Clinics in Dermatology (2015) 33, 305–315

Obesity and the metabolic syndrome in pediatric psoriasis Iris Gutmark-Little, MD a , Kara N. Shah, MD, PhD b,⁎ a

Division of Pediatric Endocrinology, Cincinnati Children’s Hospital, Cincinnati, OH Division of Pediatric Dermatology, Cincinnati Children’s Hospital, 3333 Burnet Avenue, MLC 3004, Cincinnati, OH 45229

b

Abstract Psoriasis is a common, chronic inflammatory dermatosis that often has its onset during childhood. There is increasing evidence that psoriasis in adults is associated with obesity, the metabolic syndrome, and associated comorbidities, including insulin resistance/type 2 diabetes, dyslipidemia, hypertension, and cardiovascular disease. This association is postulated to arise, at least in part, as a result of a systemic proinflammatory state that is mediated by adipose tissue. Several recent observational studies suggest that children and adolescents with psoriasis may be at increased risk of being overweight and obese as well as having an increased risk for features of the metabolic syndrome. Such an association raises concern with regards to the long-term health implications for children and adolescents with psoriasis and suggests that better awareness, evaluation, and management of overweight and obese patients and associated metabolic disease are warranted in this population. © 2015 Elsevier Inc. All rights reserved.

Introduction Epidemiology Psoriasis is a common, chronic inflammatory dermatosis. Recent analysis of data from the National Health and Nutritional Examination Survey (NHANES) from 2009 to 2010 indicated a prevalence of psoriasis in adults in the United States of 3.6%.1 In children and adolescents, the prevalence is somewhat lower. A population-based incidence cohort of patients under 18 years of age from Olmsted

⁎ Corresponding author. Tel.: + 1 513 803 7835; fax: + 1 513 636 5867. E-mail address: [email protected] (K.N. Shah). http://dx.doi.org/10.1016/j.clindermatol.2014.12.006 0738-081X/© 2015 Elsevier Inc. All rights reserved.

County, Minnesota, demonstrated an incidence of 40.8 per 100,000.2 In Germany, a recent analysis of 6.7 million individuals registered through health insurance organizations revealed an overall prevalence of 2.1%, with a prevalence of 0.4% among children and adolescents 18 years of age and younger. From the age of 1 to 18 years of age, the prevalence of psoriasis increases from 0.1% to 0.8%.3 Approximately one-third of patients note the onset of disease before 20 years of age.4

Co-morbidities: Obesity, the metabolic syndrome, and cardiovascular disease Emerging data in adults support an association between psoriasis, obesity, and metabolic disease.5,6 A recent meta-

306 analysis of 16 observational studies, which included 210,831 adults with psoriasis, determined that the pooled odds ratio for the prevalence of obesity among patients with psoriasis was 1.66.5 Patients with severe psoriasis were more likely to be obese than those with mild psoriasis. Similarly, a meta-analysis of 12 observational studies, which included 41,853 adults with psoriasis, calculated a pooled odds ratio for the prevalence of the metabolic syndrome of 2.26.6 Patients with severe psoriasis were more likely to have the metabolic syndrome than patients with mild psoriasis. Data from the NHANES from 2003 to 2006 revealed a 40% prevalence of the metabolic syndrome in adults with psoriasis, compared to 23% among controls.7 Of particular concern are data suggesting that adults with psoriasis appear to have an increased risk for cardiovascular disease, including coronary artery disease and stroke. A large cohort study of 3603 adults in the United Kingdom with severe psoriasis demonstrated increased risk of death from a number of diseases, including cardiovascular disease, infection, and diabetes8; however, in one recent study, an association with increased mortality was not definitively demonstrated.9 Some investigators have postulated that the relationship between obesity and severity of psoriasis may affect response to therapy. Obese adult psoriatric patients are reported to be less responsive to various therapies than lean patients.10–12 Several studies in adults with psoriasis have demonstrated a positive effect of weight loss on disease severity, although weight loss alone may not be sufficient to maintain clinical improvement.13–15 Interestingly, bariatric surgery may produce a rapid diminuition in psoriatic disease severity, hypothesized to be mediated by a rise in antiinflammatory molecules postoperatively.16–19

Pathophysiology of inflammation in psoriasis An evolving paradigm now suggests that psoriasis is a cutaneous manifestation of systemic inflammation, and as such, should not be considered a skin-limited disease. The pathophysiology of psoriasis involves predominantly a T helper-1 /T helper-17 (Th1/Th17)-mediated immune response, modulated by increased expression of Th1 pathway cytokines, including interferon-γ, tumor necrosis factor-a (TNF-α), interleukin-2 (IL-2), and IL-12, and Th17 pathway cytokines, including IL-1, IL-6, IL-17, IL-23, and transforming growth factor-β (TGF-β).20 The interplay of predisposing environmental and genetic factors along with systemic and cutaneous inflammatory mediators is involved in disease initiation and promotion of ongoing disease activity (Figure 1).21 Many other inflammatory cells are involved in the pathogenesis of psoriasis, including dendritic cells, monocytes/macrophages, and neutrophils, which contribute to inflammation, abnormal keratinocyte proliferation, and angiogenesis. The “psoriatic march” has been proposed as a model to explain the association between inflammation, psoriasis, and comorbidities such as cardiovascular disease.22 In this model, systemic inflammation contributes to the development of insulin resistance via the action of

I. Gutmark-Little, K.N. Shah cytokines, chemokines, and other inflammatory mediators, which results in endothelial cell dysfunction, dyslipidemia, and the subsequent development of atherosclerosis.

Obesity and the metabolic syndrome in children and adolescents Obesity in children and adolescents Obesity is defined according to the Centers for Disease Control as a body mass index (BMI) greater than the 95th percentile for age and sex, and overweight as a BMI greater than the 85th percentile. In 2007, an Expert Committee was convened to provide recommendations for the prevention, assessment, and treatment of being overweight and obesity in children and adolescents.23 Guidelines for a staged approach to the treatment of being overweight and obesity in children and adolescents are presented that take into consideration the child’s age, degree of excess weight, and social and environmental factors. A combination of dietary modifications, behavioral modification therapy, and exercise is recommended but is often unsuccessful in achieving longterm weight management in children and adolescents, with consideration for pharmacologic and/or surgical treatment in selected patients.24 Data from the NHANES from 2003 to 2004 and 2005 to 2006 revealed that for children and adolescents between the ages of 2 and 19 years, 11.3% were at or above the 97th percentile of the 2000 BMI-for-age growth charts, 16.3% were at or above the 95th percentile, and 31.6% were at or above the 85th percentile.25 Overall, the number of obese children and adolescents has tripled over the last 30 years. Data from the NHANES 2009 to 2010 indicate that for infants and toddlers under 2 years of age, the prevalence of high weight-forrecumbent length (≥ 95% for age) was 9.7%, while 16.9% of children and adolescents between 2 and 19 years of age were obese as defined by a BMI ≥ 95th percentile for age).26 The ontogeny of this “obesity epidemic” is multifactorial, with evidence for genetic and environmental factors.24 Heritable factors are thought to account for 30% to 50% of the variation in adiposity. 27 Environmental factors are thus largely responsible for the increasing prevalence of obesity in children. The most important of these are dietary quality and quantity and activity levels.28 A number of other environmental factors, including sleep deprivation, stress-induced cortisol production, medications, specific viral infections, gut microbiota, and toxins (eg, bisphenol A) have all been postulated to increase adiposity.28 Obesity in children and adolescents is associated with earlier onset of chronic health conditions such as type 2 diabetes, obesity-related sleep apnea, and nonalcoholic fatty liver disease that previously were only seen in adults.24 In addition, children who are obese between 5 to 7 years of age or in adolescence are likely to become overweight and obese adults.29 As these children grow into adults, they carry

Obesity and metabolic syndrome in psoriasis

307

Fig. 1 Proposed schema of the evolution of a psoriatic lesion from initiation to maintenance of disease. (Reprinted with permission from Nestle, F. et al. Mechanisms of Disease: Psoriasis. N Engl J Med. 2009;361:496–508.)

tremendous disease burden, both physical and psychological, that results in disability, decreased quality of life, and the potential for shortened life expectancy.

Inflammation and obesity Adipose tissue is a metabolically active endocrine organ that produces adipokines, or adipocyte-derived cytokines, as well as inflammatory cytokines. There are several inflammatory mechanisms thought to tie adiposity to insulin resistance and metabolic disease (Figure 2).30 Signaling pathways, including JNK (Jun N-terminal kinases) and IKKβ (inhibitor of nuclear factor κβ), directly inhibit steps in the insulin-signaling pathway and blunt the effects of insulin in target tissues. Adipocyte-derived chemokines recruit circulating leukocytes, which, in turn, augment inflammatory signaling. These secreted inflammatory mediators also communicate insulin resistance to systemic leukocytes, conferring an inflammatory phenotype.

Collectively, these mechanisms serve to influence the immune cell constitution of adipose tissue, both in terms of an increase in cell number and in inflammatory potential. M2 immunoregulatory cells transition to proinflammatory M1 macrophages, releasing TNFα, IL-1 β, and IL-6. Similarly, small T helper 2/ regulatory T cell populations transition to larger and more inflammatory TH1/CD8 populations.30 One of the most well characterized adipocyte-derived hormones is leptin, which in addition to regulating appetite and body weight, also plays a key role in the inflammatory response, among other biological responses. Leptin potentiates production of TNF-α and IL-6, promotes T-cell proliferation and differentiation towards a TH1 phenotype, and stimulates keratinocyte proliferation and angiogenesis.31 The exact role of leptin and other adipokines, including adiponectin, in psoriasis remains to be elucidated.32 The creation of a proinflammatory state contributes to the pathophysiology of insulin resistance, hypertriglyceridemia, and other metabolic derangements in

308

I. Gutmark-Little, K.N. Shah

A

IL-4

Eosinophils

IL-4Rα

Adiponectin STAT6 PPAR-γ, -δ KLF4

M2 genes IL-10 Treg

M2 macrophage

B

Hypertrophic adipocytes Lipolysis, stress, inflammation Insulin action

Saturated fatty acids

Inflammation CD8+ T cells TH1 T cells Neutrophils Mast cells B cells

Lean adipocytes Lipolysis, stress, inflammation Insulin action

Necrotic adipocyte

TLRs DRRs JNK NF-κB, MR IRF3

β TNFα, IL-6 IL-1β,

M1 genes

M1 macrophage

IL-1β, TNFα

Inflammatory cell recruitment via Ccl2,5,8

Fig. 2 Lean and obese adipose tissues are associated with distinct inflammatory responses. (Reprinted with permission from Odegaard, J. I., et al. Pleotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science. 2013;339:172–177.)

children and adolescents similar to that seen in adults.33 Interestingly, there is preliminary evidence from two small studies that use of the glucagon-like peptide-1 (GLP-1) agonist exenatide, an incretin-based therapy for the treatment of type 2 diabetes, may improve psoriatic disease severity in adults with type 2 diabetes by modulating inflammation.34,35 Lipid partitioning, or the distribution of adipose tissue within the body, appears to be a strong determinant of the development of insulin resistance and the metabolic syndrome. Visceral obesity, or the accumulation of excess adipose tissue in internal abdominal organs as opposed to subcutaneous tissue, is a key contributor to the development of insulin resistance, altered lipid metabolism, and inflammation.36 In an observational study in 439 obese children and adolescents, the prevalence of the metabolic syndrome increased with increasing BMI, such that those children with the highest BMI had the highest prevalence of the metabolic syndrome.37 In children, waist circumference (WC) and waist-to height ratio appear to better correlate with risk for features of the metabolic syndrome and cardiovascular risk than do age- and sex-specific BMI percentiles.38,39 Age-, sex-, and ethnicity-specific WC percentiles are available for US children and adolescents.40

The metabolic syndrome in children and adolescents The term metabolic syndrome is used to describe the co-occurrence of certain metabolic disturbances, including impaired glucose tolerance, dyslipidemia, hypertension, and

obesity. A consensus definition and criteria for the diagnosis of the metabolic syndrome in adults has been established41; however, in children there is no clear agreement on diagnostic criteria, although the International Diabetes Foundation published a consensus statement in 2007.42 These recommendations stratify children by age (6 to b 10 years; 10 to b 16 years; 16 + years). A diagnosis of the metabolic syndrome may be made in the presence of central obesity as defined by WC ≥ 90th percentile for age in addition to two of the following four criteria: elevated triglycerides (≥ 150 mg/dL or on specific treatment for elevated triglycerides), low HDL-C (b 40 mg/dL for children under 10 years of age or boys, b 50 mg/dL in girls aged 16 years or older, or on specific treatment for low HDL), hypertension (systolic blood pressure ≥ 130 mmHg or diastolic blood pressure ≥ 85 mmHg or on specific treatment for previously diagnosed hypertension), and hyperinsulinism or fasting hyperglycemia (fasting plasma glucose ≥ 100 mg/dL or known diagnosis of type 2 diabetes mellitus) (Table 1). Criticisms of these guidelines include the lack of standardization of criteria for normal waist circumference, HDL, and triglycerides in children; physiologic variation in insulin resistance during puberty; and differences in normative values for the measured parameters in different racial and ethnic populations. Regardless, the prevalence of the metabolic syndrome in children appears to be increasing, with a prevalence of 2% to 9% among adolescents in the general population and 12% to 44% in obese children, depending on the specific diagnostic criteria that were used, in an analysis of the NHANES data from 1999 to 200243; however, several studies

Obesity and metabolic syndrome in psoriasis Table 1

309

A range of the published metabolic syndrome definitions in pediatrics

Cook et al. (14)

de Ferranti et al. (42)

Three or more of the following Fasting glucose Fasting glucose N 110 mg/dl_ N 6.1 mmol/L (N 110 mg/dL) WC N 75th WC N 90th percentile percentile (age and sex specific, NHANES III) Triglycerides N 110 mg/dl_ Triglycerides (age specific, NCEP) N 1.1 mmol/L (N 100 mg/dL) FIDL-C b 40 mg/dL FIDL-C (all ages/sexes, NCEP) b 1.3 mmol/L (b 50 mg/dL) Blood pressure N 90th Blood pressure percentile (age, sex and N 90th height specific, NHBPEP) percentile

Cruz et al. (15)

Weiss et al. (13)

Impaired glucose Impaired glucose tolerance tolerance (ADA criterion) (ADA criterion) WC N 90th percentile (age, sex and race specific, NHANES III) Triglycerides N 90th percentile (age and sex specific, NHANES III) HDL-C b 10th percentile (age and sex specific, NHANES III) Blood pressure N 90th percentile (age, sex and height specific, NHBPEP)

BMI - Z score N 2.0 (age and sex specific)

Ford et al. (41)

Fasting glucose N 110 mg/dL (additional analysis with N 100 mg/dL) WC N 90th percentile (sex specific, NHANES III)

Triglycerides N 95th percentile (age, sex and race specific, NGHS) HDL-C b 5th percentile (age, sex and race specific, NGHS)

Triglycerides N 110 mg/dL (age specific, NCEP)

Blood pressure N 95th percentile (age, sex and height specific, NHBPEP)

Blood pressure N 90th percentile (age, sex and height specific, NHBPEP)

HDL-C b 40 mg/dL (all ages/sexes, NCEP)

ADA, American Diabetes Association; BMI, body mass index; HDL-C, high-density lipoprotein cholesterol; NCEP, National Cholesterol Education Program; NGHS, National Growth and Health Study; NHBPEP, National High Blood Pressure Education Program; WC, waist circumference.

have demonstrated a high degree of variability in the long-term stability of the diagnosis of the metabolic syndrome in adolescents, with a significant number of adolescents failing to meet diagnostic criteria upon long-term follow-up.44,45 Long-term follow-up of a cohort of children ages 6 to 19 years of age from the Cincinnati clinic of the National Heart, Lung, and Blood Institute LRC Prevalence Study demonstrated an association between a diagnosis of the metabolic syndrome during childhood, as defined by a BMI ≥ the age-specific 90th percentile and the following criteria: age- and height-specific references for systolic and diastolic blood pressure ≥ 90th percentile; triglyceride levels ≥ 100 mg/dL; HDL-C ≤ 50 mg/dL (female subjects) or ≤ 40 mg/dL (male subjects); fasting plasma glucose ≥ 110 mg/dL, and the development of adult cardiovascular disease 25 years later, raising significant concern with regard to the long-term complications of obesity and the metabolic syndrome in children and adolescents.46 In addition, obese adults who were overweight or obese as children have increased risks of type 2 diabetes, hypertension, dyslipidemia, and carotid artery atherosclerosis compared with obese or overweight children who become nonobese by adulthood, in whom the risks of these comorbidities are equal to those in adults who were never obese, emphasizing the importance of addressing overweight and obesity in childhood.47 The relationship between obesity and the metabolic syndrome, however, is not straightforward, as some obese adults have no evidence of the metabolic syndrome and no apparent associated morbidity, while some adults who are of normal weight have one or more features of the metabolic syndrome and its associated co-morbidities. The determination of which patients are at the highest risk for complications such as type 2 diabetes and cardiovascular disease is difficult.

Obesity, the metabolic syndrome, and psoriasis in children and adolescents In children, the association between psoriasis, obesity and the metabolic syndrome is less well characterized than in adults, but the current data are still compelling. Several studies over the last few years have attempted to better define this relationship (Table 2). The implications of determining the extent of such a relationship are significant, as they may further affect the importance of: (1) achieving and maintaining a healthy weight in children and adolescents with psoriasis; (2) recommendations for monitoring for comorbidities such as hypertension, hyperlipidemia, and insulin resistance in this population; and (3) the effect on treatment recommendations for psoriasis in children and adolescents, with an emphasis on prioritizing the use of systemic antiinflammatory, antipsoriatic medications in high-risk patients, ie, those with more severe psoriasis or other risk factors for excess morbidity from complications of the metabolic syndrome. Several studies have supported an association between obesity and psoriasis in children and adolescents. In the data published from the seminal North American study on the use of etanercept to treat psoriasis in children and adolescents, 37% of patients were noted to be obese (BMI ≥ 95th percentile).48 In a study of 332 consecutive Chinese Han patients under 15 years of age with a diagnosis of plaque psoriasis who were compared to 146 age- and sex-matched controls with a diagnosis of another skin disease, including melanocytic nevi, cutaneous infection, and mild or self-limited inflammatory dermatoses, patients with psoriasis who were more likely to be overweight or obese (OR of 2.4 [1.2-4.8, P b .05] and 2.6 [1.0-6.4, P b .05], respectively).49 Obese children were more likely to have more severe psoriasis, with a trend for increasing psoriasis area

Summary of studies evaluating the association between obesity and/or the metabolic syndrome with psoriasis in children and adolescents

Study

Design

Conclusions

HDL-C triglycerides fasting plasma glucose LDL-C total cholesterol blood pressure Physician’s Global Assessment (PGA) PASI

30% vs 5% of controls

20 children and adolescents ages 10–17 years with moderate-to-severe psoriasis (BSA ≥ 5%) and 1563 age-matched controls from NHANES (2007–2008) 1.3 million nonselected individuals in a health insurance organization, 33,981 of which had a diagnosis of psoriasis as ascertained by ICD-10 code.

HDL-C triglycerides fasting plasma glucose LDL-C total cholesterol blood pressure

30% vs 7.4% of controls

300,384 schoolchildren born between 1930 and 1984 entered into the Copenhagen School Health Records Register 1074 individuals in the National Patient Register from 1977 to 2001 admitted to hospital with a diagnosis of psoriasis as identified by ICD-8 or ICD-10 code

BMI

Patients with psoriasis had higher mean fasting blood glucose of 91.1 mg/dL compared with control of 82.9 mg/dL (P = .01) No significant difference in BMI between patients with psoriasis and controls Patients with psoriasis and metabolic syndrome had higher mean BMI percentile (88%) than patients with psoriasis without metabolic syndrome (57.6%) Patients with psoriasis had lower HDL-C (44.3 mg/dL) compared with control group (51.6 mg/dL) (P = .0017) No significant difference in average BMI The overall prevalence rate of comorbidity was increased 2-fold in patients with psoriasis (14.4% vs 7.2%). Prevalence ratios were noted as follows: Crohn disease = 3.69 (2.15-6.35), hyperlipidemia = 2.15 (1.65-2.80) diabetes mellitus = 2.01 (1.32-3.04) hypertension = 1.89 (1.47-2.67) obesity = 1.70 (1.49-1.93) Positive association between excess BMI gain at ages 12–13 years and the diagnosis of psoriasis in girls, but not in boys

Measurements

Goldminz Case–control Massachusetts, (2013) United States

20 children and adolescents ages 10–17 years with moderate-to-severe psoriasis (BSA ≥ 5%) 20 age- and sex-matched controls

Au (2012)

Massachusetts, United States

Augustin Cross-sectional Germany (2010)

Bryld Historical (2010) cohort of

Denmark

Co-morbid diagnoses, including hyperlipidemia, obesity, hypertension, diabetes mellitus, Crohn disease, and rheumatoid arthritis) were ascertained by ICD-10 code in patients ages 0–20 years.

Percentage of psoriasis patients with obesity (%)

I. Gutmark-Little, K.N. Shah

Percentage of psoriasis patients with metabolic syndrome (%)

Population

Case–control

Location

310

Table 2

BMI Waist circumference Fasting blood sugar Blood pressure LDL cholesterol HDL cholesterol Triglycerides

Koebnick Cross-sectional California, (2011) United States

710,949 patients aged 2–19 years enrolled in Kaiser Permanente Southern California health plan, including 1350 patients diagnosed with psoriasis as identified by ICD-9 code and confirmed by chart review.

BMI total cholesterol LDL cholesterol HDL cholesterol Triglycerides ALT

Zhu (2011)

Cross-sectional China

BMI, PASI

15.7% overweight vs 7.5% of controls 9% obese vs 4.1% of controls

Boccardi (2009)

Case–control

332 consecutive Chinese Han patients under 15 years of age with a diagnosis of plaque psoriasis 146 age- and sex-matched controls with other skin disease 96 children under 15 years of age with psoriasis 100 controls with other skin disease

BMI (%BMI calculated as actual weight/50th percentile weight at the age corresponding to the 50th percentile for the current height)

48% overweight vs 27% of controls

Milan, Italy

COP was associated with lower frequencies of obesity, high waist circumference, diabetes, dyslipidemia, hypertension, familial cardiovascular disease, major adverse cardiovascular events, and metabolic syndrome compared to adult onset psoriasis (AOP) Positive association with overweight (adjusted OR = 1.31 [1.13-1.49]) Positive association with moderate obesity (adjusted OR = 1.39 [1.19-1.63]) Positive association with extreme obesity (adjusted OR = 1.78 [1.24-2.14]) Positive association with severe or widespread psoriasis (as defined by patients who were treated with systemic medications, including biologics, or phototherapy) and the following: overweight (adjusted OR = 2.78 [1.43-5.42]) moderate obesity (adjusted OR = 2.93 (1.3-6.37) severe obesity (adjusted OR = 4.19 [1.81-9.68]) Patients with psoriasis had higher total cholesterol, LDL, triglycerides and ALT. Positive association with overweight (OR = 2.4, 1.2-4.8) Positive association with obesity (OR = 2.6, 1.0-6.4)

Positive association with overweight (OR = 2.55, 1.31-4.96) Positive association in boys (OR = 4.63, 1.40-15.28) Positive association in children age ≤ 10 years (OR = 3.19, 1.40-7.28) (continued on next page)

311

2201 adults with psoriasis 25% with childhood onset psoriasis (COP)

Obesity and metabolic syndrome in psoriasis

15.3% obese 24.5% obese COP – 17.9% obese COP – 7.6% obese AOP – 17.8% obese AOP-26.6% obese

Mahe Multicenter, 29 centers (2013) cross-sectional France

17.6% overweight vs 13.2% of controls 20.2% obese vs 7.3% of controls Physician’s Global Assessment (PGA) BSA BMI WC Waist to height ratio 614 children ages 5 to 17 years with a 6-month or more history of plaque psoriasis 205 controls with a diagnosis of a non-inflammatory skin disease 18 centers Multicenter, international North America cross-sectional (United States, Canada) South America (Brazil, Chile) Europe (Italy, the Netherlands, Turkey, United Kingdom) Asia (Malaysia)

Percentage of psoriasis patients with obesity (%) Measurements

Paller (2013)

Table 2 (continued)

Location Design Study

Population

Percentage of psoriasis patients with metabolic syndrome (%)

Positive association with obesity (OR = 4.92, 2.20-10.99 in severe psoriasis; OR = 3.60, 1.56-8.30 for mild psoriasis) Positive association with increased WC and severe psoriasis in the United States. (OR = 2.05, 1.12-3.76) Positive association with increased waist to height ratio (4.10, .80-9.31) No effect of disease duration on WC or waist to height ratio

I. Gutmark-Little, K.N. Shah

Conclusions

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severity index assessment with increasing BMI noted. A case– control study of 96 children under 15 years of age and 100 ageand sex-matched controls seen in a pediatric dermatology clinic in Milan noted an association between overweight as defined by greater than 110% of the calculated ratio of the actual BMI divided by the value at the 50th percentile weight at the age corresponding to the 50th percentile for the child’s height (OR 2.55 [1.31-4.96].50 Positive associations between psoriasis and overweight, particularly in boys (OR 4.63, 1.40-15.28) and in children age ≤ 10, (OR 3.19, 1.40-7.28) were noted. A study from Denmark demonstrated an association between severe psoriasis, as determined by admission to hospital for treatment, and overweight/obesity in girls as defined by increased BMI at age 12 and 13 years.51 This retrospective study reviewed school health records from the Copenhagen School Health Records register for a historical cohort of patients born between 1903 and 1984, which included data on weight and height for children between 7 and 13 years of age, and cross-referenced hospital admission data from the National Patient Register from 1977 to 2001. The authors suggested that this observation may indicate that the presence of overweight/ obesity in adolescence may contribute to increased disease severity, in particular in pubertal girls. The most comprehensive study to evaluate the relationship between psoriasis in children and adolescents and obesity is an international cross-sectional study of 614 children ages 5 to 17 years with a 6-month or more history of plaque psoriasis matched age and sex with 205 controls with a diagnosis of a noninflammatory skin disease such as warts, nevi, or molluscum, and enrolled from 18 dermatology referrals centers in nine countries.52 The OR for having a waist circumference greater than the 90th percentile in children with psoriasis compared with controls was 2.52 (1.24-5.12). For patients with severe psoriasis, as defined by a Physician’s Global Assessment (PGA) score of 4 to 5 or a PGA score of 3 with a BSA of more than 10%, the overall OR of having a WC percentile greater than the 90th percentile was 3.06 (1.53-6.15). For patients with mild psoriasis, as defined by a PGA score of 1 to 2 or a PGA score of 3 with a BSA of less than 10%, there was no difference. Most children with mild psoriasis with an elevated WC were overweight but not obese, while most patients with severe psoriasis with an elevated WC were obese. A subgroup analysis of the US population showed an OR of 1.77 (1.03-3.07) and 3.47 (1.39-8.66) for having a waist circumference percentile higher than the 75% or 90th percentile, respectively, compared with controls, and an OR of 2.05 (1.12-3.76) and 3.85 (1.64-9.00) in the severe psoriasis group. Children with severe psoriasis who transitioned to mild psoriasis at enrollment showed no change in adiposity compared with children whose psoriasis remained severe. Disease duration had no impact on waist circumference, although patients from either North or South America had a mean WC percentile that was greater than observed for patients from other continents. Within the United States, a significantly greater WC was seen for Hispanics and African Americans (59.5%) versus whites (44.5%) and Asians (40.0%). Children with mild psoriasis were still at risk for

Obesity and metabolic syndrome in psoriasis obesity (OR = 3.60, 1.56-8.30), and children with severe psoriasis were at a significantly greater risk for obesity (OR = 4.92, 2.20-10.99), with an even higher risk for children with severe psoriasis in the United States (OR = 6.61, 2.16-20.17). These risks are greater than those reported in adults with mild psoriasis and with severe psoriasis (defined as those patients who had received phototherapy or systemic therapy for the treatment of psoriasis) respectively, in the United Kingdom (severe psoriasis, 1.79 and mild psoriasis, 1.27), and for the risk of the metabolic syndrome reported in adults with psoriasis in the United States (OR = 1.96), implying that there may be a greater associated risk with obesity in childhood onset psoriasis compared with adult onset psoriasis. 7,53 Several studies have also evaluated the possible association of psoriasis in children and adolescents with the metabolic syndrome. In a small cross-sectional study of twenty children and adolescents ages 9 to 17 years of age with psoriasis involving at least 5% BSA who were compared to a cohort of age- and sex-matched controls with benign skin condition such as warts, acne, or nevi, 6 out of 20 (30%) patients with psoriasis as opposed to 1 out of 20 (5%) controls met criteria for a diagnosis of the metabolic syndrome, as defined by the presence of at least three of the following criteria: triglycerides ≥ 100 mg/dL; HDL-C b 50 mg/dL (or b 45 mg/dL for boys ages 15–17 years); fasting blood glucose ≥ 110 mg/dL; WC N 75th percentile for age, sex and height.54 Children with psoriasis and the metabolic syndrome were reported to have a higher mean BMI percentile of 88% compared with children with psoriasis but without the metabolic syndrome (57.6%) and the controls (56.4%). Multivariate regression analysis demonstrated that the diagnostic criteria that were most contributory to the metabolic syndrome were diastolic blood pressure and HDL-C. There was a small but statistically significant increase in mean fasting blood glucose in the cohort of patients with psoriasis. Otherwise, there were no statistically significant differences in the means for the other measures, including HDL-C, systolic blood pressure, diastolic blood pressure, WC, and triglycerides, although the mean values for all components trended towards increased risk for the metabolic syndrome in patients with psoriasis. Using this same cohort of 20 patients with psoriasis, investigators then compared the cohort of children to psoriasis to 1563 patients between 9 and 17 years of age included in the NHANES 2007 to 2008 database. Compared to a prevalence of 6 out of 20 (30%) in the psoriasis cohort, only 115 out of 1563 (7.4%) met diagnostic criteria for the metabolic syndrome in the control group.55 Interestingly, there was no difference in average BMI, which was 22.3 for the NHANES control group and 22.7 for the psoriasis cohort. The only statistically significant difference among diagnostic criteria was noted for HDL-C, which was lower in the cohort of psoriasis patients (44.3 mg/dL) as opposed to the control group (51.6 mg/dL, P = .0017). The results of these studies, although limited by the small number of children with psoriasis who were included, suggests that as in adults, children with psoriasis may be more likely to demonstrate features of

313 the metabolic syndrome, in particular decreased HDL-C and increased BMI. In a large, cross-sectional survey of individuals registered in a German health insurance organization, the prevalence rates of several co-morbidities, including obesity, hyperlipidemia, hypertension, and diabetes, as assessed by ICD-10 code, were increased in children and adolescents ages 0 to 20 years with psoriasis.56 The prevalence ratios were noted as follows: Crohn’s disease = 3.69, hyperlipidemia = 2.15, diabetes mellitus = 2.10, hypertension = 1.89, and obesity = 1.70. The authors note that this association may have been confounded by a possible diagnostic bias such that patients with psoriasis were more likely to come to medical attention than those without, and to therefore have a higher likelihood of having a diagnosis of a comorbid disease. In contradistinction, a large cross-sectional, multicenter study from France involving 2201 adults with psoriasis, 25% of whom had onset of disease before 18 years of age (childhood onset psoriasis, COP) had a lower prevalence of obesity, high WC, diabetes, dyslipidemia, hypertension, familial cardiovascular disease, major adverse cardiovascular events, and the metabolic syndrome on univariate analysis compared with patients with onset of disease after 18 years of age (adult onset psoriasis, AOP).57 Patients with COP, though, were significantly younger (39.1 years versus 51.8 years in the AOP group), were more often on biologic therapy (40.1% versus 30.1%), had more frequent familial disease (54.7% versus 35.2%), and had a longer duration of disease (27.5 years versus 14.3 years). Disease severity as measured by treatment with a biologic agent or a traditional systemic medication such as acitretin, cyclosporine, or methotrexate was similar between both groups, with 68.6% of COP subjects and 64.2% AOP subjects receiving systemic therapy. Given the younger mean age of the cohort of adults with COP, the authors acknowledge that age may have accounted for the lower frequency of comorbid disease (particularly cardiovascular) in adults with childhood onset psoriasis. A recent cross-sectional study of 710,949 patients ages 2 to 19 years enrolled in Kaiser Permanente Southern California health plan, including 1350 patients diagnosed with psoriasis as identified by ICD-9 code and confirmed by chart review, demonstrated an increased prevalence of psoriasis in patients who were overweight or obese, with OR for psoriasis of 1.31 (1.13-1.49), 1.39 (1.19-1.63), and 1.78 (1.24-2.14), respectively, for overweight, moderately obese, and extremely obese patients.58 The adjusted OR for severe or widespread psoriasis as defined by patients who were treated with systemic medications, including biologics or phototherapy, were 2.78 (1.43-5.42), 2.93 (1.35-6.37), and 4.19 (1.81-9.68) for overweight, moderately obese, and extremely obese patients, respectively. Among those children and adolescents who were overweight or obese, those with psoriasis were noted to have significantly higher mean total cholesterol (169.6 mg/dL versus 163.9 mg/dL, P = .021), LDL cholesterol (103.9 mg/dL versus 98.4 mg/dL, P = .007), triglycerides (114.4 mg/dL versus 100.6 mg/dL, P = .015), and

314 ALT (25.1 units/L versus 21.7 units/L, P = .016) compared with those children without psoriasis.

Conclusions It is not yet clear how the development of being overweight and obesity contributes to the onset of psoriasis or influences its severity in children and adolescents, nor is it clear that weight reduction will have a lasting effect on the severity of psoriasis in the pediatric subpopulation; however, the cumulative data support an association between psoriasis, obesity, and the metabolic syndrome in children and adolescents. Additionally, the presence of psoriasis may indicate an increased risk of future comorbidity in adulthood, particularly cardiovascular disease. Further studies are indicated to better define the relationship between overweight and obesity in children and adolescents with the development and severity of psoriasis in this population. Given these associations, it is imperative that providers caring for children and adolescents with psoriasis are aware of the potential risk for hypertension, dyslipidemia, and fasting hyperglycemia. Although screening recommendations for the evaluation for the components of the metabolic syndrome in children and adolescents with psoriasis do not exist, the National Heart, Lung, and Blood Institute does provide age-based screening recommendations for the evaluation for hypertension, dyslipidemia, and diabetes in children and adolescents (http://www.nhlbi.nih.gov/guidelines/cvd_ped/summary.htm). When caring for a child with psoriasis, there should be a low threshold on the part of the specialist as well as the primary care provider to evaluate for possible hypertension, dyslipidemia, and fasting hyperglycemia. In addition, weight, height, and BMI measurements, where appropriate, should be taken routinely and followed over time. Those pediatric patients with psoriasis who are at risk should receive appropriate ancillary care, including counseling on weight management and appropriate nutrition. Hopefully, future long-term, prospective studies will clarify the relationship between childhood-onset psoriasis, obesity, and the metabolic risk and provide appropriate evaluation and management strategies to better anticipate and manage this risk.

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