Psoriasis and metabolic syndrome in children: current

CED

Original article

Clinical and Experimental Dermatology

Psoriasis and metabolic syndrome in children: current data ski,2,3 W. Myslin ski,5 P. Chabros,1 A. Pietrzak,1 E. Grywalska,2,3 M. Walankiewicz,2 T. Lotti,4 J. Rolin ska1 and K. Reich6 D. Piekarska-Myslin 1 Department of Dermatology, Venereology and Paediatric Dermatology; 2Department of Clinical Immunology and Immunotherapy and 5Department of Internal Diseases, Medical University of Lublin, Lublin, Poland; 3St. John’s Cancer Center, Lublin, Poland; 4Department of Dermatology, University of Rome G. Marconi, Rome, Italy and 6Dermatologikum Hamburg and SCIderm Research Institute, Hamburg, Germany

doi:10.1111/ced.13014

Summary

Background. The prevalence of cardiovascular and metabolic disorders in paediatric patients with psoriasis is not well established. Aim. To conduct a meta-analysis of previously published studies dealing with the occurrence of metabolic disorders in children with psoriasis. Methods. Data from 7 studies with a total of 965 children with psoriasis were analysed using a random effects model. Results. Prevalence of metabolic syndrome (MetS) was significantly higher in patients with psoriasis than in healthy controls (HCs). In most studies, significantly decreased levels of high-density lipoprotein (HDL) cholesterol were found in children with psoriasis. Mean level of HDL cholesterol in patients with psoriasis was 2.05 mg/dL lower than in HCs. Patients with psoriasis and HCs did not differ significantly in their mean triglyceride levels, although the difference was at a threshold of statistical significance. Mean level of fasting glucose in children with psoriasis was 5.75 mg/dL higher than in HCs (P < 0.01). The two groups did not differ significantly in mean waist circumference or in systolic and diastolic arterial pressures. Conclusions. Decreased levels of HDL cholesterol and increased concentrations of fasting glucose may represent very early stages of MetS in children with psoriasis. However, a large population-based study is needed to establish the relationship between psoriasis and MetS in children, including the environmental, genetic and immunological factors leading to their co-occurrence.

Introduction Psoriasis is a multifactorial, immune-mediated skin disease, characterized by a variety of inflammatory disturbances, hyperkeratotic plaques, recurring lesions and involvement of the joints. Psoriasis affects approximately 2–5% of the population.1 Augustin et al.2 estimated the overall 1-year prevalence of this condition Correspondence: Dr Aldona Pietrzak, Department of Dermatology, Venereology and Paediatric Dermatology, Medical University of Lublin, 13 Radziwiłłowska Str., 20-080 Lublin, Poland E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. Funding: The study was supported from DS 168 grant from the Medical University of Lublin. Accepted for publication 20 March 2016

ª 2017 British Association of Dermatologists

at 2.53%, and its total prevalence in children up to 18 years of age at 0.71% (0.66% and 0.76% for boys and girls, respectively). The prevalence increased in an approximately linear manner, from 0.12% at 1 year of age to 1.24% at 18 years.2 A wide range of comorbidities may co-exist with psoriasis, with the most important being cardiovascular disease (CVD) and its risk factors: obesity, arterial hypertension (AHT), dyslipidaemia (DLP) and type 2 diabetes mellitus (T2DM). This implies that psoriasis may be associated with increased risk of metabolic syndrome (MetS), defined as the presence of at least three of five of the following conditions: abdominal obesity, elevated blood pressure, elevated fasting plasma glucose, high levels of serum triglycerides and low levels of high-density lipoprotein (HDL) cholesterol.3 All these comorbidities commonly occur in


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Psoriasis and metabolic syndrome A. Pietrzak et al.

adult psoriasis,3 but their prevalence in paediatric patients is not well established, because of the small number of studies and participants. Therefore, the aim of this study was to conduct a meta-analysis of previously published studies dealing with the occurrence of metabolic disorders in children with psoriasis.4

the results are presented as mean differences (D) or OR with 95% CI. Homogeneity of the studies was verified with T2 test based on the weighted least squares method. The threshold of statistical significance for all the analyses was set at P ≤ 0.05.

Results Methods A search of the MEDLINE and EMBASE databases from 1966 to June 2015 was carried out, using the relevant MeSH terms including all sub-headings. This was combined with a keyword search using ‘cardiovascular’ OR ‘apolipoprotein’ OR ‘apolipoproteins’ OR ‘dyslipidemia’ OR ‘dyslipidaemia’ OR ‘hypercholesterolemia’ OR ‘hypertriglyceridemia’ OR ‘triglyceride’ OR ‘triglycerides’ OR ‘lipid’ OR ‘lipids’ OR ‘cholesterol’ OR ‘HDL’ OR ‘LDL’ OR ‘lipoprotein’ OR ‘lipoproteins OR ‘body mass index’ OR ‘BMI AND ‘psoriasis’ OR ‘psoriatic AND child OR children’ OR ‘pediatric’ OR ‘pediatrics’ OR ‘infant’ OR ‘infants’ OR ‘newborn’ OR ‘newborns’. Two authors (AP and KR) performed the searches independently and reviewed the results according to the Newcastle-Ottawa Scale for assessing the quality of nonrandomized studies in meta-analyses. All discrepancies were resolved by consensus. We searched for English-language publications and human studies. Review articles, abstracts and editorials were excluded, and duplicate data were removed. Data were extracted from the publications independently by the two reviewers, and the following information was recorded: first author, year of publication, country, study design, number of patients, incidence of MetS and its components (fractions of participants meeting the diagnostic criteria for MetS overall and for its individual components) and/or values of determined metabolic parameters (blood concentrations of glucose, triglycerides and HDL cholesterol, systolic and diastolic blood pressure, and waist circumference). In total, 122 articles were found by the electronic searches. After exclusion of conference abstracts (n = 58) and of studies that did not meet the inclusion criteria based on their title and abstract (n = 43), 21 papers remained. After reviewing the full texts, 7 relevant studies4–10 with a total of 965 children with psoriasis were eligible for inclusion in the study.

Metabolic syndrome

Prevalence of MetS was assessed in 3 studies with a total of 60 children with psoriasis (Fig. 1). In all these studies, prevalence of MetS was significantly higher in patients with psoriasis than in healthy controls (HCs) (OR = 6.10, 95% CI 2.66–13.98; P < 0.001). All the studies were homogeneous (P = 0.896). High-density lipoprotein cholesterol

In all but one of the seven studies, significantly decreased levels of HDL cholesterol were found in children with psoriasis (P = 0.03). Mean level of HDL cholesterol in children with psoriasis was 2.05 mg/dL lower than in HCs (95% CI 3.89 to 0.21 mg/dL; Fig. 2), and the studies were heterogeneous (P < 0.001). Triglycerides

Serum concentrations of triglycerides were measured in 536 children with psoriasis. Patients with psoriasis and HCs did not differ significantly in their mean triglyceride levels, although the difference was at a threshold of statistical significance (D = 8.69 mg/dL,

Statistical analysis

Results were analysed with Statistica software (v10; StatSoft, Tulsa, OK, USA), using a random effects model. Depending on the type of analysed variables,

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Figure 1 Forest plot illustrating odds ratios (ORs) for metabolic

syndrome in psoriatic vs. non-psoriatic children documented in previous studies.4,7,9



Other parameters

There was no difference in mean systolic or diastolic arterial pressures or in waist circumference between children with psoriasis and HCs (P = 0.06, P = 0.78, P = 0.20, respectively).

Discussion

Figure 2 Forest plot illustrating mean differences (D) in serum

HDL cholesterol levels in psoriatic and non-psoriatic children examined in previous studies.4–6,8,9

Figure 3 Forest plot illustrating mean differences (D) in serum

fasting glucose levels in psoriatic and non-psoriatic children examined by previous studies.4,8,9

95% CI 0.26 to 17.64 mg/dL; P = 0.06). The studies were heterogeneous (P < 0.001). Fasting glucose

Mean level of fasting glucose in 40 children with psoriasis was significantly higher than in HCs (P < 0.01), with D = 5.75 mg/dL (95% CI 2.17–9.34 mg/dL; Fig. 3). The analysed studies were heterogeneous (P = 0.03).


MetS is a cluster of cardiometabolic risk factors, including central obesity, insulin resistance, glucose intolerance, DLP and increased blood pressure.11 Aside from CVD and T2DM, MetS is also associated with many other clinical conditions, such as chronic lowgrade inflammation, oxidative stress, hyperuricaemia, dyslipidaemia, hyperandrogenism, polycystic ovary syndrome, hepatic steatosis and non-alcoholic fatty liver disease, impaired glucose tolerance, obstructive sleep apnoea, hypogonadism, vascular dementia, Alzheimer disease and some cancers.12 The definition of MetS in children and adolescents has raised controversy, as no clear thresholds for metabolic parameters exist for this group.13,14 Nevertheless, it has been shown that children with MetS are at increased risk of adult MetS as well as, T2DM and CVD.15 MetS comprises a complex phenotype that correlates with obesity, but nonetheless appears to be distinct. Metabolic diseases, such as obesity and T2DM, have a common genetic background with psoriasis.16 Moreover, they appear to interact at a functional level, because both obesity and the upregulation of proinflammatory mediators observed in psoriasis seem to influence adipocyte homoeostasis, inducing nonprofessional immune functions, which may perpetuate psoriatic inflammation. In addition, a disturbed adipokine profile and psoriasis-associated inflammation may induce insulin resistance and lead to CVD.17 There appears to be an important role of tumour necrosis factor-a and other factors that are overproduced in patients with psoriasis, as these may contribute to the elevated risk of MetS.18 The metabolic profile of children with psoriasis has been examined in a relatively small number of studies. Thus, we decided to perform a meta-analysis of the available data based on the results of seven studies in children with psoriasis. We analysed blood concentrations of HDL cholesterol, triglycerides and fasting glucose, as well as waist circumference and systolic and diastolic blood pressure. Concentrations of HDL cholesterol were available in six studies, and data on waist circumference, blood pressure and fasting glucose in


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three. Our meta-analysis showed that children with psoriasis had significantly lower levels of HDL cholesterol and significantly higher concentrations of fasting glucose compared with HCs. The two groups did not differ significantly in systolic and diastolic pressures, triglyceride concentrations or waist circumference. Noticeably, a study conducted by Toruniowa et al.5 showed significant differences in mean levels of triglycerides in both boys and girls with psoriasis. No sex-specific analyses of metabolic parameters were included in the other studies. Decreased concentrations of HDL cholesterol are typically observed in patients with T2DM. The aetiology of this abnormality still remains unclear. It has been suggested that insulin resistance, enhanced synthesis of very low-density lipoprotein (LDL), and increased activities of cholesteryl ester transfer protein and endothelial lipase may play an important role in lowering HDL cholesterol concentrations.19 The results of the seven studies included in our meta-analysis strongly support suggestions that psoriasis is an inflammatory disorder that not only affects the skin, but also leads to metabolic disorders. Decreased levels of HDL cholesterol and increased concentrations of fasting glucose may represent the very early stages of a psoriasis-related metabolic disorder. It should be emphasized, however, that the participants in the analysed studies were very young and it is possible that, despite the presence of active psoriasis and some metabolic abnormalities, they would not go on to develop cardiovascular complications such as systemic hypertension or visceral obesity. Our findings imply that the levels of plasma lipids, insulin resistance and glucose (in a fasted state or during oral glucose tolerance test) should be monitored in all paediatric patients with psoriasis to detect any abnormalities early and thereby prevent clinically significant cardiovascular disorders. Augustin et al.2 found that the overall prevalence of comorbidities in patients with psoriasis aged < 20 years was double that of people without this condition, and juvenile psoriasis was shown to be associated with higher prevalence of DLP, obesity, AHT, DM, rheumatoid arthritis and CVD. Interestingly, CVD occurred 3–4 times more often in patients with psoriasis than in HCs, and the prevalence of DLP, diabetes mellitus and AHT in patients with psoriasis was double that of the general population. Another study conducted by Augustin et al.,20 based on data from a German database, demonstrated that children with psoriasis are at increased risk of DLP, DM, AHT and obesity. Similar results were obtained in Chinese and

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Italian studies, as reviewed by Wootton and Murphy.21 A significant association between paediatric MetS and CVD risk was also demonstrated in a longitudinal study with a 25-year follow-up.22 Previous studies of psoriasis-specific changes in serum concentrations of lipids in children are sparse and have produced inconclusive results. Toruniowa et al.5 analysed the serum lipid profiles of children aged 6–14 years: 47 children with generalized psoriasis (14 boys, 33 girls) and an HC group (19 boys, 15 girls). Psoriasis was shown to be associated with a decrease in HDL levels in both sexes [patients with psoriasis vs. HCs: 57.81 12.92 mg% vs. 47.60 9.69 (P < 0.03) for boys, and 56.35 11.12 vs. 49.76 9.24 mg% (P < 0.05) for girls]. There was an interesting observation for triglyceride concentration in boys with psoriasis, in whom this parameter increased to 118.38 42.95 vs. 93.39 28.37 in HCs (P < 0.09). No statistically significant differences were found for total or LDL cholesterol. According to Toruniowa et al.5 an atherogenic pattern of lipid metabolism disorders might already developed in their participants. The reasons behind the decrease in HDL cholesterol level at such a young age remain unclear. Perhaps this phenomenon may be associated with impaired synthesis of HDL cholesterol in the liver or intestines, or with impaired homeostasis at the cellular level.5 Koebnick et al.6 conducted a large population-based study and showed an association between the occurrence of psoriasis and weight gain in children. Overweight and obesity were shown to be associated with an increased risk of psoriasis in youth. Irrespective of their body weights, adolescent patients with psoriasis presented with significantly higher concentrations of total cholesterol, LDL cholesterol, triglycerides and alanine aminotransferase.6 Matusiewicz et al.23 explored the epidemiology, treatment and comorbidities of patients with juvenile psoriasis in Germany, using health insurance data for 4499 children and adolescents (≤ 18 years of age). Prevalence of comorbidities was estimated at 0.4%, ranging from 0.1% at 1 year of age to 0.8% at 18 years of age. Consequently, childhood psoriasis seems to be associated with a significantly greater comorbidity rate than that in children without this condition.23 Augustin et al.20 showed that a distinct group of comorbidities, previously attributed solely to adult psoriasis, may also develop in children with psoriasis. In their study, children with psoriasis were found to have hyperlipidaemia, T2DM, hypertension, obesity and ischaemic heart disease markedly more often than HCs, implying that the



signs of MetS may emerge irrespective of patient age and duration of psoriasis. Moreover, the results of that study20 indicated the possible presence of separate mechanisms leading to clinical disease in psoriasis and MetS. A number of authors have suggested monitoring patients with psoriasis. Au et al.7 suggested that children with psoriasis should be subject to primary prevention measures for CVD, while Koebnick et al.6 stated that paediatricians and dermatologists should screen young people with psoriasis for CVD risk factors. Similarly, Volf et al.24 highlighted the importance of screening paediatric patients with psoriasis for CVD and MetS risk factors earlier than currently recommended. They suggested the following criteria: triglycerides ≥ 100 mg/dL, HDL cholesterol < 50 mg/ dL (female) or < 45 mg/dL (males), fasting blood glucose ≥ 110 mg/dL, waist circumference > 75th percentile for age and sex, and systolic or diastolic blood pressure > 90th percentile for age, sex and body weight.24 Zhu et al.25 demonstrated that the prevalence of overweight and obesity among patients with psoriasis was significantly higher than in HCs. Overweight/obese paediatric patients with psoriasis were also shown to present with a more severe disease course than similar patients with psoriasis who had normal body weight, even after adjustment for age, sex, family history and duration of psoriasis. Furthermore, the severity of psoriasis (as measured by Psoriasis Area and Severity Index) showed a significant, albeit weak, correlation with patient body mass index (r = 0.2, P < 0.05).25 Currently, ‘preventive’ cardiovascular therapy is not a standard treatment in patients with psoriasis. However, emerging evidence of metabolic and cardiovascular complications in patients with psoriasis should stimulate discussion about the indications for early ‘protective’ therapy, especially in patients with metabolic disorders that can lead to potentially lethal complications such as myocardial infarction, stroke and peripheral artery disease. One possible solution that might contribute to early detection of the aforementioned comorbidities is the creation of nationwide registries of patients with juvenile psoriasis. Limitations of the study

There were several potential limitations to our study. There was a very limited number of studies that were eligible for the meta-analysis and therefore the results should be interpreted with caution. There was also wide variability of the analysed data within the studies


included, which limits the power of the study overall; for example, glucose measurements, although found to be raised in children with psoriasis compared with HCs, were only available for 40 children out of a total of 965 included in the meta-analysis. We tried to overcome these apparent limitations by using the random effects model.

Conclusion Decreased levels of HDL cholesterol and increased concentrations of fasting glucose may represent very early stages of MetS in children with psoriasis. However, a large population-based study is needed to establish the relationship between psoriasis and MetS in children, including the environmental, genetic and immunological factors leading to their co-occurrence.

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