Comparison of metabolic and neurological comorbidities in Asian patients with psoriasis and atopic dermatitis

Although various comorbidities have been noted to be associated with atopic dermatitis (AD) and psoriasis, few studies have compared comorbidities between the two diseases, and little is known about whether these comorbidities vary by the subtypes of psoriasis. In this study of 1:1 age- and sex-matched pair analysis between patients diagnosed with either psoriasis or AD at Asan Medical Center between 1991 and 2020, comorbidities, as determined by the International Classification of Diseases-10 codes, and likelihood ratios of metabolic and neurologic comorbidities in psoriasis compared with AD were studied using a logistic regression model. Among a total of 14,128 patients, the psoriasis group had higher odds of obesity (odds ratio [95% confidence interval]: 1.49 [1.34–1.66]), hypertension (1.14 [1.03–1.26]), diabetes mellitus (1.46 [1.29–1.66]), chronic kidney disease (1.59 [1.22–2.08]), and Parkinson's disease (2.1 [1.15–3.83]) than the AD group. Subgroup analysis revealed that patients with plaque psoriasis had higher odds of obesity (1.18 [1.05–1.33]), hypertension (1.18 [1.06–1.32]), diabetes mellitus (1.53 [1.34–1.75]), chronic kidney disease (1.66 [1.26–2.17]), and Parkinson’s disease (2.12 [1.16–3.88]) compared with AD. Meanwhile, guttate psoriasis was associated with higher odds of dementia (3.63 [1.06–12.40]) and patients with generalized pustular psoriasis showed higher odds of diabetes mellitus (5.42 [1.56–18.83]) compared with AD. In conclusion, Asian patients with all types of psoriasis should be closely monitored for the development of metabolic and neurologic diseases, especially men and those aged ≥ 40 years.


Statistical analysis
Continuous data in the two groups were presented as mean ± standard deviation and compared using t-tests or Mann-Whitney tests.Categorical variables in the two groups were compared using chi-square tests or linear association tests.Comorbidities associated with AD and psoriasis were compared after adjusting for the number of visits using logistic regression modeling.Results are presented as odds ratios (ORs) with 95% confidence intervals (CIs).All statistical analyses were performed using R version 3.5.3(R Foundation for Statistical Computing) software, with p < 0.05 considered statistically significant.

Patient characteristics
Altogether, 40,156 AD patients and 8712 psoriasis patients were identified.Matching by sex and age resulted in 14,128 patients, 7064 diagnosed with psoriasis and 7064 diagnosed with AD (shown in Supplementary Fig. S1).Their demographic, clinical, and laboratory data are summarized in Table 1.Each group consisted of 3584 male and 3480 female patients with a mean age at the time of diagnosis of 38.4 years.

Metabolic and neurological comorbidities in patients with psoriasis and atopic dermatitis according to sex
The adjusted ORs of comorbidities according to sex are shown in Fig. 2. Compared with women and men with AD, the adjusted ORs for women and men with psoriasis were 1.55 (95% CI

Discussion
Psoriasis and AD have each been reported to be independently associated with metabolic comorbidities relative to the general population [6][7][8][9]15 . Fewreports to date have compared the metabolic comorbidities associated with psoriasis and AD, especially in Asian patients [10][11][12] .German studies showed that the prevalences of arterial hypertension, hyperlipidemia, obesity, and diabetes mellitus are higher in psoriasis patients than AD patients 10,11 .Similarly, the present study found that Asian patients with psoriasis had higher ORs for obesity, hypertension, diabetes, and chronic kidney disease than age-and sex-matched AD counterparts.These findings are supported by a high BMI and abdominal circumference, frequent abnormalities in blood pressure and fasting glucose, and low GFR levels in the psoriasis group compared with the AD group.Moreover, the significantly higher CRP concentrations and ESR in psoriasis patients suggest that systemic inflammation may play a role in the more frequent development of metabolic comorbidities in association with psoriasis. It ma be noteworthy to point out that an age-matched comparator diagnosed with AD is more likely to have had the inflammatory skin disease longer than a patient with psoriasis, as AD usually begins earlier in the lifetime compared with psoriasis.However, the higher level of systemic inflammation in psoriasis supported by laboratory data shows that attention needs to be paid to inflammatory comorbidities in patients with psoriasis.
The prevalence of obesity, dyslipidemia, hypertension, diabetes mellitus, arrhythmia, CKD, atherosclerosis, dementia, and Parkinson's disease were as follows: obesity 36.3% (all ages) 16 , dyslipidemia 19.9% (all ages) 17 , hypertension 29.4% (aged 20 or over) 18 , diabetes mellitus 13.9% (aged 20 or over) 19 , arrhythmia 15% (aged 20 or over) 20 , CKD 5% (aged 35 or over) 21 , atherosclerosis 10% (aged 18 or over) 22 , dementia 6.9% (aged 60 or over) 23 , and Parkinson's disease 0.4% (aged 50 or over) 24 .The ORs for dyslipidemia were previously shown to be higher in patients with both psoriasis 25 and AD 26 compared with the general population.Although the present study found that the prevalence of dyslipidemia, as determined by ICD-10 codes, did not differ significantly between the psoriasis and AD groups, the lipid profiles, including concentrations of HDL, TGs, and total cholesterol, differed significantly between these two groups, suggesting that dyslipidemia may be relatively underdiagnosed in psoriasis patients compared with AD patients.
In agreement with previous findings, the present study found that AD patients were more likely to have concurrent eosinophilia and high serum IgE levels than psoriasis patients 27,28 .Patients with AD more frequently present with elevated serum total IgE levels and peripheral eosinophilia than those without AD, with the levels of both correlating significantly with AD severity, as measured by the Eczema Areas and Severity Index scores 28 .Regarding sex-related comorbidity statistics compared to the general population, recent reports from the United States and Germany showed that the associations of psoriasis with metabolic and cardiovascular risk factors were stronger in women than in men 29,30 .In contrast, according to Taiwanese administrative data, the prevalences of metabolic comorbidities, including hypertension, dyslipidemia, and diabetes mellitus, as well as liver and renal diseases, were significantly higher in men with psoriasis than in women with psoriasis 31 .Previous studies that compared comorbidities of psoriasis and AD did not provide data according to sex [10][11][12] .In this Korean study, the odds for obesity and diabetes mellitus were higher in both men and women with psoriasis www.nature.com/scientificreports/than with AD, but only men with psoriasis showed higher odds of hypertension, chronic kidney disease, and Parkinson's disease than men with AD.These discrepancies may be due to differences in ethnicity and possibly lifestyles and dietary styles.
Regarding age-related comorbidities compared to the general population, a recent meta-analysis showed that children with psoriasis had high pooled ORs for obesity, hypertension, diabetes, dyslipidemia, and metabolic syndrome 32 .In this study, the ORs for obesity were higher in people with psoriasis than AD, regardless of age.However, the OR for hypertension was lower in psoriasis patients aged < 40 years, but higher in those aged ≥ 40 years than in age-matched AD counterparts.While systemic medications including steroids and cyclosporine may play a role, a previous case-control study conducted in the US, which included patients aged under 18, showed that AD was associated with high odds of SBP even after adjusting for the use of steroids and cyclosporine 33 .In addition, despite the age-matching of patients in the present study, because AD begins at an earlier age than psoriasis, the disease duration before the first diagnosis may have been longer in the AD group, resulting in a higher OR for hypertension for AD patients than in those with psoriasis.
Our present study is interesting in showing that the likelihood of Parkinson's disease was higher in patients with psoriasis than in those with AD.No link between AD and Parkinson's disease has been reported before.Analyses of nationwide population-based cohort data from Taiwan and Korea have noted that the hazard ratio of Parkinson's disease was significantly higher in psoriasis patients than in a control group 34,35 .These associations were presumed to be due to chronic inflammation, including the enhanced expression of proinflammatory cytokines such as tumor necrosis factor-α, IL-1, and IL-6, with attenuation of inflammation through systemic treatment reducing the risk of Parkinson's disease 34 .Immune responses that promote T cell differentiation into Th17 cells, as well as the expression of genes such as SETD1A and BC010367, have been observed in both diseases 36,37 .In this study, the likelihood of Parkinson's disease was higher in the psoriasis group, especially in men and patients aged 40 or over.
To our knowledge, little is known about the comorbidities of guttate psoriasis, probably due to the high rate of self-remission 38 .However, persistent cases of guttate psoriasis and conversion to plaque psoriasis had been reported in about 15-40% 39,40 .Consistent with our assumption that that odds ratio of inflammatory comorbidities of guttate psoriasis may be high, we found that the odds of dementia were higher than patients with atopic dermatitis in the present study.A recent meta-analysis revealed statistically significant associations between non-vascular dementia and psoriasis with a risk ratio of 1.13 (95% CI 1.11-1.15)and vascular dementia and psoriasis with a risk ratio of 1.41 (95% CI 1.09-1.82) 41.Apolipoprotein E and IL-23/IL-17 may link psoriasis and Alzheimer's dementia, the most common non-vascular dementia 42,43 .Arterial stiffness and increased levels of inflammation and oxidative stress may explain the link between psoriasis and vascular dementia 44,45 .Although serum levels of IL-2, IL-23, interferon-γ, and LL37 were found to be elevated in patients with psoriasis, there were no differences between plaque and guttate psoriasis 46 .The early age of onset of guttate psoriasis may lead to a long exposure to inflammatory cytokines.Also, streptococcal infection in guttate psoriasis may cause indirect neuronal damage through neuroinflammation, although the pathogenesis of streptococcal infection passing through the blood brain barrier needs to be elucidated 47,48 .
Meanwhile, a previous study on GPP reported obesity (42.9%), hypertension (25.7%), hyperlipidemia (25.7%), and diabetes mellitus (23.7%) as associated comorbidities 49 .Mutations in IL36RN and CARD14, which are linked to the upregulation of pro-inflammatory cytokines such as IL-1, have been identified in some GPP patients 50 .Higher expression of neutrophil chemokines, including CXCL1, CXCL2, and CXCL8, were observed in GPP patients compared with plaque psoriasis patients 51 .As the pathophysiology of psoriasis is viewed as a spectrum between autoimmunity and autoinflammation of which GPP more involves autoinflammation axis with high expression of inflammatory cytokines and chemokines, we assumed that the odds ratio of inflammatory comorbidities might be higher in pustular psoriasis group 52 .Consistently in the present study, higher odds of diabetes mellitus in the GPP group were found compared with plaque psoriasis group.
Although PsA was reported to be associated with higher odds of metabolic syndrome (OR 1.78; 95% CI 1.08-2.95)and renal function impairment as well as a high risk ratio of dementia (2.20; 95% CI 1.29-3.78)than patients with psoriasis alone, the present study did not find significant associations 41,53,54 .This may be due to the small number of patients with PsA included in this study, consistent with the low prevalence of PsA in Korea 14 .
The strengths of our study include the extensive amount of laboratory data, which support the findings on metabolic and neurologic comorbidities.Also, compared with previous studies that were designed to use administrative data and included diagnostic codes applied by nonspecialists, this study included hospitalrecorded real clinical-based data only of patients who were diagnosed by dermatologists.Moreover, we report statistically significant ORs for metabolic and neurologic comorbidities in specific psoriasis subtypes, including guttate psoriasis and GPP.
This study also has several limitations.First, the comorbidities were based on diagnostic codes, making the accuracy of the data highly dependent on accurate coding by physicians in practice.To improve the accuracy, we checked whether the patients visited specialists for specific comorbidities.Second, this study included only those patients who visited a tertiary center for psoriasis and AD.Patients with mild disease who did not present at a tertiary center may therefore have been overlooked.Normal controls were not available since healthy individuals visiting dermatologic departments do not routinely undergo blood tests.Moreover, the comorbidities of interest were not subclassified according to their pathophysiology, limiting the interpretation of the study results.
In conclusion, Asian patients with all types of psoriasis should be closely monitored for the development of metabolic and neurologic diseases, especially men and those aged ≥ 40 years.

Figure 1 .
Figure 1.Forest plot of the adjusted odds of comorbidities in patients with psoriasis compared with age-and sex-matched patients with atopic dermatitis.OR, odds ratio; CI, confidence interval.Adjusted by the number of visits.

Figure 2 .
Figure 2. Forest plots of the adjusted odds of comorbidities in patients with psoriasis compared with age-and sex-matched patients with atopic dermatitis according to sex.(a) Female patients.(b) Male patients.OR, odds ratio; CI, confidence interval.Adjusted by the number of visits.

Figure 3 .
Figure 3. Forest plots of the adjusted odds of comorbidities in patients with psoriasis compared with age-and sex-matched patients with atopic dermatitis according to age group.(a) Patients aged < 40 years.(b) Patients aged ≥ 40 years.OR, odds ratio; CI, confidence interval.Adjusted by the number of visits.

Table 2 .
Comorbidities according to psoriasis subtypes compared with atopic dermatitis.OR, odds ratio; CI, confidence interval; BMI, body mass index; NE, not estimated.Adjusted by age, sex, and the number of visits.*p-value < 0.05.