk factors for MI, patients who had been treated with a TNF-alpha inhibitor were significantly less likely to have an MI than patients treated with topical therapy (HR 0.50, 95% CI 0.32-0.79). A reduction in risk for MI was also seen among patients who received oral therapy (including cyclosporine, acitretin, and methotrexate) or phototherapy when they were compared with the topical therapy group (HR 0.54, 95% 0.38-0.77).

Moreover, a retrospective cohort study of 2400 patients with severe psoriasis found that patients who had received treatment with a biologic agent or methotrexate had a reduced risk for cardiovascular events compared with patients who received other treatment [76]. When compared with patients treated with other therapies, the age and sex adjusted hazard ratio for death, myocardial infarction, and stroke was 0.28 (95% CI 0.12-0.64) for patients treated with a biologic agent and 0.65 (95% CI 0.42-1.00) for patients treated with methotrexate. More than 80 percent of patients treated with a biologic agent in this study received a TNF-alpha inhibitor.

Additional support for a beneficial effect of TNF-alpha inhibitors on cardiovascular risk stems from studies in rheumatoid arthritis that have demonstrated reduced rates of serious adverse cardiovascular events among patients treated with TNF-alpha inhibitors [77,78]. In addition, reduced levels of C-reactive protein (a marker for inflammation and risk for cardiovascular disease) have been detected in patients with psoriasis during etanercept therapy [79]. Further study is necessary to confirm the impact of anti-TNF therapies on cardiovascular disease in patients with psoriasis.

Concern regarding a risk for cardiovascular disease in patients treated with ustekinumab, an IL-12/23 inhibitor used for the treatment of psoriasis, led to a meta-analysis of controlled trials that did not find a statistically significant increase in risk for major adverse cardiac events among ustekinumab-treated patients [80]. In addition, a review of pooled data from four phase 2 and phase 3 randomized trials with up to five years of follow-up did not find an increased risk for major adverse cardiovascular events in patients treated with ustekinumab for psoriasis [81]. Ustekinumab and cardiovascular risk is discussed in greater detail separately. (See "Treatment of psoriasis in adults", section on 'Ustekinumab'.)

Radiologic support for a benefit of biologic therapy on coronary artery disease stems from a prospective, observer-blinded study that used coronary computed tomography (CT) to assess coronary artery disease progression in patients with moderate to severe psoriasis [82]. In the study, 28 patients treated with biologic agents (adalimumab, etanercept, infliximab, and/or ustekinumab) and 28 controls treated only with topical therapy underwent coronary artery calcium (CAC) CT and contrast-enhanced coronary CT angiography at baseline and after approximately one year. Compared with patients treated with biologic agents, patients in the control group exhibited increased progression of CAC. In addition, progression of luminal narrowing in diseased segments occurred in the control group but not in the treatment group.

Benefit of TNF-alpha inhibitors was also detected in a prospective cohort study of 319 patients with psoriasis or psoriatic arthritis in whom carotid total plaque area was assessed with ultrasound at baseline and after two to three years [83]. This study found an association between receipt of TNF-alpha inhibitor therapy and reduced progression of carotid plaques in men. A similar effect was not found in women. A second phase of the study that used fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) to assess aortic vascular inflammation in psoriatic arthritis patients receiving a TNF-alpha inhibitor (n = 21) and psoriatic arthritis patients not receiving a biologic agent (n = 13) found improvement in signs of vascular inflammation only in the TNF-alpha inhibitor group.

MALIGNANCY — Multiple studies have found an increased risk for malignancy in patients with psoriasis [84-92]. A systematic review and meta-analysis of cohort and case-control studies that assessed cancer incidence or mortality in patients with and without psoriasis supports increased risk for cancer and death from cancer among individuals with psoriasis [93]. Increased risk for cancer was found both among patients with severe psoriasis (1.22, 95% CI 1.08-1.39 based upon analysis of nine studies) and psoriasis of any severity (1.18, 95% CI 1.06-1.31 based upon analysis of seven studies). Specific types of cancer that exhibited increased risk for development among patients with psoriasis (any severity) included oral cavity cancer, squamous cell carcinoma, esophageal cancer, liver cancer, laryngeal cancer, keratinocyte cancer, kidney cancer, pancreatic cancer, lymphoma, colorectal cancer, non-Hodgkin lymphoma, and colon cancer. In addition, mortality from cancer was greater among individuals with psoriasis than individuals without psoriasis, with a relative risk of 1.18 (95% CI 1.06-1.31) for any psoriasis severity and 1.22 (95% CI 1.08-1.39) for severe psoriasis. High heterogeneity among studies and dependence on surrogate markers to classify psoriasis severity were some of the limitations of this study.

Rationale — Multiple factors may contribute to an increased rate of malignancy in patients with psoriasis, including the effects of immunosuppressive or immunomodulatory therapies and the presence of a chronic inflammatory state [94]. In patients with cutaneous T cell lymphoma, misdiagnosis of early stages of this disorder as psoriasis may be an additional factor.

Cutaneous malignancy — Knowledge of the carcinogenic effects of ultraviolet light led to inquiries regarding the risk for cutaneous malignancy after phototherapy for psoriasis. With the exception of psoralen plus ultraviolet A (PUVA) treatments, which have been linked to increased risk for skin cancer (particularly cutaneous squamous cell carcinoma) [95-97], a definitive relationship between phototherapy and skin cancer has not been established. (See "Treatment of psoriasis in adults", section on 'Ultraviolet light' and "Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on 'Skin cancer'.)

Increased rates of nonmelanoma skin cancer have been detected among patients with rheumatoid arthritis treated with biologic drugs (primarily anti-TNF drugs) [98], raising concern over whether a similar risk exists in patients with psoriasis treated with these agents. However, a meta-analysis of 20 randomized placebo-controlled trials that included more than 6800 psoriatic patients treated with TNF antagonists failed to show an increased risk for any type of cancer [99].

AUTOIMMUNE DISEASES — Compared with the general population, autoimmune disease may be more likely to occur in individuals with psoriasis. In a retrospective cohort study that included approximately 23,000 patients with psoriasis, an increased risk for multiple autoimmune diseases was detected, with the greatest risk increase observed for alopecia areata (odds ratio 2.2, 95% CI 2.0-3.0), followed by celiac disease, systemic sclerosis, Crohn's disease, vitiligo, and other disorders [100].

An association with Crohn's disease was also illustrated in a study in which 13 of 136 patients with Crohn's disease (10 percent) and only 3 of 136 controls (2 percent) had psoriasis [101]. Moreover, the patients with Crohn's disease were more likely to have a first degree relative with psoriasis (10 versus 3 percent). The shared location of susceptibility loci for these disorders on chromosome 16q may be a relevant factor in the relationship between these diseases [101,102]. In addition to Crohn's disease, ulcerative colitis has been detected at increased frequency in patients with psoriasis [103,104]. A relationship between multiple sclerosis and psoriasis is uncertain [100,105,106].

CHRONIC KIDNEY DISEASE — Patients with psoriasis may have an increased risk for chronic kidney disease. The first population-based cohort study to compare the risk of moderate to advanced chronic kidney disease in adults with and without psoriasis found an elevated risk for chronic kidney disease in patients with severe psoriasis [107]. Patients in this United Kingdom study were classified as having severe psoriasis if records revealed a history of treatments typically prescribed for patients with severe disease; the remaining patients were classified as having mild disease. After adjustment for sex, age, cardiovascular disease, diabetes, hypertension, hyperlipidemia, use of nonsteroidal antiinflammatory drugs, and body mass index, psoriasis was an independent risk factor for moderate to advanced chronic kidney disease among patients with severe psoriasis (adjusted hazard ratio [HR] 1.93, 95% CI 1.79-2.08). In contrast, a statistically significant difference in risk was not evident in the mild psoriasis population (adjusted HR 0.99, 95% CI 0.97-1.02). Age appeared to influence the change in risk for chronic kidney disease; the relative risk for chronic kidney disease was greater among younger individuals than older individuals when compared with individuals without psoriasis in the respective age groups.

Although other studies utilizing different criteria to assess for kidney disease support an association between psoriasis and kidney disease [69,108], not all studies have reached this conclusion [109,110]. As an example, a retrospective study of 753 patients with psoriasis from an academic medical center did not find an increased risk for renal failure in patients with psoriasis [109].

NONALCOHOLIC FATTY LIVER DISEASE — Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of conditions ranging from fatty liver, which is relatively benign, to nonalcoholic steatohepatitis, which may lead to fibrosis, cirrhosis, and rarely hepatocellular carcinoma. NAFLD is frequently associated with the metabolic syndrome. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults" and "Management of nonalcoholic fatty liver disease in adults", section on 'Disease course'.)

An increased risk for liver disease, particularly NAFLD and cirrhosis, has been detected in patients with psoriasis [111-114]. A cohort study of patients with psoriasis, psoriatic arthritis, or rheumatoid arthritis that included approximately 197,000 patients with psoriasis and approximately 12,000 patients with psoriatic arthritis and their matched controls found elevated risk for liver disease in both of these populations [113]. The occurrence of NAFLD was greatest among patients with psoriasis or psoriatic arthritis who were prescribed systemic therapy. In an Italian study of 130 patients with chronic plaque psoriasis and 260 matched controls, NAFLD was more common among the patients with psoriasis (47 versus 28 percent) [111]. In addition, the severity of psoriasis was greater among patients with both psoriasis and NAFLD than among patients with psoriasis alone.

Psoriasis may also be associated with greater severity of NAFLD. A study in which NAFLD was detected in 59 percent of 142 patients with psoriasis found that patients with psoriasis and NAFLD were more likely to have severe liver fibrosis than patients with NAFLD who did not have psoriasis [112].

The association of psoriasis with liver disease may be important from a therapeutic standpoint, since treatment of psoriasis may involve the use of hepatotoxic drugs, such as methotrexate [115]. Compared with patients with rheumatoid arthritis, liver toxicity due to methotrexate therapy occurs more frequently in patients with psoriasis [116].

CARDIAC ARRHYTHMIA — Patients with psoriasis may have increased risk for cardiac arrhythmias, a factor that may contribute to increased risk for cardiovascular morbidity and mortality among psoriasis patients. In a population-based cohort study based upon data from the Taiwan National Health Insurance Research Database, the incidences of arrhythmias were 15.41 per 1000 person-years among patients with psoriasis and 11.06 per 1000 person-years among patients without psoriasis (adjusted hazard ratio [HR] 1.34, 95% CI 1.29-1.39) [117]. Slightly greater risk for arrhythmia was detected among psoriasis patients with psoriatic arthritis (adjusted HR 1.46, 95% CI 1.22-1.74) than among psoriasis patients without psoriatic arthritis (adjusted HR 1.33, 95% CI 1.28-1.39). Chronic inflammation in psoriasis is postulated to contribute to an increased risk for arrhythmia; however, a mechanism for this observation remains to be confirmed.

CHRONIC OBSTRUCTIVE PULMONARY DISEASE — Increased rates of chronic obstructive pulmonary disease (COPD) have been detected in patients with psoriasis. In an Israeli case-control study of 12,500 adults with psoriasis and approximately 24,000 controls, COPD was slightly more prevalent among patients with psoriasis (6 versus 4 percent; adjusted odds ratio 1.27, 95% CI 1.13-1.42) [118]. A smaller population-based study in Taiwan also found an increased risk for COPD in patients with psoriasis [119]. Similar to psoriasis, chronic inflammation is involved in the pathogenesis of COPD [120].

OBSTRUCTIVE SLEEP APNEA — Obstructive sleep apnea (OSA) is an increasingly prevalent disorder that may occur in association with psoriasis [121-124]. Further work is needed to clarify the relationship between psoriasis and obstructive sleep apnea.

BONE DISEASE — A study of patient data obtained from 2006 to 2012 in the Nationwide Emergency Department Sample in the United States found that patients with a diagnosis of psoriasis were more likely to have a diagnosis of osteopenia, osteoporosis, osteomalacia, ankylosing spondylitis, and pathologic fractures than patients without psoriasis [125]. Additional study is necessary to confirm these findings.

PARKINSONISM — Parkinsonism is a neurologic syndrome characterized by tremor, bradykinesia, rigidity, and postural instability [126]. A retrospective study of data from a health insurance database in Taiwan found a higher risk for parkinsonism among 4885 patients with psoriasis than among 24,425 controls (adjusted hazard ratio 1.74, 95% CI 1.35-2.20). Whether chronic inflammation in psoriasis can contribute to neurologic damage resulting in the development of parkinsonism is unclear. Additional studies are necessary to explore the relationship between psoriasis and parkinsonism. (See "Epidemiology, pathogenesis, and genetics of Parkinson disease" and "Clinical manifestations of Parkinson disease".)

PSYCHOSOCIAL EFFECTS — Psoriasis can have detrimental effects on the quality of life of adults and children [127-135]. Elevated rates of various psychopathologies, including poor self-esteem, sexual dysfunction, anxiety, depression, and suicidal ideation have been reported in patients with psoriasis [127,135-140]. The significant impact of psoriasis on quality of life was evident in a study of 317 patients that found that psoriasis was associated with degrees of physical and mental impairment that were similar to cancer, arthritis, hypertension, heart disease, diabetes, and depression [141].

Occupational success may also be inhibited by psoriasis. Lower rates of employment and decreased work productivity have been linked to psoriasis [142-144].

Psychiatric disorders — One study that examined the relationship between mental health and psoriasis compared 3147 adolescents and adults with psoriasis to matched controls. After controlling for age and sex, psoriasis was associated with increased rates of depression (odds ratio [OR] 1.49; 95% CI 1.20-1.86); neurotic, stress-related, or somatoform disorders (OR 1.41; 95% CI 1.22-1.62); and personality and behavioral disorders (OR 1.58; 95% CI 1.05-2.39) [145].

Multiple other studies have corroborated the finding of increased rates of depression among individuals with psoriasis [132,137-139,146]. A cohort study of over 50,000 women from the Nurses’ Health study found higher rates of clinical depression in women with psoriasis and women with both psoriasis and psoriatic arthritis than in women without psoriasis [138]. In addition, a population-based study that included over 12,000 United States citizens and controlled for comorbidities found an association between psoriasis and major depression (OR 2.09, 95% CI 1.41-3.11) [137].

Severe manifestations of depression may occur; in a study of 217 patients with psoriasis, approximately 10 percent of patients reported a desire to be dead and 5 percent reported active suicidal ideation [147]. Because the clinical severity of skin disease does not always correlate with the emotional toll of psoriasis [127,130,148], clinicians should remain cognizant that even patients with mild psoriasis may experience significant emotional distress related to the disease.

Psychological distress may impair the response to psoriasis therapies. For example, in a cohort of psoriasis patients treated with PUVA, pathologic or high-level worry was a significant predictor of time required to achieve disease clearance [149].

ALCOHOL ABUSE — Data on the prevalence of alcohol use and abuse among patients with psoriasis are limited. Epidemiologic studies have found increased consumption of alcohol and an increased prevalence of alcohol misuse among individuals with psoriasis [139,150,151].

Additional studies suggest that alcohol consumption may contribute to the development of psoriasis. A Finnish study demonstrated that alcohol consumption prior to the onset of skin disease was greater in men with psoriasis (n = 144) than in 285 unmatched male controls who had other skin diseases [152]. In addition, an analysis of data from over 82,000 women in the Nurses' Health Study found that when compared with women who did not drink alcohol, women who consumed 2.3 or more drinks per week were more likely to develop psoriasis (relative risk 1.72, 95% CI 1.15-2.57) [153].

The mechanism through which alcohol consumption might contribute to psoriasis is unknown. Potential contributors include alcohol-related alterations in immune competence, proinflammatory cytokine production, epidermal proliferation and differentiation, and susceptibility to infections [154]. Excess alcohol consumption has been linked to more severe disease [155], and may have inhibitory effects on the response to treatment [154]. Additional study is necessary to evaluate the relevance of alcohol ingestion in psoriasis.

SMOKING — Smoking increases the risk of hypertension, peripheral vascular disease, stroke, myocardial infarction, and death. A meta-analysis of prevalence studies that assessed smoking in patients with and without psoriasis revealed a strong association of psoriasis with both current smoking (pooled odds ratio 1.78, 95% CI 1.52-2.06) and former smoking (pooled odds ratio 1.62, 95% CI 1.33-1.99) [156]. Patients with a history of smoking were also more likely to develop new onset psoriasis (odds ratio 1.39, 95% CI 1.27-1.52). Moreover, current smokers were almost twice as likely to develop psoriasis as non-smokers (odds ratio 1.93, 95% CI 1.64-2.28), and there was a possible dose-effect of smoking intensity and duration on psoriasis incidence. These studies demonstrating both an increased prevalence and incidence of smoking in patients with psoriasis, along with numerous adverse cardiovascular risks of smoking, support the concept that strong recommendations for smoking cessation should be given to psoriasis patients.

MIGRAINE — There may be an association between psoriasis and migraine [135,157]. A Danish nationwide study found a disease severity-dependent increase in risk for migraine among patients with psoriasis [157]. Adjusted incidence rate ratios for migraine in patients with mild and severe psoriasis were 1.37 (95% CI 1.30-1.45) and 1.55 (95% CI 1.29-1.86), respectively. The study also found increased risk for migraine among patients with psoriatic arthritis, demonstrating an adjusted incidence rate ratio for migraine in patients with psoriatic arthritis of 1.92 (95% CI 1.65-2.22). In contrast, a Taiwanese population-based study of 1685 adults with psoriasis and 5055 control subjects without psoriasis did not find an association between migraine and psoriasis [158].

EVALUATION AND MANAGEMENT — The recognition of psoriasis as a systemic inflammatory disease associated with increased risk for multiple other disorders and mortality supports the implementation of a comprehensive approach to the management of patients who present with this disease [159-161]. In an attempt to optimize the evaluation and management of patients with psoriasis, some academic medical centers have developed multidisciplinary clinical programs for patients with psoriasis in which professionals such as rheumatologists, cardiologists, primary care clinicians, psychiatrists, psychologists, nutritionists, and others work together in a structured manner to manage these patients.

Studies of the clinical value and cost-effectiveness of multidisciplinary clinical programs will be useful for determining the clinical value and cost-effectiveness of this approach. Moreover, additional studies that assess the impact of treatment of comorbid diseases on psoriasis and the effects of treatment of psoriasis on its comorbidities are needed.

Patient assessment — In general, patients who present with psoriasis should be assessed at the time of diagnosis and periodically thereafter for risk factors, signs, and symptoms of psoriasis comorbidities. Based upon the results of the clinical assessment, further investigation should be performed as indicated.

The 2008 American Journal of Cardiology Editor's Consensus on Psoriasis and Coronary Artery Disease recommended that patients with moderate to severe psoriasis be informed of a potential increased risk for coronary artery disease (CAD) [162]. In addition, the panel recommended implementation of the following measures for patients with moderate to severe psoriasis and consideration of these measures for patients with milder disease:

●Assessment of the personal and family history of CAD

●Annual assessment of blood pressure

●Screening of lipid profiles and fasting blood glucose

●Treatment of risk factors for CAD

A 2008 consensus statement from the National Psoriasis foundation also addressed recommendations for the assessment of psoriasis comorbidities [163]. In addition to supporting the standard recommendations for identifying and reducing cardiovascular risk (eg, smoking cessation, weight loss, and physical activity), the consensus panel recommended the following (see "Overview of primary prevention of cardiovascular disease"):

●Interventions to recognize and control depression

●Moderation of alcohol intake

●Vigilance for signs of lymphoma, cutaneous malignancies, and solid tumors (age-appropriate screening, annual skin examinations on patients on immunosuppressants or with a history of PUVA treatment, vigilance for plaques that appear atypical for psoriasis)

●Routine monitoring for the development of psoriatic arthritis (see "Clinical manifestations and diagnosis of psoriatic arthritis", section on 'Classification criteria')

Referrals to specialists such as cardiology, gastroenterology, hepatology, nephrology, psychiatry, and pulmonary medicine can be beneficial based upon the presence of signs or symptoms of particular comorbidities.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Psoriasis".)

SUMMARY AND RECOMMENDATIONS

●Overview – Increasing evidence supports the designation of psoriasis as a multisystem inflammatory disorder with multiple comorbidities. Examples of disorders associated with psoriasis include obesity, metabolic syndrome, hypertension, diabetes, atherosclerosis, malignancy, hepatic and pulmonary disorders, and psychiatric disease. (See 'Introduction' above.)

●Obesity, metabolic syndrome, and atherosclerotic disease – The chronic inflammatory nature of psoriasis may contribute to the observed association between psoriasis and obesity, metabolic syndrome, and atherosclerotic disease. Further studies are necessary to define the nature of the relationship between psoriasis and these diseases. (See 'Obesity' above and 'Metabolic syndrome' above.)

●Psychosocial impact – The psychosocial impact of psoriasis is not always proportional to the severity of skin disease. Patients with mild psoriasis may experience significant impairment of quality of life related to this disease. (See 'Psychosocial effects' above.)

●Impact on patient management – Recognition of the link between psoriasis and other diseases may facilitate early diagnosis and treatment of psoriasis comorbidities. The assessment for risk factors, signs, and symptoms of potential comorbid diseases is an important component of patient management. (See 'Evaluation and management' above.)