Risks of Comorbidities in Patients With Palmoplantar Pustulosis vs Patients With Psoriasis Vulgaris or Pompholyx in Korea

Key Points

Question  What are the risks of comorbidities in patients with palmoplantar pustulosis (PPP) compared with patients with psoriasis vulgaris or pompholyx?

Findings  In this cross-sectional study of 37 399 patients with PPP, 332 279 patients with psoriasis vulgaris, and 365 415 patients with pompholyx in Korea, a diagnosis of PPP was associated with inflammatory arthritis, cardiometabolic diseases, autoimmune diseases, and vitiligo compared with the presence of pompholyx. Among patients with PPP vs psoriasis vulgaris, the risks of ankylosing spondylitis and Graves disease were higher, whereas the risks of psoriatic arthritis and vitiligo were lower.

Meaning  These results suggest that patients with PPP have an overlapping comorbidity profile with patients with psoriasis vulgaris but not with patients with pompholyx; however, the risks of comorbidities in patients with PPP may be significantly different from those in patients with psoriasis vulgaris.

Importance  Palmoplantar pustulosis (PPP) has been reported to be accompanied by systemic conditions. However, the risks of comorbidities in patients with PPP have rarely been evaluated.

Objective  To assess the risks of comorbidities in patients with PPP compared with patients with psoriasis vulgaris or pompholyx.

Design, Setting, and Participants  This nationwide population-based cross-sectional study used data from the Korean National Health Insurance database and the National Health Screening Program collected from January 1, 2010, to December 31, 2019. Data were analyzed from July 1, 2020, to October 31, 2021. Korean patients diagnosed with PPP, psoriasis vulgaris, or pompholyx who visited a dermatologist between January 1, 2010, and December 31, 2019, were enrolled.

Exposures  Presence of PPP.

Main Outcomes and Measures  The risks of comorbidities among patients with PPP vs patients with psoriasis vulgaris or pompholyx were evaluated using a multivariable logistic regression model.

Results  A total of 37 399 patients with PPP (mean [SD] age, 48.98 [17.20] years; 51.7% female), 332 279 patients with psoriasis vulgaris (mean [SD] age, 47.29 [18.34] years; 58.7% male), and 365 415 patients with pompholyx (mean [SD] age, 40.92 [17.63] years; 57.4% female) were included in the analyses. Compared with patients with pompholyx, those with PPP had significantly higher risks of developing psoriasis vulgaris (adjusted odds ratio [aOR], 72.96; 95% CI, 68.19-78.05; P < .001), psoriatic arthritis (aOR, 8.06; 95% CI, 6.55-9.92; P < .001), ankylosing spondylitis (aOR, 1.91; 95% CI, 1.61-2.27; P < .001), type 1 diabetes (aOR, 1.33; 95% CI, 1.16-1.52; P < .001), type 2 diabetes (aOR, 1.33; 95% CI, 1.29-1.38; P < .001), Graves disease (aOR, 1.25; 95% CI, 1.11-1.42; P < .001), Crohn disease (aOR, 1.63; 95% CI, 1.11-2.40; P = .01), and vitiligo (aOR, 1.87; 95% CI, 1.65-2.12; P < .001) after adjusting for demographic covariates. The risks of ankylosing spondylitis (aOR, 1.37; 95% CI, 1.16-1.62; P < .001) and Graves disease (aOR, 1.40; 95% CI, 1.23-1.58; P < .001) were significantly higher among patients with PPP vs psoriasis vulgaris. However, the risks of psoriatic arthritis (aOR, 0.54; 95% CI, 0.47-0.63; P < .001), systemic lupus erythematosus (aOR, 0.67; 95% CI, 0.46-0.97; P = .04), Sjögren syndrome (aOR, 0.70; 95% CI, 0.50-0.96; P = .03), systemic sclerosis (aOR, 0.29; 95% CI, 0.11-0.77; P = .01), vitiligo (aOR, 0.53; 95% CI, 0.47-0.60; P < .001), and alopecia areata (aOR, 0.88; 95% CI, 0.81-0.95; P = .001) were significantly lower among those with PPP vs psoriasis vulgaris.

Conclusions and Relevance  The results of this cross-sectional study suggest that patients with PPP have an overlapping comorbidity profile with patients with psoriasis vulgaris but not patients with pompholyx. However, the risks of comorbidities among patients with PPP may be substantially different from those among patients with psoriasis vulgaris.

Palmoplantar pustulosis (PPP), also known as pustulosis palmaris et plantaris, is a chronic relapsing pustular dermatosis affecting the palms and/or soles.¹ Its prevalence has been reported as 0.01% to 0.05% in Western countries and 0.12% in Asia.^1-3 Although the origin of PPP is unclear, recent studies on its immunological and genetic pathogenesis suggest systemic involvement of the disease.⁴

Whether PPP is a variant of psoriasis or a distinct inflammatory disease remains controversial.⁵ The disease was previously classified as a clinical subtype of psoriasis.⁶ However, many epidemiological, genetic, and etiopathogenetic studies have found differences between PPP and psoriasis.^7,8

Psoriasis is associated with various systemic diseases.^9-11 Similar to psoriasis, PPP is occasionally accompanied by systemic conditions, including psoriatic arthritis and autoimmune diseases.^1,12,13 However, to our knowledge, the association of comorbidities with PPP has not been evaluated, and adjustment for possible confounders has not been performed.^5,14,15 In this study, we assessed the risks of comorbidities among patients with PPP using data from the Korean National Health Insurance (NHI) database; patients with PPP were compared with patients with the 2 major differential diagnoses of PPP: psoriasis vulgaris and pompholyx.¹

Before beginning this cross-sectional study, we performed a pilot study comparing patients with PPP to a 1:4 age- and sex-matched general population using data from the NHI Service National Sample Cohort, a population-based cohort consisting of 1 million Koreans followed up from January 1, 2002, to December 31, 2015 (eMethods in the Supplement).^16,17 The study was approved by the institutional review board of the Seoul National University Hospital. The requirement for informed consent was waived because all data were deidentified. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cross-sectional studies.

We conducted a nationwide population-based cross-sectional study using data from the Korean NHI claims database (which records diagnoses based on codes from the International Classification of Diseases, Tenth Revision) collected from January 1, 2010, to December 31, 2019. Patients diagnosed with PPP, psoriasis vulgaris, or pompholyx who visited a dermatologist between January 1, 2010, and December 31, 2019, were enrolled. Data were analyzed from July 1, 2020, to October 31, 2021. The Korean NHI provides data on all NHI claims, including sociodemographic characteristics, diagnoses, and results from the National Health Screening Program, comprising regular standardized medical examinations recommended to all insured adults in the country (eMethods in the Supplement).¹⁸ Because approximately 98% of the Korean population is covered by the NHI database, it has been used to assess reliable approximations of the prevalence of certain diseases in Korea.^19,20

Patients were identified as having PPP, psoriasis vulgaris, or pompholyx if they had 3 or more documented dermatologist visits with a diagnosis of one of those specific diseases recorded between 2010 and 2019. To minimize misclassification, 14 746 patients diagnosed with pompholyx were excluded from the PPP group, and 26 151 patients diagnosed with PPP were excluded from the pompholyx group. Patients with PPP were subclassified according to the presence of concomitant psoriasis vulgaris.

To validate diagnostic accuracy, we examined several algorithms based on the number of dermatologist visits with a diagnosis of PPP, considering that patients with PPP visit clinics regularly like those with other chronic diseases (eMethods and eTable 1 in the Supplement).^19-29 The algorithm used in our study had a sensitivity of 74.19% and a specificity of 85.71%.

The prevalence of PPP during the study period was calculated based on the assumption that the entire Korean population in 2015 was at risk. We assessed the age-adjusted prevalence using world standard population data from the World Health Organization for 2000 to 2025.^30,31

Age, region of residence, income, insurance type, health-related behaviors (smoking and alcohol consumption), and laboratory data from the National Health Screening Program were obtained from January 1 to December 31, 2015. Because the study population was Korean, assessments according to race and ethnicity were not possible. Detailed criteria for the categorization of variables are summarized in eMethods in the Supplement.

We evaluated 4 categories of comorbidities: (1) inflammatory arthritis, (2) cardiometabolic diseases, (3) autoimmune diseases (subdivided into endocrine autoimmune diseases, inflammatory bowel diseases, and connective tissue diseases), and (4) dermatological diseases. Patients were identified as having a certain disease if they had 3 or more physician visits during the study period (2010-2019) with a diagnosis of each disease. Diagnostic codes from the International Classification of Diseases, Tenth Revision, for each disease are provided in eTable 2 in the Supplement.

Subgroup analyses were performed according to sex and age (<20 years, 20-59 years, and ≥60 years). To assess the robustness of our results, sensitivity analyses were conducted among patients who had 1 or more, 2 or more, 4 or more, and 5 or more dermatologist visits with a diagnosis of PPP, psoriasis vulgaris, or pompholyx recorded during the study period.

Continuous variables were compared using t tests, and categorical variables were compared using χ² or Fisher exact tests, as appropriate. All continuous data were reported as means with SDs, and categorical data were reported as numbers with percentages.

The primary outcome was the risk of comorbidities in patients with PPP compared with patients with psoriasis vulgaris or pompholyx. Multivariable logistic regression analysis was used to evaluate the associations between PPP and various clinical factors and comorbidities after adjusting for demographic covariates (age, sex, region of residence, income, and insurance type). The outcomes from the logistic regression analysis were reported as odds ratios (ORs) with 95% CIs.

To minimize potential bias, we conducted an additional analysis with 1:5 propensity score matching. Propensity scores were computed using a nonparsimonious logistic regression model considering demographic covariates. A multivariable logistic regression analysis adjusted for body mass index (calculated as weight in kilograms divided by height in meters squared), smoking, and alcohol consumption was performed.

All statistical analyses were performed using SAS software, version 9.4 (SAS Institute, Inc). Statistical tests were 2-sided, and results were considered statistically significant at P < .05.

A total of 37 399 patients with PPP, 332 279 patients with psoriasis vulgaris, and 365 415 patients with pompholyx in Korea were included (Table 1). Among those with PPP, the mean (SD) age was 48.98 (17.20) years; 51.7% were female, and 48.3% were male. Among those with psoriasis vulgaris, the mean (SD) age was 47.29 (18.34) years; 41.3% were female, and 58.7% were male. Among those with pompholyx, the mean (SD) age was 40.92 (17.63) years; 57.4% were female, and 42.6% were male.

Patients aged 40 to 59 years represented 45.2% of all patients with PPP (Table 1; eFigure 1 in the Supplement). The unadjusted prevalence of PPP was 72.58 patients per 100 000 persons (95% CI, 71.84-73.31 patients per 100 000 persons), and the standardized prevalence (adjusted in terms of the world standard population) was 58.60 patients per 100 000 persons (95% CI, 57.97-59.23 patients per 100 000 persons) (eTable 3 in the Supplement).

Among patients with PPP, 49.0% had a history of smoking (ie, ex-smoker or current smoker), 16.5% drank alcohol heavily, and 38.7% were overweight or obese. Of those with PPP, 22.5% had psoriasis vulgaris. Compared with patients without psoriasis vulgaris, those with psoriasis vulgaris were older (mean [SD], 51.60 [14.71] years vs 48.22 [17.78] years; P < .001), and fewer were women (49.1% vs 52.4%; P < .001). More patients who had PPP with psoriasis vulgaris were current smokers (39.0%) compared with those without psoriasis vulgaris (28.0%; P < .001). No significant difference in alcohol consumption or obesity was found between the 2 groups (Table 1). Similar results were found in a pilot study comparing patients with PPP with the general population (eResults and eTable 4 in the Supplement).

We assessed the risk of developing PPP compared with the risk of developing pompholyx or psoriasis vulgaris based on the presence of various conditions (Table 2; eTable 5 in the Supplement). A logistic analysis adjusted for demographic covariates revealed that current smokers and individuals with obesity had a higher risk of developing PPP than pompholyx (current smoking: adjusted OR [aOR], 2.44 [95% CI, 2.35-2.53; P < .001]; obesity: aOR, 1.30 [95% CI, 1.24-1.37; P < .001]) or psoriasis vulgaris (current smoking: aOR, 1.71 [95% CI, 1.65-1.77; P < .001]; obesity: aOR, 1.09 [95% CI, 1.04-1.15; P = .001]). Patients who drank heavily had a higher risk of developing PPP than pompholyx (aOR, 1.13; 95% CI, 1.08-1.19; P < .001) and a lower risk of developing PPP than psoriasis vulgaris (aOR, 0.92; 95% CI, 0.88-0.96; P < .001). Higher levels of glucose (eg, ≥126 mg/dL [to convert to mmol/L, multiply by 0.0555]: aOR, 1.48; 95% CI, 1.41-1.55; P < .001), cholesterol (eg, ≥240 mg/dL [to convert to mmol/L, multiply by 0.0259]: aOR, 1.19; 95% CI, 1.15-1.24; P < .001), and triglycerides (eg, ≥500 mg/dL [to convert to mmol/L, multiply by 0.0113]: aOR, 1.43; 95% CI, 1.25-1.62; P < .001) were associated with a higher risk of developing PPP than pompholyx.

The prevalence of comorbidities in the PPP, psoriasis vulgaris, and pompholyx groups are presented in eTable 6 in the Supplement. After adjustment for demographic covariates, patients with PPP had a significantly higher risk of developing psoriasis vulgaris (aOR, 72.96 [68.19-78.05]; P < .001), psoriatic arthritis (aOR, 8.06; 95% CI, 6.55-9.92; P < .001), ankylosing spondylitis (aOR, 1.91; 95% CI, 1.61-2.27; P < .001), type 1 diabetes (aOR, 1.33; 95% CI, 1.16-1.52; P < .001), type 2 diabetes (aOR, 1.33; 95% CI, 1.29-1.38; P < .001), Graves disease (aOR, 1.25; 95% CI, 1.11-1.42; P < .001), Crohn disease (aOR, 1.63; 95% CI, 1.11-2.40; P = .01), and vitiligo (aOR, 1.87; 95% CI, 1.65-2.12; P < .001) compared with patients with pompholyx (Figure 1A). The risks of ankylosing spondylitis (aOR, 1.37; 95% CI, 1.16-1.62; P < .001) and Graves disease (aOR, 1.40; 95% CI, 1.23-1.58; P < .001) were higher in patients with PPP compared with patients with psoriasis vulgaris (Figure 1B). However, the risks of psoriatic arthritis (aOR, 0.54; 94% CI, 0.47-0.63; P < .001), systemic lupus erythematosus (aOR, 0.67; 95% CI, 0.46-0.97; P = .04), Sjögren syndrome (aOR, 0.70; 95% CI, 0.50-0.96; P = .03), systemic sclerosis (aOR, 0.29; 95% CI, 0.11-0.77; P = .01), vitiligo (aOR, 0.53; 95% CI, 0.47-0.60; P < .001), and alopecia areata (aOR, 0.88; 95% CI, 0.81-0.95; P = .001) were lower among patients with PPP vs psoriasis vulgaris. The risk of Crohn disease was higher among those with PPP (aOR, 1.36; 95% CI, 0.93-1.98) vs those with psoriasis vulgaris, although this difference was statistically insignificant (P = .11).

Analyses of propensity score–matched patients yielded consistent results. We selected 5 patients with psoriasis vulgaris and 5 patients with pompholyx for propensity score matching based on demographic covariates. After matching, covariates were comparable between the groups in each comparison (eTable 7 and eTable 8 in the Supplement). The risks of psoriatic arthritis (aOR, 7.62; 95% CI, 5.90-9.85; P < .001), ankylosing spondylitis (aOR, 1.87; 95% CI, 1.52-2.30; P < .001), type 1 diabetes (aOR, 1.34; 95% CI, 1.15-1.57; P < .001), type 2 diabetes (aOR, 1.28; 95% CI, 1.23-1.34; P < .001), Crohn disease (aOR, 1.70; 95% CI, 1.10-2.62; P = .02), and vitiligo (aOR, 1.91; 95% CI, 1.64-2.22; P < .001) were significantly higher in patients with PPP than in those with pompholyx after adjusting for body mass index, smoking, and alcohol consumption. Compared with patients with psoriasis vulgaris, patients with PPP had higher risks of ankylosing spondylitis (aOR, 1.34; 95% CI, 1.11-1.61; P = .002), Graves disease (aOR, 1.33; 95% CI, 1.15-1.55; P < .001), and Crohn disease (aOR, 1.69; 95% CI, 1.10-2.59; P = .02) and lower risks of psoriatic arthritis (aOR, 0.48; 95% CI, 0.41-0.57; P < .001), Sjögren syndrome (aOR, 0.65; 95% CI, 0.44-0.96; P = .03), systemic sclerosis (aOR, 0.33; 95% CI, 0.12-0.92; P = .03), vitiligo (aOR, 0.54; 95% CI, 0.48-0.62; P < .001), and alopecia areata (aOR, 0.86; 95% CI, 0.79-0.94; P = .001). The risk of cardiometabolic diseases was comparable (eFigure 2 in the Supplement).

Subgroup analyses revealed differences in comorbidities according to sex and age (eTable 9 in the Supplement). Compared with patients with pompholyx, male patients with PPP had a significantly higher risk of Crohn disease (aOR, 1.75; 95% CI, 1.09-2.80; P = .02), and female patients with PPP had significantly higher risks of hyperlipidemia (aOR, 1.10; 95% CI, 1.06-1.15; P < .001), type 1 diabetes (aOR, 1.54; 95% CI, 1.27-1.87; P < .001), and Graves disease (aOR, 1.39; 95% CI, 1.20-1.60; P < .001); the risk of alopecia areata was higher in women with PPP (aOR, 1.15; 95% CI, 1.03-1.29; P = .01) and lower in men with PPP (aOR, 0.84; 95% CI, 0.75-0.95; P = .005). Compared with patients with psoriasis vulgaris, male patients with PPP had a higher risk of Crohn disease (aOR, 1.58; 95% CI, 1.00-2.50; P = .049), whereas female patients with PPP had a higher risk of Graves disease (aOR, 1.51; 95% CI, 1.31-1.75; P < .001).

In the subgroup analysis by age, the risks of ankylosing spondylitis (aOR, 2.96; 95% CI, 2.07-4.24; P < .001), Crohn disease (aOR, 3.21; 95% CI, 1.60-6.46; P = .001), and vitiligo (aOR, 2.62; 95% CI, 1.85-3.70; P < .001) were significantly higher in patients with PPP who were 60 years and older compared with patients with pompholyx. The risks of ankylosing spondylitis (aOR, 2.16; 95% CI, 1.52-3.07; P < .001) and Crohn disease (aOR, 2.40; 95% CI, 1.22-4.75; P = .01) were higher in patients with PPP who were 60 years and older compared with patients with psoriasis vulgaris. Although statistically insignificant, the risks of hyperlipidemia and alopecia areata were higher in younger patients with PPP vs patients with pompholyx (eg, hyperlipidemia at age <20 years: aOR, 1.75 [95% CI, 0.87-3.53; P = .12]; alopecia areata at age <20 years: aOR, 1.76 [95% CI, 0.91-3.41; P = .10]) or psoriasis vulgaris (hyperlipidemia at age <20 years: aOR, 1.16 [95% CI, 0.58-2.33; P = .67]; alopecia areata at age <20 years: aOR, 1.16 [95% CI, 0.60-2.24; P = .66]) (Figure 2). Additional subgroup analyses in propensity score–matched patients yielded consistent results (eFigure 3 and eTable 10 in the Supplement).

All sensitivity analyses of the study populations by number of dermatologist visits with certain diagnoses consistently revealed that the risks of psoriatic arthritis (eg, ≥5 visits: aOR, 8.73; 95% CI, 6.82-11.18; P < .001), ankylosing spondylitis (≥5 visits: aOR, 2.13; 95% CI, 1.73-2.63; P < .001), type 2 diabetes (≥5 visits: aOR, 1.37; 95% CI, 1.31-1.43; P < .001), Graves disease (≥5 visits: aOR, 1.52; 95% CI, 1.32-1.75; P < .001), and vitiligo (≥5 visits: aOR, 1.94; 95% CI, 1.68-2.24; P < .001) were higher in patients with PPP compared with patients with pompholyx. The risks of ankylosing spondylitis (eg, ≥5 visits: aOR, 1.42; 95% CI, 1.17-1.72; P < .001) and Graves disease (≥5 visits: aOR, 1.66; 95% CI, 1.44-1.91; P < .001) were higher in patients with PPP compared with those with psoriasis vulgaris, whereas the risks of psoriatic arthritis (≥5 visits: aOR, 0.52; 95% CI, 0.44-0.61; P < .001) and vitiligo (≥5 visits: aOR, 0.54; 95% CI, 0.47-0.61; P < .001) were lower in those with PPP vs psoriasis vulgaris (eTables 11-14 in the Supplement).

This cross-sectional study found that the prevalence and age distribution of PPP in Korea were comparable to data reported in previous studies.^1-3,12,32,33 Unlike previous studies, the male to female ratio in the current study was relatively even, which may be a result of differences in study design, sample size, or participant race.^12,14,32,34 Further studies on the prevalence of PPP by sex are warranted.

Smoking and obesity were significant risk factors associated with PPP in the pilot study, and the aORs for smoking and obesity were higher among patients with PPP than those with pompholyx in the main study, which was consistent with findings from previous studies.^1,35,36 We found higher aORs between smoking and PPP than between smoking and psoriasis vulgaris. Smoking can induce both PPP and psoriasis through oxidative, inflammatory, and genetic mechanisms.^37,38 The overexpressed α-7 nicotinic acetylcholine receptors in the eccrine gland of patients with PPP may explain the higher aOR between smoking and PPP.^32,39

We found an increased risk of psoriasis vulgaris in patients with PPP compared with patients with pompholyx. The common pathogenesis of these diseases further supports an association between PPP and psoriasis. However, immunological and genetic differences have been reported.^4,40 Expression of interleukin 17 was increased in PPP lesions compared with healthy skin, whereas expression of interleukin 12/23 was not.⁴¹ The biologic therapies that target these cytokines in psoriasis vulgaris are often ineffective for the treatment of PPP.^1,42-44 Genetic studies have reported that interleukin 36RN, the AP1S3 gene, and the CARD14 gene may be associated with PPP, whereas the PSORS1 gene is not, unlike psoriasis vulgaris.^1,4,34 Because of these differences in underlying pathogenesis, PPP and psoriasis vulgaris would be expected to have both similarities and differences in their comorbidities.

Pompholyx is a common vesicobullous disorder that resembles PPP clinically and histopathologically.⁴⁵ Systemic involvement of pompholyx is rare; only a few skin conditions (eg, atopic dermatitis and contact sensitivity) and infections (eg, herpes zoster) have been reported to be associated with pompholyx.^46,47 Therefore, we assumed that estimating the risks of comorbidities in patients with PPP compared with the risks of comorbidities in the general population would be similar to comparing the risks of comorbidities in patients with PPP vs pompholyx, which was confirmed through the pilot study.

Joint diseases have been frequently reported in patients with PPP,^14,34 and psoriatic arthritis and ankylosing spondylitis were associated with PPP in the current study. We found a decreased risk of psoriatic arthritis in patients with PPP compared with patients with psoriasis vulgaris. Contrary to scarce reports of ankylosing spondylitis in patients with PPP,³³ our study found the risk of ankylosing spondylitis was significantly higher in patients with PPP vs psoriasis vulgaris. The spinal column is commonly affected in articular syndromes, such as synovitis-acne-pustulosis-hyperostosis-osteomyelitis syndrome and pustulotic arthro-osteitis, that are accompanied by PPP, which suggests PPP is associated with spondyloarthritis.^1,34,48

Consistent with previous reports,^{2,13,14,34,49} the risk of cardiometabolic diseases was higher in patients with PPP compared with patients with pompholyx. We found that the risk of type 2 diabetes was higher in patients with PPP compared with propensity score–matched patients with pompholyx, even after adjusting for body mass index, smoking, and alcohol consumption. In addition, the risk of cardiometabolic diseases in patients with PPP was comparable with that in propensity score–matched patients with psoriasis vulgaris. Therefore, PPP may be an independent risk factor associated with cardiometabolic diseases, similar to psoriasis vulgaris.^50,51

We found that type 1 diabetes, Graves disease, and Crohn disease were associated with PPP. This finding was consistent with previous studies reporting that PPP is associated with several autoimmune diseases.^4,13,52 The risks of Graves disease and Crohn disease were higher in patients with PPP, whereas the risks of Hashimoto thyroiditis and ulcerative colitis were not. This finding may be partially explained by the opposing consequences of smoking for the immune system.^53,54 Smokers have higher risks of Crohn disease and Graves disease and lower risks of ulcerative colitis and Hashimoto thyroiditis.^55,56 Shared immune pathways may contribute to the pathogenesis of psoriasis and connective tissue diseases.^57-59 However, in our study, the risk of connective tissue diseases was lower in patients with PPP than in those with psoriasis vulgaris, implying that PPP and psoriasis vulgaris have different immunopathogenesis.

Patients with PPP had a higher risk of vitiligo than patients with pompholyx and a lower risk than patients with psoriasis vulgaris. The association between PPP and vitiligo has been rarely reported compared with the association between psoriasis and vitiligo.^60,61 The association between psoriasis and vitiligo may be explained by the common T cell–mediated autoimmunity or Koebner phenomenon.^60,62 The immunopathogenic differences from psoriasis and the less pronounced Koebner phenomenon in PPP may explain the decreased risk of vitiligo in patients with PPP vs those with psoriasis vulgaris.^63,64

In our study, the risk of autoimmune diseases (with the exception of Crohn disease) was higher in female patients with PPP, which is consistent with the male predominance of Crohn disease in Asia.⁵⁵ The risk of cardiometabolic diseases in patients with PPP was higher in female vs male individuals. The risks of hyperlipidemia and alopecia areata in patients with PPP was higher in the younger (<20 years) population, although these risks were not statistically significant. These age and sex discrepancies require further study.

This study’s results were confirmed using 2 different statistical approaches (multivariable logistic regression analysis and analysis using propensity score matching). Multivariable regression analysis has an advantage because it simultaneously controls for many confounders. However, it might produce biased aORs, particularly when assessing rare comorbidities. Analysis using propensity score matching produces less biased, more robust, and more precise estimates, even when assessing rare events.⁶⁵ However, it has the potential weaknesses of residual confounding and loss of statistical efficiency.^66,67 The consistency of these 2 approaches increased the reliability of the results.⁶⁶

This study has several limitations. First, because the NHI claims database was used, misdiagnoses might have been included, and patients with subclinical or minimal disease might have been undetected. To overcome these limitations, we included only diagnoses made by dermatologists and defined strict diagnostic criteria based on validation. Second, disease severity and treatment modality were not recorded; thus, we could not adjust for those factors. Third, the study population was Korean, and further studies involving other ethnic groups are needed for generalizability. Nevertheless, to our knowledge, this study is one of the largest epidemiological analyses of PPP and the first to report adjusted risks of comorbidities in patients with PPP compared with patients with psoriasis vulgaris.

In this cross-sectional study, patients with PPP had an overlapping comorbidity profile (including inflammatory arthritis, cardiometabolic diseases, autoimmune diseases, and vitiligo) with patients with psoriasis vulgaris but not with patients with pompholyx. However, the risks of comorbidities in patients with PPP compared with those with psoriasis vulgaris revealed substantial differences; among patients with PPP, the risks of ankylosing spondylitis and Graves disease were higher, and the risks of psoriatic arthritis, connective tissue diseases, and vitiligo were lower. Further studies to explore the pathogenetic mechanisms of these comorbidities and elucidate their associations with PPP are warranted.

Accepted for Publication: March 9, 2022.

Published Online: April 27, 2022. doi:10.1001/jamadermatol.2022.1081

Corresponding Author: Seong Jin Jo, MD, PhD, Department of Dermatology, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea (sj.jo@snu.ac.kr).

Author Contributions: Dr Jo had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Cho, Jo.

Acquisition, analysis, or interpretation of data: Kim, Lee, Jo.

Drafting of the manuscript: Kim, Jo.

Critical revision of the manuscript for important intellectual content: Lee, Cho, Jo.

Statistical analysis: Lee, Cho, Jo.

Administrative, technical, or material support: Cho, Jo.

Supervision: Jo.

Conflict of Interest Disclosures: Dr Jo reported receiving grants from AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion Healthcare, Green Cross Laboratories, Pfizer, and UCB and personal fees from AbbVie, Eli Lilly and Company, Janssen Pharmaceuticals, LEO Pharma, Novartis, and Sanofi outside the submitted work. No other disclosures were reported.